HK1117144A - Pyridazine derivatives and their use as therapeutic agents - Google Patents

Description

Pyridazine derivatives and their use as therapeutic agents

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patent application serial No. 10/901,563 filed on 29/7/2004, which claims U.S. provisional patent application serial No. 60/491,095 filed on 30/7/2003; U.S. provisional patent application serial No. 60/546,820 filed on 23/2/2004; U.S. provisional patent application serial No. 60/553,416 filed on 3, 16, 2004; U.S. provisional patent application serial No. 60/546,934 filed on 23/2/2004; U.S. provisional patent application serial No. 60/553,446 filed on 3, 16, 2004; U.S. provisional patent application serial No. 60/546,786 filed on 23/2/2004; U.S. provisional patent application serial No. 60/553,403 filed on 3, 16, 2004; U.S. provisional patent application serial No. 60/546,898 filed on 23/2/2004; U.S. provisional patent application serial No. 60/553,404 filed on 3, 16, 2004; U.S. provisional patent application serial No. 60/546,815 filed on 23/2/2004; and priority of U.S. provisional patent application serial No. 60/553,491 filed on 3, 16, 2004; the disclosures of which are hereby incorporated by reference in their entirety. This application also claims the benefit of priority from PCT application number PCT/US2004/024658, filed on day 29, 7/2004, which claims priority from U.S. provisional patent application No. 60/491,095, filed on day 30, 7/2003, the disclosure of which is hereby incorporated by reference in its entirety.

Technical Field

The present invention relates generally to the following fields: stearoyl-coa desaturase inhibitors, such as pyridazine derivatives, and the use of such compounds in the treatment and/or prevention of various human diseases, including diseases mediated by stearoyl-coa desaturase (SCD), preferably SCD1, especially diseases associated with elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, and the like.

Background

Acyl desaturases catalyze the formation of double bonds from newly synthesized fatty acids derived from dietary sources or in the liver. Mammals synthesize fatty acid desaturases with at least three different chain length specificities that catalyze the addition of double bonds at the delta-9, delta-6 and delta-5 positions. stearoyl-CoA desaturase enzymes (SCDs) introduce a double bond at the C9-C10 positions of saturated fatty acids. Preferred substrates are palmitoyl-CoA (16: 0) and stearoyl-CoA (18: 0), which are converted to palmitoyl-CoA (16: 1) and oleoyl-CoA (18: 1), respectively. The resulting monounsaturated fatty acids are substrates for incorporation of phospholipids, triglycerides and cholesterol esters.

Many mammalian SCD genes have been cloned. For example, two genes (SCD1, SCD2) have been cloned from rats and four SCD genes (SCD1, 2, 3, and 4) have been cloned from mice. Although the basic biochemical role of SCD in rats and mice has been known since the 1970 s (Jeffcoat, R. et al, Elsevier Science (1984), Vol.4, pp.85-112; de Antueno, RJ, Lipids (1993), Vol.28, No.4, pp.285-290), it was only recently considered to be directly involved in human disease processes.

A single SCD gene, SCD1, has been characterized in humans. SCD1 is described in Brownlie et al, PCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety. A second human SCD isoform was recently identified and, because it has little sequence homology with the alternating mouse or rat isoforms, it was named human SCD5 or hSCD5(PCT published patent application, WO 02/26944, which is incorporated herein by reference in its entirety).

To date, small molecule, drug-like compounds that specifically inhibit or modulate SCD activity are not known. Historically, certain long chain hydrocarbons have been used to study SCD activity. Known examples include thia-fatty acids, cyclopropenes (cyclopropenoids) fatty acids and certain conjugated linoleic acid isomers. Specifically, cis-12, trans-10 conjugated linoleic acid is believed to inhibit SCD enzyme activity and reduce the abundance of SCD1 mRNA, whereas cis-9, trans-11 conjugated linoleic acid does not. Cyclopropene fatty acids, such as those found in phoenix tree (stercula) seeds and cottonseed, are also known to inhibit SCD activity. For example, sterculic acid (8- (2-octylcyclopropenyl) octanoic acid) and malvalic acid (7- (2-octylcyclopropenyl) heptanoic acid) are the C18 and C16 derivatives of sterculic and malvalinyl fatty acids, respectively, having cyclopropene rings at their C9-C10 positions. These substances are believed to inhibit SCD enzymatic activity by direct interaction with the enzyme, thus inhibiting delta-9 desaturation. Other substances that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also known as 8-nonylthiooctanoic acid) and other fatty acids having sulfoxy (sulfoxy) moieties.

These known modulators of delta-9 desaturase activity are not useful for the treatment of diseases and disorders associated with the biological activity of SCD 1. None of the known SCD inhibitor compounds are selective for SCD or delta-9 desaturase enzymes, as they also inhibit other desaturases and multiple enzymes. The thia-fatty acids, conjugated linoleic and cyclopropene fatty acids (malvalic and sterculic acids) were neither active at reasonable physiological doses, nor were they specific inhibitors of the biological activity of SCD1, but rather they demonstrated cross-inhibitory effects on other desaturases, in particular on delta-5 and delta-6 desaturases.

Small molecule inhibitors lacking SCD enzyme activity are a major scientific and medical disappointment as evidence now forces one to believe that SCD activity is directly related to the common human disease process: see, e.g., Attie, A.D., et al, "Relationship between stearoyl-CoAdesaturase activity and plasma trigycedes in human and methyl hypertriencerosis", J.Lipid Res. (2002), Vol.43, No.11, pp.1899-907; cohen, P. et al, "Role for stearoyl-CoA assay-1 in-mediated weight Loss", Science (2002), Vol.297, No.5579, pp.240-3, Ntambi, J.M. et al, "Loss of stearoyl-CoA assay-1 function technologies, microorganism access activity", Proc.Natl.Acad.Sci.U.S. A. (2002), Vol.99, No.7, pp.11482-6.

The present invention solves this problem by providing a new class of compounds which are useful for modulating SCD activity and modulating lipid levels, particularly plasma lipid levels, and which are useful for treating SCD-mediated diseases such as diseases associated with dyslipidemia and disorders of lipid metabolism, particularly diseases associated with elevated lipid levels, cardiovascular diseases, diabetes, obesity, metabolic syndrome and the like.

Relevant documents

U.S. patent No.6,677,452 discloses novel pyridine carboxamide or sulfonamide derivative compounds. PCT published patent applications WO 03/075929, WO 03/076400 and WO03/076401 disclose compounds having the enzymatic activity of inhibiting histone deacetylase.

Brief summary of the invention

The present invention provides pyridazine derivatives that modulate the activity of stearoyl-CoA desaturase. Also included are methods of using the derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising the derivatives.

Accordingly, in one aspect, the present invention provides a compound of formula (I), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a prodrug thereof:

Wherein:

x and y are each independently 1, 2 or 3;

w is-C (O) N (R)¹)-、-C(O)N[C(O)R^1a]-、-N(R¹)C(O)N(R¹) -or-N (R)¹)C(O)-；

V is-C (O) -, -C (S) -or-C (R)¹⁰)H；

Each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R^1aselected from hydrogen, C₁-C₆Alkyl and cycloalkyl radicals;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R³is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R³Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo (oxo) group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether orR⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

R¹⁰is hydrogen or C₁-C₃An alkyl group; and is

Each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

In another aspect, the present invention provides a compound of formula (Ia), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof,

wherein:

x and y are each independently 1, 2 or 3;

w is a direct bond, -C (O) N (R)¹)-、-C(O)N[C(O)R^1a]-、-N(R¹)C(O)N(R¹)-、-N(R¹)C(O)-、-OC(O)N(R¹)-、-N(R¹)S(O)_p- (wherein p is 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (O) -, -OS (O)₂N(R¹)-、-OC(O)-、-C(O)O-、-N(R¹)C(O)O-、-N(R¹)C(＝NR^1a)N(R¹)-、-N(R¹)C(＝S)N(R¹)-、-N(R¹)C(＝NR^1a) -or-C (═ NR)^1a)N(R¹)-；

V is-C (O) -, -C (O) O-, -C (S) -, -C (O) N (R)¹)-、-S(O)_t- (where t is 0, 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (R)¹⁰) H-or-C (═ NR)^1a)-；

Each R ¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R^1aselected from hydrogen, -OR¹Cyano, C₁-C₆Alkyl and cycloalkylalkyl;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R³is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R³Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

R¹⁰is hydrogen or C₁-C₃An alkyl group; and is

Each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

In another aspect, the present invention provides a compound of formula (II), including a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a prodrug thereof,

wherein:

x and y are each independently 1, 2 or 3;

w is selected from-C (O) N (R)¹) -and-N (R)¹)C(O)-；

Each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy ₂-C₆An alkyl group;

R²is selected from C₇-C₁₂Alkyl radical, C₃-C₁₂Alkenyl radical, C₇-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Hydroxyalkenyl, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkylalkyl radical, C₁₃-C₁₉Aralkyl radical, C₃-C₁₂Heterocyclylalkyl radical and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein some or all of the rings may be fused to each otherCombining;

R³is selected from C₃-C₁₂Alkyl radical, C₃-C₁₂Alkenyl radical, C₃-C₁₂Hydroxyalkyl radical, C₃-C₁₂Hydroxyalkenyl, C₃-C₁₂Alkoxy radical, C₃-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₅-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R³Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R⁴and R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and is

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R ⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group.

In another aspect, the present invention provides a compound of formula (III), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a prodrug thereof,

wherein:

x and y are each independently 1, 2 or 3;

a is oxygen or sulfur;

w is selected from-C (O) N (R)¹) -and-N (R)¹)C(O)-；

Each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₆Alkoxy radical, C₃-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein some or all of the rings may be fused to each other;

R³is phenyl optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C ₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹¹)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹¹)₂Cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl with the proviso that R is³Phenyl which is not substituted by optionally substituted thienyl;

R⁴and R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl;

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹and R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forming an alkylene bridge and the remainderR⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; and is

Each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl.

In another aspect, the present invention provides a compound of formula (IV), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a prodrug thereof,

wherein:

x and y are each independently 1, 2 or 3;

each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl ₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkylalkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl, aryl, C₇-C₁₂Aralkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings wherein the rings are independentIs selected from cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused to each other;

R³is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R³Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R⁴and R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and is

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R ^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group.

In another aspect, the present invention provides a compound of formula (Va), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a prodrug thereof,

wherein:

x and y are each independently 1, 2 or 3;

w is-C (O) N (R)¹)-、-N(R¹)C(O)N(R¹) -or-N (R)¹)C(O)-；

Each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R²is selected from C₇-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₇-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkylalkyl radical, C₁₃-C₁₉Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

R³is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C ₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

R⁴and R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

R¹⁰is hydrogen or C₁-C₃An alkyl group; and is

Each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group;

however, with the proviso that R²Not a pyrazinyl, pyridonyl, pyrrolidinonyl or imidazolyl group.

In another aspect, the present invention provides a compound of formula (Vb), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof,

wherein:

x and y are each independently 1, 2 or 3;

W is-C (O) N (R)¹)-、N(R¹)C(O)N(R¹) -or-N (R)¹)C(O)-；

Each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

R³is selected from C₇-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy or C₂-C₁₂Alkoxyalkyl group

R⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C ₁-C₃An alkyl group;

R¹⁰is hydrogen or C₁-C₃Alkyl radical(ii) a And is

Each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

In another aspect, the present invention provides a method of treating an SCD-mediated disease or condition in a mammal, preferably a human, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention as described above.

In another aspect, the present invention provides compounds or pharmaceutical compositions useful in the treatment, prevention and/or diagnosis of diseases or conditions associated with SCD biological activity, such as diseases encompassed by cardiovascular diseases and/or metabolic syndromes, including dyslipidemia, insulin resistance and obesity.

In another aspect, the present invention provides a method of preventing or treating a disease or condition associated with elevated lipid levels, e.g., plasma lipid levels, particularly elevated triglyceride or cholesterol levels, in a patient suffering from such elevated levels, comprising administering to the patient a therapeutically or prophylactically effective amount of a composition disclosed herein. The invention also relates to novel compounds having the therapeutic ability to reduce lipid levels, particularly triglyceride and cholesterol levels, in animals.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention as described above, and a pharmaceutically acceptable excipient. In one embodiment, the invention relates to pharmaceutical compositions comprising a compound of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride levels, or treat diseases associated with dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human. In an embodiment of this composition, the patient has elevated lipid levels, e.g., elevated plasma triglycerides or cholesterol, prior to administration of the compound, and the compound is present in an amount effective to reduce the lipid levels.

In another aspect, the invention provides a method of treating a patient having, or preventing the development of, a disease or condition mediated by stearoyl-coa desaturase (SCD), comprising administering to a patient having, or at risk of developing, the disease or condition a therapeutically effective amount of a compound that, when administered to a patient, inhibits SCD activity in the patient.

In another aspect, the invention provides methods of treating a range of diseases involving lipid metabolism using compounds identified by the methods disclosed herein. According to this aspect, disclosed herein is a series of compounds having such activity and useful in the treatment of human disorders or conditions associated with serum lipids, such as triglyceride levels, VLDL, HDL, LDL and/or total cholesterol, based on a screening assay to identify therapeutic agents from a library of test compounds that modulate the biological activity of SCD.

Detailed Description

Definition of

The shorthand notation preceding a particular chemical group as named herein denotes the total number of carbon atoms found in the chemical group shown. For example; c₇-C₁₂Alkyl describes alkyl having a total of 7 to 12 carbon atoms, C, as defined below ₄-C₁₂Cycloalkylalkyl describes cycloalkylalkyl groups having a total of 4 to 12 carbon atoms as defined below. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in a substituent of the group.

Accordingly, unless specified to the contrary, the following terms used in the specification and appended claims have the indicated meanings:

"methoxy" means-OCH₃A group.

"cyano" refers to the group-CN.

"nitro" means-NO₂A group.

"trifluoromethyl" means-CF₃A group.

"oxo" refers to an ═ O substituent.

"thio" means ═ S substituent.

"alkyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is free of unsaturation, has from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms or from 1 to 6 carbon atoms, and which is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, n-pentyl, 1-dimethylethyl (t-butyl), and the like. Unless specifically stated otherwise in the specification, an alkyl group may be optionally substituted with one of the following groups: alkyl, alkenyl, halogen, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)(S(O)_tR¹⁶) (wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R is¹⁶Each is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents, unless otherwise indicated, is unsubstituted.

“C₁-C₃Alkyl "refers to an alkyl group as defined above containing 1 to 3 carbon atoms. C₁-C₃Alkyl groups may be optionally substituted as defined for alkyl.

“C₁-C₆Alkyl "refers to an alkyl group as defined above containing 1 to 6 carbon atoms. C₁-C₆Alkyl groups may be optionally substituted as defined for alkyl.

“C₁-C₁₂Alkyl "refers to an alkyl group as defined above containing from 1 to 12 carbon atoms. C₁-C₁₂Alkyl groups may be optionally substituted as defined for alkyl.

“C₂-C₆Alkyl "means an alkyl group as defined above containing from 2 to 6 carbon atoms. C₂-C₆Alkyl groups may be optionally substituted as defined for alkyl.

“C₃-C₆Alkyl "means an alkyl group as defined above containing from 3 to 6 carbon atoms. C₃-C₆Alkyl groups may be optionally substituted as defined for alkyl.

“C₃-C₁₂Alkyl "means an alkyl group as defined above containing from 3 to 12 carbon atoms. C₃-C₁₂Alkyl groups may be optionally substituted as defined for alkyl.

“C₆-C₁₂Alkyl "means an alkyl group as defined above containing from 6 to 12 carbon atoms. C₆-C₁₂Alkyl groups may be optionally substituted as defined for alkyl.

“C₇-C₁₂Alkyl "means an alkyl group as defined above containing from 7 to 12 carbon atoms. C₇-C₁₂Alkyl groups may be optionally substituted as defined for alkyl.

"alkenyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, and which is attached to the remainder of the molecule by a single bond, e.g., vinyl, prop-1-enyl, but-1-enyl, pent-1, 4-dienyl, and the like. Unless specifically stated otherwise in the specification, an alkenyl group may be optionally substituted with one of the following groups:alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -OR ¹⁴、-OC(O)-R¹⁴、-N(R¹⁴)₂、-C(O)R¹⁴、-C(O)OR¹⁴、-C(O)N(R¹⁴)₂、-N(R¹⁴)C(O)OR¹⁶、-N(R¹⁴)C(O)R¹⁶、-N(R¹⁴)(S(O)_tR¹⁶) (wherein t is 1 to 2), -S (O)_tOR¹⁶(wherein t is 1 to 2), -S (O)_tR¹⁶(wherein t is 0 to 2) and-S (O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein R¹⁴Each independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R is¹⁶Each is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

“C₃-C₁₂Alkenyl "means an alkenyl group as defined above containing from 3 to 12 carbon atoms. C₃-C₁₂The alkenyl group may be optionally substituted as described for the alkenyl group.

“C₂-C₁₂Alkenyl "means an alkenyl group as defined above containing 2 to 12 carbon atoms. C₂-C₁₂The alkenyl group may be optionally substituted as described for the alkenyl group.

"alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain that links the remainder of the molecule to a group, consists only of carbon and hydrogen, is free of unsaturation, and has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the remainder of the molecule and the group by one carbon in the chain or by any two carbons in the chain.

"alkenylene" and "alkenylene chain" refer to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a group, consists only of carbon and hydrogen, contains at least one double bond, and has 2 to 12 carbon atoms, such as ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain may be attached to the rest of the molecule by a single bond and to a group by a double or single bond. The point of attachment of the alkenylene chain to the rest of the molecule and the group may be through one or any two carbons in the chain.

"alkylene bridge" means a straight or branched chain divalent hydrocarbon bridge, which connects two different carbons of the same ring structure, consists only of carbon and hydrogen, is free of unsaturation and has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene bridge may connect any two carbons within the ring structure.

"alkoxy" means a group of the formula-OR_aWherein R is_aIs an alkyl group as defined above. The alkyl portion of the alkoxy group may be optionally substituted as defined above for alkyl.

“C₁-C₆Alkoxy "refers to an alkoxy group as defined above containing 1 to 6 carbon atoms. C₁-C₆The alkyl portion of the alkoxy group may be optionally substituted as defined above for alkyl.

“C₁-C₁₂Alkoxy "refers to an alkoxy group as defined above containing 1 to 12 carbon atoms. C₁-C₁₂The alkyl portion of the alkoxy group may be optionally substituted as defined above for alkyl.

“C₃-C₁₂Alkoxy "refers to an alkoxy group as defined above containing 3 to 12 carbon atoms. C₃-C₁₂The alkyl portion of the alkoxy group may be optionally substituted as defined above for alkyl.

"alkoxyalkyl" means a group of the formula-R_a-O-R_aWherein R is_aEach independently is an alkyl group as defined above. Oxygen atom can be connected withAny carbon on an alkyl group is attached. The alkyl portion of an alkoxyalkyl group can each be optionally substituted as defined above for alkyl.

“C₂-C₁₂Alkoxyalkyl "refers to an alkoxyalkyl group as defined above that contains from 2 to 12 carbon atoms. C₂-C₁₂The alkyl portion of an alkoxyalkyl group can each be optionally substituted as defined above for alkyl.

“C₃Alkoxyalkyl "refers to an alkoxyalkyl group as defined above that contains 3 carbon atoms. C₃The alkyl portion of the alkoxyalkyl group can be optionally substituted as defined above for alkyl.

“C₃-C₁₂Alkoxyalkyl "refers to an alkoxyalkyl group as defined above that contains from 3 to 12 carbon atoms. C₃-C₁₂The alkyl portion of the alkoxyalkyl group can be optionally substituted as defined above for alkyl.

"alkylsulfonyl" means a radical of the formula-S (O)₂R_aWherein R is_aIs an alkyl group as defined above. The alkyl moiety of the alkylsulfonyl group may be optionally substituted as defined above for alkyl.

“C₁-C₆Alkylsulfonyl "refers to alkylsulfonyl groups as defined above having from 1 to 6 carbon atoms. C₁-C₆Alkylsulfonyl may be optionally substituted as defined above for alkylsulfonyl.

"aryl" means an aromatic monocyclic or polycyclic hydrocarbon ring system consisting exclusively of hydrogen and carbon and containing 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, wherein the ring system may be partially or fully saturated. Aryl groups include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "aryl-" (e.g., in "aralkyl") is intended to include aryl groups optionally substituted with one or more substituents selected from alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, aryl radicalsAlkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)(S(O)_tR¹⁶) (wherein t is 1 to 2), -R¹⁵-S(O)_tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R ¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein R¹⁴Each independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; r¹⁵Each independently is a direct bond or a straight or branched alkylene or alkenylene chain; and R is¹⁶Each is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

"aralkyl" means a group of the formula-R_aR_bWherein R is_aIs alkyl as defined above, and R_bIs one or more aryl groups as defined above, such as benzyl, diphenylmethyl, and the like. The aryl portion of an aralkyl group may be optionally substituted as defined above for aryl. The alkyl group of the aralkyl group may be optionally substituted as defined above for the alkyl group.

“C₇-C₁₂Aralkyl "refers to an aralkyl group as defined above containing from 7 to 12 carbon atoms. C₇-C₁₂The aryl portion of an aralkyl group may be optionally substituted as defined above for aryl. C₇-C₁₂The alkyl portion of the aralkyl group may be optionally substituted as defined above for alkyl.

“C₁₃-C₁₉Aralkyl "refers to an aralkyl group as defined above, which contains from 13 to 19 carbon atoms. C ₁₃-C₁₉The aryl portion of an aralkyl group may be optionally substituted as defined above for aryl. C₁₃-C₁₉The alkyl portion of the aralkyl group may be optionally substituted as defined above for alkyl.

"aralkenyl" means a group of formula-R_cR_bWherein R is_cIs alkenyl as defined above and R_bIs one or more aryl groups as defined above, which may be optionally substituted as described above. The aryl portion of the aralkenyl may be optionally substituted as described above for aryl. The alkenyl moiety of the aralkenyl may be optionally substituted as defined above for alkenyl.

"aryloxy" means a group of the formula-OR_bWherein R is_bIs an aryl group as defined above. The aryl moiety of the aryloxy group may be optionally substituted as defined above.

"aryl-C₁-C₆Alkyl "means a group of the formula-R_h-R_iWherein R is_hIs an unbranched alkyl group having 1 to 6 carbons and R_iIs an aryl group attached to the terminal carbon of an alkyl group.

"cycloalkyl" means a stable nonaromatic monocyclic or bicyclic hydrocarbon radical consisting exclusively of carbon and hydrogen, having from 3 to 15 carbon atoms, preferably from 3 to 12 carbon atoms, which is saturated or unsaturated and is linked to the remainder of the molecule by a single bond, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl and the like. Unless specifically stated otherwise in the specification, the term "cycloalkyl" is intended to include cycloalkyl optionally substituted with one or more substituents selected from alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R ¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)(S(O)_tR¹⁶) (wherein t is 1 to 2), -R¹⁵-S(O)_tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein R¹⁴Each independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; r¹⁵Each independently is a direct bond or a straight or branched alkylene or alkenylene chain; and R is¹⁶Each is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

“C₃-C₆Cycloalkyl "means a cycloalkyl group as defined above having 3 to 6 carbon atoms. C₃-C₆Cycloalkyl groups may be optionally substituted as defined above for cycloalkyl groups.

“C₃-C₁₂Cycloalkyl "means a cycloalkyl group as defined above having 3 to 12 carbon atoms. C₃-C₁₂Cycloalkyl groups may be optionally substituted as defined above for cycloalkyl groups.

"cycloalkylalkyl" means a compound of the formula-R_aR_dWherein R is_aIs alkyl as defined above and R_dIs cycloalkyl as defined above. The cycloalkyl portion of a cycloalkyl group may be optionally substituted as defined above for cycloalkyl. The alkyl portion of the cycloalkyl group may be optionally substituted as defined above for alkyl.

“C₄-C₁₂Cycloalkylalkyl "means a cycloalkyl group as defined above having 4 to 12 carbon atomsAn alkyl group. C₄-C₁₂Cycloalkylalkyl groups may be optionally substituted as defined above for cycloalkylalkyl.

"halogen" means bromine, chlorine, fluorine or iodine.

"haloalkyl" means an alkyl group, as defined above, which is substituted with one or more halo groups, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl portion of the haloalkyl may be optionally substituted as defined above for alkyl.

"haloalkenyl" means an alkenyl group, as defined above, which is optionally substituted with one or more halogen groups, as defined above, e.g., 2-bromovinyl, 3-bromoprop-1-enyl, and the like. The alkenyl moiety of the haloalkenyl group may be optionally substituted as defined above for alkyl.

"heterocyclyl" refers to a stable 3-to 18-membered non-aromatic cyclic group consisting of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. For the purposes of the present invention, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atom on the heterocyclyl may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopyrazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in the specification, the term "heterocyclyl" is intended to include a heterocyclyl group as defined above optionally substituted with one or more substituents selected from From alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, oxo, thio, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)(S(O)_tR¹⁶) (wherein t is 1 to 2), -R¹⁵-S(O)_tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein R¹⁴Each independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; r¹⁵Each independently is a direct bond or a straight or branched alkylene or alkenylene chain; and R is¹⁶Each is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

“C₃-C₁₂Heterocyclyl "means a heterocyclyl group as defined above having 3 to 12 carbons. C₃-C₁₂The heterocyclyl group may be optionally substituted as defined above for the heterocyclyl group.

"Heterocyclylalkyl" means a compound of the formula-R_aR_eWherein R is_aIs alkyl as defined above and R_eIs a heterocyclic group as defined above, and if the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group may be attached to an alkyl group on the nitrogen atom. The alkyl portion of the heterocyclylalkyl group may be optionally substituted as defined above for alkyl. The heterocyclyl portion of the heterocyclylalkyl group may be as described above for the heterocyclyl group Optionally substituted as defined.

“C₃-C₁₂Heterocyclylalkyl "refers to a heterocyclylalkyl group as defined above having 3 to 12 carbons. C₃-C₁₂Heterocyclylalkyl groups may be optionally substituted as defined above for heterocyclylalkyl groups.

"heteroaryl" refers to a 5-to 18-membered aromatic cyclic group consisting of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. For the purposes of the present invention, heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atom on the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4, 6 ] benzofuranyl]Imidazo [1, 2-a ]]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidinyl, isoquinolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. Unless specifically stated otherwise in the specification, the term "heteroaryl" is intended to include heteroaryl as defined above optionally substituted with one or more substituents selected from alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, oxo, thio, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl Heteroarylalkyl, -R¹⁵-OR¹⁴、-R¹⁵-OC(O)-R¹⁴、-R¹⁵-N(R¹⁴)₂、-R¹⁵-C(O)R¹⁴、-R¹⁵-C(O)OR¹⁴、-R¹⁵-C(O)N(R¹⁴)₂、-R¹⁵-N(R¹⁴)C(O)OR¹⁶、-R¹⁵-N(R¹⁴)C(O)R¹⁶、-R¹⁵-N(R¹⁴)(S(O)_tR¹⁶) (wherein t is 1 to 2), -R¹⁵-S(O)_tOR¹⁶(wherein t is 1 to 2), -R¹⁵-S(O)_tR¹⁶(wherein t is 0 to 2) and-R¹⁵-S(O)_tN(R¹⁴)₂(wherein t is 1 to 2) wherein R¹⁴Each independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; r¹⁵Each independently is a direct bond or a straight or branched alkylene or alkenylene chain; and R is¹⁶Each is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and wherein each of the foregoing substituents is unsubstituted.

“C₁-C₁₂Heteroaryl "refers to heteroaryl as defined above having 1 to 12 carbon atoms. C₁-C₁₂Heteroaryl groups may be optionally substituted as defined above for heteroaryl groups.

“C₅-C₁₂Heteroaryl "refers to heteroaryl as defined above having 5 to 12 carbon atoms. C₅-C₁₂Heteroaryl groups may be optionally substituted as defined above for heteroaryl groups.

"Heteroaralkyl" means a group of formula-R_aR_fGroup, wherein R_aIs alkyl as defined above and R_fIs heteroaryl as defined above. The heteroaryl portion of the heteroarylalkyl group may be optionally substituted as defined above for heteroaryl. The alkyl portion of the heteroaralkyl may be optionally substituted as defined above for alkyl.

“C₃-C₁₂Heteroaralkyl "means a heteroaralkyl as defined above having 3 to 12 carbon atoms. C₃-C₁₂Heteroaralkyl groups may be optionally substituted as defined above for heteroaralkyl.

"Heteroarylcycloalkyl" means a compound of the formula-R_dR_fWherein R is_dIs cycloalkyl as defined above and R_fIs heteroaryl as defined above. The cycloalkyl portion of the heteroarylcycloalkyl group may be optionally substituted as defined above for cycloalkyl. The heteroaryl portion of the heteroarylcycloalkyl group may be optionally substituted as defined above for heteroaryl.

"Heteroarylalkenyl" means a group of formula-R_bR_fWherein R is_bIs alkenyl as defined above and R_fIs heteroaryl as defined above. The heteroaryl portion of the heteroarylalkenyl group may be optionally substituted as defined above for heteroaryl. The alkenyl moiety of the heteroarylalkenyl group may be optionally substituted as defined above for alkenyl.

"hydroxyalkyl" means a group of the formula-R_aA group of-OH, wherein R_aIs alkyl as defined. The hydroxyl group may be attached to the alkyl group at any carbon within the alkyl group. The alkyl portion of the hydroxyalkyl group may be optionally substituted as defined above for alkyl.

“C₂-C₁₂Hydroxyalkyl "means a hydroxyalkyl group as defined above comprising from 2 to 12 carbon atoms. C ₂-C₁₂The alkyl portion of the hydroxyalkyl group may be optionally substituted as defined above for alkyl.

“C₃-C₁₂Hydroxyalkyl "means a hydroxyalkyl group as defined above comprising 3 to 12 carbon atoms. C₃-C₁₂The alkyl portion of the hydroxyalkyl group may be optionally substituted as defined above for alkyl.

“C₇-C₁₂Hydroxyalkyl "means a hydroxyalkyl radical as defined above comprising 7 to 12 carbon atoms。C₇-C₁₂The alkyl portion of the hydroxyalkyl group may be optionally substituted as defined above for alkyl.

"hydroxyalkenyl" means a group of the formula-R_cA group of-OH, wherein R_cIs alkenyl as defined above. The hydroxyl group may be attached to the alkenyl group at any carbon within the alkenyl group. The alkenyl moiety of the hydroxyalkenyl group may be optionally substituted as defined above for alkenyl.

“C₂-C₁₂By "hydroxyalkenyl" is meant a hydroxyalkenyl group as defined above comprising 2 to 12 carbon atoms. C₂-C₁₂The alkenyl moiety of the hydroxyalkenyl group may be optionally substituted as defined above for alkenyl.

“C₃-C₁₂By "hydroxyalkenyl" is meant a hydroxyalkenyl group as defined above comprising 3 to 12 carbon atoms. C₃-C₁₂The alkenyl moiety of the hydroxyalkenyl group may be optionally substituted as defined above for alkenyl.

"hydroxy-C₁-C₆-alkyl "means a radical of the formula-R_hA group of-OH, wherein R_hIs an unbranched alkyl group having 1 to 6 carbons and the hydroxyl group is attached to the terminal carbon.

"Trihaloalkyl" means an alkyl group, as defined above, substituted with three halo groups, as defined above, e.g., trifluoromethyl. The alkyl portion of the trihaloalkyl group may be optionally substituted as defined above for alkyl.

“C₁-C₆Trihaloalkyl "refers to trihaloalkyl groups as defined above having 1 to 6 carbon atoms. C₁-C₆The trihaloalkyl group may be optionally substituted as defined above for trihaloalkyl.

"Trihaloalkoxy" means a compound of the formula-OR_gWherein R is_gIs a trihaloalkyl group as defined above. The trihaloalkyl moiety of the trihaloalkoxy group may be optionally substituted as defined above for trihaloalkyl.

“C₁-C₆Trihaloalkoxy "refers to trihaloalkoxy groups as defined above having 1 to 6 carbon atoms. C₁-C₆Trihaloalkoxy may be optionally substituted as defined above for trihaloalkoxy.

"polycyclic structure" means a polycyclic ring system consisting of 2 to 4 rings wherein the rings are independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl as defined above. Each cycloalkyl group may be optionally substituted as defined above for cycloalkyl. Each aryl group may be optionally substituted as defined above for aryl. Each heterocyclyl group may be optionally substituted as defined above for the heterocyclyl group. Each heteroaryl group may be optionally substituted as defined above for heteroaryl. The rings may be connected to another ring through a direct bond or a part or all of the rings may be fused to each other. Examples include, but are not limited to, cycloalkyl substituted with aryl; cycloalkyl substituted with an aryl group, said aryl group in turn being substituted with another aryl group; and so on.

By "prodrug" is meant a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention, which is pharmaceutically acceptable. When administered to a subject in need of treatment, the prodrug may be inactive, but it converts in vivo to the active compound of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds often offer advantages in terms of solubility, histocompatibility or sustained release in mammalian organisms (see Bundgard, h., Design of produgs (1985), pp.7-9, 21-24(Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T.S., et al, "Pro-drugs as novelderlivery Systems," A.C.S.Symphosis Series, Vol.14 and in Bioreversible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

The term "prodrug" is also meant to include any covalently bonded carriers that release the active compounds of the invention in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present invention may be prepared by modifying functional groups present in the compounds of the present invention in such a way that the variant cleaves in a conventional manner or in vivo to form the parent compound of the present invention. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the compound of the present invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the compounds of the present invention, and the like.

"stabilizing compound" and "stable structure" are intended to mean that a compound is present in a sufficiently stable form when isolated from a reaction mixture to achieve a useful purity and formulation into an effective therapeutic agent.

"mammal" includes humans and domestic animals, such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits, and the like.

"optional" or "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes substituted aryl groups as well as unsubstituted aryl groups.

A "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. food and drug administration as being useful for human or livestock.

"pharmaceutically acceptable salts" include acid addition salts and base addition salts.

"pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with the following acids: inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, cinnamic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and the like.

"pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts, and the like. Preferred inorganic acid salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, including naturally occurring substituted amines, cyclic amines, and cation exchange resins, such as salts of ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzphetamine, N' -dibenzylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

Crystallization typically produces solvates of the compounds of the invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including the monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate and tetrahydrate, and the like, as well as the corresponding solvate forms. The compounds of the invention may be true solvates, while in other cases the compounds of the invention may retain only the entrained water or be a mixture of water plus some entrained solvent.

"pharmaceutical composition" refers to a formulation of a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers, diluents or excipients therefor.

"therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a mammal, preferably a human, is sufficient to effectively treat an SCD-mediated disease or condition in the mammal, preferably a human, as defined below. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the disclosure of this specification.

As used herein, "treating" or "treatment" covers the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from said disease or disorder of interest, and includes:

(i) preventing the occurrence of the disease or condition in a mammal, particularly when the mammal is susceptible to the condition, but has not yet been diagnosed as having the condition;

(ii) inhibiting, i.e., arresting the development of, the disease or condition; or

(iii) Ameliorating the disease or condition, i.e., causing regression of the disease or condition.

As used herein, the terms "disease" and "condition" are used interchangeably or are distinguished in that a particular disease or condition may not have a known causative factor (such that the etiology is not yet clarified), and thus, it is still not considered a disease, but merely an undesirable condition or syndrome, in which a more or less specific set of symptoms has been identified by a clinician.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms which, in absolute stereochemistry, may be defined as (R) -or (S) -or, for amino acids, (D) -or (L) -. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column. When a compound described herein contains an olefinic double bond or other geometric asymmetric center, or unless otherwise specified, it is meant that the compound includes both E and Z geometric isomers. Likewise, all tautomeric forms are also included.

"stereoisomers" refers to compounds made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

"tautomer" refers to the movement of a proton from one atom of a molecule to another atom of the same molecule. The invention includes tautomers of any of the compounds.

The chemical naming schemes and structural schematics used herein are used and rely on the chemical naming features used as in Chemdraw 7.0.1 version (available from Cambridge corp., Cambridge, MA). For complex chemical names used herein, a substituent is named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl backbone with cyclopropyl substituents. In the chemical structure diagram, all bonds are identified except for some carbon atoms that are assumed to be attached with enough hydrogen atoms to complete the valency.

For example, a compound of formula (III) as described above in the summary of the invention, wherein x and y are both 1; a is oxygen; w is-N (R) ¹)C(O)-；R¹、R⁴、R⁵、R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen; r²Is 2-cyclopropylethyl, and R³Is 2, 5-dichlorophenyl, i.e. a compound of the formula:

is designated herein as 6- [4- (2, 5-dichlorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.

Certain groups of the compounds of the present invention are described herein as bonds between two moieties of the compounds of the present invention. For example in the following formula (I):

w is described, for example, as being-N (R)¹)C(O)-、-C(O)N(R¹) -or-N (R)¹)C(O)N(R¹) -; and V is described as-C (O) -, -C (S) -or-C (R)¹⁰) -. The description is meant to describe the following with R²Group-attached W group: r²-N(R¹)C(O)-、R²-C(O)N(R¹) -or R²-N(R¹)C(O)N(R¹) -; and is meant to describe the following and R³Group-attached V group: -C (O) -R³、-C(R¹⁰)-R³or-C (S) -R³. In other words, the description of the W and V bond groups means to read from left to right in view of the formula (I) described above.

Embodiments of the invention

In one embodiment of the invention as described in the summary of the invention above, a class of compounds of formula (II) relates to compounds wherein x and y are each 1; w is selected from-C (O) N (R)¹) -and-N (R)¹) C (O) -; each R¹Independently selected from hydrogen or C₁-C₆An alkyl group; r²Is selected from C₇-C₁₂Alkyl radical, C₃-C₁₂Alkenyl radical, C₇-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Hydroxyalkenyl, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkylalkyl radical, C ₁₃-C₁₉Aralkyl radical, C₃-C₁₂Heterocyclylalkyl radical and C₃-C₁₂A heteroaralkyl group; each R²Optionally substituted by one or more substituents selected from halogen, C₁-C₃Alkyl, -OR¹¹、-C(O)OR¹¹、C₁-C₆Trihaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; r³Is selected from C₃-C₁₂Alkyl radical, C₃-C₁₂Alkenyl radical, C₃-C₁₂Hydroxyalkyl radical, C₃-C₁₂Hydroxyalkenyl, C₃-C₁₂Alkoxy radical, C₃-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkylalkyl radical, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₅-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group; each R³Optionally substituted by one or more substituents selected from C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkoxy radical, C₁-C₆Alkylsulfonyl, halogen, cyano, nitro, hydroxy, -N (R)¹²)₂，-C(O)OR¹¹，-S(O)₂N(R¹²)₂Cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaryl cycloalkyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl, aryl or aralkyl; and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Of the class of compounds of formula (II), a subset of compounds relates to compounds wherein W is-N (R) ¹)C(O)-；R¹Is hydrogen; r²Is C₄-C₁₂A cycloalkylalkyl group; r³Is C₃-C₁₂Alkyl or C₃-C₁₂Alkenyl, each optionally substituted with one or more halo groups; r⁴And R⁵Each is hydrogen; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

Another subclass of this class of compounds of formula (II) relates to compounds wherein W is-N (R)¹)C(O)-；R¹Is hydrogen; r²Is C₄-C₁₂A cycloalkylalkyl group; r³Is C₃-C₁₂Cycloalkyl optionally substituted by one or more groups selected from hydroxy, C₁-C₆Trihaloalkyl or C₁-C₆Alkyl substituent substitution; r⁴And R⁵Each is hydrogen; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

Another subclass of this class of compounds of formula (II) relates to compounds wherein W is-N (R)¹)C(O)-；R²Is C₄-C₁₂Cycloalkylalkyl and R³Is C₃-C₁₂Hydroxyalkyl, optionally substituted with one or more halogen groups; r⁴And R⁵Each is hydrogen; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

Another subclass of this class of compounds of formula (II) relates to compounds wherein W is-N (R)¹)C(O)-；R¹Is hydrogen; r²Is C₄-C₁₂A cycloalkylalkyl group; r³Is C₃-C₁₂An alkoxy group; r⁴And R⁵Each is hydrogen; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

Another subclass of this class of compounds of formula (II) relates to compounds wherein W is-N (R)¹)C(O)-；R¹Is hydrogen; r²Is C₄-C₁₂A cycloalkylalkyl group; r³Is C₇-C₁₂Aralkyl optionally substituted with one or more substituents independently selected from halogen or C ₁-C₆Trihaloalkyl substituent; r⁴And R⁵Each is hydrogen; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

Another subclass of this class of compounds of formula (II) relates to compounds wherein W is-N (R)¹)C(O)-；R¹Is hydrogen; r²Is C₄-C₁₂A cycloalkylalkyl group; r³Is C₃-C₁₂Heterocyclyl or C₅-C₁₂Heteroaryl, each optionally substituted by one or more substituents independently selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl or aralkyl; r⁴And R⁵Each is hydrogen; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

In another embodiment of the invention as described in the summary of the invention above, a class of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen or sulfur; w is selected from-C (O) N (R)¹) -and-N (R)¹) C (O) -; each R¹Independently selected from hydrogen or C₁-C₆An alkyl group; r²Is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₆Alkoxy radical, C₃-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group; each R²Optionally substituted by one or more substituents selected from halogen, cyano, oxo, thio, C₁-C₃Alkyl, -OR¹¹、-C(O)R¹¹、-OC(O)R¹¹、-C(O)OR¹¹、-C(O)N(R¹²)₂、-N(R¹²)₂、C₁-C₆Trihaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; r ³Is phenyl optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂Cycloalkyl, heterocyclyl and heteroaryl cycloalkyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; r⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; r⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; or R⁶And R^6aTogether or R⁹And R^9aTogether are an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl, and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Of the class of compounds of formula (III), a subset of the compounds relates to compounds of whichx and y are each 1; a is oxygen or sulfur; w is-N (R)¹)C(O)-；R¹Is hydrogen, methyl or ethyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group.

Within this subclass of compounds of formula (III), one group of compounds relates to compounds wherein R is²Is C₄-C₁₂Cycloalkylalkyl optionally substituted with one OR more groups selected from-OR ¹¹、C₁-C₃Alkyl or aryl; r³Is phenyl optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂And a cycloalkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl; and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Another group of compounds of this subclass of formula (III) relates to compounds wherein a is oxygen; r²Is C₁-C₁₂Alkyl or C₂-C₁₂Alkenyl, each optionally substituted with one or more groups selected from halogen, aryloxy, -C (O) R¹¹、-OC(O)R¹¹OR-C (O) OR¹¹Substituted with the substituent(s); r³Is phenyl optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂And a cycloalkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Another group of compounds of this subclass of formula (III) relates to compounds wherein a is oxygen; r²Is C₂-C₁₂Hydroxyalkyl radical, C ₂-C₁₂(ii) hydroxyalkenyl, each optionally substituted with one or more halo groups; r³Is phenyl optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂And a cycloalkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Another group of compounds of this subclass of formula (III) relates to compounds wherein a is oxygen; r²Is C₇-C₁₂Aralkyl radical, wherein C₇-C₁₂The aryl portion of an aralkyl group is optionally substituted with one or more substituents independently selected from halogen, C₁-C₃Alkyl, -OR¹¹、-C(O)OR¹¹、C₁-C₆Substituted by trihaloalkyl, cycloalkyl and aryl radicals, and C₇-C₁₂The alkyl portion of an aralkyl group is optionally substituted with one OR more substituents independently selected from hydroxy, halo, -OR¹¹and-OC (O) R¹¹Substituted with the substituent(s); r³Is optionally one ofOr phenyl substituted by more than one substituent selected from halogen, cyano, nitro, hydroxyl, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂And a cycloalkyl group; each R¹¹Independently selected from hydrogen, C ₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Another group of compounds of this subclass of formula (III) relates to compounds wherein a is oxygen; r²Is C₁-C₆Alkoxy or C₃-C₁₂Alkoxyalkyl, each optionally substituted with one or more substituents independently selected from halogen or C₃-C₆Cycloalkyl substituents; r³Is phenyl optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂And a cycloalkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Another group of compounds of this subclass of formula (III) relates to compounds wherein a is oxygen; r²Is aryl, optionally substituted with one or more substituents independently selected from halogen, cyano, C₁-C₃Alkyl, -OR¹¹、-C(O)R¹¹、-OC(O)R¹¹、-C(O)OR¹¹、-C(O)N(R¹²)₂、C₁-C₆Trihaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; r³Is phenyl, optionally substituted by C₁-C₆Trihaloalkyl or C ₁-C₆Trihaloalkoxy substitution; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Another group of compounds of this subclass of formula (III) relates to compounds wherein a is oxygen; r²Is C₁-C₁₂Heteroaryl, optionally substituted with one or more substituents selected from halogen, cyano, oxo, thio, C₁-C₃Alkyl, -OR¹¹、-C(O)R¹¹、-OC(O)R¹¹、-C(O)OR¹¹、-C(O)N(R¹²)₂And C₁-C₆Trihaloalkyl; r³Is phenyl, optionally substituted by C₁-C₆Trihaloalkyl or C₁-C₆Trihaloalkoxy substitution; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Of the group of compounds of formula (III), a subset of the compounds relates to compounds in which C is₁-C₁₂Heteroaryl is selected from pyridyl, purinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, imidazolyl, tetrazolyl, triazolyl, isoxazolyl, pyrazolyl, pyrimidinyl, thiadiazolyl, thiazolyl, and pyridazinyl.

Another group of compounds of this subclass of formula (III) relates to compounds wherein a is oxygen; r ²Is C₃-C₁₂Heterocyclic ringsBase, C₃-C₁₂Heterocyclylalkyl radical or C₃-C₁₂Heteroaralkyl, each optionally substituted with one or more substituents selected from halogen, cyano, oxo, thioxo, C₁-C₃Alkyl, -OR¹¹、-C(O)R¹¹、-OC(O)R¹¹、-C(O)OR¹¹、-C(O)N(R¹²)₂And C₁-C₆Trihaloalkyl substituent; r³Is phenyl, optionally substituted by halogen, C₁-C₆Trihaloalkyl or C₁-C₆Trihaloalkoxy substitution; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Within this class of compounds of formula (III) as described above, another subclass of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen; w is-C (O) N (R)¹)-；R¹Is hydrogen, methyl or ethyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group.

Among the subclasses, one group of compounds of formula (III) relates to compounds in which R is²Is C₃-C₁₂Cycloalkyl or C₄-C₁₂Cycloalkylalkyl, each optionally substituted with one OR more groups selected from-OR¹¹、C₁-C₃Alkyl radical, C₁-C₆Trihaloalkyl or aryl; r³Is phenyl optionally substituted by one or more substituents selected from halogen, C ₁-C₆Trihaloalkyl and C₁-C₆Trihaloalkoxy; and each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl.

Another group of compounds of this subclass of formula (III) relates to compounds wherein R is²Is C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₁-C₆Alkoxy or C₃-C₁₂Alkoxyalkyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, oxo, thio, C₁-C₃Alkyl, -OR¹¹、-C(O)R¹¹、-OC(O)R¹¹、-C(O)OR¹¹、-C(O)N(R¹²)₂、-N(R¹²)₂、C₁-C₆Trihaloalkyl, cycloalkyl and aryl; r³Is phenyl, optionally substituted by halogen, C₁-C₆Trihaloalkyl or C₁-C₆Trihaloalkoxy substitution; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Another group of compounds of this subclass of formula (III) relates to compounds wherein R is²Is C₇-C₁₂Aralkyl optionally substituted with one or more substituents selected from halogen, cyano, oxo, thio, C₁-C₃Alkyl, -OR¹¹、-C(O)R¹¹、-OC(O)R¹¹、-C(O)OR¹¹、-C(O)N(R¹²)₂、-N(R¹²)₂、C₁-C₆Trihaloalkyl, cycloalkyl and aryl; r³Is phenyl, optionally substituted by halogen, C₁-C₆Trihaloalkyl or C₁-C₆Trihaloalkoxy substitution; each R¹¹Independently selected from hydrogen, C ₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aralkyl or aryl (optionally substituted with one or more halo groups); and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen; w is-N (R)¹)C(O)-；R¹Is hydrogen, methyl or ethyl; r²Is a cyclopropylethyl or a cyclopropylmethyl group; r³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each is hydrogen; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen; w is-N (R)¹)C(O)-；R¹Is hydrogen, methyl or ethyl; r²Is optionally substituted by-C (O) OR¹¹Substituted C₁-C₆An alkyl group; r³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each is hydrogen; r⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen; and R is¹¹Is hydrogen, methyl, ethyl or 1, 1-dimethylethyl.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen; w is-N (R) ¹)C(O)-；R¹Is hydrogen, methyl or ethyl; r²Is 2-phenylethyl OR 3-phenylpropyl, wherein the phenyl group is optionally substituted with one OR more groups independently selected from chloro, fluoro OR-OR¹¹Substituted with the substituent(s); r³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each is hydrogen; r⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen; and R is¹¹Is hydrogen, methyl, ethyl or 1, 1-dimethylethyl.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen; w is-C (O) N (R)¹)-；R¹Is hydrogen, methyl or ethyl; r²Is a cyclopropylethyl, cyclopropylmethyl or cyclopentylethyl group; r³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen; w is-C (O) N (R)¹)-；R¹Is hydrogen, methyl or ethyl; r²Is C₁-C₆An alkyl group; r ³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (III) relates to compounds wherein x and y are each 1; a is oxygen; w is-C (O) N (R)¹)-；R¹Is hydrogen, methyl or ethyl; r²Is 3-phenylpropyl; r³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each independently of the otherIs selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

In another embodiment of the invention as described in the summary of the invention above, a class of compounds of formula (IV) relates to compounds wherein x and y are each 1; each R¹Is hydrogen or C₁-C₆An alkyl group; r²Is selected from C₃-C₁₂Alkyl radical, C₃-C₁₂Alkenyl radical, C₃-C₁₂Hydroxyalkyl radical, C₃-C₁₂Hydroxyalkenyl, C₃-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkylalkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl, aryl, C₇-C₁₂Aralkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group; each R²Optionally substituted by one or more substituents selected from halogen, oxo, thio, C ₁-C₃Alkyl, -OR¹¹、-C(O)OR¹¹、C₁-C₆Trihaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; r³Is selected from C₃-C₁₂Alkyl radical, C₃-C₁₂Alkenyl radical, C₃-C₁₂Hydroxyalkyl radical, C₃-C₁₂Hydroxyalkenyl, C₃-C₁₂Alkoxy radical, C₃-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C_{1 2}Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group; wherein R above³Each of which is optionally substituted with one or more substituents selected from C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkoxy radical, C₁-C₆Alkylsulfonyl, halogen, cyano, nitro, hydroxy, -N (R)¹²)₂、-C(O)OR¹¹、-S(O)₂N(R¹²)₂Cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; r⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; r⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; or R⁶And R^6aTogether or R⁷And R^7aTogether are an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C ₃-C₆Alkyl, aryl or aralkyl; and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Of the class of compounds of formula (IV), a subset of compounds relates to compounds wherein R is²Is C₃-C₁₂Cycloalkyl or C₄-C₁₂Cycloalkylalkyl, each optionally substituted with one OR more groups selected from-OR¹¹、C₁-C₃Alkyl or aryl radicalsSubstituted with the substituent(s); r³Is phenyl optionally substituted by one or more substituents selected from halogen, C₁-C₆Trihaloalkyl and C₁-C₆Trihaloalkoxy; and each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl.

Another subclass of this class of compounds of formula (IV) relates to compounds wherein R is²Is C₇-C₁₂Aralkyl optionally substituted with one OR more substituents selected from halogen, -OR¹¹Or C₁-C₃An alkyl group; r³Is phenyl optionally substituted by one or more substituents selected from halogen, C₁-C₆Trihaloalkyl and C₁-C₆Trihaloalkoxy; and each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl.

Another subclass of this class of compounds of formula (IV) relates to compounds wherein R is²Is aryl, optionally substituted with one OR more substituents selected from the group consisting of halogen, -OR ¹¹Or C₁-C₃An alkyl group; r³Is phenyl optionally substituted by one or more substituents selected from halogen, C₁-C₆Trihaloalkyl and C₁-C₆Trihaloalkoxy; and each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl.

Another subclass of this class of compounds of formula (IV) relates to compounds wherein R is²Is C₃-C₁₂Alkyl radical, C₃-C₁₂Hydroxyalkyl or C₃-C₁₂Alkoxyalkyl, each optionally substituted with one OR more substituents selected from halogen, -OR¹¹OR-C (O) OR¹¹Substituted with the substituent(s); r³Is phenyl optionally substituted by one or more substituents, whichThe substituent is selected from halogen and C₁-C₆Trihaloalkyl and C₁-C₆Trihaloalkoxy; and each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (IV) relates to compounds wherein x and y are each 1; each R¹Is hydrogen, methyl or ethyl; r²Is benzyl; r³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is ⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

In another embodiment of the invention as described in the summary of the invention above, another class of compounds of formula (IV) relates to compounds wherein x and y are each 1; each R¹Is hydrogen, methyl or ethyl; r²Is a pentyl group; r³Is phenyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro and trifluoromethyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and R is⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach is hydrogen.

In another embodiment of the invention as described in the summary of the invention above, a class of compounds of formula (Va) relates to compounds wherein x and y are each independently 1; w is-N (R)¹) C (O) -; each R¹Is hydrogen or C₁-C₆An alkyl group; r²Is selected from C₇-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₇-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkylalkyl radical, C₁₃-C₁₉Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group; each R²Optionally substituted by one or more substituents selected from halogen, cyano, oxo, thio, C₁-C₃Alkyl, -OR¹¹、-C(O)R¹¹、-OC(O)R¹¹、-C(O)OR¹¹、-C(O)N(R¹²)₂、-N(R¹²)₂、C₁-C₆Trihaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroarylcycloalkyl; r ³Is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group; each R³Optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂Cycloalkyl, heterocyclyl and heteroaryl cycloalkyl; r⁴And R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group; r¹⁰Is hydrogen or C₁-C₃An alkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl; and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

Of the class of compounds of formula (Va), a subset of compounds relates to compounds in which R is²Is C₃-C₁₂Cycloalkyl or C₄-C₁₂Cycloalkylalkyl, each optionally substituted by one or more groups selected from halogen, C₁-C₆Trihaloalkyl, -OR¹¹、C₁-C₃Alkyl or aryl; r³Is phenyl optionally substituted by one or more substituents selected from halogen, cyano, nitro, hydroxy, C ₁-C₆Alkyl radical, C₁-C₆Trihaloalkyl, C₁-C₆Trihaloalkoxy, C₁-C₆Alkylsulfonyl, -N (R)¹²)₂、-OC(O)R¹¹、-C(O)OR¹¹、-S(O)₂N(R¹²)₂And a cycloalkyl group; each R¹¹Independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, aryl or aralkyl; and each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

In another embodiment of the invention as described in the summary of the invention above, a class of compounds of formula (Ia) relates to compounds wherein W is-N (R)¹) C (o) -and V is-C (═ NH) -.

Another class of compounds of formula (Ia) relates to compounds in which W is-N (R)¹)C(＝NR^1a)-。

Another class of compounds of formula (Ia) relates to compounds in which W is-N (R)¹)C(＝NR^1a)N(R¹) -or-N (R)¹)C(＝S)N(R¹)-。

Specific embodiments of the above classes, subclasses and groups of compounds of formula (II), (III), (IV), (Va) and (Ia) are disclosed herein in the reaction schemes and examples set forth below.

In one embodiment, the methods of the present invention relate to the treatment and/or prevention of diseases mediated by stearoyl-coa desaturase (SCD), especially by human SCD (hscd), preferably diseases associated with dyslipidemia and disorders of lipid metabolism, especially diseases associated with elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like, by administering an effective amount of a compound of the present invention.

The invention also relates to pharmaceutical compositions comprising the compounds of the invention. In one embodiment, the present invention relates to compositions comprising a compound of the present invention in a pharmaceutically acceptable carrier and in an amount sufficient to modulate triglyceride levels or treat diseases associated with dyslipidemia and disorders of lipid metabolism when administered to an animal, preferably a mammal, most preferably a human patient. In one embodiment of this composition, prior to administration of the compound of the invention, the patient has elevated lipid levels, such as elevated triglycerides or cholesterol, and the compound of the invention is present in an amount effective to reduce the lipid levels.

Utility and testing of the Compounds of the invention

The present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of diseases mediated by stearoyl-coa desaturase (SCD), preferably human SCD (hscd), preferably diseases associated with dyslipidemia and disorders of lipid metabolism, especially diseases associated with elevated plasma lipid levels, especially cardiovascular diseases, diabetes, obesity and metabolic syndrome, and the like, by administering to a patient in need of such treatment an effective amount of an SCD-modulator, especially an inhibitor.

In general, the present invention provides a method of treating or protecting a patient from a disease and/or disorder associated with dyslipidemia, wherein the lipid level of an animal, especially a human, is outside the normal range (i.e. an abnormal lipid level, such as an increased plasma lipid level), in particular at a level higher than normal, preferably wherein the lipid is a fatty acid, such as a free or complex fatty acid, a triglyceride, a phospholipid or cholesterol, such as wherein the LDL-cholesterol level is increased, or the HDL-cholesterol level is decreased, or any combination thereof, wherein the lipid-related condition or disease is an SCD-mediated disease or condition, the method comprising administering to the animal, such as a mammal, in particular, a human patient, is administered a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, wherein the compound modulates the activity of SCD, preferably human SCD 1.

The compounds of the present invention modulate, preferably inhibit the activity of human SCD enzyme, particularly human SCD1 enzyme.

General values for the activity of the compounds of the invention to modulate, in particular inhibit SCD, can be determined using the assays described in example 33 below. Alternatively, general values for the compounds to treat disorders and diseases may be established in industry standard animal models demonstrating the efficacy of the compounds in treating obesity, diabetes, or elevated triglyceride or cholesterol levels, or improving glucose tolerance. Such models include Zucker obese fa/fa rats (purchased from Harlan sprague dawley, Inc. (Indianapolis, Indiana)), or Zucker diabetic obese rats (ZDF/GmiCrl-fa/fa) (purchased from Charles River laboratories (montre al, Quebec)).

The compounds of the present invention are inhibitors of delta-9 desaturase and are useful in the treatment of diseases and disorders of humans and other organisms, including all those human diseases and disorders that result from abnormal delta-9 desaturase biological activity or that can be ameliorated by modulation of delta-9 desaturase biological activity.

As defined herein, SCD-mediated diseases or conditions include, but are not limited to, the following diseases or conditions or diseases or conditions related thereto: cardiovascular disease, dyslipidemia (including but not limited to triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, fatty acid desaturation index (e.g. the ratio of 18: 1/18: 0 fatty acids as defined elsewhere herein, or other fatty acids), cholesterol and total cholesterol, hypercholesterolemia, as well as cholesterol disorders (including disorders characterized by defective reverse cholesterol transport), familial complex hyperlipidemia, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (including but not limited to stroke, ischemic stroke and Transient Ischemic Attack (TIA)), peripheral vascular disease, and ischemic retinopathy. The compounds of the invention will raise the HDL level and/or lower the triglyceride level and/or lower the LDL or non-HDL-cholesterol level in a subject.

SCD-mediated diseases or conditions also include metabolic syndrome (including, but not limited to, dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricemia, and hypercoagulability), syndrome X, diabetes, insulin resistance, impaired glucose tolerance, non-insulin dependent diabetes mellitus, type II diabetes, type I diabetes, diabetic complications, weight disorders (including, but not limited to, obesity, overweight, cachexia, and anorexia), weight loss, diseases associated with body mass index and leptin. In a preferred embodiment, the compounds of the present invention are also useful for the treatment of diabetes and obesity.

As used herein, the term "metabolic syndrome" is a well-known clinical term used to describe a condition that includes a combination of type II diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal circumference, hypertriglyceridemia, low HDL, hyperuricemia, hypercoagulability, and/or microalbuminemia.

SCD-mediated diseases or conditions also include fatty liver, hepatic steatosis, hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepatogenic protoporphyrinopathy, iron overload disease, hereditary hemochromatosis, liver fibrosis, cirrhosis, liver tumors, and conditions related thereto.

SCD-mediated diseases or conditions also include, but are not limited to, diseases or conditions that are or are associated with primary hypertriglyceridemia, or hypertriglyceridemia secondary to other disorders or diseases, such as hyperlipoproteinemia, familial histiocytosis, lipoprotein lipase deficiency, and apolipoprotein deficiency (e.g., ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or undefined etiology.

SCD-mediated diseases or conditions also include polyunsaturated fatty acid (PUFA) disorders, or skin disorders, including but not limited to eczema, acne, psoriasis, keloid scarring, or preventing diseases associated with mucosal products or secretions, such as monounsaturated fatty acids and wax esters, and the like.

SCD-mediated diseases or conditions also include inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and premenstrual syndrome.

SCD-mediated diseases or conditions also include, but are not limited to, the following diseases or conditions or diseases or conditions related thereto: cancer, neoplasia, malignant tumor, metastasis, tumor (benign or malignant), carcinogenesis, liver cancer, and the like.

SCD-mediated diseases or conditions also include conditions in which it is desirable to increase lean body mass or lean muscle mass, for example to enhance performance through muscle building. Myopathies and lipid myopathies such as carnitine palmitoyl transferase deficiency (CPT I or CPT II) are also included herein. Such treatment is useful in the human and animal husbandry industries, including administration to bovine, porcine or avian livestock or any other animal to reduce triglyceride production and/or provide a leaner meat product and/or provide a healthier animal.

SCD-mediated diseases or conditions also include the following diseases or conditions or diseases or conditions related thereto: neurological diseases, psychiatric disorders, multiple sclerosis, ocular diseases and immune disorders.

SCD-mediated diseases or conditions also include the following diseases or conditions or diseases or conditions related thereto: viral diseases or infections including, but not limited to, all positive strand RNA viruses, coronaviruses, SARS viruses, SARS-associated coronaviruses, togaviruses, picornaviruses, coxsackieviruses, yellow fever viruses, flaviviridae, alphaviruses (Togaviridae), including rubella viruses, eastern equine encephalitis viruses, western equine encephalitis viruses, Venezuelan equine encephalitis viruses, Sindbis viruses, Semliki forest viruses, chikungunya viruses, Ornitania-Nintella viruses, Ross river viruses, Mariro viruses, alphaviruses; astroviridae, including astrovirus, human astrovirus; caliciviridae, including porcine herpes simplex virus, norwalk virus, calicivirus, bovine calicivirus, porcine calicivirus, hepatitis E; coronaviridae including coronavirus, SARS virus, avian infectious bronchitis virus, bovine coronavirus, canine coronavirus, feline infectious peritonitis virus, human coronavirus 299E, human coronavirus OC43, murine hepatitis virus, porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, porcine infectious gastroenteritis virus, rat coronavirus, turkey coronavirus, rabbit coronavirus, dermomycosis virus, bradada virus; flaviviridae, including hepatitis c virus, west nile virus, yellow fever virus, st-louis encephalitis virus, dengue group, hepatitis g virus, japanese encephalitis virus, murexi valley encephalitis virus, central european tick-borne encephalitis virus, distal east tick-borne encephalitis virus, kosarnoulli forest virus, sudak jump virus, powassan virus, ebonsk hemorrhagic fever virus, Kumilinge virus, Absetarov and zalova hypr virus, brazilian encephalitis virus, rots virus, langat virus, plague virus, bovine viral diarrhea, swine fever virus, Rio Bravo group, Tyuleniy group, Ntaya group, machiend virus group, mohoku group; picornaviridae, including coxsackie a, rhinovirus, hepatitis a, encephalitis myocarditis, mengo, encephalomyocarditis, human poliovirus type 1, coxsackie B; potyviruses family, including potyvirus, lolium mosaic virus (Rymovirus), barley yellow mosaic virus (Bymovirus). In addition, it may be a disease or infection caused by or associated with hepatitis virus, hepatitis b virus, hepatitis c virus, Human Immunodeficiency Virus (HIV), and the like. Treatable viral infections include those in which the virus employs an RNA intermediate as part of the replication cycle (hepatitis or HIV); in addition, it may be a disease or infection caused by or associated with RNA negative strand viruses such as influenza and parainfluenza viruses.

The compounds identified in this specification inhibit desaturation of various fatty acids (e.g., C9-C10 desaturation of stearoyl-CoA) by a delta-9 desaturase, such as stearoyl-CoA desaturase 1(SCD 1). Thus, these compounds inhibit the formation of various fatty acids and their downstream metabolites. This can lead to the accumulation of stearoyl-coa or palmitoyl-coa and other upstream precursors of various fatty acids; this may result in a negative feedback loop that causes a global change in fatty acid metabolism. Any of these consequences can ultimately result in the full therapeutic benefit provided by these compounds.

Typically, a successful SCD-inhibiting therapeutic will meet some or all of the following criteria. The oral availability should be at or above 20%. The animal model efficacy is less than about 2mg/Kg, 1mg/Kg, or 0.5mg/Kg, with the target human dose being 50-250mg/70Kg, although doses outside this range may be acceptable. ("mg/Kg" means milligrams of compound per kilogram of body weight of the patient to which it is administered). The therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 100. The potency (expressed as IC50 value) should be less than 10. mu.M, preferably less than 1. mu.M, most preferably less than 50 nM. IC (integrated circuit) ₅₀("inhibitory concentration-50%") is the amount of compound required to achieve 50% inhibition of SCD activity in an SCD biological activity assay over a specified period of timeAnd (6) measuring. Any method of determining the activity of an SCD enzyme, preferably a mouse or human SCD enzyme, can be used to determine the activity of a compound suitable for use in the methods of the present invention to inhibit said SCD activity. Compounds of the invention show IC in a 15 minute microsomal assay₅₀Preferably less than 10. mu.M, less than 5. mu.M, less than 2.5. mu.M, less than 1. mu.M, less than 750nM, less than 500nM, less than 250nM, less than 100nM, less than 50nM, most preferably less than 20 nM. The compounds of the invention may exhibit reversible inhibition (i.e., competitive inhibition), preferably without inhibiting other iron binding proteins. The dosage required should preferably not be more than about once or twice a day or at mealtimes.

The identification of the compounds of the invention as inhibitors of SCD is readily accomplished using Brownlie et al, the SCD enzyme and microsomal assay methods described hereinabove. When assayed in this assay, the compounds of the invention have less than 50% residual SCD activity at a concentration of 10 μ M of the test compound, preferably less than 40% residual SCD activity at a concentration of 10 μ M of the test compound, more preferably less than 30% residual SCD activity at a concentration of 10 μ M of the test compound, even more preferably less than 20% residual SCD activity at a concentration of 10 μ M of the test compound, thereby demonstrating that the compounds of the invention are potent inhibitors of SCD activity.

These results provide the basis for the analysis of the structure-activity relationship (SAR) between test compounds and SCD. Certain R groups tend to provide more potent inhibitory compounds. SAR analysis is one of the tools that those skilled in the art can now use to identify preferred embodiments of the compounds of the invention for use as therapeutic agents.

Other methods of testing the compounds disclosed herein are readily available to those skilled in the art. Thus, additionally, the contacting can be accomplished in vivo. In such an embodiment, said contacting in step (a) is accomplished by the following procedure: administering the chemical to an animal having a Triglyceride (TG) -or Very Low Density Lipoprotein (VLDL) -related disorder, and subsequently detecting a change in plasma triglyceride levels in the animal, thereby identifying a therapeutic agent suitable for treating the Triglyceride (TG) -or Very Low Density Lipoprotein (VLDL) -related disorder. In this embodiment, the animal can be a human, e.g., a human patient suffering from such a disorder and in need of treatment for the disorder.

In a particular embodiment of this in vivo process, said alteration of SCD1 activity in said animal is a reduction in activity, preferably wherein said SCD1 modulator does not substantially inhibit the biological activity of a delta-5 desaturase, delta-6 desaturase or fatty acid synthase.

Model systems suitable for compound assessment may include, but are not limited to, the use of liver microsomes, e.g., from mice maintained on a high carbohydrate diet, or from human donors, including humans with obesity. Immortalized cell lines such as HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1 (from mouse adipocytes) can also be used. Primary cell lines, such as mouse primary hepatocytes, are also suitable for testing the compounds of the invention. When whole animals are used, mice used as a source of primary hepatocytes may also be used, where the mice have been maintained on a high carbohydrate diet to increase SCD activity in the microparticles and/or to increase plasma triglyceride levels (i.e., 18: 1/18: 0 ratio); alternatively, mice fed a normal diet or mice with normal triglyceride levels may be used. Mouse models using transgenic mice designed for hypertriglyceridemia are also available, as are mouse phenotyping databases. Rabbits and hamsters are also suitable for use in animal models, especially those expressing CETP (cholesteryl ester transfer protein).

Another suitable method for determining the in vivo efficacy of the compounds of the invention is to indirectly measure their effect on SCD enzyme inhibition by measuring the desaturation index of the subject after administration of the compound. As used herein, "desaturation index" refers to the ratio of product to substrate of SCD enzyme when measured from a given tissue sample. It can be calculated using three different equations: 18: 1 n-9/18: 0 (oleic acid to stearic acid); 16: 1 n-7/16: 0 (palmitoleic acid to palmitic acid); and/or 16: 1n-7+ 18: 1 n-7/16: 0 (all reaction products of 16: 0 desaturation were measured with 16: 0 substrate). The desaturation index is measured primarily in liver or plasma triglycerides, but can also be measured in other selected lipid fractions of various tissues. In general, the desaturation index is a tool for characterizing plasma lipids.

Many human diseases and disorders are caused by aberrant SCD1 biological activity, which can be ameliorated by modulation of SCD1 biological activity using the therapeutic agents of the present invention.

Inhibition of SCD expression may also affect the fatty acid composition of membrane phospholipids, as well as the production or levels of triglycerides and cholesterol esters. The fatty acid composition of phospholipids ultimately determines membrane fluidity, while the effects on triglyceride and cholesterol ester composition can affect lipoprotein metabolism and obesity.

In practicing the methods of the present invention, it is of course understood that reference to particular buffers, media, reagents, cells, culture conditions, and the like, is not intended to be limiting, but should be taken as including all relevant materials that one of ordinary skill in the art would consider interesting or valuable in presenting the particular context of the discussion. For example, it is often possible to exchange one buffer system or medium for another, while still achieving similar, if not identical, results. Those skilled in the art will have sufficient knowledge of such systems and methodologies to make such substitutions, without undue experimentation, that will best serve their purpose in using the methods and procedures disclosed herein.

Pharmaceutical compositions and administration of the invention

The invention also relates to pharmaceutical compositions comprising the compounds of the invention disclosed herein. In one embodiment, the present invention relates to compositions comprising a compound of the present invention in a pharmaceutically acceptable carrier in an amount effective to modulate triglyceride levels or to treat disorders associated with dyslipidemia and disorders of lipid metabolism when administered to an animal, preferably a mammal, most preferably a human patient. In one embodiment of the composition, prior to administration of the compound of the invention, the patient has an elevated lipid level, such as an elevated triglyceride or cholesterol level, and the compound of the invention is present in an amount effective to reduce the lipid level.

Pharmaceutical compositions suitable for use in the present application also comprise a pharmaceutically acceptable carrier (including any suitable diluent or excipient), which includes any pharmaceutical substance that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, and ethanol, and the like. A detailed discussion of pharmaceutically acceptable carriers, diluents and other excipients is provided in REMINGTON' S PHARMACEUTICAL compositions (Mack pub.co., current version n.j.).

Those skilled in the art will know how to determine the appropriate dosage of compounds for treating the diseases and disorders of interest herein. Therapeutic doses are typically determined by human dose range studies based on preliminary evidence obtained from animal studies. The dosage must be sufficient to result in the desired therapeutic benefit without causing undesirable side effects to the patient. Preferred animal dosages range from 0.001mg/Kg to 10,000mg/Kg, including 0.5mg/Kg, 1.0mg/Kg, and 2.0mg/Kg, although outside of this range may be acceptable. The dosing regimen may be once or twice a day, although greater or lesser numbers of administrations may also be satisfactory.

Those skilled in the art are also familiar with determining methods of administration (oral, intravenous, inhalation, subcutaneous, etc.), dosage forms, appropriate pharmaceutical excipients, and other considerations relevant to delivering a compound to a subject in need of delivery.

In an alternative use of the invention, the compounds of the invention may be used as exemplary agents in comparative studies, in vitro or in vivo, to find other compounds that are also useful in treating the various diseases disclosed herein or in protecting against such diseases.

Preparation of the Compounds of the invention

It is to be understood that in the following description, combinations of substituents and/or variables of the formulas described are permissible only if such combinations result in stable compounds.

It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected with suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for a mercapto group include-C (O) -R "(where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed according to standard techniques well known to those skilled in the art and described herein.

The use of protecting Groups is described in detail in Green, T.W. and P.G.M.Wutz, Protective Groups in organic Synthesis (1999), 3rd Ed., Wiley. The protecting group may also be a polymer resin such as Wang resin or 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art that although such protected derivatives of the invention may not possess pharmacological activity per se, they may be administered to a mammal and so metabolised in vivo to form the compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of the compounds of the present invention are included within the scope of the present invention.

The following reaction scheme illustrates a method for preparing the compounds of the present invention. It is understood that one skilled in the art would be able to prepare these compounds by similar methods or by methods known to those skilled in the art. In general, starting components can be obtained from a variety of sources, such as SigmaAldrich, Lancaster Synthesis, Inc., Maybrid, Matrix Scientific, TCI, and Fluorochem USA, or synthesized according to sources known to those of skill in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition (Wiley, December 2000)), or prepared as described in the present invention.

With respect to the compounds of formula (I), formula (Ia) and formula (IV), x, y, W, V, R, unless otherwise indicated in the following description ¹、R^1a、R²、R³、R⁴、R⁵、R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aAs defined above in the summary of the invention. It will be appreciated that the compounds of formula (II), (III), (Va) and (Vb) may be prepared by methods analogous to those described below. In addition, the compounds of the present invention may be prepared according to methods analogous to those described in the priority document PCT/US2004/024658, which is incorporated herein by reference in its entirety.

In general, compounds in which W is-N (R) can be synthesized according to the general procedure described in reaction scheme 1¹) C (O) -the compounds of the invention of formula (I) and formula (Ia).

Reaction scheme 1

Formula (I) or formula (Ia)

The starting materials for the above reaction schemes can be purchased commercially or prepared according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

compound 101. The carboxylic acid of formula (100) can be readily converted to the ester of formula (101) following standard procedures in the literature known to those skilled in the art.

Compound 102. The mixture of the compound of formula (101) and phosphorous oxychloride obtained above is heated carefully to reflux for 2-8 hours. The reaction mixture is then cooled and the excess phosphorous acid chloride is removed. The residue was then poured into ice water. The resulting precipitate was collected by filtration and washed with saturated NaHCO ₃And water, followed by drying to give the compound of formula (102).

Compound 104. A mixture of compound of formula (102) (1 equivalent) and compound of formula (103) (3 equivalents) in a solvent such as, but not limited to, N-dimethylformamide or acetonitrile is refluxed for 1 to 4 hours. The solvent was then removed in vacuo. The residue is dissolved in a solvent such as, but not limited to, dichloromethane or ethyl acetate. The resulting solution was washed with water, brine, and then MgSO₄And (5) drying. The organic phase is concentrated in vacuo to provide the compound of formula (104).

Compound 106. To a stirred solution of compound of formula (104) (1 equivalent) in a solvent such as, but not limited to, dichloromethane, toluene or THF, at 0 ℃ is added a solution of chloride or bromide of formula (105) (1 equivalent) in the presence of a base such as, but not limited to, triethylamine or Hunigs base. The resulting mixture was stirred at ambient temperature for 6-18 hours and then quenched with water. The organic phase was washed with water, brine, MgSO₄Drying and then concentration in vacuo afforded the product of formula (106), which is further purified by chromatography or crystallization.

Compound 107. A solution of the compound of formula (106) obtained as above is dissolved in a suitable solvent and the ester is converted to the carboxylic acid under standard conditions known to those skilled in the art to give the carboxylic acid of formula (107).

A compound of formula (I) or formula (Ia). To a compound of formula (107) (1 equivalent) in a solvent such asBut not limited to, dichloromethane, toluene or THF, followed by the addition of a base such as, but not limited to, triethylamine or Hunigs base (2.5 equivalents), followed by a coupling agent such as N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide (1.1 equivalents). The resulting mixture was stirred for 15 minutes to 1 hour and the amine of formula (108) (1.1 eq) was added. The mixture was stirred for 8-24 hours, then washed with water, MgSO₄Dried and concentrated in vacuo. Purification by column chromatography or crystallization from a suitable solvent affords the compound of formula (I) or formula (Ia).

Alternatively, compounds wherein W is-N (R) can be synthesized according to the general procedure described in scheme 2¹) C (O) -of the present invention a compound of formula (I) or formula (Ia).

Reaction scheme 2

Formula (I) or formula (Ia)

The starting materials for the above reaction schemes can be purchased commercially or prepared according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

compound 111. To a solution of substituted 6-chloropyridazinyl-3-carboxylic acid of formula (109) (1 equivalent) in a solvent such as, but not limited to, dichloromethane, toluene or THF is added a base such as, but not limited to, triethylamine or Hunigs base (2.5 equivalents), followed by a coupling agent such as N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide (1.1 equivalents). The resulting mixture was stirred for 15 minutes to 1 hour and the amine of formula (110) (1.1 eq) was added. The mixture was stirred for 8-24 hours, then washed with water, MgSO ₄Dried and concentrated in vacuo. Purification by column chromatography or crystallization from a suitable solvent affords the compound of formula (111).

Compound 113. Converting the Compound of formula (111) (1 equivalent) and formula (112)A mixture of compound (3 equivalents) in a solvent such as, but not limited to, N-dimethylformamide or acetonitrile is refluxed for 1 to 4 hours. The solvent was then removed in vacuo. The residue is dissolved in a solvent such as, but not limited to, dichloromethane or ethyl acetate. The resulting solution was washed with water, brine, and then MgSO₄And (5) drying. The organic phase is concentrated in vacuo to provide the compound of formula (113).

A compound of formula (I) or formula (Ia). To a stirred solution of compound of formula (113) (1 equivalent) in a solvent such as, but not limited to, dichloromethane, toluene or THF, is added at 0 ℃ a solution of chloride or bromide of formula (114) (1 equivalent) in the presence of a base such as, but not limited to, triethylamine or Hunigs base. The resulting mixture was stirred at ambient temperature for 6-18 hours and then quenched with water. The organic phase was washed with water, brine, MgSO₄Drying and then concentration in vacuo gives the compound of formula (I) or formula (Ia), which is further purified by chromatography or crystallization.

Alternatively, compounds wherein W is-C (O) N (R) can be synthesized according to the general procedure described in scheme 3 ¹) -and PG is a nitrogen protecting group of the compounds of formula (I) or formula (Ia) of the invention.

Reaction scheme 3

The starting materials for the above reaction schemes can be purchased commercially or prepared according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

compound 117. To a stirred solution of amine of formula (115) (1 equivalent) in a solvent such as, but not limited to, dichloromethane or toluene is added a solution of chloride or bromide of formula (116) (1 equivalent) in a solvent such as, but not limited to, dichloromethane or toluene in the presence of a base such as, but not limited to, triethylamine or Hunigs base. At ambient temperatureThe resulting mixture was stirred for a sufficient time and then quenched with water. The organic phase was washed with water, brine, MgSO₄Drying and then concentration in vacuo afforded the product of formula (117).

Compound 118. The solution of the compound of formula (117) obtained above is dissolved in a suitable solvent and the protecting group PG is removed under standard deprotection conditions, such as hydrolysis or hydrogenation, to give the amine of formula (118).

Compound 120. The chloropyridazine of formula (119) (1 equivalent) and the amine of formula (118) (1.5 equivalents) obtained as above were heated at reflux of the mixture in a suitable solvent for 4-24 hours. An alkaline solution such as NaOH solution is added to the reaction mixture. The aqueous layer is extracted with an organic solvent such as dichloromethane or ethyl acetate. The combined organic phases were dried and then evaporated to dryness. The crude compound is purified by column chromatography or crystallization to give the compound of formula (120).

A compound of formula (I) or formula (Ia).

Method A. To a stirred solution of compound of formula (120) (1 equivalent) in a solvent such as, but not limited to, dichloromethane, acetonitrile or toluene at 0 ℃ is added a solution of compound of formula (121) (1 equivalent) in the presence of a base such as, but not limited to, triethylamine or Hunigs base (1 equivalent). The resulting mixture was stirred at ambient temperature for 8-24 hours and then quenched with water. The organic phase was washed with water, brine, dried and concentrated in vacuo. Further purification by column chromatography or crystallization from a suitable solvent gives the compound of formula (I).

Method B. To a solution of carboxylic acid of formula (122) (1 equivalent) in a solvent such as, but not limited to, dichloromethane, toluene or THF is added a base such as, but not limited to, triethylamine or Hunigs base (2.5 equivalents), followed by a coupling agent such as, but not limited to, (3-dimethylaminopropyl) ethylcarbodiimide (1.1 equivalents). The resulting mixture was stirred for 15 minutes to 1 hour and the amine of formula (120) (1.1 eq) was added. The mixture was stirred at ambient temperature for 8-24 hours, then washed with water, dried and concentrated in vacuo. Purification by column chromatography or crystallization from a suitable solvent gives the compound of formula (I).

Alternatively, compounds wherein W is-N (R) can be synthesized according to the general procedure described in scheme 4¹) Compounds of formula (Ia) of the present invention having the formula (Ia) wherein C (o) -and V are-C (═ NH) -.

Reaction scheme 4

The starting materials for the above reaction schemes can be purchased commercially or prepared according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

a compound of formula (Ia): a lewis acid such as, but not limited to, trimethylaluminum in a solvent such as, but not limited to, benzene or toluene (1 equivalent) is added to a solution of (113) (1 equivalent) in a solvent such as 1, 4-dioxane at a reduced temperature. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirring was continued. The compound of formula (125) (1.1 eq) was then added and the reaction mixture was heated to reflux for 8-24 hours, then cooled to ambient temperature and poured into a slurry of silica gel in chloroform. Filtration and evaporation of the solvent gave the crude product, which was purified by crystallization or column chromatography.

Alternatively, compounds of formula (Ia) of the present invention wherein W is-n (h) C (═ NH) -may be synthesized according to the general procedure described in reaction scheme 5.

Reaction scheme 5

The starting materials for the above reaction schemes can be purchased commercially or prepared according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

compound 127: under nitrogen, (118) (1 eq), (126) (1 eq), a base such as K, are reacted at 120 deg.C₂CO₃(2 equiv.), degassed mixture of ligands such as, but not limited to, 8-hydroquinoline and CuI in a solvent such as, but not limited to, DMSO is heated for 12-24 hours. The reaction mixture was cooled to ambient temperature and filtered. After purification, the compound of formula (127) is obtained.

Compound 128: under nitrogen, (127) (1.2 equiv.), a cyanide reagent such as, but not limited to, Zn (CN)₂(1 equivalent), ligands such as, but not limited to, 1, 1' -bis (diphenylphosphino) ferrocene (DPPF) and palladium catalysts such as, but not limited to, Pd₂dba₃The degassed mixture in a solvent mixture such as, but not limited to, DMF and water is heated to 120 ℃ for 12-24 hours. The reaction mixture was cooled to ambient temperature and filtered. After purification, the compound of formula (128) is obtained.

A compound of formula (Ia): a lewis acid such as, but not limited to, trimethylaluminum in a solvent such as benzene or toluene (1 equivalent) is added to a solution of (129) (1 equivalent) in a solvent such as, but not limited to, 1, 4-dioxane at a reduced temperature. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirring was continued. The compound of formula (128) (1.1 eq) was then added and the reaction mixture was heated to reflux for 8 to 24 hours, then cooled to ambient temperature and poured into a slurry of silica gel in chloroform. Filtration and evaporation of the solvent gave the compound of formula (Ia) as a crude product, which was purified by crystallization or column chromatography.

Alternatively, the general procedure described in scheme 6 can be followed to synthesize compounds in which W is-N (R)¹) C (═ NH) N (h) -or-N (R)¹) C (═ S) n (h) -the compounds of formula (Ia) of the invention.

Reaction scheme 6

The starting materials for the above reaction schemes can be prepared commercially or according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

wherein W is-N (R)¹) A compound of formula (Ia) C (═ S) n (h) -: a mixture of the compound of formula (120) (1 equivalent), a base such as, but not limited to, triethylamine (1 equivalent) and isothiocyanate (130) (2 equivalents) in a solvent such as, but not limited to, N-dimethylformamide or N-methyl-2-pyrrolidone is stirred for 10-16 hours. The solvent was then removed in vacuo. The residue is dissolved in a solvent such as, but not limited to, dichloromethane or ethyl acetate. The resulting solution was washed with water, brine, dried and then purified by flash chromatography to give the compound of formula (Ia).

Wherein W is-N (R)¹) A compound of formula (Ia) of C (═ NH) n (h) -: adding mercuric oxide and ammonium hydroxide to the solution, wherein W is-N (R)¹) A compound of formula (Ia) C (═ S) n (h) -, in a stirred solution in ethanol and the mixture is stirred at ambient temperature for 8-24 hours. The resulting mixture was diluted with ethyl acetate and filtered through a pad of celite. The filtrate is then dried, concentrated, and purified by flash chromatography to provide a compound wherein W is-N (R) ¹) A compound of formula (Ia) of C (═ NH) n (h) -.

Alternatively, the general procedure described in scheme 7 can be followed to synthesize compounds in which W is-N (R)¹)C(＝NR^1a) N (H) -of the invention.

Reaction scheme 7

The starting materials for the above reaction schemes can be prepared commercially or according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

compound 132. A mixture of a compound of formula (127) (1 equivalent) and hydrazine (5 equivalents) in a solvent such as, but not limited to, N-dimethylformamide or N-methyl-2-pyrrolidone or dioxane is heated to 90 ℃ for 5-16 hours. The solvent was then removed in vacuo. The residue is dissolved in a solvent such as, but not limited to, dichloromethane or ethyl acetate. The resulting solution was washed with water, brine, dried, and then purified to give the compound of formula 132.

Compound 133. Reacting a compound of formula (132) with Fe (NO)₃)₃The mixture in a solvent such as, but not limited to, methyl chloride is refluxed for 5 hours. The mixture was diluted with methyl chloride, and the resulting solution was washed with water, brine, dried, and then purified to give a compound of formula (133).

A compound of formula (Ia). Triphenylphosphine (1.2 equivalents) is added to a solution of compound of formula (133) (1 equivalent) in a solvent such as, but not limited to, THF at ambient temperature. After 10 minutes, the isocyanate compound (135) (1.2 equivalents) was added and the solution was heated at 70 ℃ for 12-24 hours. Amine (137) (2.0 equivalents) was added and the mixture was further heated at 70 ℃ for 1-4 hours. The resulting mixture was diluted with ethyl acetate and the resulting solution was washed with water, brine, dried over sodium sulfate and then purified by flash chromatography to give a compound wherein W is-N (R)¹)C(＝NR^1a) The compound of the formula (Ia) of N (H) -.

Alternatively, compounds wherein W is-N (R) can be synthesized according to the general procedure described in reaction scheme 8¹)C(＝N-CN)N(R¹) The compounds of the formula (Ia) according to the invention.

Reaction scheme 8

The starting materials for the above reaction schemes can be prepared commercially or according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

compound 139. A mixture of the compound of formula 120 (1 equivalent), cyanogen isothiocyanate (2 equivalents) in a solvent such as, but not limited to, N-dimethylformamide or N-methyl-2-pyrrolidone or THF is heated to 50-90 ℃ for 5 to 16 hours. The solvent was then removed in vacuo. The residue is dissolved in a solvent such as, but not limited to, dichloromethane or ethyl acetate. The resulting solution was washed with water, brine, dried, and then purified by flash chromatography to give the compound of formula (139).

A compound of formula (Ia). A stirred solution of compound (139) (1 equivalent) and amino compound (140) (1.2 equivalents) in N, N-dimethylformamide or N-methyl-2-pyrrolidone was treated with EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (1.2 equivalents) or other coupling reagent and the mixture was stirred at ambient temperature for 1-4 hours. The resulting mixture was diluted with ethyl acetate and the resulting solution was washed with water, brine, dried over sodium sulfate and then purified by flash chromatography to give a compound wherein W is-N (R)¹)C(＝N-CN)N(R¹) A compound of formula (Ia) of (Ia).

Alternatively, the compounds of formula (IV) of the present invention may be synthesized according to the general procedure described in reaction scheme 9.

Reaction scheme 9

The starting materials for the above reaction schemes can be prepared commercially or according to methods known to those skilled in the art or by the methods described herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows:

a compound of formula (IV):

method C. To a stirred solution of compound of formula (120) (1 equivalent) in an anhydrous solvent such as but not limited to DMF is added isocyanate of formula (123) (3 equivalents) and the mixture is then heated to 60-80 ℃ for 4-24 hours. The mixture was concentrated in vacuo. The crude product is purified by column chromatography or crystallization from a suitable solvent to give the compound of formula (IV).

Method D. The compound of formula (120) (1 equivalent) is slowly added to an ice-cold solution of 1, 1' -carbonyldiimidazole (1.5 to 2.5 equivalents) in an anhydrous solvent such as dichloromethane. The temperature was then raised to ambient temperature and the reaction mixture was stirred for an additional 2-8 hours. The amine of formula (124) (1 eq) was then added to the reaction mixture, which was stirred overnight at ambient temperature under a nitrogen atmosphere. The reaction mixture was then washed with saturated sodium bicarbonate and brine solution, concentrated and purified by flash column chromatography to give the compound of formula (IV).

Although the compounds of the present invention can be prepared by one of skill in the art in light of the general techniques described above, more specific details regarding the synthetic techniques of the compounds of the present invention are provided elsewhere in the specification for convenience. Furthermore, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and are available from common commercial sources.

Preparation example 1

Synthesis of 2-cyclopropylethylamine

Concentrated sulfuric acid (20.66mL) was added dropwise to a vigorously stirred suspension of lithium aluminum hydride (764.4mmol) in 800mL of anhydrous ether (40mL) at 0 ℃ for a period of at least 2 hours. The reaction mixture was warmed to ambient temperature and stirred for 1 hour, and a solution of cyclopropylacetonitrile (246.5mmol) in 100mL of anhydrous ether was added dropwise. The resulting mixture was heated to reflux for 2 hours Then cooled to 0 ℃ and carefully quenched with crushed ice. A solution of 38g NaOH in 350mL of water was added and the organic layer was decanted from the resulting aluminum hydroxide precipitate. The precipitate was washed well with diethyl ether (3X 600 mL). All ether extracts were combined and washed with anhydrous Na₂SO₄Drying and evaporation of the solvent gave 172.5mmol of 2-cyclopropylethylamine as a colorless liquid (bp 100 ℃ C.). The yield thereof was found to be 70%.

Preparation example 2

Synthesis of 6-chloropyridazine-3-carboxylic acid

To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6mmol) in 140mL of concentrated sulfuric acid was slowly added finely powdered potassium dichromate (55.40g) maintaining the temperature below 50 ℃. When the addition was complete, stirring was continued for another 4 hours at 50 ℃. The viscous, dark green liquid was then cooled and crushed ice was carefully added. The reaction mixture was extracted with ethyl acetate (6X 400 mL). Combining the ethyl acetate extracts with anhydrous Na₂SO₄And (5) drying. The solvent was concentrated in vacuo to give 6-chloropyridazine-3-carboxylic acid (106.6mmol) in a reddish color. This material was used in the next reaction without further purification. The yield thereof was found to be 69%. Melting point 145 deg.C (decomposition).¹H NMR(300MHz，DMSO-d₆)δ13.1，8.20，8.05。

Preparation example 3

Synthesis of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

To a solution of 6-chloropyridazine-3-carboxylic acid (15.8mmol) in dichloromethane (95mL) at ambient temperature under a nitrogen atmosphere were added diisopropylethylamine (46.7mmol), 1-hydroxybenzotriazole monohydrate (23.7mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (23.7 mmol). The resulting mixture was stirred for 15 min and 2-cyclopropylethylamine (20.2mmol) was added. After stirring at ambient temperature for 36 hours, the reaction mixture was diluted with dichloromethane (100mL), then washed with water and Na anhydrous ₂SO₄And (5) drying. The solvent was removed in vacuo. Purification by column chromatography (30% ethyl acetate in hexanes) gave the title compound (8.70 mmol). Yield 55％。

Preparation example 4

Synthesis of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide

A mixture of 6-oxo-1, 6-dihydropyridazine-3-carboxylic acid monohydrate (3.16 g; 20.0mmol), dimethylformamide (0.5mL) and thionyl chloride (5-7mL) in chloroform (70mL) was kept overnight at 50-60 ℃. The reaction mixture was evaporated to dryness in vacuo. The solid residue was dissolved in dichloromethane (70mL) at ambient temperature and added dropwise to a mixture of 3-methylbutylamine (30mmol, 2.7mL) and triethylamine (5mL) in dichloromethane (150 mL). The mixture was stirred for 30 minutes, then saturated NaHCO with 10% HCl solution₃And water, followed by MgSO₄And (5) drying. The final compound was isolated by recrystallization from ether: hexane (5: 1) (19.76 mmol). Yield: 98 percent.

Preparation example 5

Synthesis of [4- (6-aminopyridazin-3-yl) piperazin-1-yl ] (2-trifluoromethyl-phenyl) methanone

A. To a stirred solution of 1-Boc-piperazine (1.96g, 10.5mmol) in dichloromethane (50mL) in the presence of triethylamine (3mL) was added 2-trifluoromethylbenzoyl chloride (2.09g, 10.0mmol) as a dichloromethane solution at 0 ℃. The resulting mixture was stirred at ambient temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, saturated NaCl, MgSO ₄Drying and then concentration in vacuo gave the desired product as a dark yellow solid which was used in the next reaction without further purification.

B. A solution of the compound (10mmol) obtained above in 50mL of a 1: 4 mixture of trifluoroacetic acid and dichloromethane was stirred at ambient temperature for 5 hours. After concentration in vacuo, the residue was dissolved in dichloromethane (100mL) and washed successively with 1N NaOH (10mL), water, saturated NaCl, and then MgSO₄Drying, filtration and concentration in vacuo afforded piperazin-1-yl- (2-trifluoromethylphenyl) methanone as a pale yellow oil. By adding the compound to a solution of the compound in 10mL of dichloromethane10mL of 2N HCl in ether and 100mL of anhydrous ether, the oil was converted to the HCl salt. The white solid formed was filtered and dried to give the HCl salt.

C. A mixture of 3-amino-6-chloropyridazine (0.648g, 5.00mmol) and the HCl salt (7.5mmol) obtained above was heated at 150 ℃ for 24 h. To the reaction mixture were added 10mL of 1N NaOH and 100mL of dichloromethane, and the aqueous layer was extracted twice with 100mL of dichloromethane. With Na₂SO₄The combined organic phases were dried and evaporated to dryness. The crude compound was purified by flash chromatography to afford the title compound as a yellow solid.

Preparation example 6

Synthesis of (5-fluoro-2-trifluoromethylphenyl) piperazin-1-yl methanone

A. To a solution of 1-benzylpiperazine (4.65g, 4.58mL, 26.4mmol) in dichloromethane (200mL) was added diisopropylethylamine (4.65g, 6.2mL, 36.0mmol) followed by 5-fluoro-2- (trifluoromethyl) benzoyl chloride (5.43g, 3.63mL, 23.9mmol) at 0 ℃. The reaction solution was stirred at ambient temperature for 16 h, then diluted with dichloromethane (100mL) and washed with water (3X 100 mL). After removal of the solvent in vacuo, the product was obtained as a viscous oil (9.81g, quantitative yield) and used in the next reaction without further purification.

B. The viscous oil was diluted in methanol (100mL) and Pd/C (981mg) was added. The mixture was stirred under H2 for 16 hours. After filtration, the filtrate was concentrated in vacuo to give 6.98g (94%) of the product.

Preparation example 7

Synthesis of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

A mixture of piperazine (1.48g, 17.2mmol) and 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (1.29g, 5.73mmol) in acetonitrile (60mL) was heated at reflux for 16 h. After cooling the reaction mixture, the gum was diluted with dichloromethane (50mL), washed with water (2X 20mL), and MgSO ₄And (5) drying. After filtration, the filtrate was concentrated in vacuo. Passing column colorThe crude material was purified by chromatography eluting with dichloromethane (100%) followed by methanol: dichloromethane (1: 9) to give 1.18g (75%) of the product as a solid.

Preparation example 8

Synthesis of 2-amino-1-cyclopropylethanol

A. To a stirred mixture of cyclopropanecarboxaldehyde (1.00g, 14.3mmol) and nitromethane (0.765g, 14.3mmol) in MeOH was added dropwise a solution of NaOH (0.57g) in water at 0 deg.C. The reaction mixture was stirred continuously for 1 hour and a white solid precipitated. Glacial acetic acid (0.807mL) was then added dropwise to the mixture. The organic layer was extracted with ether (3X 7mL) and MgSO₄Drying to give 2-nitro-1-cyclopropylethanol, which was used in the next reaction without further purification.

B. The nitro compound obtained above was dissolved in 4mL of anhydrous ether under reflux over 1 hour, and then added dropwise to a stirred slurry of lithium aluminum hydride (0.997g, 26.3mmol) in anhydrous ether (30 mL). Reflux was maintained for an additional 2 hours, then 2-propanol (9mL) was added, followed by saturated NaCl solution (3 mL). The mixture was stirred for an additional 20 minutes and then extracted with a mixture of 2-propanol: ether (1: 3). The solvent was removed to obtain 2-amino-1-cyclopropylethanol and used in the next reaction without further purification.

Preparation example 9

Synthesis of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide

To a solution of 6-chloropyridazine-3-carboxylic acid (375mg, 2.37mmol) in 5mL of dioxane was added thionyl chloride (420mg, 3.56 mmol). The mixture was refluxed for 4 hours and the solvent was removed in vacuo. 2-amino-1-cyclopropylethanol in 5mL of dioxane (479mg, 4.73mmol) was added to the residue, and triethylamine (0.2mL) was then added. The mixture was stirred at ambient temperature overnight. Water was added to the mixture, which was then extracted with ethyl acetate. The organic extract was separated and washed with water and brine; with Na₂SO₄And (5) drying. Removing solvent and then introducingThe residue was purified by column chromatography (eluting with ethyl acetate: hexane (70: 30)) to give 58mg of the desired compound as a white color.

Preparation example 10

Synthesis of piperazin-1-yl- (2-trifluoromethylphenyl) methanone

2-Trifluoromethylbenzoyl chloride was added dropwise over 15 min to a cooled (0 ℃ C.) and stirred solution of 1-Boc-piperazine (0.100mol) and triethylamine (0.12mol) in dichloromethane (250 mL). The resulting mixture was stirred at ambient temperature for 6 hours. Water (100mL) was then added to the mixture and the aqueous phase was extracted with dichloromethane (2 x 100mL), the combined organic phases were washed with water and brine; with Na ₂SO₄Drying and then concentration in vacuo gave the product in quantitative yield.

B. A solution of tert-butyl 4- (2-trifluoromethylbenzoyl) piperazine-1-carboxylate (10mmol) obtained above in a mixture of trifluoroacetic acid and dichloromethane (1: 4, 50mL) was stirred at ambient temperature for 5 hours. After concentration in vacuo, the residue was dissolved in dichloromethane (100mL) and washed successively with saturated sodium bicarbonate, water and brine; with anhydrous Na₂SO₄Drying and concentration gave piperazin-1-yl- (2-trifluoromethylphenyl) -methanone in 97% yield.

Preparation example 11

Synthesis of 6-piperazin-1-ylpyridazine-3-carboxylic acid (3-methylbutyl) amide

A solution of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide (2.52g, 11.0mmol) and piperazine (2.83g, 32.8mmol) in acetonitrile (30mL) was heated to reflux for 2 h. The solvent was removed by evaporation, the residue was dissolved in water (50mL) and extracted with dichloromethane (3X 100 mL). With anhydrous Na₂SO₄The organic extracts were dried and then evaporated. The residue was passed through a pad of silica gel and concentrated to give 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (2.68g, 88% yield). MS (ES +) M/z 278(M + 1).

Preparation example 12

Synthesis of 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

A solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (7.8g, 34mmol) and piperazine (8.93g, 103mmol) in acetonitrile (100mL) was heated to reflux for 2 h. The solvent was removed by evaporation and the residue was dissolved in water (100 mL). The aqueous solution was extracted with dichloromethane (5X 100mL) and dried over anhydrous Na₂SO₄The organic extracts were dried, filtered through a pad of silica gel and concentrated to give 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (8.2g, 88%).¹H NMR(300MHz，CDCl₃)δ7.90-7.87，6.89，3.78-3.50，3.12-2.90，1.77-1.49，0.83-0.60，0.51-0.36，0.15-0.01。

Preparation example 13

Synthesis of 6-chloropyridazine-3-carboxylic acid [2- (3-fluorophenyl) ethyl ] amide

To a solution of 6-chloropyridazine-3-carboxylic acid (0.31g, 1.94mmol) in dichloromethane (15.5mL) was added diisopropylethylamine (0.73mL, 4.19mmol), followed by 1-hydroxybenzotriazole monohydrate (0.28g, 2.1mmol) and 1- (3-dimethylamino) propyl-3-ethylcarbodiimide (0.37mL, 2.1 mmol). The resulting mixture was stirred for 15 minutes, followed by the addition of 3-fluorophenethylamine (0.28mL, 2.1 mmol). After stirring at ambient temperature for 27 h, the reaction mixture was diluted with dichloromethane (200mL), washed with water (4X 25mL), and Na₂SO₄Dried and concentrated in vacuo. Purification by column chromatography (eluting with dichloromethane: ethyl acetate (2: 1)) gave the product as a white powder (0.205 g). ¹H NMR(400MHz，CDCl₃)δ8.26，8.12，7.67，7.28-7.23，6.95-6.89，3.80-3.75，2.95。

Preparation example 14

(E) Synthesis of (E) -2-trifluoromethylcyclopropanecarboxylic acid

A. To a stirred solution of trimethylsulfoxonium iodide (4.85g, 22.0mmol) in DMSO (20mL) was added sodium hydride in mineral oil (0.88g,22 mmol). After the evolution of hydrogen had ended (30 minutes), a solution of ethyl 4, 4, 4-trifluorocrotonate (3.36g, 3mL, 20mmol) in DMSO (10mL) was added dropwise so that the temperature did not exceed 35 ℃. The resulting mixture was stirred at 25-30 ℃ for 30 minutes and then at 55-60 ℃ for 1 hour. The mixture was poured into 150mL of an aqueous solution of ammonium chloride (4 g). The solution was extracted with diethyl ether and the diethyl ether extract was extracted with Na₂S0₄Dried and concentrated to give the crude product.

B. To a solution of the crude product obtained above was added tetrahydrofuran (75mL), water (38mL) and lithium hydroxide (3.36g, 80 mmol). The mixture was stirred and heated to 80 ℃ for 5.5 hours, then evaporated to remove tetrahydrofuran. The aqueous layer was extracted with hexane (2X 30mL), acidified with concentrated HCl, and extracted with dichloromethane (3X 100 mL). With Na₂S0₄The organic layer was dried. The solvent was removed to give 2-trifluoromethylcyclopropane-carboxylic acid (1.53 g).

Preparation example 15

Synthesis of 6-chloropyridazine-3-carboxylic acid pentanamide

To a flask containing 6-chloropyridazine-3-carboxylic acid (375mg, 2.37mmol) in dioxane (5mL) was added thionyl chloride (420mg, 0.26mL, 3.56 mmol). While stirring, the brown mixture was refluxed under nitrogen for 6 hours. After cooling to ambient temperature, the solvent was removed by rotary evaporator. The gummy black material was diluted with dioxane (5mL) and the resulting solution was cooled in an ice-water bath. To the cooled solution was added pentylamine (410mg, 0.55mL, 4.74 mmol). The resulting black reaction solution was stirred at ambient temperature under nitrogen for 16 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (25 mL). The solution was washed with water (2X 10mL) and MgSO ₄The organic layer was dried, the solid filtered off and concentrated to give a gum-like material which was purified by column chromatography eluting with dichloromethane to give 310mg (57%) of the product as a colourless solid. The melting point is 98-101 ℃.¹H NMR(300MHz，CDCl₃)δ8.28，8.05，7.68，3.51，1.69-1.63，0.90。MS(ES+)m/z 228(M+1)。

Preparation example 16

Synthesis of 3-cyclopropylpropylamine

A. P-toluenesulfonyl chloride (7.20g, 37.8mmol) was added to a cooled (0 ℃ C.) solution of 2-cyclopropylethanol (4.00g, 46.4mmol) in pyridine (10mL) and dichloromethane (60 mL). The reaction mixture was stirred at ambient temperature overnight, then diluted with ether (200mL) and washed with water, 10% HCl, water and brine in that order, then anhydrous Na₂SO₄And (5) drying. After removal of the solvent, toluene-4-sulfonic acid 2-cyclopropylethyl ester (8.1g, 89%) was obtained and used in the next reaction without further purification.

B. A mixture of toluene-4-sulfonic acid 2-cyclopropylethyl ester (8.1g, 33.7mmol), sodium cyanide (5.0g, 102mmol) and tetrabutylammonium iodide (0.5g) in DMF (30mL) was heated at 90 ℃ overnight. The reaction mixture was then cooled to ambient temperature, diluted with ether (200mL), washed with water and brine, and washed with anhydrous Na₂SO₄And (5) drying. After removal of the solvent, 3-cyclopropylpropionitrile (3.2g, 99%) was obtained.

C. Concentrated sulfuric acid (2.73mL) was added dropwise to a vigorously stirred solution of lithium aluminum hydride (3.792g, 99.43mmol) in 40mL of diethyl ether at 0 deg.C. The reaction mixture was then warmed to ambient temperature and stirred for 1 hour. A solution of 3-cyclopropylpropionitrile (3.085g, 32.47mmol) in diethyl ether (10mL) was added dropwise. The resulting mixture was heated at reflux for 2 hours, then cooled to 0 ℃, followed by slow quenching with water. A solution of NaOH (2g in 18mL of H) was added ₂O) and the organic phase is decanted from the resulting aluminum hydroxide precipitate, which is washed with diethyl ether (3 × 20 mL). All ether fractions were combined and the solvent was evaporated to give 3-cyclopropylpropylamine as a pale yellow liquid (2.01g, 62.5%).

Preparation example 17

Synthesis of 6- (3, 5-dimethyl-piperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

To 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (0.57g, 2.52 m)mol) and Bu₄To a solution of NBr (0.16g, 0.50mmol) in dioxane (20mL) was added 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU) (0.75mL, 0.77g, 5.04 mmol). The brown reaction mixture was heated at reflux for 16 hours and then cooled to ambient temperature. The solvent was removed in vacuo. The crude material was diluted with ethyl acetate (50 mL). The solution was washed with water (3X 20mL), MgSO₄And (5) drying. After filtration, the solvent of the filtrate was removed in vacuo. The product was isolated as a brown gum-like material (0.72g, 74%) which was used in the next step without further work-up.

Preparation example 18

Synthesis of 6- [1, 4] diazepan-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

A. A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (0.15g, 0.665mmol), [1, 4] diazepane-1-carboxylic acid tert-butyl ester (0.133g, 0.665mmol) and triethylamine (0.093mL, 0.665mmol) was heated to reflux in toluene for 18 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography to give the product (0.226g, 87%) which was used in the next reaction without further purification.

B. The product obtained above was dissolved in a 2: 1 mixture of dichloromethane/trifluoroacetic acid and the mixture was stirred for 15 minutes. The solvent was then removed in vacuo. The residue was diluted with dichloromethane and the resulting solution was washed with 10% aqueous sodium hydroxide, dried and concentrated to give 6- [1, 4] diazepan-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.

Preparation example 19

Synthesis of 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl) amide

A. To a solution of cyclobutanemethanol (4.00g, 46.4mmol) in dichloromethane (60mL) at 0 deg.C was added pyridine (10mL) followed by p-toluenesulfonyl chloride (7.20g, 37.8 mmol). The reaction mixture was stirred at ambient temperature for 23 hours, then diluted with ether (350mL) and successively with water, 1% aqueous HClWater and brine wash. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo to give the product (9.00g, 80.7%).

B. To a solution of cyclobutyl methyl toluene-4-sulfonate (9.00g, 37.5mmol) in DMF (34mL) was added sodium cyanide (5.62g, 114.6mmol) and tetra-n-butylammonium iodide (0.56g, 1.41 mmol). The reaction mixture was stirred at 90 to 95 ℃ for 6.5 hours. After cooling to ambient temperature, the reaction mixture was diluted with ether (450mL) and washed with water and brine. Na for organic layer ₂SO₄Dried and concentrated at atmospheric pressure to give the product (3.50 g).

C. Concentrated sulfuric acid (1.71mL, 32.6mmol) was added dropwise to a vigorously stirred solution of lithium aluminum hydride (2.47g, 65.1mmol) in 65mL of diethyl ether at 0 deg.C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour, and a solution of cyclobutylacetonitrile (2g, 21.03mmol) in 9mL of diethyl ether was added dropwise. The resulting mixture was heated at reflux for 3.5 hours and then stirred at ambient temperature for 21 hours. The reaction mixture was cooled to 0 ℃ and quenched slowly with water (16 mL). A solution of sodium hydroxide (7.85g) in water (69mL) was added and the organic phase was decanted from the resulting aluminum hydroxide precipitate, rinsing it with three 50-mL portions of diethyl ether. All ether fractions were combined and the solvent was evaporated to leave 2-cyclobutylethylamine as a colorless liquid (1.9g, 91%).

D. To a 100-mL round-bottom flask, 6-oxo-1, 6-dihydropyridazine-3-carboxylic acid monohydrate (0.64g, 3.6mmol), chloroform (14mL), dimethylformamide (0.1mL) and thionyl chloride (1.2mL) were added. The reaction mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was evaporated to dryness in vacuo. The solid residue was dissolved in dichloromethane (13mL) at ambient temperature and added dropwise to a mixture of cyclobutylethylamine (0.47g, 4.74mmol) a and triethylamine (0.8mL) in dichloromethane (25 mL). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane (100mL) and successively with 10% aqueous HCl, saturated NaHCO ₃And water washing. Na for organic layer₂SO₄Dried and evaporated in vacuo. Purification by column chromatography (silica gel, hexane/EtOAc (2: 1)) afforded the form of a white powderProduct of (4) (0.572g, 59%).¹H NMR(300MHz，CDCl₃)δ 8.25，7.97，7.65，3.42，2.36，2.08，1.91-1.59。

Preparation example 20

Synthesis of 3-cyclobutyl propylamine

A. A solution of trimethylphosphine in toluene (1M, 60mL, 60mmol) was diluted with toluene (30mL) and tetrahydrofuran (30mL) at 0 deg.C under nitrogen. Iodoacetonitrile (4.2mL, 9.69g, 58mmol) was then added dropwise with vigorous stirring, thereby precipitating a colorless solid. When the addition was complete, the ice bath was removed and stirring continued at ambient temperature for 51 hours. The mixture was filtered, the solid washed with toluene and dried under reduced pressure. Recrystallization from acetonitrile (37.5mL) gave the compound (9.89g, yield: 70%) as colorless crystals.

B. To a mixture of cyclobutanemethanol (0.861g, 10mmol) and (cyanomethyl) -trimethyl- * -iodide (6.20g, 25.5mmol) was added propionitrile (20mL) and diisopropylethylamine (5.5mL, 32mmol), and the mixture was stirred at 97 ℃ for 48 h. Water (1mL, 55.5mmol) was added and stirring continued at 97 ℃ for another 18 h. Water (125mL) and concentrated hydrochloric acid (5mL, 60mmol) were added and the mixture was extracted with dichloromethane (3X 100 mL). The combined extracts were washed once with brine, dried over magnesium sulfate, and concentrated at atmospheric pressure to give the product (1.09 g).

C. Concentrated sulfuric acid (3.15mL, 60.05mmol) was added dropwise to a vigorously stirred solution of lithium aluminum hydride (4.35g, 113.8mmol) in 114mL of diethyl ether at 0 deg.C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour, and a solution of cyclobutylpropionitrile (1.09g, 10mmol) in 15mL of diethyl ether was added dropwise. The resulting mixture was heated at reflux for 2 hours and then stirred at ambient temperature for 48 hours. The reaction mixture was cooled to 0 ℃ and quenched slowly with water (12 mL). A solution of sodium hydroxide (5.89g) in water (52mL) was added and the organic phase was decanted from the resulting aluminum hydroxide precipitate and washed with three 50-mL portions of diethyl ether. All ether fractions were combined and the solvent was evaporated, leaving 0.36g (32%) of 2-cyclobutylaropylamine as a colorless liquid.

Preparation example 21

Synthesis of 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclobutylethyl) amide

To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl) -amide (1.2g, 5.00mmol) in acetonitrile (40mL) was added piperazine (1.29g, 15.00 mmol). The reaction mixture was heated to reflux overnight. The mixture was evaporated and the solid residue was dissolved in ethyl acetate (100mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2X 100 mL). With Na ₂SO₄The combined ethyl acetate was dried and concentrated in vacuo to give the title compound as a yellow solid (1.14g, 78.4% yield).

Preparation example 22

Synthesis of 2, 2- (dimethylcyclopropyl) methylamine

Lithium aluminum hydride (7.77g, 0.194mmol) was added to a solution of 2, 2-dimethylcyclopropanecarboxamide (10.0g, 88.3mmol) in THF (200mL) at 0 deg.C. The reaction mixture was heated to reflux for 5 hours, then cooled to 0 ℃, quenched with water, and extracted with diethyl ether. With anhydrous Na₂SO₄The combined ether layers were dried and diluted to give the title compound (3.2g) in 36% yield. b.p.94-96 ℃.¹H NMR(300MHz，CDCl₃)δ2.68-2.53，1.13，1.03，1.00，0.70-0.61，0.38-0.34，-0.02-0.05。

Preparation example 23

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid

A. To a solution of 6-oxo-1, 6-dihydropyridazine-3-carboxylic acid monohydrate (5.00g, 31.6mmol) in methanol was added thionyl chloride (0.36mL, 0.59g, 4.94 mmol). The reaction mixture was heated to reflux at 80 ℃ for 16 hours. After cooling the reaction mixture to ambient temperature, the product crystallized. The crystals were collected and washed with methanol, the mother liquor was concentrated and crystallized again. The total amount of product isolated was 4.954g (100% yield).

B. The mixture of methyl 6-hydroxypyridazine-3-carboxylate and phosphorous oxychloride obtained above was heated carefully to reflux temperature and held there for 2.5 hours. The reaction mixture was then cooled and evaporated in vacuo to remove excess phosphorus oxychloride, and the residue was poured into ice water. The precipitate was collected by filtration and washed with saturated NaHCO ₃And water, and dried in vacuo to give the product as a yellow solid (4.359g, 79% yield).

C. In the presence of K₂CO₃(10.14g, 73.4mmol) and tetra-n-butylammonium iodide (0.071g, 0.192mmol), a solution of methyl 6-chloropyridazine-3-carboxylate (4.359g, 25.3mmol) obtained above in dioxane (145mL) was treated with 1- (2-trifluoromethyl-benzoyl) piperazine hydrochloride (7.80g, 26.5 mmol). The reaction mixture was heated to reflux for 24 hours and evaporated to remove the dioxane. The residue was purified by column chromatography to give the desired product (8.666g, 87% yield).

D. To 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]To a solution of pyridazine-3-carboxylic acid methyl ester (4.436g, 11.25mmol) in tetrahydrofuran (50mL) and water (25mL) was added lithium hydroxide monohydrate (2.30g, 54.81 mmol). The reaction mixture was stirred at 0 ℃ for 23 hours at ambient temperature and the pH of the solution was adjusted to-3 with concentrated hydrochloric acid (5.3 mL). The mixture was concentrated. Ethyl acetate (100mL) was added to the residue and the product was precipitated. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to give the title compound (3.60 g). The aqueous layer was extracted with ethyl acetate and Na ₂SO₄Drying and concentration gave a second portion of the title compound (0.463 g). The total amount of product was 4.063g (95% yield).

Preparation example 24

Synthesis of 6-piperazin-1-ylpyridazine-3-carboxylic acid pent-4-enamide

A. To a solution of 4-penten-1-ol (4.8mL, 4.00g, 46.4mmol) in dichloromethane (60mL) at 0 deg.C was added pyridine (10mL), followed by p-toluenesulfonyl chloride (7.2g, 3)7.8 mmol). The reaction mixture was stirred at ambient temperature for 21 hours. The reaction mixture was then diluted with ether (350mL) and washed successively with water, 1% HCl, water and brine. With Na₂SO₄The organic layer was dried and concentrated to give the product (8.48g) in 93% yield, which was used in the next reaction without further purification.

B. To a solution of the pent-4-enyl toluene-4-sulfonate (3.42g, 14.3mmol) obtained above in THF (55mL) was added ammonium hydroxide (28.0-30.0% ammonia content) (100mL, 1532.6 mmol). The reaction mixture was stirred at ambient temperature for 5 days. The reaction mixture was extracted with diethyl ether. The combined ether solution was taken with Na₂SO₄Dried and distilled at 50 ℃ under atmospheric pressure to give a solution of pent-4-enamine in THF, which was used in the next reaction without further purification.

C. 6-oxo-1, 6-dihydropyridazine-3-carboxylic acid monohydrate (1.60g, 10.1mmol), chloroform (36mL), dimethylformamide (0.25mL) and thionyl chloride (3.05mL) were added to a 100-mL round bottom flask. The reaction mixture was stirred at 69 ℃ for 43 hours and then evaporated to dryness. The solid residue was dissolved in dichloromethane at ambient temperature and the solution was added dropwise to a mixture of pent-4-enamine and triethylamine in THF prepared as above. After stirring for 1 hour, the reaction mixture was diluted with dichloromethane and diluted with 10% HCl, saturated NaHCO ₃And water washing. Na for organic layer₂SO₄Dried and evaporated in vacuo. Purification by column chromatography gave the product as a white powder (1.08g, 61.6% yield).

D. To a solution of 6-chloropyridazine-3-carboxylic acid pent-4-enamide (1.08g, 4.79mmol) synthesized above in acetonitrile (39mL) was added piperazine (1.25g, 14.5 mmol). The reaction mixture was heated to reflux overnight (TLC showed the reaction was complete). The mixture was evaporated and the solid residue was dissolved in a mixture of ethyl acetate (100mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. With Na₂SO₄The combined ethyl acetate layers were dried and concentrated to give the title compound as a yellow solid (1.169g, 88.6%Yield).

The synthesis of the compounds of the present invention is illustrated by, but not limited to, the following examples.

Example 1

Synthesis of 4-methylpentanoic acid {6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazin-3-yl } amide

To [4- (6-aminopyridazin-3-yl) piperazin-1-yl group]To a stirred solution of (2-trifluoromethyl-phenyl) methanone (0.226g, 0.645mmol) in tetrahydrofuran (10.0mL) was added 4-methylpentanoic acid (0.500g, 4.30mmol) followed by (3-dimethylaminopropyl) -ethylcarbodiimide (1.0 mL). The mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. With Na ₂SO₄The combined organic layers were dried, concentrated, and the residue was redissolved in a small amount of ethyl acetate. The solid precipitated by the dropwise addition of hexane was filtered off and dried in vacuo to give the title product (0.070g) as a white solid in 24% yield.¹H NMR(300MHz，CDCl₃)δ9.15，8.36，7.74，7.63，7.56，7.36，7.05，4.03-3.98，3.93-3.89，3.69-3.62，3.55-3.53，3.33-3.31，2.51，1.63-1.61，0.91。

Example 1.1

4-phenyl-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } butanamide

Following the procedure of example 1, only substituting 4-phenylbutyric acid for 4-methylpentanoic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (9% yield).¹H NMR(300MHz，CDCl₃)δ9.13，8.36，7.74，7.62，7.56，7.36，7.28-7.25，7.19-7.16，7.05，4.03-3.98，3.93-3.88，3.69-3.60，3.54-3.52，3.33-3.31，2.70，2.52，2.06。

Example 1.2

4- (4-methoxyphenyl) -N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } butanamide

Following the procedure of example 1, only following the replacement of 4-methylpentanoic acid with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with 4- (4-methoxyphenyl) butyric acid](2-trifluoromethylphenyl) -methanone the reaction was varied as required to obtain the title compound as a white powder (20% yield).¹HNMR(300MHz，CDCl₃)δ9.14，8.29，7.67，7.55，7.49，7.30，7.01，6.98，6.73，3.95-3.91，3.86-3.81，3.70，3.61-3.55，3.48-3.45，3.26-3.24，2.57，2.45，1.96。

Example 2

Synthesis of 2-benzyloxy-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } acetamide

To [4- (6-aminopyridazin-3-yl) piperazin-1-yl group ]To a stirred solution of (2-trifluoromethylphenyl) methanone (1.30g, 3.7mmol) in dichloromethane (60mL) was added diisopropylethylamine (1.5g), followed by 1-hydroxybenzotriazole monohydrate (1.1g) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide (2 mL). The resulting mixture was stirred for 15 minutes, then benzyloxyacetic acid (1.2mL) was added. After stirring for 2 hours, the reaction mixture was washed with 10% HCl, 1N NaOH and water, anhydrous Na₂SO₄Drying and concentration in vacuo afforded the final amide as a dark yellow oil which was purified by column chromatography (dichloromethane: MeOH 98: 2) to afford 1.64g of pure final compound as a white solid in 89% yield.¹H NMR(300MHz，CDCl₃)δ9.12，8.29，7.72，7.63-7.49，7.35-7.33，6.99，4.65，4.10，4.05-3.83，3.66-3.54，3.33-3.29。MS(ES+)m/z 500.2(M+1)。

Example 2.1

4-cyclohexyl-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } butanamide

Following the procedure of example 2, only substituting 4-cyclohexylbutyric acid for benzyloxyacetic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methylThe ketone reaction required changes to obtain the title compound as a white powder (18% yield).¹H NMR(300MHz，CDCl₃)δ9.04，8.32，7.68，7.56，7.49，7.30，7.04-7.00，3.99-3.23，2.40，1.89-1.83，1.69-0.84。

Example 2.2

2-ethoxy-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } -acetamide

Following the procedure of example 2, only following the use of ethoxyacetic acid instead of benzyloxyacetic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl ](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a yellow solid (67% yield).¹H NMR(300MHz，CDCl₃)δ9.18，8.35，7.75，7.63，7.56，7.37，7.04，4.08，4.04-3.88，3.70-3.64，3.60-3.58，3.35-3.33，1.31。MS(ES+)m/z 438.4(M+1)。

Example 2.3

2-Cyclopropylmethoxy-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } acetamide

Following the procedure of example 2, only following the use of cyclopropylmethoxyacetic acid instead of benzyloxyacetic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (41% yield).¹H NMR(300MHz，CDCl₃)δ9.17，8.32，7.72，7.61，7.54，7.35，4.10，4.01-3.88，3.69-3.61，3.57-3.55，3.43，3.33-3.30，1.14-1.08，0.61-0.57，0.27-0.24。MS(ES+)m/z 464.5(M+1)。

Example 2.4

2- (2-methoxyethoxy) -N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } acetamide

Following the procedure of example 2, only following the replacement of benzyloxyacetic acid with [4- (6-aminopyridazin-3-yl) piperazines with (2-methoxyethoxy) acetic acidOxazin-1-yl](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (72% yield).¹H NMR(300 MHz，CDCl₃)δ 9.53，8.34，7.74，7.63，7.56，7.34，7.02，4.16，4.04-3.89，3.80-3.77，3.69-3.65，3.63-3.61，3.59-3.56，3.46，3.34-3.32。MS(ES+)m/z 468.3(M+1)。

Example 2.5

2, 2, 3, 3-Tetramethylcyclopropanecarboxylic acid {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } amide

Following the procedure of example 2, only following the use of 2, 2, 3, 3-tetramethylcyclopropanecarboxylic acid instead of benzyloxyacetic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl ](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white powder (48% yield).¹HNMR(300MHz，CDCl₃)δ 8.77，8.28，7.72，7.60，7.53，7.34，6.99，4.01-3.85，3.63-3.60，3.52-3.45，3.31-3.27，1.78-1.74，1.28，1.20。MS(ES+)m/z 476.3(M+1)。

Example 2.6

Cyclopropanecarboxylic acid {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } amide

Following the procedure of example 2, only following the use of cyclopropanecarboxylic acid instead of benzyloxyacetic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white powder (32% yield).¹H NMR(300MHz，CDCl₃)(10.07，8.40，7.72，7.61，7.53，7.34，7.03，4.02-3.82，3.67-3.55，3.49-3.46，3.30-3.27，2.09-2.01，1.09-1.04，0.88-0.82。MS(ES+)m/z 420.2(M+1)。

Example 2.7

1-trifluoromethylcyclopropanecarboxylic acid {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } amide

Following the procedure of example 2, the title compound was obtained as a white powder (16% yield) with the sole changes required to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl ] (2-trifluoromethylphenyl) -methanone using 1-trifluoromethylcyclopropanecarboxylic acid instead of benzyloxyacetic acid. 1H NMR (300MHz, CDCl3) (8.62, 8.18, 7.74, 7.63, 7.56, 7.34, 7.01, 4.03-3.89, 3.71-3.62, 3.60-3.58, 3.34-3.32, 1.54-1.52, 1.39-1.36. MS (ES +) M/z 487.9(M + 1).

Example 2.8

N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } -2- (3, 3, 3-trifluoropropoxy) acetamide

Following the procedure of example 2, only following the replacement of benzyloxyacetic acid with [4- (6-aminopyridazin-3-yl) piperazin-1-yl using (3, 3, 3-trifluoropropoxy) acetic acid](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (50% yield).¹H NMR(300MHz，CDCl₃)δ 9.03，8.32，7.75，7.63，7.56，7.37，7.03，4.13，4.03-3.98，3.94-3.89，3.84，3.71-3.63，3.60-3.58，3.35-3.32，2.56-2.48。MS(ES+)m/z506.5(M+1)。

Example 2.9

3-methoxy-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } propionamide

Following the procedure of example 2, only following the replacement of benzyloxyacetic acid with [4- (6-aminopyridazin-3-yl) piperazin-1-yl using 3-methoxypropionic acid](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white powder (11% yield).¹H NMR(300MHz，CDCl₃)δ 9.44，8.31，7.74，7.63，7.55，7.36，7.02，4.02-3.98，3.94-3.89，3.73，3.70-3.61，3.57-3.54，3.43，3.33-3.31，2.73。MS(ES+)m/z438.1(M+1)。

Example 2.10

3-phenoxy-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } propionamide

Following the procedure of example 2, only following the replacement of benzyloxyacetic acid with [4- (6-aminopyridazin-3-yl) piperazin-1-yl using 3-phenoxypropionic acid](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (52% yield).¹H NMR(300MHz，CDCl₃)δ 10.08，8.40，7.74，7.61，7.55，7.34，7.26-7.22，7.05，6.93，6.88，4.34，4.01-3.96，3.92-3.86，3.68-3.60，3.55-3.53，3.29-3.27，3.08。MS(ES+)m/z 500.3(M+1)。

Example 2.11

3- (4-fluorophenyl) -N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } propionamide

Following the procedure of example 2, only following the replacement of benzyloxyacetic acid with [4- (6-aminopyridazin-3-yl) piperazin-1-yl using 3- (4-fluorophenyl) propionic acid ](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white solid (58.5% yield).¹H NMR(300MHz，CDCl₃)δ 10.33，8.40，7.78，7.67，7.60，7.36，7.14，7.08，6.85，3.90，3.51，3.20，3.02，2.92。MS(ES+)m/z 502.7(M+1)。

Example 2.12

2-butoxy-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } acetamide

Following the procedure of example 2, only substituting butoxyacetic acid for benzyloxyacetic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white powder (40.8% yield).¹H NMR(300MHz，CDCl₃)δ 9.19，8.35，7.72，7.55，7.33，7.03，4.05，3.94，3.60，3.31，1.64，1.43，0.93。MS(ES+)m/z 465.6(M+1)。

Example 2.13

2-methyl-1- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-ylcarbamoyl } propanaminium chloride

Following the procedure of example 2, only substituting 2-amino-3-methylbutyric acid for benzyloxyacetic acid and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the reaction was varied as required and then treated with HCl to give the HCl salt of the title compound as a white powder (48% yield).¹H NMR(300MHz，DMSO-d₆)δ 11.53，8.50，8.12，7.84，7.76，7.68，7.62，7.54，3.90，3.36，3.25，2.20，0.98。MS(ES+)m/z451.2(M+1)。

Example 2.14

5- [1, 2] dithiolan-3-yl-pentanoic acid {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } amide

Following the procedure of example 2, only following the replacement of benzyloxyacetic acid with [4- (6-aminopyridazin-3-yl) piperazin-1-yl using lipoic acid ](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white solid (yield 8%).¹H NMR(300MHz，CDCl₃)δ10.11，8.37，7.72，7.61，7.53，7.35，7.04，4.08-3.84，3.70-3.57，3.56-3.46，3.33-3.30，3.17-3.02，2.59，2.39，1.84，1.78-1.56，1.51-1.37。¹³C NMR(300MHz，CDCl₃)：172.52，167.57，157.94，150.00，134.42，132.38，129.45，127.79，127.29，127.14，126.93，126.88，126.82，121.92，116.27，56.34，46.47，45.65，45.33，41.25，40.26，38.49，37.05，34.74，28.85，25.14。MS(ES+)m/z 540.1(M+1)。

Example 2.15

2- (2-Cyclopropylethoxy) -N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } acetamide

Following the procedure of example 2, only following the replacement of benzyloxyacetic acid with [4- (6-aminopyridazin-3-yl) piperazin-1-yl using 5- (2-cyclopropylethoxy) acetic acid](2-trifluoromethylphenyl) methanone changes requiredThe title compound was obtained as a white solid (0.056g, 41% yield).¹H NMR(300MHz，CDCl₃)δ 9.15，8.32，7.73-7.7，7.61-7.53，7.35-7.33，7.0，4.07，3.97-3.89，3.64，3.57-3.54，3.32-3.29，1.57-1.51，0.85-0.75，0.52-0.48，0.09-0.07。¹³C NMR(75MHz，CDCl₃)δ 168.8，167.5，158.3，148.3，134.4，132.3，129.3，127.7，127.5，127.2，127.1，126.8，126.7，126.3，125.4，121.8，120.9，115.5，72.2，70.2，46.4，45.5，45.1，41.2，34.5，7.8，4.2。MS(ES+)m/z 478.3(M+1)。

Example 3

Synthesis of 6- [4- (isoxazole-5-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

To a stirred solution of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (277mg, 1mmol) in dichloromethane (15mL) at ambient temperature in the presence of triethylamine (0.4mL) was added isoxazol-5-carbonyl chloride (1.0mmol) as a solution in dichloromethane. After 1 hour, the mixture was evaporated and the residue was subjected to column chromatography. The final product was isolated as a solid (0.107g, 29% yield).¹H NMR(300MHz，CDCl₃)δ 8.34，8.05，7.83，7.00，6.86，3.90-3.84，3.51-3.45，1.75-1.62，1.53-1.46，0.92。MS(ES+)m/z373.3(M+1)。

Example 3.1

6- [4- (1-methyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (3-methylbutyl) amide

The title compound was obtained as a white powder (47% yield) following the procedure of example 3, changing only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride instead of isoxazole-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.04，7.82，7.54，6.99，3.97，3.90-3.54，3.51-3.44，1.75-1.62，1.53-1.46，0.92。MS(ES+)m/z 454.3(M+1)。

Example 3.2

6- [4- (4-methylpiperazine-1-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (79% yield) varying only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 4-methylpiperazine-1-carbonyl chloride instead of isoxazole-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.01，7.83，6.96，3.77-3.73，3.51-3.44，3.42-3.38，3.36-3.33，2.44-2.41，2.31，1.75-1.62，1.48，0.92。MS(ES+)m/z 404.4(M+1)。

Example 3.3

6- (4-Benzoylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (92% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using benzoyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.04，7.97，7.44，6.98，3.99-3.62，3.55，1.50，0.80-0.66，0.48-0.42，0.11-0.06。MS(ES+)m/z 380.2(M+1)。

Example 3.4

6- [4- (2-ethylbutanoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

The title compound was obtained as a white solid (71% yield) according to the procedure of example 3, varying only as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2-ethylbutyryl chloride instead of isoxazol-5-carbonyl chloride. ¹H NMR(300MHz，CDCl₃)δ 8.07，8.00，7.00，3.86-3.90，3.76，3.68，3.57，2.57，1.70，1.50-1.55，0.90，0.45，0.10。MS(ES+)m/z 374(M+1)。

Example 3.5

6- (4-Cyclohexanecarbonylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (58% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide using cyclohexane carbonyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.06，7.99，6.99，3.88，3.79，3.68，3.56，2.50，1.67-1.84，1.48-1.60，1.24-1.34，0.76，0.47，0.10。MS(ES+)m/z 386(M+1)。

Example 3.6

6- [4- (2-trifluoromethoxybenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

The title compound was obtained as a white solid (83% yield) according to the procedure of example 3, only changing as required to react using 2-trifluoromethoxybenzoyl chloride instead of isoxazol-5-carbonyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide.¹H NMR(400MHz，CDCl₃)δ 8.06，7.85，7.53-7.32，7.01，4.12-3.36，1.75-1.66，1.54-1.48，0.98。MS(ES+)m/z 466.2(M+1)。

Example 3.7

6- [4- (5-chloro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (80%) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 5-chloro-2-trifluoromethylbenzoyl chloride instead of isoxazole-5-carbonyl chloride. Melting point 148-.¹H NMR(400MHz，CDCl₃)δ 8.06，7.85，7.67，7.54-7.50，7.35，7.01，4.05-3.34，1.73-1.46，0.98。MS(ES+)m/z 484.3(M+1)。

Example 3.8

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, only the changes required to react using 2-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a white solid (92%). The melting point is 95-98 ℃.¹H NMR(300MHz，CDCl₃)δ 8.05，7.96，7.74，7.65-7.52，7.35，6.99，4.08-3.22，1.55-1.46，0.80-0.67，0.48-0.42，0.10-0.07。¹³C NMR(75MHz，CDCl₃)(167.6，162.9，160.0，145.4，134.2，132.3，129.5，127.2，127.1，126.9，121.8，118.2，112.5，46.3，44.5，44.4，41.2，39.6，34.5，8.6，4.2。MS(ES+)m/z 448.2(M+1)。

Example 3.9

6- [4- (2-chloro-5-fluorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (94% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2-chloro-5-fluorobenzoyl chloride instead of isoxazole-5-carbonyl chloride. Melting point 194 ℃ and 196 ℃.¹H NMR(300MHz，CDCl₃)δ 8.05，7.96，7.41-7.37，7.11-7.03，7.00，4.07-3.34，1.55-1.46，0.79-0.68，0.48-0.42，0.11-0.06。¹³C NMR(75MHz，CDCl₃)δ 165.7，163.0，160.0，159.7，145.5，136.7，131.5，127.1，125.3，117.8，115.2，112.5，46.0，44.8，44.6，41.2，39.6，34.5，8.6，4.2。MS(ES+)m/z 432.2(M+1)。

Example 3.10

6- [4- (3, 3, 3-trifluoro-2-methyl-2-trifluoromethylpropionyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, only according to the use of (3, 3, 3-trifluoro-2-carba)The reaction of yl-2-trifluoromethylpropionyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide instead of isoxazol-5-carbonyl chloride required to make the changes to give the title compound as a white solid (35% yield). ¹H NMR(300MHz，CDCl₃)δ 8.02，7.96，6.80，3.91-3.75，3.58，1.58-1.48，0.78-0.63，0.48-0.43，0.11-0.04。MS(ES+)m/z 468.2(M+1)。

Example 3.11

6- [4- (2, 2-dimethylpropionyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (64% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2, 2-dimethylpropionyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.05，8.01，6.98，3.86-3.73，3.57，1.57-1.48，0.79-0.70，0.52-0.45，0.16-0.12。MS(ES+)m/z 360.0(M+1)。

Example 3.12

6- [4- (5-chloro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (58% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 5-chloro-2-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride. Melting point 164-.¹H NMR(300MHz，CDCl₃)δ 8.07，7.96，7.69，7.54，7.02，4.07-3.35，1.52，0.79-0.68，0.48-0.43，0.14-0.08。MS(ES+)m/z482.1(M+1)。

Example 3.13

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, based only on the use of 5-fluoro-2-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride reacted with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide with the required changes to obtain the title compound as a white powder (65% yield). ¹HNMR(400MHz，CDCl₃)δ 8.05，7.98，7.74，7.27-7.24，7.09-7.06，7.00，4.08-3.96，3.94-3.68，3.55，3.36，1.50，0.79-0.69，0.48-0.42，0.11-0.09。

Example 3.14

6- [4- (2, 6-difluorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (44% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2, 6-difluorobenzoyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(400MHz，CDCl₃)δ 8.07，8.07-7.99，7.44-7.38，7.02-6.96，4.0-3.99，3.86-3.83，3.58-3.50，3.39-3.38，1.52，1.15-1.10，0.77-0.74，0.49-0.45，0.11-0.08。

Example 3.15

6- [4- (pyrrolidine-1-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (54% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using pyrrolidine-1-carbonyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(400MHz，CDCl₃)δ 8.04，7.98，6.99，3.79，3.56，3.47-3.45，3.40，1.87-1.85，1.52，0.80-0.72，0.48-0.46，0.10-0.09。

Example 3.16

6- [4- (2, 5-bis-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, based only onThe desired reaction between 2, 5-bis-trifluoromethylbenzoyl chloride instead of isoxazole-5-carbonyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide was varied to obtain the title compound as a white powder (50% yield).¹H NMR(400MHz，CDCl₃)δ 8.08，7.99，7.92-7.9，7.85-7.84，7.65，7.02，4.13-4.08，3.95-3.71，3.57-3.55，3.38-3.36，1.57-1.44，0.8-0.7，0.48-0.46，0.16-0.08。

Example 3.17

6- [4- (2, 4-bis-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (29% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2, 4-bis-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(400MHz，CDCl₃)δ 8.08，8.02-7.98，7.91，7.54，7.03，3.97-3.86，3.85-3.72，3.57，3.36，1.52，0.77-0.74，0.49-0.46，0.12-0.09。

Example 3.18

6- [4- (2, 5-difluorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (53% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide using 2, 5-difluorobenzoyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(400MHz，CDCl₃)δ 8.08，8.0，7.17-7.11，7.03，4.02-3.92，3.85-3.83，3.59-3.5，1.52，0.74-0.69，0.46-0.40，0.09-0.04。

Example 3.19

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide

According to implementationThe procedure of example 3 was varied only as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide using 5-fluoro-2-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride to give the title compound as a white powder (28% yield). ¹HNMR(400MHz，CDCl₃)δ 8.07，7.89，7.76，7.28-7.24，7.10-7.08，7.02，4.06-4.03，3.90-3.86，3.82-3.72，3.51，3.37，1.76-1.70，1.30，0.70-0.67，0.44-0.40，0.03-0.003。

Example 3.20

6- [4- (2-chloro-4-trifluoromethylpyrimidine-5-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (35% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride instead of isoxazol-5-carbonyl chloride.¹HNMR(300MHz，CDCl₃)δ 8.77，8.08，7.97，7.01，4.06-3.68，3.55，3.39，1.50，0.76-0.71，0.48-0.42，0.10-0.05。

Example 3.21

6- [4- (2-fluorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (20.3% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2-fluorobenzoyl chloride instead of isoxazole-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.04，7.98，7.47-7.40，7.26-7.21，7.15-7.09，6.99，3.95-3.78，3.58-3.5，1.54-1.47，0.78-0.69，0.48-0.42，0.11-0.05。

Example 3.22

6- [4- (3-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (31% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 3-fluoro-2-trifluoromethylbenzoyl chloride instead of isoxazole-5-carbonyl chloride. ¹H NMR(300MHz，CDCl₃)δ 8.05，7.97，7.65-7.59，7.29，7.12，6.99，4.05-3.99，3.89-3.72，3.54，3.35，1.50，0.76-0.71，0.48-0.42，0.10-0.05。

Example 3.23

6- [4- (4-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (49% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide using 4-fluoro-2-trifluoromethylbenzoyl chloride instead of isoxazole-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.04，7.87，7.45-7.3，6.99，4.09-3.98，3.89-3.67，3.49，3.33，1.75-1.66，1.28，0.69-0.62，0.43-0.37，0.04-0.03。

Example 3.24

6- [4- (5-chloro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (73% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide using 5-chloro-2-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride.¹HNMR(300MHz，CDCl₃)δ 8.05，7.86，7.68-7.65，7.53-7.5，7.35，6.99，4.05-3.99，3.89-3.67，3.52-3.46，3.37-3.34，1.75-1.6，1.31-1.24，0.71-0.62，0.43-0.37，0.02-0.03。¹³C NMR(75MHz，CDCl₃)(165.9，162.9，159.9，145.4，138.8，135.93，135.9，129.7，128.6，128.4，121.4，1 12.6，46.3，44.5，44.3，41.3，39.2，31.9，29.5，10.5，4.4。MS(ES+)m/z 496.3 (M+1)。

Example 3.25

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl [ pyridazine-3-carboxylic acid (4-methylpentyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (10% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (4-methylpentyl) amide using 5-fluoro-2-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride. ¹H NMR(300MHz，CDCl₃)δ 8.04，7.86，7.75-7.71，7.26-7.22，7.08-7.04，6.98，4.10-3.98，3.90-3.70，3.46-3.40，3.36-3.33，1.61-1.50，1.28-1.20，0.85。¹³C NMR(75MHz，CDCl₃)δ 166.0，162.9，162.6，159.9，145.5，136.8，129.7，127.6，127.7，127.2，125.1，123.3，121.4，116.8，116.5，114.9，114.6，113.9，112.5，46.3，44.5，44.3，41.3，39.7，36.0，27.8，27.4，22.5。MS(ES+)m/z 482.4(M+1)。

Example 3.26

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-methylpentyl) amide

The title compound was obtained as a white solid (65.5% yield) according to the procedure of example 3, varying only as required to react using 2-trifluoromethylbenzoyl chloride instead of isoxazol-5-carbonyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (4-methylpentyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.03，7.86，7.74-7.72，7.62-7.54，7.36-7.34，6.98，4.08-3.98，3.92-3.65，3.47-3.4，3.35-3.31，1.62-1.53，1.28-1.21，0.86。¹³C NMR(75MHz，CDCl₃)δ 167.5，162.9，159.9，145.3，134.2，132.3，129.4，127.0，126.7，126.2，125.4，121.7，112.5，46.3，44.5，44.3，41.2，39.6，35.9，27.7，27.4，22.4。MS(ES+)m/z 464.5(M+1)。

Example 3.27

6- [4- (4-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, only as required to react using 4-fluoro-2-trifluoromethylbenzoyl chloride instead of isoxazole-5-carbonyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a white solid (83.5% yield).¹HNMR(300MHz，CDCl₃)δ 8.05，7.97，7.46-7.42，7.39-7.29，6.97，4.07-4.01，3.89-3.67，3.58-3.51，3.36-3.32，1.53-147，0.76-0.69，0.48-0.42，0.10-0.06。¹³C NMR(75MHz，CDCl₃)δ 166.7，163.9，162.8，160.6，159.9，145.4，129.6，129.5，127.0，119.7，119.4，114.8，114.7，114.4，114.38，112.5，44.4，44.5，44.3，41.3，39.6，34.4，8.6，4.1。MS(ES+)m/z 466.1(M+1)。

Example 3.28

6- [4- (2-nitrobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 3, the title compound was obtained as a white solid (72% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 2-nitrobenzoyl chloride instead of isoxazole-5-carbonyl chloride.¹H NMR(500MHz，CDCl₃)δ 8.24，8.07，7.84，7.76，7.63，7.44，7.01，4.12-4.26，3.75-3.95，3.50，3.41，1.65-1.76，1.52，0.94。MS(ES+)m/z 427(M+1)。

Example 3.29

6- [4- (2-chlorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

The title compound was obtained as a white solid (94% yield) following the procedure of example 3, with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 2-chlorobenzoyl chloride instead of isoxazole-5-carbonyl chloride.¹H NMR(500MHz，CDCl₃)δ 8.05，7.85，7.43-7.46，7.31-7.40，7.00，4.04-4.10，3.75-3.94，3.34-3.52，1.65-1.75，1.52，0.94。MS(ES+)m/z 416(M+1)。

Example 3.30

6- [4- (2, 4-Dichlorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

The title compound was obtained as a white solid (90% yield) according to the procedure of example 3, varying only as required to react using 2, 4-dichlorobenzoyl chloride instead of isoxazol-5-carbonyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide.¹H NMR(500MHz，CDCl₃)(8.07，7.85，7.47，7.35，7.28，7.01，4.02-4.09，3.75-3.93，3.33-3.52，1.65-1.75，1.52，0.94。MS(ES+)m/z 450(M)。

Example 3.31

Acetic acid 2- {4- [6- (2-cyclopropylethylcarbamoyl) pyridazin-3-yl ] -piperazine-1-carbonyl } phenyl ester

Following the procedure of example 3, only as required to make changes using acetylsalicyloyl chloride instead of isoxazol-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a white solid (39% yield). 1H NMR (500MHz, CDCl3) (8.06, 8.00, 7.00, 7.47, 7.34-7.29, 7.18, 6.98, 4.00-3.72, 3.60-3.48, 2.28, 1.52, 0.76, 0.48, 0.10. MS (ES +) M/z 438(M + 1).

Example 3.32

6- [4- (5-chloro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclobutylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (71% yield) with the sole changes required to react 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclobutyl-ethyl) amide using 5-chloro-2- (trifluoromethyl) benzoyl chloride instead of isoxazol-5-carbonyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.07，7.81，7.66，7.51，7.34，3.86-3.66，3.40-3.34，2.33，2.03，1.86-1.57。¹³C NMR(75MHz，CDCl₃)δ 166.0，162.8，159.8，145.5，138.9，135.9，129.8，128.5，127.5，127.3，125.6，125.2，112.7，46.4，44.6，44.5，41.3，37.6，36.5，33.7，28.3，18.6。MS(ES+)m/z496.5(M+1)。

Example 3.33

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclobutylethyl) amide

Following the procedure of example 3, the title compound was obtained as a white powder (71% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclobutylethyl) amide using 5-fluoro-2- (trifluoromethyl) benzoyl chloride instead of isoxazol-5-carbonyl chloride.¹HNMR(300MHz，CDCl₃)δ 8.03，7.83-7.71，7.20，7.06，6.95，4.01，3.88-3.67，3.40-3.28，2.35，1.89-1.57。¹³C NMR(300MHz，CDCl₃)δ166.0，162.8，162.6，159.9，145.5，137.0，19.7，127.2，125.1，121.5，116.9，116.6，115.0，114.7，112.6，46.4，44.6，44.4，41.3，37.6，36.5，33.7，28.3，18.6。MS(ES+)m/z 480.5(M+1)。

Example 3.34

6- [4- (5-chloro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid hexanamide

The title compound was obtained as a white powder (55% yield) according to the procedure of example 3, only as required to react using 5-chloro-2- (trifluoromethyl) benzyl chloride instead of isoxazol-5-carbonyl chloride with 6-piperazin-1-yl-pyridazine-3-carboxylic acid hexanamide. ¹H NMR(300MHz，CDCl₃)δ 8.07，7.86，7.66，7.51，7.34，7.00，4.00，3.88-3.66，3.47-3.33，1.62-1.53，1.38-1.27，0.85。¹³C NMR(75MHz，CDCl₃)δ 166.0，162.9，159.9，145.5，138.9，135.9，129.8，128.5，127.5，127.2，125.6，125.1，121.5，112.7，46.4，44.6，41.3，39.5，31.5，29.5，26.6，22.6，14.0。MS(ES+)m/z 498.2(M+1)。

Example 3.35

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) - [1, 4] diazepan-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 3, only the 5-fluoro-2-trifluoromethylbenzoyl chloride was used instead of isoxazole-5-carbonyl chloride and 6- [1, 4]]Diazepan-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl) amide the desired change was made to obtain the title compound as a white solid (60% yield).¹H NMR(CDCl₃，300MHz)δ 8.07-7.85，7.71-7.6，7.23-7.08，6.94-6.88，6.34-6.31，4.24-4.12，3.98-3.73，3.67-3.36，3.29-3.25，2.19-1.73，1.53-1.46，0.81-0.68，0.48-0.4，0.11-0.03。¹³C NMR(CDCl₃，75MHz)δ 167.3，167.2，165.7，163.1，162.9，162.3，158.9，158.4，144.8，144.6，137.1，129.7-129.2，127.4，127.2，125.0，121.4，116.7，116.6，116.4，116.3，114.9，114.8，114.6，114.5，111.5，111.3，48.8，48.6，47.6，47.5，45.8，45.7，44.1，39.6，34.5，26.8，25.4，8.6，4.2。MS(ES+)m/z 480.1(M+1)。

Example 4

Synthesis of 6- (4-benzylpiperazin-1-yl) pyridazine-3-carboxylic acid (3-methylbutyl) amide

6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide (0.113g, 0.5mmol), 1-benzylpiperazine (90mg, 0.5mmol), tetrabutylammonium bromide (27mg, 0.084mmol) and 1, 8-diazabicyclo [5.4.0]A stirred mixture of undec-7-ene (152mg, 1.0mmol) was heated under reflux in dioxane (10mL) overnight. The solvent was evaporated. The residue was treated with 2% methanol in water (25 mL). The precipitated solid was filtered off and dried in vacuo to give 138mg (0.376mmol) of the title compound in 75% yield.¹H NMR(300MHz，CDCl₃)δ7.98，7.87，7.36-7.32，6.94，3.76-3.74，3.57，3.50-3.46，2.60-2.58，1.74-1.68，1.52-1.48，0.94。MS(ES+)m/z 368.2(M+1)。

Example 5

Synthesis of 1- (2-phenylcyclopropyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

To [4- (6-aminopyridazin-3-yl) piperazin-1-yl group ]To a solution of (2-trifluoromethyl-phenyl) methanone (123mg, 0.35mmol) in DMF (20.0mL) was added (2-isocyanatocyclopropyl) benzene (111mg, 0.7 mmol). The mixture was stirred at 60 ℃ overnight. After cooling, the mixture was poured into water (120 mL). The precipitated white solid was filtered off and dried in vacuo to give the title product (162mg) as a white solid in 90% yield.¹H NMR(300MHz，CDCl₃)δ 8.01-7.97，7.73，7.60，7.55，7.32，7.22-7.10，7.06，4.00-3.95，3.87-3.86，3.62-3.52，3.43-3.41，3.25-3.22，2.85-2.82，2.14-2.10，0.91-0.86。MS(ES+)m/z 511.2(M+1)。

Example 5.1

3- (3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } ureido) propionic acid ethyl ester

Following the procedure of example 5, only using ethyl 3-isocyanatopropionate instead of (2-isocyanatocyclopropyl) benzene and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (37% yield).¹H NMR(300MHz，CDCl₃)δ 8.12，7.92，7.74，7.62，7.55，7.36，7.11，6.65，3.95-3.90，3.59，3.49-3.40，3.28，2.36-2.33，1.63-1.61，0.94-0.93。

Example 5.2

1-pentyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 5, only using pentyl isocyanate instead of (2-isocyanatocyclopropyl) benzene and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl group) The methanone reaction required changes to obtain the title compound as a white solid (45.5% yield). ¹HNMR(400MHz，CDCl₃)δ 10.60，7.82，7.74，7.13，7.63，7.56，7.52，7.36，7.08，4.29，4.0-4.09，3.85-3.95，3.50-3.70，3.40-3.47，3.25-3.36，1.50-1.60，1.22-1.36，0.80-0.92。MS(ES+)m/z 465(M+1)。

Example 5.3

1-benzyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 5, only substituting benzyl isocyanate for (2-isocyanatocyclopropyl) benzene and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white solid (45.6% yield).¹HNMR(500MHz，CDCl₃)δ 12.0，8.28，7.80，7.67，7.62，7.32，7.23，7.02-7.14，4.54，3.85-3.91，3.69-3.76，3.28-3.40，2.94-3.10。

Example 5.4

1- (4-fluorophenyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } urea

Following the procedure of example 5, only following the replacement of (2-isocyanatocyclopropyl) benzene with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with 4-fluorophenyl isocyanate](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white solid (32.3% yield).¹H NMR(500MHz，CDCl₃)δ 12.0，8.20，7.53，7.64，7.59，7.39，7.33，7.16，6.91-6.98，3.96-4.04，3.83-3.90，3.52-3.65，3.37-3.45，3.20-3.26。MS(ES+)m/z 489(M+1)。

Example 5.5

1- (2-fluorophenyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } urea

Following the procedure of example 5, based on the use of 2-fluorobenzene isocyanate onlyEster substitution of (2-isocyanatocyclopropyl) benzene with [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white solid (32% yield). ¹H NMR(500MHz，CDCl₃)δ 7.90-8.30，7.99，7.75，7.63，7.57，7.34，7.10-7.17，7.01-7.07，3.94-4.01，3.85-3.92，3.56-3.66，3.41-3.49，3.24-3.29。

Example 5.6

1-phenethyl-3- {6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl ] -pyridazin-3-yl } urea

Following the procedure of example 5, only following the replacement of (2-isocyanatocyclopropyl) benzene with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with 2-phenylethyl isocyanate](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white solid (19% yield).¹H NMR(500MHz，CDCl₃)(7.92，7.60，7.64，7.58，7.37，7.13-7.24，7.09，3.96-4.03，3.82-3.89，3.40-3.56，3.22-3.34，2.86。

Example 5.7

1- (4-fluorobenzyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } urea

Following the procedure of example 5, only substituting 4-fluorobenzyl isocyanate for (2-isocyanatocyclopropyl) benzene and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white solid (56% yield).¹HNMR(500MHz，CDCl₃)δ 8.13，7.78，7.66，7.60，7.33，7.21，7.09，6.83，4.50，3.91-4.00，3.73-3.80，3.34-3.48，3.05-3.22。MS(ES+)m/z503(M+1)。

Example 5.8

1-butyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 5, only depending on the applicationReplacement of (2-isocyanatocyclopropyl) benzene with [4- (6-aminopyridazin-3-yl) piperazin-1-yl by butyl cyanate](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white solid (92% yield). ¹HNMR(500MHz，CDCl₃)δ 7.84，7.74，7.63，7.56，7.36，7.08，4.00-4.07，3.88-3.94，3.54-3.66，3.42-3.46，3.27-3.36，1.51-1.57，1.30-1.40，0.89。MS(ES+)m/z 451(M+1)。

Example 5.9

1-cyclopentyl-3- {6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 5, only following the replacement of (2-isocyanatocyclopropyl) benzene with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with cyclopentyl isocyanate](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white solid (91% yield).¹HNMR(500MHz，DMSO-d₆)δ 9.02，7.82，7.75，7.65，7.58，7.51，7.34，3.91-3.98，3.67-3.80，3.46-3.58，3.36-3.44，3.11-3.35，1.80-1.88，1.46-1.67，1.30-1.40。MS(ES+)m/z 451(M+1)。

Example 5.10

1-hexyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 5, only following the replacement of (2-isocyanatocyclopropyl) benzene with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with hexyl isocyanate](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (50% yield).¹HNMR(300MHz，CD₃OD)δ 7.83，7.76，7.69，7.52，7.44，7.39，3.87-4.00，3.66，3.50，3.25-3.43，1.53-1.67，1.28-1.48，0.84-0.98。MS(ES+)m/z479(M+1)。

Example 5.11

1-heptyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 5, only substituting heptylisocyanate for (2-isocyanatocyclopropyl) benzene and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white powder (46% yield).¹HNMR(300MHz，DMSO-d₆)δ 9.12，7.82，7.75，7.65，7.50-7.57，7.35，3.69-3.80，3.45-3.60，3.38-3.43，3.28-3.34，3.20-3.26，3.06-3.17，1.45，1.15-1.28，0.85。

Example 5.12

1- (3, 4-dichlorobenzyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } urea

Following the procedure of example 5, only substituting 3, 4-dichlorobenzyl isocyanate for (2-isocyanato-cyclopropyl) benzene and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white powder (44% yield).¹H NMR(300MHz，DMSO-d₆)δ 9.38，8.30，7.85，7.77，7.67，7.59，7.52-7.57，7.39，7.29，4.38，3.70-3.82，3.50-3.62，3.42-3.47，3.34-3.38，3.23-3.29，3.15-3.20。MS(ES+)m/z 553(M+1)。

Example 5.13

1-cyclohexyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } urea

Following the procedure of example 5, only substituting cyclohexyl isocyanate for (2-isocyanatocyclopropyl) benzene and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) -methanone the desired change was made to obtain the title compound as a white powder (34% yield).¹HNMR(300MHz，DMSO-d₆)δ 9.05，7.82，7.74，7.65，7.55，7.52，7.35，3.69-3.79，3.44-3.58，3.35-3.42，3.20-3.26，3.11-3.18，1.75-1.84，1.58-1.67，1.47-1.55，1.10-1.35。

Example 6

Synthesis of 2-phenoxy-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } acetamide:

to [4- (6-aminopyridazin-3-yl) -piperazin-1-yl ] at 0 deg.C]To a stirred solution of (2-trifluoromethyl-phenyl) methanone (105mg, 0.300mmol) in dichloromethane (10mL) was added phenoxyacetyl chloride (56mg, 0.32mmol) followed by triethylamine (0.15 mL). The mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate (2X 15 mL). The combined organic layers were washed successively with dilute HCl, sodium bicarbonate and brine solution, then Na ₂SO₄Drying and concentrating. The residue was redissolved in a small amount of dichloromethane and purified by column chromatography. The title compound was isolated as a white solid in 34% yield (50 mg).¹HNMR(300MHz，CDCl₃)δ 9.28，8.38，7.75，7.64，7.56，7.35，7.04，4.65，4.01，3.68，3.34。

Example 6.1

2-Phenylcyclopropanecarboxylic acid (2-phenylcyclopropanecarbonyl) {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } amide and 2-phenylcyclopropanecarboxylic acid {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } amide

Following the procedure of example 6, only following the replacement of phenoxyacetyl chloride with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with 2-phenylcyclopropanecarbonyl chloride]The (2-trifluoromethylphenyl) -methanone reaction requires a change from which two compounds are obtained. Separation by column chromatography (eluting with EtOAc: hexane ═ 40: 60) and yielded 2-phenylcyclopropanecarboxylic acid (2-phenylcyclopropanecarbonyl) {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] as a white powder]Pyridazin-3-yl } amide (20% yield).¹H NMR(300MHz，CDCl₃) δ 7.73, 7.62, 7.54, 7.34, 7.22, 7.16, 7.04, 6.84, 3.99, 3.82, 3.63, 3.28, 2.62, 2.31, 1.76, 1.38. MS (ES +) M/z 640.3(M + 1). Separation by column chromatography (eluting with EtOAc: hexane ═ 50: 50) and yielded 2-phenylcyclopropanecarboxylic acid {6- [4- (2-trifluoromethyl) as a white powder Radical-benzoyl) piperazin-1-yl]Pyridazin-3-yl } amide (16% yield).¹H NMR(300MHz，CDCl₃)δ 10.36，8.39，7.76，7.64，7.57，7.34，7.18，7.12，3.92，3.52，3.37，3.18，2.64，2.30，1.34。MS(ES+)m/z 496.3(M+1)。

Example 6.2

Hexanoic acid {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } amide

Following the procedure of example 6, only following the replacement of phenoxyacetyl chloride with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with hexanoyl chloride](2-trifluoromethylphenyl) methanone the desired changes were made to obtain the title compound as a white solid (30% yield).¹H NMR(300MHz，CDCl₃)δ 11.65，8.62，7.75，7.65，7.58，7.46-7.53，7.37，4.08，3.88，3.52-3.78，3.30-3.40，2.63，1.72-1.79，1.24-1.40，0.90。MS(ES+)m/z449.7(M+1)。

Example 6.3

4-fluoro-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } benzamide

Following the procedure of example 6, only following the replacement of phenoxyacetyl chloride with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with 4-fluorobenzoyl chloride](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a pale yellow solid (62% yield).¹H NMR(400MHz，DMSO-d₆)δ 7.78-7.85，7.77，7.66，7.52，7.44，7.25-7.35，3.10-3.80。

Example 7

Synthesis of {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } carbamic acid butyl ester

To [4- (6-aminopyridazin-3-yl) piperazin-1-yl in the presence of triethylamine (0.313mmol) at 0 deg.C]To a stirred solution of (2-trifluoromethyl-phenyl) methanone (100mg, 0.285mmol) in dichloromethane (5mL) was added n-butyl chloroformate (0.285 mmol). Obtained by stirring at ambient temperature The mixture was quenched for 24 hours then with water (10 mL). The organic phase was washed with water, saturated NaCl, MgSO₄Drying, followed by concentration in vacuo, gave the desired product as a white solid (0.095g, 74% yield).¹H NMR(500MHz，CDCl₃)δ 8.10，7.73，7.63，7.55，7.36，7.04，4.19，3.96-4.02，3.89-3.95，3.61-3.66，3.52-3.56，3.32，1.64-1.70，1.38-1.46，0.95。

Example 7.1

{6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } carbamic acid propyl ester

Following the procedure of example 7, only using propyl chloroformate instead of n-butyl chloroformate and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired changes were made to obtain the title compound as a white solid (72% yield).¹H NMR(500MHz，CDCl₃)δ 8.10，7.73，7.62，7.55，7.37，7.04，4.14，3.96-4.02，3.88-3.94，3.61-3.66，3.52-3.56，3.32，1.66-1.75，0.98。MS(ES+)m/z438(M+1)。

Example 7.2

{6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } carbamic acid isobutyl ester

Following the procedure of example 7, only using propyl 2-methylchloroformate instead of n-butyl chloroformate and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the reaction was varied as required to obtain the title compound as a white solid (47% yield).¹H NMR(500MHz，CDCl₃)δ 8.09，7.73，7.65，7.63，7.55，7.36，7.04，3.96，3.95-4.02，3.88-3.94，3.61-3.65，3.52-3.56，3.32，1.94-2.04，0.96。MS(ES+)m/z 452(M+1)。

Example 7.3

{6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } carbamic acid ethyl ester

Following the procedure of example 7, only using ethyl chloroformate instead of n-butyl chloroformate and [4- (6-aminopyridazin-3-yl) piperazin-1-yl ](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a pale yellow solid (35% yield).¹H NMR(300MHz，DMSO-d₆)δ 10.30，7.82-7.85，7.76，7.67，7.52，7.37，4.15，3.15-3.85，1.10。MS(ES+)m/z 424(M+1)。

Example 8

Synthesis of 1- (3-cyclopropylpropyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Reacting [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone (200mg, 0.57mmol) was slowly added to an ice-cold solution of 1, 1' -carbonyldiimidazole (110mg, 0.683mmol) in dry dichloromethane (15 mL). The temperature was then raised to ambient temperature and the reaction mixture was stirred for an additional 4 hours. 3-Cyclopropylpropylamine (48.5mg, 0.569mmol) was then added to the reaction mixture, which was stirred under nitrogen at ambient temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate and brine solution, concentrated and purified by flash column chromatography to give the product as a white solid (23mg, 8.5% yield).¹HNMR(300MHz，CDCl₃)δ 10.2，7.68-7.83，7.72，7.65，7.63，7.55，7.36，7.04，3.95-4.02，3.83-3.95，3.50-3.68，3.40-3.50，3.26-3.38，1.60-1.72，1.17-1.30，0.71-0.80，0.44-0.50，-0.06-0.013。MS(ES+)m/z477(M+1)。

Example 8.1

1- {6- [4- (2, 6-difluorobenzoyl) piperazin-1-yl ] pyridazin-3-yl } -3- (3-methylbutyl) urea

Following the procedure of example 8, only substituting 3-methylbutylamine for 3-cyclopropylpropylamine and [4- (6-aminopyridazin-3-yl) piperazin-1-yl]The (2, 5-difluorophenyl) methanone reaction required changes to obtain the title compound as a white solid (27% yield). ¹H NMR(300MHz，CDCl₃)δ 9.75，7.68，7.32-7.43，7.07，6.89-7.00，3.85-4.00，3.25-3.75，1.40-1.65，0.89。MS(ES+)m/z 432.8(M+1)。

Example 8.2

1-cyclopropylmethyl-3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only following the replacement of 3-cyclopropylpropylamine with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with cyclopropylmethylamine](2-trifluoromethylphenyl) methanone the desired changes were made to obtain the title compound as a white solid (50% yield).¹H NMR(400MHz，CDCl₃)δ 7.80-7.54，7.37，7.09，4.07-3.18，1.12-0.98，0.52-0.46，0.27-0.22。MS(ES+)m/z 449.9(M+1)。

Example 8.3

1- (3, 3-dimethylbutyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only substituting 3, 3-dimethylbutylamine for 3-cyclopropylpropylamine and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound as a white solid (56% yield).¹H NMR(400MHz，CDCl₃)δ 8.04-7.54，7.37，7.09，4.08-3.16，1.52-1.44，0.88。MS(ES+)m/z 479.3(M+1)。

Example 8.4

1- (2-Cyclopropylethyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only substituting 2-cyclopropylethylamine for 3-cyclopropylpropylamine and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired changes were made to obtain the title compound as a yellow solid (65% yield). The melting point is greater than 300 ℃. ¹H NMR(300MHz，CDCl₃)δ 7.73，7.62，7.55，7.36，7.07，4.04-7.00，3.94-3.89，3.64-3.56，3.47-3.45，3.40-3.32，1.46，0.69-0.66，0.47-0.38，0.06-0.00。MS(ES+)m/z 463(M+1)。

Example 8.5

1- (2-Isopropoxyethyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only following the replacement of 3-cyclopropylpropylamine with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with the 2-isopropoxyethylamine]The (2-trifluoromethylphenyl) methanone reaction was varied to obtain the title compound as a yellow solid (15% yield). The melting point is greater than 300 ℃.¹H NMR(300MHz，CDCl₃)δ 7.69，7.60-7.56，7.51，7.35，3.98-3.92，3.74-3.64，3.45-3.44，3.38-3.19，3.09-2.97，2.95-2.86，2.84-2.77，2.00-1.74，1.77-1.74，1.38。MS(ES+)m/z 470(M+1)。

Example 8.6

1- (3-hydroxy-4, 4-dimethylpentyl) -3- {6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazin-3-yl } urea

The title compound was obtained as a yellow solid (32% yield) according to the procedure of example 8, changing only as required to react with [4- (6-aminopyridazin-3-yl) piperazin-1-yl ] (2-trifluoromethylphenyl) -methanone using 3-hydroxy-4, 4-dimethylpentanylamine instead of 3-cyclopropylpropylamine. Melting point 218-. MS (ES +) M/z 470(M + 1).

Example 8.7

1- (2-Cyclopropylethyl) -3- {6- [4- (2-fluoro-6-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only substituting 2-cyclopropylethylamine for 3-cyclopropylpropylamine and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-fluoro-6-trifluoromethylphenyl) -methanone the title compound was obtained as a white powder (48% yield) with the changes required. ¹H NMR(400MHz，CDCl₃)δ 8.14，7.58-7.54，7.43，7.38-7.34，7.10-7.05，4.01-3.94，3.58-3.32，1.46，0.72-0.67，0.45-0.39，0.08-0.02。

Example 8.8

1- (2-Cyclopropylethyl) -3- {6- [4- (5-fluoro-2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only substituting 2-cyclopropylethylamine for 3-cyclopropylpropylamine and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](5-fluoro-2-trifluoromethylphenyl) -methanone the title compound was obtained as a white powder (30% yield) with the changes required.¹H NMR(400MHz，CDCl₃)δ 8.30，7.76-7.71，7.23，7.10-7.06，4.00-3.97，3.91-3.87，3.65-3.45，3.88-3.40，1.26-1.24，0.74-0.68，0.44-0.43，0.05-0.04。

Example 8.9

1- (2-Cyclopropylethyl) -3- {6- [4- (2, 6-difluorobenzoyl) piperazin-1-yl ] -pyridazin-3-yl } urea

Following the procedure of example 8, only substituting 2-cyclopropylethylamine for 3-cyclopropylpropylamine and [4- (6-aminopyridazin-3-yl) piperazin-1-yl]The (2, 6-difluorophenyl) methanone reaction required changes to obtain the title compound as a white powder (14.1% yield).¹H NMR(400MHz，CDCl₃)δ 9.16，7.89，7.62-7.52，7.37，7.26-7.21，3.81-3.78，3.58-3.52，3.44-3.37，3.32-3.28，3.24-3.18，1.36，0.70-0.65，0.42-0.37，0.07-0.03。

Example 8.10

1- (3-cyclopropyl-propyl) -3- {6- [4- (5-fluoro-2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only using [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone instead of [4- (6-aminopyridazin-3-yl) piperazin-1-yl]The desired change in the reaction of (5-fluoro-2-trifluoromethylphenyl) methanone with 3-cyclopropylpropylamine gave the title compound as a white powder (15% yield). ¹H NMR(400MHz，CDCl₃)8.32-8.31，7.76-7.73，7.76-7.73，7.25-7.22，7.13-7.06，4.14-3.98，3.95-3.85，3.68-3.52，3.40-3.32，1.70-1.60，1.28-1.21，0.65-0.62，0.40-0.36，0.03-0.02。

Example 8.11

1- (4-methylpentyl) -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea

Following the procedure of example 8, only following the replacement of 3-cyclopropylpropylamine with [4- (6-aminopyridazin-3-yl) piperazin-1-yl with 4-methylpentamamine](2-trifluoromethylphenyl) methanone the desired changes were made to obtain the title compound as a white solid (0.039g, 29% yield).¹H NMR(300MHz，CDCl₃)δ 10.7-10.2，7.85-7.77，7.73，7.65-7.5，7.35，7.1-7.07，4.08-3.95，3.94-3.83，3.64-3.52，3.48-3.38，3.35-3.21，1.6-1.45，1.25-1.12，0.83。¹³C NMR(75MHz，CDCl₃)δ 167.5，156.8，155.8，151.7，134.4，132.3，129.4，127.2，126.8，126.7，125.4，121.8，121.3，118.4，46.4，46.02，45.8，40.3，36.1，28.3，27.8，22.5。MS(ES+)m/z 479.4(M+1)。

Example 9

Synthesis of 6- [4- (2, 5-dichlorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (0.255mmol), 2, 5-dichlorobenzoic acid (0.31mmol), 1, 8-diazabicyclo [5.4.0 ] at ambient temperature]A mixture of undec-7-ene (0.51mmol) and 1-hydroxybenzotriazole hydrate (0.31mmol) in DMF (2mL) was stirred for 15 min. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.31mmol) was then added. The mixture was stirred at ambient temperature overnight, then diluted with EtOAc (50mL) and saturated NaHCO₃Aqueous (2X 20mL) and brine (2X 20 mL). With anhydrous Na₂SO₄The organic extracts were dried, concentrated, and purified by flash chromatography to give the title compound as a white solid (102mg, 89% yield). ¹H NMR(500MHz，CDCl₃)δ 8.07，7.85，7.32-7.40，7.01，4.01-4.08，3.77-3.93，3.35-3.55，1.65-1.75，1.52，0.94。MS(ES+)m/z 450(M+1)。

Example 9.1

6- [4- (5-methyl-2-trifluoromethylfuran-3-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (53% yield) only varying as required to use 5-methyl-2-trifluoromethylfuran-3-carboxylic acid instead of 2, 5-dichlorobenzoic acid for reaction with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide. Melting point 128-.¹H NMR(500MHz，CDCl₃)δ 8.08，7.99，7.01，6.15，3.89-3.94)，3.77-3.82，3.52-3.60，2.39，1.52，0.71-0.80，0.45-0.49，0.08-0.13。MS(ES+)m/z 452(M+1)。

Example 9.2

6- [4- (2-Chloropyridine-3-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (44% yield) with the sole changes required to react 2-chloropyridine-3-carboxylic acid instead of 2, 5-dichlorobenzoic acid with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.50，8.08，7.99，7.71，7.37，7.02，4.05-4.13，3.78-3.95，3.34-3.60，1.51，0.71-0.80，0.45-0.49，0.08-0.12。MS(ES+)m/z 415(M+1)。

Example 9.3

6- [4- (2-methyl-5-trifluoromethyloxazole-4-carbonyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, only substituting 2-methyl-5-trifluoromethyloxazole-4-carboxylic acid for that reacted with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amideChanges were made to obtain the title compound as a white solid (58% yield). ¹HNMR(300MHz，CDCl₃)δ 8.05，7.98，6.99，3.75-3.95，3.50-3.59，2.55，1.51，0.71-0.80，0.45-0.49，0.06-0.12。MS(ES+)m/z 453(M+1)。

Example 9.4

6- [4- (2, 6-dichloropyridine-3-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (19% yield) only varying as required to react 2, 6-dichloropyridine-3-carboxylic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2, 6-dichloropyridine-3-carboxylic acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.06，7.97，7.65，7.37，7.01，3.70-4.10，3.29-3.61，1.52，0.68-0.80，0.42-0.49，0.06-0.13。MS(ES+)m/z 449(M+1)。

Example 9.5

6- [4- (1-benzyl-5-trifluoromethyl-1H- [1, 2, 3] triazole-4-carbonyl) -piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, only using 1-benzyl-5-trifluoromethyl-1H- [1, 2, 3]Triazole-4-carboxylic acid was reacted with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide with the required changes to obtain the title compound as a white powder (32% yield).¹H NMR(300MHz，DMSO-d₆)δ 8.03，7.81，7.33-7.27，6.86，5.92，5.39，3.71，3.47，3.05，2.63，2.43，1.65，1.48，0.92。MS(ES+)m/z531.2(M+1)。

Example 9.6

6- [4- (3-benzyl-5-trifluoromethyl-3H- [1, 2, 3] triazole-4-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, only using 3-benzyl-5-trifluoromethyl-3H- [1, 2, 3]Triazole-4-carboxylic acidInstead of the required change to react 2, 5-dichlorobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide, the title compound was obtained as a white powder (37% yield). ¹H NMR(300MHz，DMSO-d₆)δ 8.04，7.83，7.36，7.28，6.99，5.69，3.94，3.84，3.70，3.46，1.75-1.61，1.49，0.91。MS(ES+)m/z 531.2(M+1)。

Example 9.7

6- [4- (2-methyl-5-trifluoromethyl-2H- [1, 2, 3] triazole-4-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, only using 2-methyl-5-trifluoromethyl-2H- [1, 2, 3]Triazole-4-carboxylic acid was reacted with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide with the required changes to obtain the title compound as a white powder (15% yield).¹H NMR(300 MHz，DMSO-d₆)δ 8.05，7.83，7.00，4.28，3.97-3.67，3.51-3.45，1.75-1.68，1.49，0.92。MS(ES+)m/z 455.2(M+1)。

Example 9.8

6- [4- (5-trifluoromethyl-3H-imidazole-4-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (48% yield) varying only as required to react 2, 5-dichlorobenzoic acid with 6-piperazin-1-ylpyridazine-3-carboxylic acid (3-methylbutyl) amide using 5-trifluoromethyl-3H-imidazole-4-carboxylic acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，DMSO-d₆)δ 8.03，7.86，7.70，6.99，3.80，3.46，1.75-1.62，1.48，0.92。MS(ES+)m/z 440.2(M+1)。

Example 9.9

6- [4- (2-Methylsulfonylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, only in accordance with the replacement of 2-methylsulfonylbenzoic acidThe reaction of 2, 5-dichlorobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide was varied as required to give the title compound as a white solid (97% yield). ¹H NMR(400MHz，CDCl₃)δ 8.11，8.03，7.85，7.74-7.62，7.38，4.32-3.33，3.27，1.73-1.62，1.52-1.46，0.94。MS(ES+)m/z 484.3(M+1)。

Example 9.10

6- [4- (2, 2-dimethylbutyryl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (46% yield) with the sole changes required to react 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl) amide with 2, 2-dimethylbutyric acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.05，8.01，6.98，3.86-3.73，3.57，1.68，1.52，0.92，0.80-0.72，0.49-0.45，0.14-0.08。MS(ES+)m/z 374.3(M+1)。

Example 9.11

6- [4- (2, 2-Dimethylpentanoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (61% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2, 2-dimethylpentanoic acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.05，7.96，6.98，3.85-3.72，3.56，1.64-1.45，1.23，0.96，0.82-0.62，0.49-0.45，0.12-0.07。MS(ES+)m/z 388.2(M+1)。

Example 9.12

6- [4- (5-fluoro-2-methoxybenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

The procedure of example 9 was followed, only using 5-fluoro-2-methoxybenzoic acid instead of 2, 5-dichlorobenzoic acid and 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide the desired change was made to obtain the title compound as a white solid (61% yield).¹H NMR(300MHz，CDCl₃)δ 8.03，7.96，7.10-6.98，6.86-6.84，4.03-3.37，1.51，0.80-0.72，0.49-0.44，0.15-0.10。MS(ES+)m/z 428.1(M+1)。

Example 9.13

6- [4- (2-dimethylaminobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (61% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2-dimethylaminobenzoic acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.04，7.96，7.36-7.25，7.05-6.94，4.17-3.40，2.80，1.51，0.80-0.73，0.47-0.42，0.12-0.07。

Example 9.14

6- [4- (2-chloro-5-dimethylaminobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (53% yield) only as required to react 2-chloro-5-dimethylaminobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.04，7.96，7.39，6.94，6.66，6.55，4.14-3.32，2.93，1.52，0.75-0.69，0.48-0.42，0.11-0.05。MS(ES+)m/z 457.4(M+1)。

Example 9.15

6- [4- (2, 5-Dimethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, only following the use of 2, 5-dimethylbenzoic acid instead of 2, 5-dichlorobenzoic acid and 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide the desired change was made to obtain the title compound as a white solid (56% yield).¹H NMR(300MHz，CDCl₃)δ 8.05，7.96，7.16-7.11，7.03-6.97，4.12-3.67，2.23，2.22，1.52，0.82-0.69，0.48-0.42，0.11-0.05。MS(ES+)m/z 408.3(M+1)。

Example 9.16

6- [4- (2, 5-Dichlorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (56% yield) with the sole changes required to use 2, 5-dichlorobenzoic acid instead of 2, 5-dichlorobenzoic acid for reaction with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.05，7.96，7.38-7.30，6.97，4.12-3.23，1.50，0.80-0.67，0.51-0.38，0.16-0.06。MS(ES+)m/z 448.2(M+1)。

Example 9.17

6- [4- (1-methyl-1H-pyrrole-2-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (51.8% yield) only varying as required to use 1-methyl-1H-pyrrole-2-carboxylic acid instead of 2, 5-dichlorobenzoic acid for reaction with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide.¹HNMR(500MHz，CDCl₃)δ 8.07，8.01，7.00，6.75，6.40，6.12，4.00-3.80，3.58，1.52，0.76，0.48，0.10。MS(ES+)m/z 383(M+1)。

Example 9.18

6- [4- (4, 4, 4-trifluorobut-2-enoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, only following the replacement of 2, 5-dichlorobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-ring) by 4, 4, 4-trifluorobut-2-enoic acidPropylethyl) amide the reaction was varied as required to obtain the title compound as a white powder (19.6% yield).¹H NMR(500MHz，CDCl₃)δ 8.09，8.00，7.00，6.81，3.96-3.88，3.78，3.57，1.53，0.76，0.48，0.10。MS(ES+)m/z 398(M+1)。

Example 9.19

6- [4- (1-Hydroxycyclopropanecarbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (53.4% yield) only varying as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 1-hydroxycyclopropanecarboxylic acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(500MHz，CDCl₃)δ 8.07，8.03，7.01，3.98-3.73，3.58，1.53，1.16，1.02，0.76，0.48，0.10。MS(ES+)m/z 360(M+1)。

Example 9.20

6- [4- (4, 4, 4-trifluoro-3-hydroxy-3-trifluoromethylbutyryl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (45.6% yield) only varying as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 4, 4, 4-trifluoro-3-hydroxy-3-trifluoromethylbutyric acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.08，8.03，7.98，7.00，3.95-3.71，3.56，2.89，1.55，0.75，0.48，0.10。¹³C NMR(CDCl₃)δ 168.5，162.8，159.8，145.8，127.3，112.5，45.5，44.5，44.1，41.3，39.7，34.5，27.2，8.6，4.2。MS(ES+)m/z 484(M+1)。

Example 9.21

6- [4- (4, 4, 4-trifluoro-3-hydroxy-3-methylbutyryl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (50.1% yield) only varying as required to react 2, 5-dichlorobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 4, 4, 4-trifluoro-3-hydroxy-3-methylbutyric acid instead of 2, 5-dichlorobenzoic acid. ¹HNMR(300MHz，CDCl₃)δ 8.07，7.96，6.98，6.23，4.05-3.52，2.90，2.47，1.53-1.43，0.76，0.46，0.09。MS(ES+)m/z 430(M+1)。

Example 9.22

6- (4-Cyclobutanecarbonylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (45.6% yield) with the sole changes required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 4-cyclobutanecarboxylic acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.03，7.97，6.97，3.82-3.64，3.57-3.49，3.26，2.43-2.27，2.22-2.05 2.02-1.81，1.50，0.75，0.46，0.08。MS(ES+)m/z 358(M+1)。

Example 9.23

6- [4- (2-trifluoromethylcyclopropanecarbonyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (30.9% yield) with the sole change in using 2-trifluoromethylcyclopropanecarboxylic acid instead of 2, 5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.03，7.98，7.00，3.97-3.57，2.20，1.65，1.50，1.26，0.75，0.46，0.09。MS(ES+)m/z 412(M+1)。

Example 9.24

6- [4- (4, 4, 4-trifluoro-3-trifluoromethylbut-2-enoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (45.4% yield) only varying as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 4, 4, 4-trifluoro-3-trifluoromethylbut-2-enoic acid instead of 2, 5-dichlorobenzoic acid. ¹H NMR(CDCl₃)δ 8.07，7.97，7.10，7.01，3.87-3.74，3.58-3.50，1.54-1.47，0.78-0.68，0.48-0.42，0.10-0.05。¹³C NMR(CDCl₃)δ 162.8，161.1，159.8，145.8，135.2，135.1，127.3，124.5，112.7，45.5，44.4，44.3，40.9，39.7，34.5，8.6，4.2。MS(ES+)m/z 466(M+1)。

Example 9.25

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid cyclobutylmethylamide

Following the procedure of example 9, the title compound was obtained as a white powder (45.0% yield) only varying as required to react 2-trifluoromethylbenzoic acid instead of 2, 5-dichlorobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid cyclobutylmethylamide.¹H NMR(CDCl₃)δ 8.04，7.83，7.72，7.64-7.51，7.32，7.00，4.10-4.01，3.90-3.66，3.49-3.27，2.63-2.47，2.11-1.67。¹³C NMR(CDCl₃)δ 167.7，162.9，159.8，145.4，134.2，132.4，129.6，127.4，126.9，126.8，125.4，121.8，112.8，46.4，44.6，41.2，35.1，25.7，18.3。MS(ES+)m/z 448(M+1)。

Example 9.26

6- {4- [2- (2-trifluoromethylphenyl) acetyl ] piperazin-1-yl } pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (78.7% yield) only varying as required to react using (2-trifluoromethylphenyl) acetic acid instead of 2, 5-dichlorobenzoic acid with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl) -amide.¹H NMR(300MHz，CDCl₃)δ 8.03，7.97，7.67-7.64，7.53-7.48，7.39-7.35，6.96，3.91，3.87-3.67，3.66-3.6，3.58-3.51，1.53-1.46，0.78-0.64，0.48-0.42，0.10-0.06。¹³C NMR(75 MHz，CDCl₃)δ 168.8，162.9，159.9，145.3，133.2，132.0，131.5，128.5，128.2，127.2，127.0，126.3，126.2，125.5，112.3，45.0，44.7，44.2，41.2，39.6，37.13，37.11，34.4，8.6，4.2。MS(ES+)m/z 462.2(M+1)。

Example 9.27

6- [4- (2-Cyanobenzoyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white solid (25.8% yield) only varying as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2-cyanobenzoic acid instead of 2, 5-dichlorobenzoic acid.¹H NMR(300MHz，CDCl₃)δ 8.05，7.97，7.76-7.72，7.69-7.66，7.58-7.55，7.53-7.43，6.99，4.3-3.94，3.88-3.85，3.58-3.51，1.49，0.78-0.65，0.48-0.37，0.16-0.02。¹³C NMR(75MHz，CDCl₃)δ 166.5，162.8，159.9，145.3，139.3，133.3，133.04，129.9，127.6，127.03，116.8，112.4，109.9，46.4，44.7，44.6，41.6，39.6，34.4，8.6，4.1。MS(ES+)m/z 405.2(M+1)。

Example 9.28

6- [4- (4-trifluoromethylpyridine-3-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (69% yield) only varying as required to react 2, 5-dichlorobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 4-trifluoromethylpyridine-3-carboxylic acid instead.¹H NMR(300MHz，CDCl₃)δ 8.87，8.69，8.05，7.82，7.62，7.00，4.10-3.69，3.51-3.44，3.38-3.35，1.75-1.61，1.52-1.45，0.90。MS(ES+)m/z 451.3(M+1)。

Example 9.29

6- [4- (4, 4, 4-trifluoro-3-methylbut-2-enoyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (62% yield) varying only as required to react 2, 5-dichlorobenzoic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 4, 4, 4-trifluoro-3-methylbut-2-enoic acid instead.¹H NMR(300MHz，CDCl₃)δ 8.05，7.83，7.00，6.55，3.86-3.83，3.80-3.73，3.62-3.60，3.48，2.01，1.75-1.62，1.49，0.92。MS(ES+)m/z 414.4(M+1)。

Example 9.30

6- [4- (1-trifluoromethylcyclopropanecarbonyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (72% yield) with the sole changes required to react using 1-trifluoromethylcyclopropanecarboxylic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.05，7.83，6.98，3.90-3.80，3.48，1.66，1.48，1.39-1.35，1.18-1.14，0.92。MS(ES+)m/z 414.2(M+1)。

Example 9.31

6- [4- (pyridine-2-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (70% yield) with the sole changes required to react using pyridine-2-carboxylic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.60-8.58，8.03，7.98，7.86-7.79，7.73-7.71，7.39-7.35，6.98，3.96-3.83，3.54，1.50，0.78-0.69，0.47-0.41，0.08-0.05。MS(ES+)m/z 381.2(M+1)。

Example 9.32

6- [4- (2-trifluoromethylfuran-3-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 9, the title compound was obtained as a white powder (71% yield) only as required to react using 2-trifluoromethylfuran-3-carboxylic acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide.¹H NMR(300MHz，CDCl₃)δ8.04，7.96，7.56，7.00，6.54，3.9-3.7，3.6-3.5，1.49，0.79-0.66，0.47-0.41，0.09-0.04。¹³C NMR(300MHz，CDCl₃)δ 161.78，160.01，145.60，145.05，138.14，137.57，127,15，121.74，120.54，112.54，110.88，46.33，44.59，41.43，39.67，34.52，8.64，4.23。MS(ES+)m/z 438.2(M+1)。

Example 10

Synthesis of 6- [4- (5-trifluoromethyl-3H- [1, 2, 3] triazole-4-carbonyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (3-methylbutyl) amide

Mixing 6- [4- (3-benzyl-5-trifluoromethyl-3H- [1, 2, 3)]Triazole-4-carbonyl) piperazin-1-yl]Pyridazine-3-carboxylic acid (3-methylbutyl) amide (0.4g, 0.75mmol) was dissolved in 10mL of MeOH with 3 drops of acetic acid, and 0.2g of 10% Pd/C was added. At ambient temperature and normal pressure H₂The reaction mixture was kept overnight. After filtration, the reaction mixture was evaporated under reduced pressure and the residue was recrystallized from 3mL EtOH to give 120mg (36% yield) of 6- [4- (5-trifluoromethyl-3H- [1, 2, 3) as a white powder ]Triazole-4-carbonyl) -piperazin-1-yl]Pyridazine-3-carboxylic acid (3-methylbutyl) amide.¹H NMR (500MHz, acetone-d₆)δ 8.18，7.91，7.32，3.92-3.72，3.45，1.67，1.52，0.92。

Example 11

Synthesis of 6- [4- (2-trifluoromethylbenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Heating and stirring 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methyl) at 60 ℃Butyl) amide (0.255mmol), 2-trifluoromethylbenzyl chloride (0.255mmol) and 1, 8-diazabicyclo [5.4.0]A mixture of undec-7-enes (0.77mmol) was left overnight. The reaction mixture was then diluted with EtOAc (100mL) and saturated NaHCO₃Aqueous (2X 20mL) and brine (2X 20 mL). With anhydrous Na₂SO₄The organic layer was dried, concentrated, and purified by flash chromatography to give the title compound as a white solid (80mg, 72% yield).¹H NMR(500MHz，CDCl₃)δ 8.00，7.86，7.82，7.65，7.55，7.37，6.95，3.74-3.79，3.73，3.46-3.52，2.62，1.65-1.76，1.52，0.94。MS(ES+)m/z 436(M+1)。

Example 11.1

6- [4- (2-trifluoromethylbenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 11, the title compound was obtained as a white solid (32% yield) only as required to react with 2-trifluoromethylbenzyl chloride using 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide instead of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide. Melting point 106-. ¹H NMR(500MHz，CDCl₃)δ 7.97-8.04，7.83，7.65，7.55，7.37，6.96，3.77，3.73，3.56，2.63，1.52，0.71-0.80，0.45-0.49，0.08-0.13。MS(ES+)m/z 434(M+1)。

Example 11.2

6- [4- (5-fluoro-2-trifluoromethylbenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 11, only as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 5-fluoro-2-trifluoromethylbenzyl chloride instead of 2-trifluoromethylbenzyl chloride, the title compound was obtained as a white solid (40% yield).¹H NMR(300MHz，CDCl₃)δ 7.95-8.01，7.57-7.68，7.04，6.95，3.79，3.71，3.56，2.64，1.51，0.68-0.82，0.43-0.51，0.06-0.13。MS(ES+)m/z 452(M+1)。

Example 11.3

6- [4- (4-fluoro-2-trifluoromethylbenzyl) -piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 11, the title compound was obtained as a white solid (38% yield) only as required to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 4-fluoro-2-trifluoromethylbenzyl chloride instead of 2-trifluoromethylbenzyl chloride.¹H NMR(300MHz，CDCl₃)δ 7.96-8.04，7.81，7.36，7.20-7.29，6.96，3.76，3.68，3.56，2.61，1.51，0.68-0.84，0.43-0.51，0.06-0.13。MS(ES+)m/z452(M+1)。

Example 11.4

6- [4- (5-chloro-2-trifluoromethylbenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 11, the title compound was obtained as a white solid (48% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 5-chloro-2-trifluoromethylbenzyl chloride instead of 2-trifluoromethylbenzyl chloride. ¹H NMR(300MHz，CDCl₃)δ 7.96-8.05，7.87，7.58，7.34，6.97，3.80，3.70，3.56，2.64，1.53，1.51，0.70-0.83，0.43-0.51，0.07-0.13。MS(ES+)m/z468(M+1)。

Example 11.5

6- [4- (2-chloro-4-fluorobenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 11, only as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2-chloro-4-fluorobenzyl chloride instead of 2-trifluoromethylbenzyl chloride, the title compound was obtained as a white solid (26% yield).¹H NMR(300MHz，CDCl₃)δ 7.92-8.03，7.38-7.50，7.06-7.14，6.88-7.03，3.68-3.78，3.62，3.46-3.58，2.55-2.69，1.42-1.54，0.68-0.80，0.40-0.49，0.02-0.13。MS(ES+)m/z 418(M+1)。

Example 11.6

6- [4- (2, 5-dichlorobenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 11, the title compound was obtained as a white solid (43% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2, 5-dichlorobenzyl chloride instead of 2-trifluoromethylbenzyl chloride.¹H NMR(300MHz，CDCl₃)δ 7.96-8.04，7.53，7.16-7.33，6.96，3.75-3.84，3.64，3.56，2.62-2.70，1.53，1.51，0.70-0.83，0.43-0.51，0.06-0.13。MS(ES+)m/z434(M+1)。

Example 11.7

6- [4- (5-fluoro-2-trifluoromethylbenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 11, the title compound was obtained as a white solid (34% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 5-fluoro-2-trifluoromethylbenzyl chloride instead of 2-trifluoromethylbenzyl chloride.¹H NMR(300MHz，CDCl₃)δ 8.02，7.82-7.92，7.57-7.68，7.00-7.09，6.96，3.79，3.71，3.50，2.64，1.64-1.78，1.51，0.94。MS(ES+)m/z 454(M+1)。

Example 11.8

6- [4- (2, 4-dichlorobenzyl) -piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 11, the title compound was obtained as a light yellow solid (75% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 2, 4-dichlorobenzyl chloride instead of 2-trifluoromethylbenzyl chloride.¹H NMR(300MHz，CDCl₃)δ 7.95-8.02，7.44，7.38，7.23，6.93，3.70-3.77，3.60-3.63，3.54，2.60-2.65，1.50，0.74，0.45，0.08。MS(ES+)m/z 434(M+1)。

Example 11.9

6- [4- (5-fluoro-2-trifluoromethylbenzyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide

Following the procedure of example 11, only as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide using 5-fluoro-2-trifluoromethylbenzyl chloride instead of 2-trifluoromethylbenzyl chloride, the title compound was obtained as a pale yellow solid (34% yield).¹HNMR(300MHz，CDCl₃)δ 7.98，7.88，7.55-7.65，7.2，6.93，3.68-3.85，3.50，2.60，1.70，1.25，0.65，0.40，0.09。MS(ES+)m/z 466(M+1)。

Example 11.10

Synthesis of 6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid pent-4-enamide

Following the procedure of example 11, the title compound was obtained as a white powder (17.3% yield) only as required to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid pent-4-enamide using 5-fluoro-2- (trifluoromethyl) benzyl chloride instead of 2-trifluoromethylbenzyl chloride.¹H NMR(300MHz，CDCl₃)δ 7.99，7.92，7.77，7.27，7.11，7.00，5.91-5.78，5.09-4.95，4.08-3.65，3.47-3.27，2.18-2.11，1.75-1.65。¹³C NMR(75MHz，CDCl₃)δ 166.1，165.7，162.9，162.7，160.2，145.5，138.0，129.3，129.6，129.5，116.7，114.9，114.8，114.6，112.4，46.3，44.4，41.2，38.7，31.1，28.9。MS(ES+)m/z 466.3(M+1)。

Example 12

Synthesis of 6- [4- (2-aminobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

6- [4- (2-nitrobenzoyl) at 1 atm at ambient temperature using 10mg of 10% Pd/C as catalystYl) piperazin-1-yl]Pyridazine-3-carboxylic acid (3-methyl-butyl) amide (100mg, 0.235mmol) was hydrogenated for 24 h. The mixture was filtered through a celite cake. The filtrate was concentrated and purified by flash chromatography (ethyl acetate) to give a white solid (83% yield).¹HNMR(500MHz，CDCl₃)δ 8.05，7.86，7.19-7.23，7.10-7.13，6.99，4.40，3.74-3.88，3.50，1.65-1.75，1.52，0.94。MS(ES+)m/z 397(M+1)。

Example 13

Synthesis of 3, 3-dimethylbutyl {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } carbamate

To [4- (6-aminopyridazin-3-yl) piperazin-1-yl group]To a solution of (2-trifluoromethyl-phenyl) methanone (200mg, 0.57mmol) in 10mL of dioxane was added trichloromethyl chloroformate (112.7mg, 0.57mmol) and stirred at ambient temperature. After 30 min, 3-dimethylbut-1-ol (175.5mg, 1.71mmol) and triethylamine (57.6mg, 0.57mmol) were added and the temperature was raised to 80 ℃. In N₂The mixture was stirred for 3 hours and then concentrated. The residue was dissolved in dichloromethane (100mL) and washed with 1N HCl (2X 20mL), saturated NaHCO₃Washed (2X 20mL) and finally washed with brine (2X 20 mL). With anhydrous Na₂SO₄The combined organic extracts were dried, concentrated, and then purified by column chromatography (eluting with hexane: ethyl acetate (1: 2)). The product was obtained as a white solid (30mg, 11% yield). ¹HNMR(300MHz，DMSO-d₆)δ 10.38，7.89，7.83，7.77，7.67，7.54，7.47，4.14，3.10-3.90，1.55，0.95。

Example 13.1

{6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } carbamic acid 2-cyclopropylethyl ester

Following the procedure of example 13, only substituting 2-cyclopropylethanol for 3, 3-dimethylbut-1-ol and [4- (6-aminopyridazin-3-yl) piperazin-1-yl](2-trifluoromethylphenyl) methanone the desired change was made to obtain the title compound (8) as a white solid.3% yield).¹HNMR(500MHz，CDCl₃)δ 8.11，7.73，7.65，7.63，7.55，7.36，7.04，4.25，3.95-4.02，3.88-3.94，3.61-3.65，3.52-3.56，3.32，1.58，0.71-0.80，0.44-0.50，0.05-0.013。MS(ES+)m/z 464(M+1)。

Example 14

Synthesis of 6- [4- (4, 4, 4-trifluoro-2-methylbutyryl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

A TFA salt of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide (100mg, 0.25mmol), 4, 4, 4-trifluoro-2-methylbutyric acid (47.8mg, 0.31mmol), 1, 8-diazabicyclo [5.4.0 mmol) at ambient temperature]A mixture of undec-7-ene (77.8mg, 0.51mmol) and 1-hydroxybenzotriazole hydrate (41.4mg, 0.31mmol) in DMF (2mL) was stirred for 15 min. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (47.6mg, 0.31mmol) was added to the solution. The reaction mixture was stirred at ambient temperature overnight, then diluted with ethyl acetate (50mL) and saturated NaHCO₃The aqueous solution (2X 20mL) was washed and finally washed with brine (2X 20 mL). With anhydrous Na ₂SO₄The organic extracts were dried, concentrated, and then purified by column chromatography (eluting with hexane: ethyl acetate (1: 2)). The product was obtained as a white flaky solid (80mg, 75% yield).¹H NMR(300MHz，CDCl₃)δ 8.07，7.85，7.01，3.60-4.00，3.50，3.15，2.80，2.21，1.70，1.50，1.25，0.95。MS(ES+)m/z 416(M+1)。

Example 14.1

6- [4- (4, 4, 4-trifluoro-3-methylbutyryl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 14, the title compound was obtained as a white flaky solid (63% yield) only as required to react 4, 4, 4-trifluoro-2-methylbutyric acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 4, 4, 4-trifluoro-3-methylbutyric acid instead of 4, 4, 4-trifluoro-2-methylbutyric acid.¹H NMR(300MHz，CDCl₃)δ 8.07，7.85，7.00，3.69-3.98，3.67，3.50，3.00，2.71，2.35，1.70，1.50，1.20，0.95。MS(ES+)m/z 415(M+1)。

Example 14.2

6- [4- (4, 4, 4-trifluorobutanoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 14, the title compound was obtained as a white flaky solid (49% yield) only varying as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 4, 4, 4-trifluorobutyric acid instead of 4, 4, 4-trifluoro-2-methylbutyric acid.¹HNMR(300MHz，CDCl₃)δ 8.07，7.85，7.00，3.91，3.82，3.72，3.67，3.50，2.50-2.67，1.70，1.50，0.95。MS(ES+)m/z 402(M+1)。

Example 14.3

6- [4- (6-chloropyridine-2-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 14, the title compound was obtained as a white flaky solid (12% yield) only as required to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide using 6-chloropyridine-2-carboxylic acid instead of 4, 4, 4-trifluoro-2-methylbutyric acid. ¹HNMR(300MHz，CDCl₃)(8.05，7.87，7.82，7.70，7.43，7.00，3.80-4.00，3.50，1.70，1.53，0.95。MS(ES+)m/z 417(M+1)。

Example 14.4

6- [4- (2-methylcyclohexanecarbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 14, only making changes as required to use 2-methylcyclohexanecarboxylic acid instead of 4, 4, 4-trifluoro-2-methylbutyric acid for reaction with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a white solid (60% yield).¹H NMR(300MHz，CDCl₃)δ 8.08，8.00，7.00，3.50-4.00，2.70，2.05，1.20-1.90，0.90，0.75，0.45，0.10。MS(ES+)m/z 400(M+1，)。

Example 14.5

6- [4- (3-methylcyclohexanecarbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 14, only changing as required to react 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide using 3-methylcyclohexanecarboxylic acid instead of 4, 4, 4-trifluoro-2-methylbutyric acid, the title compound was obtained as a white solid (27% yield).¹H NMR(300MHz，CDCl₃)δ 8.06，7.99，6.99，3.89，3.79，3.65-3.72，3.56，2.55，1.20-1.86，0.99，0.92，0.75，0.47，0.10。MS(ES+)m/z 400(M+1)。

Example 14.6

6- [4- (4-methylcyclohexanecarbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 14, only changing as required to react 4-methylcyclohexanecarboxylic acid instead of 4, 4, 4-trifluoro-2-methylbutyric acid with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a white solid (43% yield). ¹H NMR(300MHz，CDCl₃)δ 8.07，7.09，7.05，3.89，3.79，3.64-3.70，3.56，2.40-2.60，1.65-1.88，1.50-1.62，0.99，0.91，0.75，0.48，0.10。MS(ES+)m/z 400(M+1)。

Example 14.7

Methyl 2- {4- [6- (2-cyclopropylethylcarbamoyl) pyridazin-3-yl ] piperazine-1-carbonyl } benzoate:

following the procedure of example 14, only making changes as required to use monomethyl phthalate instead of 4, 4, 4-trifluoro-2-methylbutyric acid for reaction with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide, the title compound was obtained as a pale yellow solid (97% yield).¹HNMR(300MHz，CDCl₃)δ 8.02-8.06，7.96，7.88，7.60，7.48，7.30，6.98，3.72-4.02，3.54，3.33，1.49，0.74，0.45，0.08。MS(ES+)m/z 438(M+1)。

Example 14.8

6- [4- (3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 14, the title compound was obtained as a white solid (55% yield) only varying as required to use 3, 3, 3-trifluoro-2-hydroxy-2-methylpropionic acid instead of 4, 4, 4-trifluoro-2-methylbutyric acid for reacting with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl) amide. Melting point 181-.¹H NMR(300MHz，CDCl₃)δ 8.07，7.98，7.01，4.86，3.92-3.81，3.55，1.74，1.51，0.81-0.68，0.46，0.09。¹³C NMR(75MHz，CDCl₃)δ 167.2，163.1，160.0，145.4，127.1，126.3，122.5，112.5，76.8-75.6(q，J＝117Hz，C-¹⁹F)，44.6，39.7，35.3，20.5，8.5，4.8。MS(ES+)m/z 416(M+1)。

Example 15

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide

To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide (58mg, 0.24mmol) in 10mL DMF was added 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.109g), piperazin-1-yl- (2-trifluoromethylphenyl) methanone (86.7mg, 0.33mmol) and Bu ₄NI (4mg, 0.01 mmol). The mixture was heated at 80 ℃ overnight. Water was added and the mixture was extracted with ethyl acetate (2X 15 mL). The organic extracts were washed with dilute HCl, followed by bicarbonate solution and brine, then Na₂SO₄Dried and concentrated. The residue was dissolved in a small amount of dichloromethane and purified by column chromatography (eluting with ethyl acetate) to give the product as a white solid (35.5 mg, 32% yield).¹H NMR(300MHz，CDCl₃)δ8.24，8.02，7.73，7.58，7.34，6.98，4.04，3.85，3.52，3.33，3.10，2.60-2.41，0.95，0.52，0.32。MS(ES+)m/z 464.3(M+1)。

Example 15.1

4-methyl-2- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazine-3-carbonyl } amino) pentanoic acid methyl ester:

following the procedure of example 15, only using 2- [ (6-chloropyridazine-3-carbonyl) amino]Methyl (4-methylpentanoate) was reacted with piperazin-1-yl- (2-trifluoromethylphenyl) -methanone instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide with the required changes to obtain the title compound as a white solid (36% yield).¹H NMR(400MHz，CDCl₃)δ 8.16，8.04，7.85，7.66-7.53，7.28，7.00，4.82-4.77，4.14-3.68，3.58-3.51，1.83-1.60，1.03-0.95。

Example 15.2

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid cyclopropylmethylamide

Following the procedure of example 15, the title compound was obtained as a white solid (31% yield) only as required to react 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using cyclopropylmethylamide 6-chloropyridazine-3-carboxylic acid. ¹H NMR(500MHz，CDCl₃)δ 8.16-7.88，7.75，7.68-7.46，7.18，7.00，4.17-3.64，3.21-3.12，1.07-1.00，0.61-0.44，0.26-0.20。

Example 15.3

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (4-methoxy (methoxy) phenyl) ethyl ] amide:

following the procedure of example 15, only using 6-chloropyridazine-3-carboxylic acid [2- (4-methoxyphenyl) ethyl]Amide substituted 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide and piperazin-1-yl- (2-trifluoromethylphenyl) methanoneThe reaction required changes to obtain the title compound as a white solid (12% yield).¹H NMR(400MHz，CDCl₃)δ 8.04，7.93，7.74，7.63，7.56，7.36，7.12，6.92，6.81，4.08-3.46，3.33，2.87。

Example 15.4

6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazine-3-carboxylic acid (3-phenylpropyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (15% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-phenylpropyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.05，7.93，7.74，7.63，7.56，7.39，7.29-7.13，6.92，4.12-3.29，2.68，2.02-1.83。

Example 15.5

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (4-chlorophenoxy) ethyl ] amide

Following the procedure of example 15, only using 6-chloropyridazine-3-carboxylic acid [2- (4-chlorophenoxy) ethyl]The amide was reacted with piperazin-1-yl- (2-trifluoromethylphenyl) methanone instead of 6-chloro-pyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide with the required changes to obtain the title compound as a white solid (13% yield). ¹H NMR(400MHz，CDCl₃)δ 8.27，8.05，7.74，7.64，7.57，7.37，7.25-7.20，7.00，6.85-6.82，4.02-3.32。

Example 15.6

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (4-fluorophenoxy) ethyl ] amide

Following the procedure of example 15, only using 6-chloropyridazine-3-carboxylic acid [2- (4-fluorophenoxy) ethyl]Amide substitution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide with piperazine-1The reaction was performed with variations as required to obtain the title compound as a white solid (49% yield).¹H NMR(500MHz，CDCl₃)δ 8.28，8.05，7.74，7.63，7.56，7.35，7.03-6.92，6.87-6.81，4.02-3.30。

Example 15.7

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (2, 4-difluorophenyl) ethyl ] amide

The procedure of example 15 was followed, only using 6-chloropyridazine-3-carboxylic acid [2- (2, 4-difluorophenyl) ethyl]The amide was reacted with piperazin-1-yl- (2-trifluoromethylphenyl) methanone with the required changes instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to obtain the title compound as a white solid (33% yield). Melting point 179-.¹H NMR(400MHz，CDCl₃)δ 8.04，7.91，7.75，7.61，7.37，7.30-6.89，4.09-3.66，3.38-3.32，2.88。MS(ES+)m/z 520(M+1)。

Example 15.8

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3, 3-dimethylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (17% yield) with the sole changes required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3, 3-dimethylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. ¹H NMR(400MHz，CDCl₃)δ 8.05，7.83-7.72，7.64，7.57，7.38，6.98，4.09-3.66，3.50-3.45，3.37-3.34，1.57-1.52，0.96。MS(ES+)m/z 464.6(M+1)。

Example 15.9

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-phenylcyclopropylmethyl) amide

Following the procedure of example 15, only using 6-chloropyridazine-3-carboxylic acid (2-phenylcyclopropylmethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide reacted with piperazin-1-yl- (2-trifluoromethylphenyl) methanone with the changes required to obtain the title compound as a white solid (25% yield).¹H NMR(400MHz，CDCl₃)δ 8.09-8.03，7.76，7.64，7.57，7.36，7.28-7.21，7.17-7.12，7.07-6.96，4.09-3.32，1.92-1.86，1.47-1.38，1.01-0.96。MS(ES+)m/z 510.4(M+1)。

Example 15.10

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (28% yield) with the sole changes required to react piperazine-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(400MHz，CDCl₃)δ 8.04，7.89，7.73，7.65，7.58，7.38，6.99，4.08-3.67，3.54-3.46，3.39-3.31，1.77-1.66，1.34-1.23，0.72-0.62，0.45-0.36，0.06-0.04。MS(ES+)m/z 462.2(M+1)。

Example 15.11

4- [6- (2-Cyclopropylethylcarbamoyl) pyridazin-3-yl ] piperazine-1-carboxylic acid tert-butyl ester

Following the procedure of example 15, the title compound was obtained as a white solid (47% yield) only as required to react with tert-butyl piperazine-1-carboxylate using 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. ¹H NMR(400MHz，CDCl₃)δ 8.04-7.95，6.97，3.62-3.54，1.59-1.44，1.34-1.23，0.72-0.62，0.45-0.36，0.06-0.04。MS(ES+)m/z 376.3(M+1)。

Example 15.12

6- [4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (47% yield) with the sole changes required to react piperazine-1-yl- (tetrahydrofuran-2-yl) methanone using 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(400MHz，CDCl₃)δ 8.12-7.88，6.97，4.64-4.60，3.93-3.42，2.56-2.35，2.10-1.93，1.52-1.38，0.84-0.62，0.50-0.38，0.17-0.05。MS(ES+)m/z 374.3(M+1)。

Example 15.13

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (3-fluorophenyl) ethyl ] amide

The procedure of example 15 was followed, using only 6-chloropyridazine-3-carboxylic acid [2- (3-fluorophenyl) ethyl ] ethyl]The amide was reacted with piperazin-1-yl- (2-trifluoromethylphenyl) methanone with the required changes instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to obtain the title compound as a white solid (71% yield).¹H NMR(400MHz，CDCl₃)δ 8.05，7.93，7.74，7.64-7.56，7.37-7.35，7.26-7.24，7.01-6.90，4.10-4.03，3.89-3.70，3.36-3.33，2.92。

Example 15.14

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (4-fluorophenyl) ethyl ] amide

The procedure of example 15 was followed, using only 6-chloropyridazine-3-carboxylic acid [2- (4-fluorophenyl) ethyl ] ethyl]The amide was reacted with piperazin-1-yl- (2-trifluoromethylphenyl) methanone with the required changes instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to obtain the title compound as a white powder (59.8% yield). ¹H NMR(400MHz，CDCl₃)δ 8.05，7.92，7.72-7.76，7.66-7.54，7.38-7.34，7.20-7.14，7.0-6.94，4.10-4.02，3.92-3.84，3.80-3.68，3.37-3.36，2.90。

Example 15.15

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (2-fluorophenyl) ethyl ] amide

The procedure of example 15 was followed, using only 6-chloropyridazine-3-carboxylic acid [2- (2-fluorophenyl) ethyl ] ethyl]The amide was reacted with piperazin-1-yl- (2-trifluoromethylphenyl) methanone with the required changes instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to obtain the title compound as a white powder (70.7% yield).¹H NMR(400MHz，CDCl₃)δ 8.04，7.95，7.75-7.72，7.63，7.55，7.36，7.22-7.15，7.05-6.97，4.07-4.02，3.89-3.83，3.79-3.67，3.35-3.32，2.96。

Example 15.16

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (4-chlorophenyl) ethyl ] amide

The procedure of example 15 was followed, only using 6-chloropyridazine-3-carboxylic acid [2- (4-chlorophenyl) ethyl ] ethyl]Amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide with piperazin-1-yl- (2-trifluoromethylphenyl) methanone the title compound was obtained as a light yellow powder (46.5% yield) with the changes required.¹H NMR(500MHz，CDCl₃)δ 8.10，7.95，7.75，7.65，7.58，7.35，7.25，7.15，7.00，4.10，3.95-3.66，3.38，2.90。

Example 15.17

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (3-chlorophenyl) ethyl ] amide

The procedure of example 15 was followed, only using 6-chloropyridazine-3-carboxylic acid [2- (3-chlorophenyl) ethyl ] ethyl]Amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide with piperazin-1-yl- (2-trifluoromethylphenyl) methanone the title compound was obtained as a light yellow powder (59.6% yield) with the changes required. ¹H NMR(500MHz，CDCl₃)δ 8.05，7.94，7.75，7.64，7.57，7.37，7.26，7.24-7.19，7.12，7.00，4.10，3.95-3.66，3.38，2.90。

Example 15.18

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-phenylpropyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (63.2% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-phenylpropyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 7.97，7.80，7.68，7.57，7.50，7.30，7.24，7.20-7.12，6.92，3.98，3.80，3.74-3.60，3.53，3.28，3.00，1.28。

Example 15.19

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-biphenyl-4-yl-ethyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (63.2% yield) only varying as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-biphenyl-4-yl-ethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.07，7.98，7.76，7.64，7.60-7.52，7.44，7.38-7.30，7.00，4.06，3.88，3.82-3.68，3.36，2.98。

Example 15.20

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder, varying only as required to react 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide Material (63.2% yield).¹H NMR(500MHz，CDCl₃)δ 8.05，7.98，7.75，7.64，7.57，7.37，7.00，4.06，3.89，3.82-3.64，3.49，3.36，1.70，1.50，0.95。

Example 15.21

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-hydroxybutyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (30% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (4-hydroxybutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.05，7.98，7.75，7.63，7.57，7.37，6.99，4.06，3.88，3.82-3.67，3.52，3.36，1.70。

Example 15.22

(R) -6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (64.5% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using (R) -6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.28，8.05，7.76，7.64，7.58，7.44-7.32，7.29，7.00，4.96，4.08，3.92-3.68，3.61，3.36。

Example 15.23

(S) -6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide

Following the procedure of example 15, only following the procedure using (S) -6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide and piperazin-1-yl- (2-trifluoromethyl) Phenyl) methanone the reaction was varied as required to obtain the title compound as a white powder (64.5% yield).¹H NMR(500MHz，CDCl₃)δ 8.28，8.05，7.76，7.64，7.58，7.44-7.32，7.29，7.00，4.96，4.08，3.92-3.68，3.61，3.36。MS(ES+)m/z 500(M+1)。

Example 15.24

4- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carbonyl } amino) butanoic acid ethyl ester

Following the procedure of example 15, only using 2- [ (6-chloropyridazine-3-carbonyl) amino]Ethyl butyrate was varied as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide to obtain the title compound as a white powder (37.8% yield).¹H NMR(500MHz，CDCl₃)δ 8.05，7.96，7.75，7.65，7.57，7.37，7.00，4.16-4.04，3.92-3.70，3.56，3.36，2.40，1.25。MS(ES+)m/z 494(M+1)。

Example 15.25

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-hydroxy-4, 4-dimethylpentyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (39% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-hydroxy-4, 4-dimethylpentyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.18，8.05，7.74，7.63，7.56，7.36，6.99，4.05，3.92-3.67，3.45-3.32，3.26，1.76，1.55，0.88。MS(ES+)m/z 494(M+1)。

Example 15.26

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl) amide

Procedure according to example 15Procedure only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide, to obtain the title compound as a white powder (46.4% yield). ¹H NMR(500MHz，CDCl₃)δ 8.30，8.05，7.75，7.65，7.57，7.37，6.98，4.06，3.88，3.81-3.69，3.64，3.40-3.32，1.80，1.64，1.30。MS(ES+)m/z 466(M+1)。

Example 15.27

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-ethoxyethyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (24.8% yield) merely as a function of the required change to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-ethoxyethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.18，8.07，7.76，7.65，7.58，7.38，7.00，4.07，3.90，3.83-3.65，3.60，3.52，3.36，1.20。MS(ES+)m/z 452(M+1)。

Example 15.28

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid pentanamide

Following the procedure of example 15, the title compound was obtained as a white solid (94% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid pentanamide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. Melting point 123-.¹H NMR(300MHz，CDCl₃)δ 8.03，7.85，7.62，7.54，7.35，6.97，4.06-3.99，3.91-3.69，3.44，3.33，1.62-1.55，1.37-1.33，0.95-0.81。¹³C NMR(75MHz，CDCl₃)δ 167.6，162.9，160.0，145.5，132.4，129.5，127.2，127.1，126.9-127.8，112.5，77.2，46.4，44.6，44.4，41.3，39.4，29.3，29.1，22.4，14.0。MS(ES+)m/z 450.2(M+1)，472.2(M+Na)。

Example 15.29

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-hydroxy-3, 3-dimethylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a brown solid (75% yield) only following the changes required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3, 3-dimethylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. Melting point 236-240 ℃. ¹H NMR(300MHZ，CDCl₃)δ 7.90，7.83-7.79，7.75-7.73，7.69-7.65，7.54-7.52，7.30，4.29，3.91-3.73，3.43-3.32，3.20-3.11，2.81，2.77，0.95。MS(ES+)m/z 480(M+1)。

Example 15.30

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-hydroxy-3, 3-dimethylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a brown solid (51% yield) only following the changes required to react with piperazin-1-yl- (5-fluoro-2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3, 3-dimethylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. Melting point 186-.¹H NMR(300MHz，CDCl₃)δ 8.20，8.04，7.75，7.22，7.07，6.98，4.06-3.98，3.91-3.71，3.47-3.23，2.45，0.96。¹³C NMR(75MHz，CDCl₃)δ 166.3，164.1，160.1，160.0，130.1，127.2，116.9，116.6，115.0，114.7，112.4，79.4，46.4，44.5，44.3，41.9，41.3，34.4，25.7。MS(ES+)m/z 498(M+1)。

Example 15.31

6- [4- (2-Methylcyclopropanecarbonyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (88% yield) with the sole changes required to react piperazine-1-yl- (2-methylcyclopropyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹³C NMR(75MHz，CDCl₃)δ 177.1，163.5，159.5，144.9，131.3，126.4，115.1，49.7，45.2，39.5，37.5，37.2，35.3，34.6，29.9，28.5，26.5，23.4，8.6，4.2。MS(ES+)m/z 360(M+1)。

Example 15.32

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid pentanamide

Following the procedure of example 15, the title compound was obtained as a white solid (31% yield) only varying as required to react piperazine-1-yl- (5-fluoro-2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid pentanamide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. Melting point 162-. ¹H NMR(300MHz，CDCl₃)δ 8.05，7.87，7.24，7.07，6.99，4.08-3.99，3.90-3.66，3.45，3.35，1.65-1.55，1.37-1.30。¹³C NMR(75MHz，CDCl₃)δ 166.1，162.9，160.0，145.7，129.7，127.2，116.9，116.6，115.0，114.7，112.6，77.2，46.4，44.6，44.4，41.3，39.4，29.3，29.1，22.4，14.0。

Example 15.33

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-methylpentyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (36% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (4-methylpentyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. Melting point 43-45 ℃.¹H NMR(300MHz，CDCl₃)δ 7.71，7.66-7.52，7.34，6.96，4.06-3.98，3.87-3.68，3.63，3.53，3.19，3.25，3.09，1.65-1.58，1.36-1.33，1.26-1.12，0.85。¹³C NMR(75MHz，CDCl₃)δ167.6，166.9，166.2，159.0，158.9，149.5，149.4，134.4，132.4，129.5，129.2，127.2，126.9，126.8，112.6，112.5，51.4，48.8，46.4，44.7，44.4，41.3，37.8，34.8，34.0，29.7，29.0，28.7，27.1，26.7，22.5，22.3，14.0，13.9。MS(ES+)m/z 464.2(M+1)，486.2(M+Na)。

Example 15.34

6- [4- (5-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (28.3% yield) only varying as required to react piperazine-1-yl- (5-fluoro-2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(400MHz，CDCl₃)δ 8.05，7.86，7.78-7.75，7.28-7.22，7.12-7.08，7.02，4.08-4.01，3.91-3.86，3.82-3.68，3.55-3.46，3.38，1.73-1.65，1.56-1.48，0.94。

Example 15.35

6- [4- (4-fluoro-2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (63.8% yield) only varying as required to react piperazine-1-yl- (4-fluoro-2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. ¹H NMR(400MHz，CDCl₃)δ 8.08，7.85，7.48-7.46，7.41-7.32，7.02，4.08-4.05，3.95-3.88，3.80-3.68，3.52-3.45，3.35，1.73-1.68，1.51，0.94。

Example 15.36

6- [4- (2-fluoro-6-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (16.8% yield) only varying as required to react piperazin-1-yl- (6-fluoro-2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(400MHz，CDCl₃)δ 8.06，7.85，7.57-7.55，7.39-7.36，7.01，4.04-3.94，3.86-3.79，3.49，3.44-3.36，1.73-1.68，1.52，0.94。

Example 15.37

6- [4- (2, 6-difluorobenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (42.2% yield) only in accordance with the changes required to react with piperazin-1-yl- (2, 6-difluorophenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(400MHz，CDCl₃)δ 8.07，7.85，7.44-7.38，7.03-6.97，4.0-3.99，3.86-3.83，3.52-3.48，1.73-1.67，1.51，0.94。

Example 15.38

6- [4- (2, 2, 3, 3-tetramethylcyclopropanecarbonyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (35% yield) only in accordance with the changes required to react piperazin-1-yl- (2, 2, 3, 3-tetramethylcyclopropyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. ¹H NMR(400MHz，CDCl₃)δ 8.07，8.01，7.01，3.91-3.89，3.81-3.65，3.57，1.21，1.19，0.79-.072，0.49-0.46，0.11-0.10。MS(ES+)m/z 400(M+1)。

Example 15.39

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-methylcyclopropylmethyl) amide

Following the procedure of example 15, the title compound was obtained as a white solid (26% yield) only as required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-methylcyclopropylmethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.06，7.96，7.75，7.65，7.58，7.38，7.01，4.04-4.10，3.86-3.93，3.69-3.83，3.25-3.42，1.12，1.05，0.71-0.80，0.64-0.72，0.39-0.45，0.25-0.30。MS(ES+)m/z448(M+1)。

Example 15.40

4- [6- (3-methylbutylcarbamoyl) pyridazin-3-yl ] piperazine-1-carboxylic acid tert-butyl ester

Following the procedure of example 15, the title compound was obtained as a white solid (83% yield) only as required to react with tert-butyl piperazine-1-carboxylate using 6-chloropyridazine-3-carboxylic acid (3-methylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(500MHz，CDCl₃)δ 8.03，7.86，6.97，3.75，3.56-3.63，3.49，1.65-1.76，1.52，0.94。MS(ES+)m/z 378(M+1)。

Example 15.41

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclobutylethyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (47% yield) only following the change required to react with piperazin-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. ¹H NMR(300MHz，CDCl₃)δ 8.02，7.74，7.73，7.57，7.35，6.98，4.03，3.89-3.66，3.40-3.31，2.36，2.09-2.00，1.92-1.57。¹³C NMR(75MHz，CDCl₃)(167.6，134.3，132.4，129.5，127.2，127.0，126.9，126.8，126.7，125.5，121.8，1126，46.4，46.4，41.3，37.6，36.5，33.7，28.3，18.6。MS(ES+)m/z 462.3(M+1)。

Example 15.42

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid hexanamide

Following the procedure of example 15, the title compound was obtained as a white powder (35% yield) only as required to react with piperazin-1-yl- (2-trifluoromethyl-phenyl) methanone using 6-chloropyridazine-3-carboxylic acid hexanamide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.02，7.85，7.72，7.56，7.34，6.97，4.00，3.90-3.64，3.48-3.28，1.58，1.29，0.85。¹³C NMR(75MHz，CDCl₃)δ 167.6，162.9，160.0，145.5，134.3，132.8，129.5，127.6，127.2，126.9，125.4，46.4，44.6，44.4，41.3，39.4，31.5，29.5，26.6，22.6，14.0。MS(ES+)m/z(％)464(M+1)。

Example 15.43

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-cyclobutylpropyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (28% yield) with the sole changes required to react piperazine-1-yl- (2-trifluoromethylphenyl) methanone using 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpropyl) amide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.03，7.85，7.73，7.57，7.34，6.99，4.05，3.89-3.65，3.45，3.33，2.27，1.99，1.76，1.58-1.39。¹³C NMR(75MHz，CDCl₃)δ 167.6，162.8，159.9，145.4，134.2，132.4，129.5，127.2，126.9，126.7，112.7，46.4，44.6，44.5，41.2，39.4，35.7，34.1，28.3，27.2，18.4。MS(ES+)m/z 475.9(M+1)。

Example 15.44

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid heptylamide

Following the procedure of example 15, the title compound was obtained as a white powder (41% yield) only as required to react with piperazin-1-yl- (2-trifluoromethyl-phenyl) methanone using 6-chloropyridazine-3-carboxylic acid heptylamide instead of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide. ¹H NMR(300MHz，CDCl₃)δ 8.05，7.85，7.72，7.58，7.34，6.98，4.03，3.94-3.64，3.47-3.28，1.58，1.32-1.25，0.84。¹³C NMR(75MHz，CDCl₃)δ 167.6，162.9，160.0，145.5，134.3，132.4，129.5，126.9，126.3，125.4，121.8，1 12.6，46.4，44.5，41.3，39.4，31.7，29.6，29.0，26.9，22.6，14.1。MS(ES+)m/z 478.2(M+1)。

Example 15.45

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-cyclopropylbutyl) amide

Following the procedure of example 15, the title compound was obtained as a white powder (21% yield) merely as required to react with piperazin-1-yl- (2-trifluoromethyl-phenyl) methanone using 6-chloropyridazine-3-carboxylic acid (4-cyclopropylbutyl) amide instead of 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpropyl) amide.¹H NMR(300MHz，CDCl₃)δ 8.03，7.86，7.72，7.58，7.34，6.98，4.05，3.89-3.62，3.48-3.31，1.64-1.41，1.20，0.60，0.39-0.30，-0.04。¹³C NMR(75MHz，CDCl₃)δ 167.6，162.9，160.0，145.4，134.3，132.4，129.5，127.2，126.9，126.7，125.4，121.8，112.6，46.4，44.6，44.4，41.2，39.5，34.4，29.4，27.0，10.7，4.4。MS(ES+)m/z 476.1(M+1)。

Example 16

Synthesis of 4-methyl-2- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carbonyl } amino) pentanoic acid

Lithium hydroxide monohydrochloride (25mg, 0.595mmol) was added to 4-methyl-2- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]To a solution of pyridazine-3-carbonyl } -amino) pentanoic acid methyl ester (130mg, 0.256mmol) in tetrahydrofuran (3mL) and water (1.5mL) the reaction mixture was stirred at ambient temperature for 3 hours, THF was removed by evaporation, the residue was adjusted to pH about 6 with 5% citric acid and diluted with ethyl acetate, washed with water and brine, dried (Na)₂SO₄) And concentrated to give 4-methyl-2- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]Pyridazine-3-carbonyl } amino) pentanoic acid (94mg, 74%).¹H NMR(400MHz，CDCl₃)δ 8.17，8.02，7.78，7.66-7.53，7.38，6.99，6.72，4.88-4.73，4.25-3.60，3.44-3.21，1.79-1.06，1.33-1.19，1.03，0.99。

Example 17

Synthesis of 6- {4- [1- (2-trifluoromethylphenyl) ethyl ] piperazin-1-yl } -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide hydrochloride

Titanium isopropoxide (0.6mL, 2.0mmol) was added to a solution of 6-piperazin-1-yl-pyridazine-3-carboxylic acid 2- (cyclopropylethyl) amide (282mg, 1.02mmol) and 2- (trifluoromethyl) acetophenone (0.23mL, 1.53mmol) in THF (3 mL). The resulting mixture was stirred at ambient temperature for 4 hours. Sodium cyanoborohydride (130mg, 1.96mmol) was added and stirring was continued for another 13 hours. Aqueous sodium hydroxide (2.0mL, 1.0M) was added. After stirring at ambient temperature for 5 minutes, the reaction mixture was diluted with ethyl acetate (50mL) and then washed with water and brine. With anhydrous Na₂SO₄The organic layer was dried and concentrated. Purification by flash chromatography gave 6- {4- [1- (2-trifluoromethylphenyl) ethyl]Piperazin-1-yl } -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (126 mg). Dissolving the product in CH₂Cl₂(2mL), then HCl in ether (7M, 0.2mL, 1.4mmol) was added.The mixture was kept at ambient temperature for 2 hours. The white precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to give the title compound as a white solid (104mg, 21% yield). Melting point 158-. ¹H NMR(300MHz，DMSO-d₆)δ 12.10，8.81，8.67，7.90-7.81，7.64，7.40，4.70-2.85，1.69，1.38，0.72-0.58，0.40-0.32，0.023-0.02。MS(ES+)m/z374.3(M+1-HCl)。

Example 18

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-oxo-2-phenylethyl) amide

To 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl group with stirring in a cold water bath]To a solution of pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide (0.517g, 1.03mmol) in dichloromethane (10mL) was added 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-benzodioxole (benzidoxol) -3(1H) -one (0.53g) in one portion. After stirring in a cold water bath for 15 minutes and then at ambient temperature for 2 hours, the reaction mixture was diluted with diethyl ether (20 mL). The mixture was poured into a solution of sodium thiosulfate (1.176g, 7.44mmol) in saturated aqueous sodium bicarbonate (29 mL). The mixture was extracted with ethyl acetate (100 mL). With saturated NaHCO₃The organic layer was washed with aqueous solution (2X 15mL) and water (2X 15 mL). The combined aqueous washes were then extracted with ethyl acetate (2X 80 mL). With Na₂SO₄The combined organic phases were dried and filtered, then the solvent was removed in vacuo. The crude product was purified by column chromatography eluting with hexane: ethyl acetate (1: 1), hexane: ethyl acetate (1: 2) and pure ethyl acetate in that order. The product was obtained as a white powder (0.261g, 51% yield). Melting point 196 ℃ 198 ℃. ¹H NMR(300MHz，CDCl₃)δ 8.72，7.97-8.06，7.74，7.47-7.66，7.36，6.99，4.96，4.02-4.11，3.70-3.92，3.27-3.42。¹³C NMR(CDCl₃)δ 193.4，167.7，163.4，160.0，145.1，134.6，134.2，134.0，132.4，129.6，128.9，128.0，127.2，126.9，126.8，112.3，46.4，44.7，44.4，41.3。MS(ES+)m/z 498(M+1)。

Example 19

Synthesis of 1-phenyl-2- ({6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl ] pyridazin-3-carbonyl } amino) ethyl acetate

To 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]To a solution of pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide (50mg, 0.1mmol) in chloroform (2mL) were added acetic anhydride (0.25mL), triethylamine (0.25mL) and 4-dimethylaminopyridine (18 mg). After stirring at ambient temperature for 6 hours, the reaction mixture was diluted with ethyl acetate (100mL), washed with water (3X 10mL) and Na₂SO₄And (5) drying. The crude product obtained after removal of the solvent was purified by column chromatography (eluting with hexane: ethyl acetate 1: 1 and 1: 2 in sequence) to give a white powder (49.6mg, 91.5% yield).¹H NMR(500MHz，CDCl₃)δ 8.10，8.04，7.75，7.65，7.57，7.40-7.28，7.00，5.92，4.07，3.98，3.90，3.82-3.68，3.36，2.10。MS(ES+)m/z 508(M+1)。

Example 19.1

1, 1-dimethyl-3- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazine-3-carbonyl } amino) propyl acetate

Following the procedure of example 19, only using 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]Pyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl) amide instead of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]Pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl) amide was reacted with acetic anhydride with the desired change to obtain the title compound as a white powder (80% yield). ¹H NMR(500MHz，CDCl₃)δ 8.05，8.01，7.75，7.65，7.57，7.37，6.99，4.06，3.88，3.81-3.67，3.58，3.36，2.06，2.01，1.52。MS(ES+)m/z 508(M+1)。

Example 20

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-methoxy-3, 3-dimethylbutyl) amide

To 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]To a solution of pyridazine-3-carboxylic acid (2-hydroxy-3, 3-dimethylbutyl) amide (81.6mg, 0.17mmol) in THF (1.0mL) was added sodium hydride (5.0mg, 0.19mmol) followed by methyl iodide (15mL, 0.26 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, then the solvent was removed. The gum was diluted with dichloromethane (5mL), washed with water (2X 2mL), and MgSO₄Dry and filter off the solid. After concentrating the solvent to dryness, the crude material was subjected to column chromatography (eluting with ethyl acetate: hexane (1: 1) and ethyl acetate in that order) to give 25.3mg (30%) of the product as a solid. The melting point is 65-68 ℃.¹H NMR(300MHz，CDCl₃)δ 7.73-7.69，7.62，7.53，7.33，6.98-6.93，4.18-3.59，3.48，3.41，3.37-3.26，3.18，3.03-2.98，1.76，0.98，0.75。¹³C NMR(75MHz，CDCl₃)δ 167.6，166.4，158.9，149.8，149.3，134.3，132.4，129.5，129.4，129.3，129.1，127.2，126.9-126.7，112.7，88.1，61.7，61.4，52.7，52.0，46.4，44.7，44.6，44.5，44.4，41.3，41.2，40.5，35.8，35.3，35.0，26.0，25.9，25.7。MS(ES+)m/z 508(M+1)。

Example 21

Synthesis of 6- [3, 5-dimethyl-4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

To a solution of 6- (3, 5-dimethylpiperazin-1-yl) pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (0.40g, 1.33mmol) in dichloromethane (15mL) was added diisopropylethylamine (0.34g, 0.46mL, 2.66mmol) followed by 2-trifluoromethylbenzoyl chloride (0.31g, 0.22mL, 1.46mmol) at ambient temperature. The reaction solution was stirred for 16 hours and poured into cold water (10 mL). The organic layer was extracted with dichloromethane (50mL) and saturated NaHCO ₃The solution (2X 10mL) was washed and MgSO₄And (5) drying. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography (eluting with ethyl acetate (100%) to give 0.18g of a colorless solid (28% yield).¹H NMR(300MHz，CDCl₃)δ 8.03-7.91，7.70，7.63-7.49，7.32，6.99-6.95，5.00，4.39-4.22，3.64，3.55-3.47，3.39-3.17，1.51-1.38，1.24-1.14，0.76-0.67，0.42，0.05。¹³C NMR(75MHz，CDCl₃)δ168.0，163.0，160.9，144.9，132.3，131.9，129.4，129.3，127.2，127.0，126.8，111.5，50.4，49.1，48.7，48.5，48.2，45.5，45.3，39.6，34.6，20.2，19.5，8.6，4.2。

Example 22

Synthesis of 6- [2, 5-dimethyl-4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid pentanamide

To a mixture of 6-chloropyridazine-3-carboxylic acid pentanamide (304mg, 1.00mmol) in 2-propanol (12mL) was added 2, 5-dimethylpiperazine (1.37g, 12.0 mmol). The reaction mixture was refluxed for 2 days. An additional 0.25g of 2, 5-dimethylpiperazine and 1.0mL of triethylamine were added to the reaction mixture and heating was continued for an additional 24 hours. After cooling the reaction mixture to ambient temperature, the solvent was removed by rotary evaporator. To a solution of the crude material in dichloromethane (20mL) was added a solution of 2-trifluoromethylbenzoyl chloride (0.63g, 3.00mmol) in dichloromethane (20mL) and the reaction mixture was stirred at ambient temperature for 16 h. The organic layer was diluted with dichloromethane (50mL) and washed with 10% HCl, MgSO₄And (5) drying. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography (eluting with ethyl acetate (100%) to give 300mg (31% yield) of the product as a colourless solid. ¹H NMR(300MHz，CDCl₃)δ7.74-7.43，7.36-7.24，5.17-5.04，4.91-4.79，4.52，4.52，3.68-3.57，3.54-3.44，3.39-3.11，2.93，2.85-2.71，1.36-1.31，1.27-1.15，1.23-1.05。

Example 23

Synthesis of 2- {4- [6- (2-cyclopropylethylcarbamoyl) pyridazin-3-yl ] piperazine-1-carbonyl } benzoic acid

Lithium hydroxide monohydrate (0.066g, 1.57mmol) was added to 2- {4- [6- (2-cyclopropylethylcarbamoyl) pyridazin-3-yl which was stirred overnight at ambient temperature]Piperazine-1-carbonyl } benzoic acid methyl ester (0.230g) in tetrahydrofuran (10mL) and water (5 mL). THF was removed in vacuo and the residue was dissolved in ethyl acetate (100mL), neutralized by addition of 5% HCl solution, washed with brine, and washed with anhydrous Na₂SO₄Dried and concentrated. The residue was recrystallized from dichloromethane and hexane to give 0.107g of the title compound (42% yield).¹H NMR(300MHz，CDCl₃)δ 8.67，9.07-7.87，7.54，7.41，7.26-7.24，6.95，4.12-3.27，1.55-1.40，0.77-0.64，0.50-0.34，0.13-0.01；¹³C NMR(75MHz，CDCl₃)δ 170.7，168.2，163.2，159.9，145.0，137.7，133.1，131.2，129.2，127.9，127.2，126.6，112.6，46.2，44.1，41.4，39.7，34.4，8.6，4.2；MS(ES+)m/z 424.2(M+1)。

Example 24

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid 2, 2- (dimethylcyclopropylmethyl) amide

To 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]To a solution of pyridazine-3-carboxylic acid (1.00mmol) in dichloromethane (20mL) were added diisopropylethylamine (0.8mL, 4.60mmol), 1-hydroxybenzotriazole hydrate (0.203g, 1.50mmol) and 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (0.384mg, 2.00 mmol). The resulting mixture was stirred for 15 minutes, then 2, 2- (dimethylcyclopropyl) methylamine (0.149mg, 1.5mmol) was added. Stirring was continued for another 24 hours. The reaction mixture was diluted with dichloromethane (100mL), washed successively with water and brine, then anhydrous Na ₂SO₄Dried and concentrated. Purification by silica gel (ethyl acetate) flash chromatography and recrystallization from ethyl acetate and hexane afforded the title compound (0.089g, 19%). Melting point 132-.¹H NMR(300MHz，CDCl₃)δ8.06-8.02，1.90-7.80，7.75，7.64-7.52，7.34，6.98，4.05-3.33，1.11，1.04，0.89-0.79，0.50-0.46，0.16-0.13；¹³C NMR(75MHz，CDCl₃)δ167.6，162.7，159.9，145.4，134.2，132.3，129.5，127.2，126.8，125.4，121.8，112.5，46.3，44.6，44.4，40.5，27.1，23.5，19.9，18.7，15.9；MS(ES+)m/z 462(M+1)。

Example 24.1

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-thiophen-2-yl-ethyl) amide

Following the procedure of example 24, only substituting 2-thiophen-2-yl-ethylamine for 2, 2- (dimethylcyclopropyl) methylamine and 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]Pyridazine-3-carboxylic acid required to make the changes to obtain the title compound as a white powder (40% yield).¹HNMR(300MHz，CDCl₃)δ 8.01，7.73，7.58，7.34，7.12，6.98，6.90，6.84，4.03，3.89-3.55，3.33，3.12。¹³C NMR(75MHz，CDCl₃)δ 167.6，163.1，160.0，145.2，141.1，134.2，132.4，129.5，127.2，127.0，126.9，125.3，123.9，121.8，112.5，46.4，44.6，44.4，41.3，40.9，30.9。MS(ES+)m/z 490.0(M+1)。

Example 24.2

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (6-chloropyridazin-3-yl) amide

Following the procedure of example 24, only substituting 3-amino-6-chloropyridazine for 2, 2- (dimethylcyclopropyl) methylamine and 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]Pyridazine-3-carboxylic acid required to make the changes to obtain the title compound as a white powder (8% yield).¹HNMR(300MHz，CDCl₃)δ 10.75，8.62，8.06，7.75-7.50，7.36，7.03，4.12-3.76，3.36。¹³C NMR(75MHz，CDCl₃)δ 167.7，162.2，160.1，154.0，152.3，143.8，134.1，132.4，129.7，129.6，127.3，127.2，126.94，126.88，126.7，120.7，112.2，46.3，44.6，44.3，41.3。MS(ES+)m/z492.1(M+1)。

Example 25

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyclopropyl-2-oxoethyl) amide

Dess-Martin periodinane (0.55g, 1.3mmol) was added to 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ]To a solution of pyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl) amide (0.50g, 1.07mmol), the resulting reaction mixture was stirred at ambient temperature for 2 hours, then diluted with ethyl acetate, followed by 10% Na₂S₂O₃Solution, saturated NaHCO₃And a brine wash. With anhydrous Na₂SO₄The organic layer was dried and concentrated. The residue was purified by flash chromatography and recrystallized from ethyl acetate-hexane to give the title compound (0.43g) in 87% yield.¹H NMR(300MHz，CDCl₃)δ 8.45-8.41，8.02，7.72，7.63-7.51，7.34，7.00，4.48，4.47-3.28，2.00-1.94，1.18-1.11，1.10-0.82。¹³C NMR(75MHz，CDCl₃)δ 204.4，167.6，163.1，159.8，144.9，134.2，132.3，129.5，129.0，127.5，127.2，126.9，121.8，118.1，112.4，49.5，46.3，44.6，44.4，41.2，18.7，11.4。MS(ES+)m/z 462.0(M+1)。

Example 26

Synthesis of 6- [4- (2-sulfamoylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methylbutyl) amide

To 6- [4- (2-methanesulfonylbenzoyl) piperazin-1-yl]Pyridazine-3-carboxylic acid (3-methylbutyl) amide (0.078g, 0.17mmol) was added to a cooled ice-cold solution in 5mL THF was methylmagnesium chloride (0.071mL, 0.212 mmol). The resulting mixture was stirred at 0 ℃ for 15 minutes and then at ambient temperature for 30 minutes. The reaction mixture was cooled again to 0 ℃ and tributylborane (0.255mL, 0.255mmol) was then added. The mixture was stirred at ambient temperature for 30 minutes and then heated to reflux for 18 hours. After cooling the mixture to 0 ℃, sodium acetate, water and hydroxylamine-o-sulfonic acid (0.067g) were added. The mixture was stirred for 3 hours, then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried and concentrated in vacuo. The residue was purified by flash column chromatography (using 20% methanol in ethyl acetate) to give The title product (0.033g, 42% yield).¹H NMR(300MHz，CDCl₃)δ 8.58，7.98，7.81，7.75-7.68，7.64-7.58，7.43，7.19，4.03-3.88，3.78-3.59，3.21-3.20，3.152-3.147，1.65-1.50，1.46-1.35，0.85。¹³C NMR(75MHz，CDCl₃)δ 170.1，165.5，161.7，146.3，139.1，137.3，135.5，131.3，130.9，128.8，127.9，114.4，45.6，45.2，44.96，42.6，39.5，38.8，27.1，22.9。MS(ES+)m/z 460.1(M+1)。

Example 27

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-chlorophenyl) amide

2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (0.105g, 0.60mmol) was added to cooled (0 ℃ C.) 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl]Pyridazine-3-carboxylic acid (0.190g, 0.50mmol) and methylmorpholine (0.07mL, 0.63mmol) in THF (10 mL). The reaction mixture was stirred at 0 ℃ for 15 minutes and then at ambient temperature for 1 hour. 4-chloroaniline (0.0765g, 0.60mmol) was then added. After stirring at ambient temperature for 20 h, the reaction mixture was diluted with ethyl acetate (100mL), washed with water, brine, and anhydrous Na₂SO₄Dried and concentrated. Purification by flash chromatography and recrystallization from ethyl acetate/hexanes gave the title compound (0.164g) in 67% yield.¹H NMR(300MHz，CDCl₃)δ9.79，8.08，7.82-7.55，7.36-7.28，7.02，4.10-4.00，3.93-3.68，3.35。¹³C NMR(75MHz，CDCl₃)δ 167.6，160.7，160.0，144.8，136.2，134.2，132.4，129.5，129.2，129.1，127.2，126.9，126.8，126.7，125.4，121.8，120.7，112.6，46.3，44.5，44.3，41.2。MS(ES+)m/z 490.1(M+1)。

Example 27.1

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-chloropyridin-2-yl) amide

Following the procedure of example 27, based only on the use of 2-amino-The title compound was obtained as a white powder (36% yield) with the changes required to replace 4-chloroaniline with 5-chloropyridine.¹HNMR(300MHz，CDCl₃)δ 10.32，8.32，8.27，8.08，7.83-7.47，7.36，7.02，4.11-4.03，3.92-3.71，3.36。¹³C NMR(75MHz，CDCl₃)δ 167.6，161.4，160.0，149.4，146.9，144.4，137.8，134.1，132.4，129.5，127.2，126.9，126.8，126.7，125.4，121.8，114.5，112.2，46.3，44.5，44.3，41.2。MS(ES+)m/z 491.0(M+1)。

Example 27.2

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 2-difluoro-2-pyridin-2-ylethyl) amide

Following the procedure of example 27, varying only as required to use 2, 2-difluoro-2-pyridin-2-ylethylamine in place of 4-chloroaniline, the title compound was obtained as a white powder (49%).¹H NMR(300MHz，CDCl₃)δ 8.65，8.27，8.01，7.81-7.46，7.38-7.32，6.96，4.43-4.31，4.12-3.64，3.32。13C NMR(75MHz，CDCl3)(167.6，163.3，159.9，153.4，153.1，149.4，144.8，137.2，134.2，132.3，129.5，127.4，127.2，126.9，126.8，126.7，126.3，125.4，125.2，121.95，121.81，120.6，120.5，118.7，115.5，112.4，46.3，44.5，44.4，43.4，43.0，42.6，41.2；MS(ES+)m/z 521.2(M+1)。

Example 27.3

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 2-difluoro-2-phenylethyl) amide

Following the procedure of example 27, varying only as required to use 2, 2-difluoro-2-phenylethylamine instead of 4-chloroaniline, the title compound was obtained as a white powder (53%).¹H NMR(300MHz，CDCl₃)δ 8.17，8.00，7.71，7.64-7.50，7.41-7.27，6.97，4.17-4.01，3.89-3.66，3.33。¹³C NMR(75MHz，CDCl₃)δ 167.6，163.2，159.9，144.6，134.6，134.1，132.3，130.3，129.5，128.5，127.3，127.2，126.8，125.3，121.8，120.3，117.1，112.4，46.3，45.3，44.5，44.3；MS(ES+)m/z 520.2(M+1)。

Example 27.4

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [2- (3-fluorophenyl) -2-hydroxyethyl ] amide

Following the procedure of example 27, the title compound was obtained as a white powder (34%) with the only changes required to use 2-amino-1- (3-fluorophenyl) ethanol instead of 4-chloroaniline. Melting point 117-.¹H NMR(300MHz，CDCl₃)δ 8.25，8.98，7.72，7.64-7.52，7.35-7.23，7.14-7.10，6.97-6.78，4.93，4.05-3.31，3.31。¹³CNMR(75MHz，CDCl₃)δ 167.6，164.5，164.3，161.3，159.9，144.8，144.6，144.5，134.1，132.3，130.0，129.9，129.5，127.5，127.2，127.1，126.9，126.8，126.7，125.4，121.8，121.4，114.7，114.4，113.0，112.7，112.4，73.1，47.5，47.0，46.3，44.5，44.3，41.2；MS(ES+)m/z 518.3(M+1)。

Example 28

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carboxylic acid pyridin-2-ylamide

To a solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (0.400g, 1.052mmol) were added DMF (0.03mL) and thionyl chloride (0.5 mL). The reaction mixture was refluxed at 70 ℃ for 17.5 hours. The mixture was evaporated and the residue was dried overnight. The dried residue was dissolved in dichloromethane (8mL) as the acid chloride stock solution for the next reaction.

To a solution of 2-aminopyridine (0.038g, 0.395mmol) and triethylamine (0.1mL) in dichloromethane (2mL) was added dropwise the above acid chloride solution (0.1315M, 2mL, 0.263mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours, then diluted with ethyl acetate (100mL) and washed with water and brine in that order. With Na₂SO₄The organic layer was dried and evaporated. The crude product was purified by column chromatography to give the title compound in 37% yield (0.044 g).¹H NMR(300MHz，CDCl₃)δ 10.30，8.35，8.09，7.75-6.69，7.65-7.52，7.35，7.09-6.96，4.10-4.02，3.92-3.71，3.35。¹³C NMR(75MHz，CDCl₃)δ167.7，161.5，160.1，151.1，148.3，144.8，138.2，134.2，132.4，129.6，127.2，126.9，126.8，125.5，121.8，119.9，114.0，112.2，46.4，44.6，44.3，41.3。MS(ES+)m/z 457.3(M+1)。

Example 28.1

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid pyridazin-3-ylamide

Following the procedure of example 28, only substituting pyridazin-3-ylamine for 2-aminopyridine and 6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl]The pyridazine-3-carbonyl chloride reaction required changes to obtain the title compound as a white powder (17.3% yield).¹H NMR(300MHz，CDCl₃)δ 10.81，9.05，8.70，8.13，7.87-7.57，7.39，6.95，4.16-3.80，3.40。¹³C NMR(300MHz，CDCl₃)δ 167.7，162.3，160.1，148.6，144.1，132.4，129.6，128.1，127.2，126.9，118.3，112.1，43.4，44.6，44.3，41.3。MS(ES+)m/z 458.3(M+1)。

Example 28.2

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-pyridin-2-ylethyl) amide

Following the procedure of example 28, only following the replacement of 2-aminopyridine with 6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl with 2-pyridin-2-ylethylamine]The pyridazine-3-carbonyl chloride reaction required changes to obtain the title compound as a white powder (30%). Melting point 151-. ¹H NMR(300MHz，DMSO-d₆)δ 9.07，8.78，8.43，7.99-7.61，7.52，7.34，3.79-3.60，3.35-3.14。MS(ES+)m/z 485.3(M+1)。

Example 29

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (benzo [1, 3] dioxol-5-yl-methyl) amide

A. A solution of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (0.300g, 0.789mmol) in dichloromethane (12mL) and THF (6mL) was cooled to 0 ℃. N-methylmorpholine (0.806g, 0.789mmol) was added followed by dropwise addition of isobutyl chloroformate (0.109g, 0.789 mmol). After stirring at 0 ℃ for 20 minutes and at ambient temperature for 1.5 hours, the mixture was evaporated. The residue was dissolved in dichloromethane (60mL) and the solution was cooled to 0 ℃. Water (5mL) was added to the solution with stirring. The mixture was quickly transferred to a 100mL separatory funnel. After rapid separation from water, the organic layer was evaporated at 10 ℃. The dried residue was then dissolved in anhydrous dichloromethane (15mL) and ready for the next reaction.

B. To the above mixed anhydride stock solution (0.053M, 5mL, 0.263mmol) was added dropwise a solution of piperylamine in dichloromethane (0.5M, 0.52mL, 0.26mmol) at ambient temperature over 5 minutes. The reaction was stirred at ambient temperature for 16 hours. The mixture was evaporated and dried under reduced pressure to give the title compound in 93% yield (0.136 g).

Example 30

Synthesis of 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (pyridin-2-yl-methyl) amide

Reacting 6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl at ambient temperature]A mixture of pyridazine-3-carboxylic acid methyl ester (0.099g, 0.25mmol), pyridin-2-yl-methylamine (0.7mL), and sodium cyanide (0.245g, 0.5mmol) was stirred overnight and purified by column chromatography to give the title compound in 48% yield (0.057 g). Melting point 179-.¹H NMR(300MHz，CDCl₃)δ 8.81，8.59，8.12，7.78-7.50，7.37，7.21-7.13，6.93，4.83，4.17-3.66，3.37。13C NMR(75MHz，CDCl3)(167.6，163.3，160.0，156.5，149.0，145.3，137.0，134.2，132.4，129.5，127.2，122.5，121.9，112.3，46.4，44.6，44.4，41.3。MS(ES+)m/z 471(M+1)。

Example 30.1

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-benzo [1, 3] dioxol-5-yl-ethyl) amide

Following the procedure of example 30, based only on the use of 2-benzo [1, 3]]The desired change in dioxol-5-ylethylamine to replace pyridin-2-ylmethylamine gave the title compound as a white powder (99%). Melting point 162-.¹H NMR(300MHz，CDCl₃)δ 8.02，7.89，7.72，7.64-7.51，7.34，6.97，6.72-6.63，5.89，4.10-3.63，3.34-3.31，2.81。¹³C NMR(75MHz，CDCl₃)δ 167.6，163，159.9，147.7，146.1，145.2，134.2，132.4，132.3，129.5，127.2，127.1，126.9，126.8，126.7，121.6，112.4，109.0，108.4，100.8，46.3，44.5，44.4，41.2，40.8，35.5。MS(ES+)m/z 528.2(M+1)。

Example 31

Synthesis of 6- [4- (2-trifluoromethylsulfanylbenzoyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (2-cyclopropylethyl) amide

A. A mixture of tert-butyl 4- (2-trifluoromethylbenzoyl) piperazine-1-carboxylate (3.58g, 10.0mmol) and Lawesson's reagent (2.12g, 5.2mmol) in toluene was heated to reflux for 4 hours and then concentrated. The residue was purified by flash column chromatography to give tert-butyl 4- (2-trifluoromethylsulfanylbenzoyl) piperazine-1-carboxylate (2.87g, 76%). ¹H NMR(300MHz，CDCl₃)δ 7.64，7.54，7.42，7.21，4.53-4.45，4.27-4.19，3.71-3.25，1.42。

B. A solution of tert-butyl 4- (2-trifluoromethylsulfanylbenzoyl) piperazine-1-carboxylate (2.1g, 5.61mmol) in dichloromethane and trifluoroacetic acid (30mL, 2: 1) was stirred overnight at ambient temperature and the solvent was removed by evaporation. The residue was dissolved in ethyl acetate and taken up with saturated NaHCO₃Aqueous solutionAnd washed with brine and anhydrous Na₂SO₄Drying and concentration gave piperazin-1-yl- (2-trifluoromethylphenyl) thione (1.47g, 5.36mmol), which was used directly in the next reaction without further purification.

C. Piperazin-1-yl- (2-trifluoromethylphenyl) thione (1.1g, 4.0mmol), 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl) amide (0.98g, 3.98mmol), K₂CO₃(0.83g, 6.0mmol) and n-Bu₄A mixture of NI (0.010g) in dioxane (10mL) was heated to reflux for 21 h and then concentrated. The residue was purified by column chromatography and recrystallized from ethyl acetate and hexane to give the title compound in 76% yield (1.42 g). Melting point 117-.¹H NMR(300MHz，CDCl₃)δ 8.05-7.93，7.65，7.55，7.44，7.24，6.98，4.61-4.40，3.98-3.40，1.51-1.47，0.73-0.64，0.44-0.35，0.07-0.01。13C NMR(75MHz，CDCl3)(197.0，162.8，159.6，145.6，140.2，132.4，128.8，127.2，127.0，126.9，125.5，124.8，124.4，124.0，121.8，112.5，50.4，47.6，44.2，43.6，40.0，39.6，34.4，8.6，4.2。MS(ES+)m/z 464.0(M+1)。

Example 32

By the above synthesis method, the following compounds were synthesized:

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-phenoxyethyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [3- (4-fluorophenyl) propyl ] amide;

1- [1- (4-fluorophenyl) ethyl ] -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea;

1- [3- (4-fluorophenyl) propyl ] -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } urea;

3-cyclopentyl-N- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-yl } propionamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid phenethylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-trifluoromethylpyridin-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-carbamoylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-carbamoylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid m-tolylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid p-tolylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid o-tolylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-propylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazine-3-carboxylic acid (4-propylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-isopropylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-isopropylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyano-3-fluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 4-dimethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 5-dimethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 6-dimethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 3-dimethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3, 5-dimethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3, 4-dimethyl-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-ethyl-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-ethyl-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-fluoro-2-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-fluoro-4-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-fluoro-2-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-fluoro-5-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-fluoro-5-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-fluoro-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-fluoro-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-fluoro-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 4-difluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 5-difluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3, 4-difluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 3-difluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 6-difluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (7H-purin-6-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carboxylic acid piperazin-2-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid indolin-1-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (1H-tetrazol-5-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2H- [1, 2, 4] triazol-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methyl-isoxazol-5-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-methyl-isoxazol-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (1H-pyrazol-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-methyl-1H-pyrazol-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid pyrimidin-2-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carboxylic acid piperazin-2-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-methyl-pyrimidin-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-oxo-2, 3-dihydropyrimidin-4-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (6-oxo-1, 6-dihydropyrimidin-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-oxo-1, 3-diazabicyclo [3.1.0] hex-3-en-4-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-oxo-4, 5-dihydro-1H-pyrazol-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid [1, 3, 4] thiadiazol-2-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carboxylic acid thiazol-2-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid indolin-5-ylamide;

6- [4- (2-trifluoromethyl-benzoyl) piperazin-1-yl ] pyridazin-3-carboxylic acid pyridin-2-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carboxylic acid pyridin-3-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carboxylic acid pyridin-4-ylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (6-oxo-1, 6-dihydro [1, 3, 5] triazin-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-fluoro-pyridin-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-cyano-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-cyano-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-cyano-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-cyano-pyridin-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4, 6-dimethylpyrimidin-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-pyridin-4-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (1H-indol-6-yl) -amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (1H-indol-4-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (1H-indazol-5-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (1H-indazol-6-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-methyl-thiazol-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-methyl-thiazol-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-thioxo-4, 5-dihydro-1H- [1, 2, 4] triazol-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (1H-benzimidazol-2-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (6-methylpyridazin-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (6-methoxypyridazin-3-yl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-chloro-phenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-chloro-2-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-3-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 5-dichlorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-5-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-6-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-chloro-2-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-chloro-3-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-chloro-4-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-4-methylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-5-fluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-chloro-2-fluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 5-difluorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 6-dichlorophenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-trifluoromethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (4-trifluoromethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazine-3-carboxylic acid (3-trifluoromethylphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid phenylamide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (5-chloro-2-methoxyphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2, 5-dimethoxyphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-chloro-4-methoxyphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) -piperazin-1-yl ] pyridazine-3-carboxylic acid (4-methoxyphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (2-methoxyphenyl) amide;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3-methoxyphenyl) amide;

4- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carbonyl } amino) -benzoic acid methyl ester;

4- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carbonyl } amino) -benzoic acid;

2- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carbonyl } amino) -benzoic acid methyl ester;

2- ({6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazin-3-carbonyl } amino) -benzoic acid;

6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] pyridazine-3-carboxylic acid (3, 4-dichlorophenyl) amide;

1- [1- (4-fluorophenyl) ethyl ] -3- {6- [4- (2-trifluoromethylbenzoyl) piperazin-1-yl ] -pyridazin-3-yl } urea.

Example 33

Measurement of stearoyl-coenzyme A of test Compounds Using mouse liver microsomes

Desaturase inhibitory Activity

The identification of the compounds of the present invention as inhibitors of SCD is readily accomplished using the SCD enzyme and microsomal assay described in Brownlie et al, PCT published patent application WO 01/62954.

Preparation of mouse liver microsomes:

male ICR mice fed a high carbohydrate, low fat diet were sacrificed by exsanguination under anesthesia with desflurane (15% in mineral oil) during the highly enzymatic active phase. The livers were immediately rinsed with cold 0.9% NaCl solution, weighed, and minced with scissors. All manipulations were carried out at 4 ℃ unless otherwise stated. Using a 4-paddle (Strokes) Potter-Elvehjem tissue homogenizer containing 0.25M sucrose, 62MM Potassium phosphate buffer (pH 7.0), 0.15MKCl, 1.5mM N-acetylcysteine, 5mM MgCl₂And 0.1mM EDTA (1: 3 w/v) to homogenize the liver. The homogenate was centrifuged at 10,400 Xg for 20 minutes to remove mitochondria and cellular debris. The supernatant was filtered through a three-layer cheesecloth and centrifuged at 105,000 Xg for 60 minutes. The microsomal pellet was gently resuspended in the same homogenizer solution using a small glass/teflon homogenizer and stored at-70 ℃. Enzymes assess the absence of mitochondrial contaminants. Protein concentration was measured using bovine serum albumin as a standard.

Mouse liver microsomes incubated with test compounds：

2mg of microsomal protein was added to a solution of 0.20. mu. Ci of a substrate fatty acid (1-¹⁴Cpalmitate) containing 42mM NaF, 0.33mM nicotinamide, 1.6mM ATP, 1.0mM NADH, 0.1mM coenzyme a and 10 μ M concentration of test compound. After vortexing the tube vigorously and incubating in a shaking water bath (37 ℃) for 15 minutes, the reaction was stopped and the fatty acids were analyzed.

Fatty acids were analyzed as follows: saponifying the reaction mixture with 10% KOH to obtain free fatty acids, and reacting with BF₃The free fatty acids are further methylated by the methanol solution of (a). Fatty acid methyl esters were analyzed by High Performance Liquid Chromatography (HPLC) using hewlett packard 1090, Series II chromatograph equipped with diode array detector set at 205 nm, radioisotope detector with solid scintillation vial (model 171, Beckman, CA) (for¹⁴C-assay 97% efficiency) and reversed phase ODS (C-18) Beckman column (250mm x 4.6mm i.d.; particle size of 5 μm). The fatty acid methyl esters were separated with acetonitrile/water (95: 5 v: v) at a flow rate of 1mL/min without a gradient and identified by comparison to a real standard. Alternatively, fatty acid methyl esters can be analyzed by capillary column Gas Chromatography (GC) or Thin Layer Chromatography (TLC).

Those skilled in the art are aware of variations on this assay that can be used to determine the inhibitory effect of test compounds on microsomal stearoyl-coa desaturase activity.

When tested in this assay, typical compounds of the invention show activity as SCD inhibitors. This activity is defined as the% SCD enzyme activity remaining at the desired concentration of test compound.

*****

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application data sheet, are incorporated herein by reference, in their entirety.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims (15)

1. A method of inhibiting the activity of human stearoyl-CoA desaturase (hSCD) comprising contacting a source of hSCD with a compound of formula (Ia), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a prodrug thereof

Wherein:

x and y are each independently 1, 2 or 3;

w is a direct bond, -C (O) N (R)¹)-、-C(O)N[C(O)R^1a]-、-N(R¹)C(O)N(R¹)-、-N(R¹)C(O)-、-OC(O)N(R¹)-、-N(R¹)S(O)_p- (wherein p is 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (O) -, -OS (O)₂N(R¹)-、-OC(O)-、-C(O)O-、-N(R¹)C(O)O-、-N(R¹)C(＝NR^1a)N(R¹)-、-N(R¹)C(＝S)N(R¹)-、-N(R¹)C(＝NR^1a) -or-C (═ NR)^1a)N(R¹)-；

V is-C (O) -, -C (O) O-, -C (S) -, -C (O) N (R)¹)-、-S(O)_t- (where t is 0, 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (R)¹⁰) H-or-C (═ NR)^1a)-；

Each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R^1aselected from hydrogen, -OR¹Cyano, C₁-C₆Alkyl and cycloalkylalkyl;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein of the rings Some or all may be fused to each other;

R³is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R³Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R⁴and R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

R¹⁰is hydrogen or C₁-C₃An alkyl group; and is

Each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

2. A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (Ia), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a prodrug thereof,

Wherein:

x and y are each independently 1, 2 or 3;

w is a direct bond, -C (O) N (R)¹)-、-C(O)N[C(O)R^1a]-、-N(R¹)C(O)N(R¹)-、-N(R¹)C(O)-、-OC(O)N(R¹)-、-N(R¹)S(O)_p- (wherein p is 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (O) -, -OS (O)₂N(R¹)-、-OC(O)-、-C(O)O-、-N(R¹)C(O)O-、-N(R¹)C(＝NR^1a)N(R¹)-、-N(R¹)C(＝S)N(R¹)-、-N(R¹)C(＝NR^1a) -or-C (═ NR)^1a)N(R¹)-；

V is-C (O) -, -C (O) O-, -C (S) -, -C (O) N (R)¹)-、-S(O)_t- (where t is 0, 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (R)¹⁰) H-or-C (═ NR)^1a)-；

Each R¹Independently selected from hydrogen; optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethylC substituted by a substituent of a radical₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R^1aselected from hydrogen, -OR¹Cyano, C₁-C₆Alkyl and cycloalkylalkyl;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R³is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C ₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R³Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R⁴and R⁵Each independently selected from hydrogen, fluorine, chlorine, methyl and methylOxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

R¹⁰is hydrogen or C₁-C₃An alkyl group; and is

Each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

3. The method of claim 2, wherein the mammal is a human.

4. The method of claim 3, wherein the disease or condition is selected from the group consisting of type II diabetes, impaired glucose tolerance, insulin resistance, obesity, fatty liver, non-alcoholic steatohepatitis, dyslipidemia and metabolic syndrome and any combination of these.

5. The method of claim 4, wherein the disease or condition is type II diabetes.

6. The method of claim 4, wherein the disease or condition is obesity.

7. The method of claim 4, wherein the disease or condition is metabolic syndrome.

8. The method of claim 4, wherein the disease or condition is fatty liver.

9. The method of claim 4, wherein the disease or condition is non-alcoholic steatohepatitis.

10. A compound of formula (Ia), a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof,

wherein:

x and y are each independently 1, 2 or 3;

w is a direct bond, -C (O) N (R)¹)-、-C(O)N[C(O)R^1a]-、-N(R¹)C(O)N(R¹)-、-N(R¹)C(O)-、-OC(O)N(R¹)-、-N(R¹)S(O)_p- (wherein p is 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (O) -, -OS (O)₂N(R¹)-、-OC(O)-、-C(O)O-、-N(R¹)C(O)O-、-N(R¹)C(＝NR^1a)N(R¹)-、-N(R¹)C(＝S)N(R¹)-、-N(R¹)C(＝NR^1a) -or-C (═ NR)^1a)N(R¹)-；

V is-C (O) -, -C (O) O-, -C (S) -, -C (O) N (R)¹)-、-S(O)_t- (it)Wherein t is 0, 1 or 2), -S (O)_pN(R¹) - (wherein p is 1 or 2), -C (R)¹⁰) H-or-C (═ NR)^1a)-；

Each R¹Independently selected from hydrogen; c optionally substituted by one or more substituents selected from halogen, methyl or trifluoromethyl₁-C₆An alkyl group; and C optionally substituted with one or more substituents selected from methoxy and hydroxy₂-C₆An alkyl group;

R^1aselected from hydrogen, -OR¹Cyano, C ₁-C₆Alkyl and cycloalkylalkyl;

R²is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R²Is a polycyclic structure having 2 to 4 rings, wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl and wherein some or all of the rings may be fused to each other;

R³is selected from C₁-C₁₂Alkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Hydroxyalkyl radical, C₂-C₁₂Hydroxyalkenyl, C₁-C₁₂Alkoxy radical, C₂-C₁₂Alkoxyalkyl group, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkyl alkyl, aryl, C₇-C₁₂Aralkyl radical, C₃-C₁₂Heterocyclic group, C₃-C₁₂Heterocyclylalkyl radical, C₁-C₁₂Heteroaryl and C₃-C₁₂A heteroaralkyl group;

or R³Is a polycyclic ring having 2 to 4 ringsWherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl and wherein some or all of the rings may be fused to each other;

R⁴and R⁵Each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or-N (R)¹²)₂；

R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶And R^6aTogether, or R⁷And R^7aTogether, or R⁸And R^8aTogether, or R ⁹And R^9aTogether are an oxo group, with the proviso that when V is-C (O) -, R⁷And R^7aTogether or R⁸And R^8aTogether do not form an oxo group, and the remaining R⁶、R^6aR⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

or R⁶、R^6a、R⁷And R^7aOne and R⁸、R^8a、R⁹And R^9aOne together forms an alkylene bridge and the remaining R⁶、R^6a、R⁷、R^7a、R⁸、R^8a、R⁹And R^9aEach independently selected from hydrogen or C₁-C₃An alkyl group;

R¹⁰is hydrogen or C₁-C₃An alkyl group; and is

Each R¹²Independently selected from hydrogen or C₁-C₆An alkyl group.

11. The compound of claim 10, wherein W is-N (R)¹) C (o) -and V is-C (═ NH) -.

12. The compound of claim 10, whereinW is-N (R)¹)C(＝NR^1a)-。

13. The compound of claim 10, wherein W is-N (R)¹)C(＝NR^1a)N(R¹) -or-N (R)¹)C(＝S)N(R¹)-。

14. A method of treating a disease or condition mediated by stearoyl-coa desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 10.

15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 10.