EA049140B1 - SUBSTITUTED CONDENSED HETEROAROMATIC BICYCLIC COMPOUNDS AS KINASE INHIBITORS AND THEIR APPLICATION - Google Patents

Abstract

The present invention provides novel substituted fused heteroaromatic compounds represented by Formula I, wherein Ai-A6 and R1-R4 are as defined herein. The compounds of Formula I are kinase inhibitors, particularly ATR kinase inhibitors. The compounds of the invention can therefore be used to treat ATR-mediated diseases, disorders, and conditions, such as cancer.

Description

Field of technology

The present invention relates to the field of medicinal chemistry. In particular, the invention relates to substituted condensed heteroaromatic bicyclic compounds and the use of these compounds as therapeutically effective kinase inhibitors and anticancer drugs.

Prior art

Ataxia-telangiectasia and Rad3-related kinase (ATR) is a protein kinase that acts in cells involved in DNA damage. Activated ATR can regulate the cell life process through various signals, including cell cycle interruption, inhibition of replication origin, replication fork initiation, DNA double strand repair, etc. (Enriquez-Rios V, et al., 2017). ATR kinase regulates the cellular response to DNA damage, which is commonly called the DNA damage response (DDR), by acting together with ATM (ataxia-telangiectasia-mutated) kinase and many other proteins. When a cell recognizes DNA damage through DDR, it will immediately initiate the DNA repair process, activate the cell cycle checkpoint, and interfere with the normal cell cycle process, thereby providing the time needed for DNA repair. Without the DDR mechanism, cells are more sensitive to endogenous cell damage or DNA damage caused by chemotherapy and radiation therapy in the case of cancer treatment, and are more likely to die.

Healthy cells can rely on various proteins required for DNA repair, including ATM, ATR kinase in the DDR, and so on. Under normal conditions, these proteins can repair DNA by regulating downstream regulatory factors. However, many cancer cells have defects in the DNA repair pathway, so they rely heavily on intact DNA repair proteins, including ATR. ATR is a key member of the DDR that responds to the replication of damaged DNA, and its presence is important for maintaining genomic stability and integrity and enhancing cell viability. When DNA damage occurs within a cell, ATR is recruited to the site of DNA damage, which in turn leads to the involvement of various proteins in regulating ATR activation. Activated ATR regulates several important cellular processes. Many cancer cells lack key tumor suppressor genes, which may account for the greater reliance of cancer cells on the ATR-mediated pathway compared to normal cells to regulate DNA damage repair and improve cell viability, making ATR a promising target for cancer treatment.

ATR inhibitors can be used alone or in combination with DNA-damaging agents to treat cancer because they block the DNA replication machinery, which is more important for cell viability in many cancer cells than in healthy normal cells. Indeed, ATR inhibitors have been shown to be effective as single active agents in cancer cells and as sensitizers for radiotherapy and chemotherapy. However, ATR inhibitors can also be used in combination with other DDR-related targeted drugs, such as PARP (poly(ADP-ribose) polymerase) inhibitors.

Various ATR kinase inhibitors have been described. For example, WO2011154737 discloses morpholinopyrimidine compounds as ATR kinase inhibitors; WO2016020320 discloses 2(morpholin-4-yl)-1,7-naphthyridine compounds as ATR kinase inhibitors; WO2018153968 discloses an ATR kinase inhibitor for use in a method of treating a hyperproliferative disorder; WO2020049017 discloses 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives as ATR kinase inhibitors; and WO2020087170 discloses morpholino-containing 5-membered heterocyclic fused pyridine compounds as ATR kinase inhibitors.

Brief summary of the invention

According to the present invention, there are provided a substituted condensed heteroaromatic bicyclic compound represented by formula I

R ₂

I, or its stereoisomer, tautomer, isotopically substituted derivative, or pharmaceutically acceptable salt, where:

R ₁ is sulfonyl substituted with C ₁ -C ₄ alkyl, or pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1 or 2 substituents selected from the group consisting of

- 1 049140

C ₁ -C ₄ alkyl, halogen, hydroxyl, C1-C ₄ alkoxy and amino;

R2 is C3-C6cycloalkyl, a heterocyclic group, C6- _C14aryl or heteroaryl, wherein each of said C3-C6cycloalkyl, heterocyclic group, C6- _C14aryl and heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of N-N-alkyl optionally substituted with 1-5 halogens, cyano, halogen, C1- _{C4alkylsulfinyl} and C1- _{C4alkylsulfonyl} ;

R ₃ and R4 independently represent hydrogen or ^-^alkyl;

wherein the heterocyclic group is a saturated or partially saturated 3-7 membered monocyclic or 7-10 membered bicyclic ring system that consists of carbon atoms and one to four heteroatoms independently selected from O, N and S;

wherein heteroaryl is a group having 5-14 ring atoms consisting of carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein 6, 10 or 14 π-electrons are shared in the cyclic structure;

where the penta-fused hexa-heteroaryl containing A ₁ , A2, A ₃ , A4, A ₅ and A6 is:

where *1, *2 and *3 denote the points of attachment of this group to morpholinyl, R1 and R2 in this compound, respectively;

wherein the isotopically substituted derivative is a derivative in which at least one atom is replaced by an atom having the same atomic number, but its atomic mass differs from the atomic mass most often found in nature, which is ^selected from ^2H , ^3H , 11C, ^13C , ^14C , ^15N , ^17O , ^18O , ^35S , ^18F , ^36Cl and ^125I , which can be used as kinase inhibitors.

The compounds of the invention are preferably a compound of formula II, IIIa or IIIb:

R ₂

P,

_{R2r2 ​}

Sha IIIb, or a stereoisomer, tautomer, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, wherein the penta-fused hexa-heteroaryl containing A ₁ -A ₆ , R 1 , R 2 and R 4 are as defined above.

Preferably, in the compounds of the invention, R2 is optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl or optionally substituted pyrrolopyridyl; wherein the substituent on _R2 is selected from the group consisting of C1-C4 alkyl, halogen and _C1 - _C4 alkylsulfonyl; and/or

R4 is C ₁ -C ₄ alkyl.

Preferably, in the compounds of the invention, the penta-fused hexa-heteroaryl containing A ₁ -A ₆ is

- 2 049140

R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C1- _C4 alkyl; _R2 is heteroaryl optionally substituted with one or two C1- _C4 alkyl, _C6 - _C14 aryl optionally substituted with 1-2 substituents selected from the group consisting of C1- _C4 alkylsulfonyl and halogen, or a heterocyclic group optionally substituted with one or two C1- _C4 alkyl; one of R3 and _R4 is H and the other is C1- _C4 alkyl;

or penta-fused hexa-heteroaryl containing A ₁ -A ₆ is

R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C1- _C4 alkyl; R2 is heteroaryl optionally substituted with one or two substituents selected from the group consisting of halogen, C1- _C4 alkylsulfonyl, C1- _C4 alkylsulfinyl, C1- _C4 alkyl optionally substituted with one to three halogen atoms, _C6 - _C14 aryl optionally substituted with 1-2 substituents selected from the group consisting of C1- _C4 alkyl, -CN, C1- _C4 alkylsulfonyl and halogen, or a heterocyclic group optionally substituted with one or two C1- _C4 alkyl; R3 and _R4 are independently selected from the group consisting of H and C1- _C4 alkyl; or a penta-fused hexa

heteroaryl containing A ₁ -A ₆ is

R1 is pyrazolyl optionally substituted with C1- _C3 alkyl; R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1- _C4 alkyl substituted with one to three halogen atoms; R3 and _R4 are independently selected from the group consisting of H and C1- _C4 alkyl.

More preferably, in the compounds of the invention, the penta-fused hexa-heteroaryl,

containing A ₁ -A ₆ , is

R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C1- _C4 alkyl; R2 is pyrazolyl, pyridinyl, pyrrolopyridinyl or imidazolyl optionally substituted with one or two C1- _C4 alkyl, phenyl optionally substituted with 1-2 substituents selected from the group consisting of C1- _C4 alkylsulfonyl and halogen, or morpholinyl optionally substituted with one or two _C1 - _C4 alkyl; one of R3 and _R4 is H, the other is _C1 - _C4 alkyl; or penta-fused hexa-heteroaryl containing _A1 - _A6 is

by yourself

R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C1- _C4 alkyl; R2 is pyrazolyl, pyrrolyl, pyridinyl, pyrrolopyridinyl, pyrimidinyl, triazolyl or imidazolyl optionally substituted with one or two substituents selected from the group consisting of halogen, C1- _C4 alkylsulfonyl, C1- _C4 alkylsulfinyl, C1- _C4 alkyl optionally substituted with one to three halogen atoms, phenyl optionally substituted with 1-2 substituents selected from the group consisting of C1- _C4 alkyl, -CN, C1- _C4 alkylsulfonyl and halogen, or morpholinyl, dihydropyranyl or tetrahydropyranyl optionally substituted with one or two C1- _C4 alkyl; R3 and _R4 are independently selected from the group consisting of H and C1- _C4 alkyl; or penta-fused hexa

heteroaryl containing A ₁ -A ₆ is

R1 is pyrazolyl optionally substituted with C1- _C3 alkyl; R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1- _C4 alkyl substituted with one to three halogen atoms; R3 and _R4 are independently selected from the group consisting of H and C1- _C4 alkyl.

- 3 049140

A preferred compound of the invention is selected from the group consisting of:

(R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imide azo[1,2L]pyridazin-6-yl)morpholine;

^)-3-methyl-4-(8-(1-ethyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine;

(R)-3 -methyl-4-(8-( 1 -isopropyl-1 H-pyrazol-5 -yl)-3 -(1 H-pyrazol-5 yl)imidazo[1,2-b]pyridazin-6-yl)morpholine;

(R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine;

^)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine;

^)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine;

^)-3-methyl-4-(8-(2-fluorophenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6·yl)morpholine;

^)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine;

(2S,6R)-2,6-dimethyl-4-(6-((R)-3-methylmorpholine)-3-(lH-pyrazol-5yl)imidazo[1,2-b]pyridazin-8-yl)morpholine;

- 4 049140

4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1 H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2·yl)morpholine;

4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3b]pyridazin-6-yl)morpholine;

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine;

^)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine;

(R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5a]pyrimidin-5-yl)morpholine;

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5L]pyridazin-2-yl)morpholine;

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-2-yl)imidazo[1,5L]pyridazin-2-yl)morpholine;

(R)-4-(7-(1 H-imidazol-4-yl)-4-(1-methyl-1 H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine;

(R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine;

^)-4-(4-(2-fluorophenyl)-7-(1 H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3 methylmorpholine;

^)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine;

(R)-4-(4,7-n and (1 H-pyrazol-5-yl)imidazole[1,5-b]pyridazin-2-yl)-3 methylmorpholine;

^)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5a]pyrimidin-2-yl)morpholine;

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-3-yl)imide azo[5,1 f][1,2,4]triazin-2-yl)morpholine;

^)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine;

(8)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)morpholine;

- 5 049140 (3R, 5R)-3,5-dimethyl-4-(4-( 1 -methyl-1 H-pyrazol-5 -yl)-7-( 1 H-pyrazol-5 yl)imidazo[1,5-b]pyridazin-2-yl)morpholine;

(R)-3-methyl-4-(4-(4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine;

(R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imide azo[1,5b]pyridazin-2-yl)-3-methylmorpholine;

(R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazine·2-yl)-3-methylmorpholine;

(R)-3-methyl-4-(4-(3-methyl-1 H-pyrazol-4-yl)-7-(1 H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine;

(R)-3-methyl-4-(7-(3-methyl-1H-pyrazol-5-yl)-4-(6-methylpyridin-3yl)imidazo[1,5-b]pyridazin-2-yl)morpholine;

(R)-4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3 methylmorpholine;

^)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine;

(R)-3-methyl-4-(4-(2-methyl pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 b]pyridazin-2-yl)morpholine;

(R)-4-(4-(3-fluoropyridopyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)-3-methylmorpholine;

(R)-3-methyl-4-(4-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine;

(R)-3-methyl-4-(4-(4-methyl pyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine;

^)-3-methyl-4-(4-morpholino-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine;

(R)-4-(7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine;

(R)-3-methyl-4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine;

^)-3-methyl-4-(4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5yl)imidazo[1,5-b]pyridazin-2-yl)morpholine;

- 6 049140 (ЗК)-3-methyl-4-(4-(2-methyl-6-(methylsulfinyl)pyridin-3-yl)-7-(1H-pyrazol-5yl)imidazo[1,5-Ь]pyridazin-2-yl)morpholine;

(R)-3-methyl-4-(4-(3-methylpyridin-4-yl)-7-(1H-pyrazol-5-yl)imide azo[1,5b]pyridazin-2-yl)morpholine;

(R)-3 -(2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imide azo[1,5-b]pyride azin-4yl)benzonitrile;

(R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine;

(R)-4-(7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine;

^)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine;

(R)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)-3-methylmorpholine;

(R)-3-methyl-4-(4-(1-methyl-1H-imidazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine;

(R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)-3-methylmorpholine;

(R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine;

(R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine;

(R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine;

or its stereoisomer, tautomer, isotopically substituted derivative, or pharmaceutically acceptable salt.

According to the invention, there is also provided the use of a compound of the invention or a stereoisomer, tautomer, isotopically substituted derivative, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an ATR (ataxia telangiectasia and Rad3-related) kinase-mediated disease. Preferably, the ATR kinase-mediated disease is a cancer selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small cell lung carcinoma, gastric carcinoma, colon carcinoma, malignant insulinoma of the pancreas, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, carcinoma of the head and neck, osteosarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tract carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostate carcinoma.

According to the invention, a pharmaceutical composition is also provided, comprising a compound of formula I and a pharmaceutically acceptable carrier. A preferred pharmaceutical composition further comprises at least one known anticancer drug or pharmaceutically acceptable salts thereof selected from the group consisting of: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platinum, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, ara-C,

- 7 049140 pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, nivolumab, pembrolizumab, TDM1, olaparib, niraparib, rucaparib, talazoparib and senaparib.

Detailed description of the invention

It should be understood that the characteristics of the embodiments described in the present invention can be arbitrarily grouped to achieve the technical solution of the present invention. The definition of each group mentioned in this description can be used with respect to any of the embodiments described in the present invention. For example, the definitions of alkyl substituents in this description are applicable to any of the embodiments described in the present invention if the alkyl substituents are not clearly defined in this embodiment.

Specifically, the present invention provides compounds represented by formula I:

R ₂

I or their stereoisomers, tautomers, isotopically substituted derivatives, or pharmaceutically acceptable salts, where:

R ₁ is sulfonyl substituted with C1-C ₄ alkyl, or pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C ₄ alkyl, halogen, hydroxyl, C1-C ₄ alkoxy and amino;

_R2 is C3-C6cycloalkyl, heterocyclic group, C6- _C14aryl or heteroaryl, wherein each of said C3-C6cycloalkyl, heterocyclic group, C6- _C14aryl and heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of C-C2alkyl optionally substituted with 1-5 halogens, cyano, halogen, C1- _{C4alkylsulfinyl} and C1- _{C4alkylsulfonyl} ;

R3 and R4 independently represent hydrogen or Q-C^alkyl;

wherein the heterocyclic group is a saturated or partially saturated 3-7 membered monocyclic or 7-10 membered bicyclic ring system that consists of carbon atoms and one to four heteroatoms independently selected from O, N and S;

wherein heteroaryl is a group having 5-14 ring atoms consisting of carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein 6, 10 or 14 π-electrons are shared in the cyclic structure;

where the penta-fused hexa-heteroaryl containing A1, A2, _A3 , A4, _A5 and _A6 is:

*3 , *3 , *3 OR *3 where *1, *2 and *3 denote the points of attachment of this group to the morpholinyl, R1 and R2 in this compound, respectively;

wherein the isotopically substituted derivative is a derivative in which at least one atom is replaced by an atom having the same atomic number, but its atomic mass is different from the atomic mass most commonly found in nature, which is selected from ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ^{15 N, 17 O} , ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I.

In one or more of the above embodiments of the compound of formula I, three of A ₁ -A ₆ are N.

Preferably, in some embodiments, A ₂ in the compound of formula I is N and A ₃ is C.

Preferably, in some embodiments, A ₅ is N.

In one or more of the above embodiments of the compounds of formula I, at least A1, _A2 and _A5 are N.

Preferably, in some embodiments, the penta-fused hexa-heteroaryl containing A ₂ and A ₃ is:

*3 , *3 OR *3

- 8 049140 where *1, *2 and *3 denote the points of attachment of this group to morpholinyl, R1 and _R2 in the compound of formula I, respectively.

In one or more of the above embodiments of the compound of formula I, the heteroaryl in _R2 is a 5- or 6-membered heteroaryl containing at least one nitrogen atom; preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, R2 is optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl, optionally substituted pyridyl, optionally substituted pyrimidinyl or optionally substituted pyrrolopyridyl.

In one or more of the above embodiments of the compound of formula IR ₃ is hydrogen; R4 is C1- _C4 alkyl, such as methyl. Preferably, R ₃ is in the R-configuration.

In some embodiments of the compound of Formula I, R1 is unsubstituted pyrazolyl, unsubstituted pyrrolyl, or unsubstituted imidazolyl.

In one or more of the above embodiments of the compound of formula I, the isotopically substituted derivative of the compound of formula I is a compound in which one or more hydrogen atoms are replaced by one or more D atoms.

One group of preferred compounds of the present invention are represented by compounds of formula II:

Ё2

II, or their stereoisomers, tautomers, isotopically substituted derivatives, or pharmaceutically acceptable salts, where:

A1-A6, R1, R2 and R4 are as defined in formula I.

Preferably, in some embodiments, Ar in the compound of formula II is N, A ₃ is C.

Preferably, in some embodiments, A ₅ is N.

Preferably, in some embodiments, the penta-fused hexa-heteroaryl containing A ₂ and A ₃ is:

z , z or z where *1, *2 and *3 denote the places of attachment of the given group to morpholinyl, R1 and R2 in the compound of formula II, respectively.

In one or more of the above embodiments of the compound of formula II, the heteroaryl in R2 is a 5- or 6-membered heteroaryl containing at least one nitrogen atom; preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, R2 is optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl or optionally substituted pyrrolopyridyl. In some embodiments, R2 is pyrazolyl optionally substituted with 1, 2 or 3 N-C2-alkyl groups; preferably, one or two N atoms of pyrazolyl are substituted with C-C alkyl; preferably, C-C ₆ alkyl may be further substituted with 1 to 5 halogens. In some embodiments, R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1-C ₄ alkyl and C1-C ₄ alkyl substituted with 1 to 3 halogens.

In one or more of the above embodiments of the compound of formula II, R ₄ is C1-C ₄ alkyl, such as methyl. Preferably, R4 is in the R-configuration.

In some embodiments of the compound of formula II, R1 is unsubstituted pyrazolyl, unsubstituted pyrrolyl, or unsubstituted imidazolyl.

One group of preferred compounds of the present invention is represented by compounds of formulas IIIa and IIIb:

- 9 049140

or their stereoisomers, tautomers, isotopically substituted derivatives, or pharmaceutically acceptable salts, wherein A1, A4, A5, A6, R1, R2 and _R4 are as defined in formula I or II.

Preferably, in some embodiments, A5 is N.

Preferably, in some embodiments, A ₆ is CH.

Preferably, in some embodiments, the penta-fused hexa-heteroaryl containing A1, A4, A5 and _A6 is:

where *1, *2 and *3 denote the points of attachment of the given group to the morpholinyl, R1 and R2 in the compound of formula IIIa or IIIb, respectively.

In some embodiments of compounds of formulas IIIa and IIIb, R1 is unsubstituted pyrazolyl, unsubstituted pyrrolyl, or unsubstituted imidazolyl.

In one or more of the above embodiments of the compounds of formulae IIIa and IIIb, the heteroaryl in R2 is a 5- or 6-membered heteroaryl containing at least one nitrogen atom; preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, R2 is optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl or optionally substituted pyrrolopyridyl. In some embodiments, _R2 is pyrazolyl optionally substituted with optionally substituted C1- _C6 alkyl, and preferably one or two ring N atoms of the pyrazolyl are substituted; preferably, C1- _C6 alkyl may be further substituted with 1-5 halogens. In some embodiments, R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1- _C4 alkyl substituted with 1-3 halogens.

In one or more of the above embodiments of the compounds of formulae IIIa and IIIb, R ₄ is C ₁ -C ₄ alkyl, such as methyl.

One group of preferred compounds of the present invention are represented by compounds of formula IV:

or their stereoisomers, tautomers, isotopically substituted derivatives, or pharmaceutically acceptable salts, where:

A ₄ , A5 , A ₆ , R1 , R2 and R4 are as defined in formula I, II or IIIa or IIIb.

Preferably, in some embodiments, A ₅ is N.

Preferably, in some embodiments, A ₆ is CH.

Preferably, in some embodiments, the penta-fused hexa-heteroaryl containing _A4 , _A5 and _A6 is selected from the following groups:

- 10 049140 *

f * 3 OR 3 where *1, *2 and *3 denote the points of attachment of the given group to morpholinyl, R ₁ and R2 in the compound of formula IV, respectively.

In some embodiments of the compound of formula IV, R1 is unsubstituted pyrazolyl, unsubstituted pyrrolyl, or unsubstituted imidazolyl.

In one or more of the above embodiments of the compound of formula IV, the heteroaryl in R2 is a 5- or 6-membered heteroaryl containing at least one nitrogen atom; preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, R2 is optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl or optionally substituted pyrrolopyridyl. In some embodiments, R2 is pyrazolyl optionally substituted with optionally substituted _C1C6 alkyl, and preferably one or two ring N atoms of the pyrazolyl are substituted; preferably, _C1 - _C6 alkyl may be further substituted with 1-5 halogens. In some embodiments, R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1- _C4 alkyl substituted with 1-3 halogens.

In one or more of the above embodiments of the compound of formula IV, R ₄ is C ₁ -C ₄ alkyl, such as methyl.

Preferably, in some embodiments of compounds of formulas I, II, IIIa, IIIb and IV, the pentafused hexa-heteroaryl is:

*z, *z or *z preferably, R2 is optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl, optionally substituted pyridyl, optionally substituted pyrimidinyl or optionally substituted pyrrolopyridyl; more preferably, R2 is pyrazolyl optionally substituted with unsubstituted _C1 - _C6alkyl or _C1 - _C6alkyl substituted with 1-3 halogens, and preferably one or two ring N atoms of pyrazolyl are substituted;

R ₃ is H; and

R4 is C1- _C4 alkyl, preferably methyl.

In one or more preferred embodiments of the compounds of formula I, A1 is N, A2 is N, _A3 is C, A4 is CH, _A5 is CH, _A6 is N; _R1 is pyrazolyl, pyrrolyl and imidazolyl optionally substituted with 1-2 N-N-alkyls, such as pyrazolyl optionally substituted with _C1 - _C3- alkyl; R2 is heteroaryl (preferably pyrazolyl, pyridinyl, pyrrolopyridinyl and imidazolyl) optionally substituted with one or two C1- _C4 alkyl, aryl (preferably phenyl) optionally substituted with 1-2 substituents selected from the group consisting of C1- _C4 alkylsulfonyl and halogen, or a heterocyclic group (preferably morpholinyl) optionally substituted with one or two C1-C4 alkyl, such as 2,6-diC1-C4 alkyl-morpholinyl; and one of _R3 and R4 is H, the other is C1- _C4 alkyl.

In one or more preferred embodiments of the compounds of formula IA, _A1 is N, A2 is N, _A3 is C, A4 is CH, _A5 is N, _A6 is CH; _R1 is pyrazolyl, pyrrolyl and imidazolyl (more preferably pyrazolyl) optionally substituted with 1-2 C1- _C4 alkyl, such as pyrazolyl optionally substituted with _C1 - _C3 alkyl; R2 is heteroaryl (preferably pyrazolyl, pyrrolyl, pyridinyl, pyrrolopyridinyl, pyrimidinyl, triazolyl and imidazolyl) optionally substituted with one or two substituents selected from the group consisting of halogen, C1- _C4 alkylsulfonyl, C1- _C4 alkylsulfinyl, N-N-alkyl optionally substituted with one to three halogen atoms, aryl (preferably phenyl) optionally substituted with 1 to 2 substituents selected from the group consisting of C1- _C4 alkyl, -CN, C1- _C4 alkylsulfonyl and halogen, or a heterocyclic

- 11 049140 group (preferably morpholinyl, dihydropyranyl and tetrahydropyranyl), optionally substituted with one or two C1- _C4 alkyl; and R3 and R4 are independently selected from the group consisting of H and C1- _C4 alkyl.

In one or more preferred embodiments of the compounds of formula I, A1 is N, A2 is N, A3 is C, A4 is CH, A5 is N, A6 is CH; R1 is pyrazolyl optionally substituted with C1- _C3 alkyl; R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1- _C4 alkyl substituted with one to three halogen atoms; and R3 and R4 are independently selected from the group consisting of H and C1- _C4 alkyl. In other preferred embodiments, R ₂ is pyrazolyl substituted with one or two substituents selected from the group consisting of unsubstituted C1-C ₄ alkyl and C1-C ₄ alkyl substituted with one to three halogen atoms, wherein at most one of the pyrazolyl nitrogen atoms is substituted with the substituent; preferably, one pyrazolyl nitrogen atom is substituted. In other or alternative embodiments, one of R ₃ and R ₄ is H and the other is methyl.

In one or more preferred embodiments of the compounds of formula I, R1 is pyrazolyl optionally substituted with C1-C4 alkyl; R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1- _C4 alkyl substituted with one to three halogen atoms; and R3 and R4 are independently selected from the group consisting of H and C1- _C4 alkyl.

In one or more of the above embodiments, preferred compounds of formula I include, but are not limited to:

(K)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2B]pyridazin-6-yl)morpholine (Example 2);

(K)-3-methyl-4-(8-(1-ethyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine (example 3);

(R)-3 -methyl-4-(8-( 1 -isopropyl-1 H-pyrazol-5 -yl)-3 -(1 H-pyrazol-5 yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (example 4);

(R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2B]pyridazin-6-yl)morpholine (Example 5);

(R)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine (Example 6);

- 12 049140 (R)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine (example 7);

(K)-3-methyl-4-(8-(2-fluorophenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6·yl)morpholine (Example 8);

(K)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine (example 9);

(28,6K)-2,6-dimethyl-4-(6-((K)-3-methylmorpholino)-3-(1H-pyrazol-5yl)imidazo[1,2-b]pyridazin-8-yl)morpholine (example 10);

4-(4-(1-methyl-1 H-pyrazol-5-yl)-7-(1 H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine (example I);

4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3b]pyridazin-6-yl)morpholine (Example 12);

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine (Example 13);

(R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine (Example 15);

(R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5a]pyrimidin-5-yl)morpholine (Example 16);

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5L]pyridazin-2-yl)morpholine (Example 21);

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-2-yl)imidazo[1,5L]pyridazin-2-yl)morpholine (Example 22);

(R)-4-(7-(1 H-imidazol-4-yl)-4-(1-methyl-1 H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine (Example 23);

(R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine (Example 24);

^)-4-(4-(2-fluorophenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine (example 25);

^)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine (example 26);

^)-4-(4,7-di(1H-pyrazol-5-yl)imidazole[1,5-b]pyridazin-2-yl)-3methylmorpholine (example 27);

- 13 049140 (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imide azo[1,5a]pyrimidin-2-yl)morpholine (example 28);

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-3-yl)imide azo[5,1 1][1,2,4]triazin-2-yl)morpholine (Example 29);

^)-4-(4-cyclopropyl-7-(1 H-pyrazol-5-yl)imidazo[1,5 -b]pyridazin-2-yl)-3 methylmorpholine (example 32);

(S)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)morpholine (Example 33);

(3R, 5R)-3,5-dimethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 34);

(R)-3-methyl-4-(4-(4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine (Example 35);

(R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imide azo[1,5 B]pyridazin-2-yl)-3-methylmorpholine (Example 36);

(R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazine·2-yl)-3-methylmorpholine (Example 37);

(R)-3-methyl-4-(4-(3-methyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)morpholine (Example 38);

(R)-3-methyl-4-(7-(3-methyl-1H-pyrazol-5-yl)-4-(6-methylpyridin-3yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 39);

(R)-4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3 methylmorpholine (Example 40);

(R)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine (Example 41);

(R)-3-methyl-4-(4-(2-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine (Example 42);

(R)-4-(4-(3-fluoropyrimidin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)-3-methylmorpholine (Example 43);

(R)-3-methyl-4-(4-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 44);

(R)-3-methyl-4-(4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine (Example 45);

- 14 049140 (K)-3-methyl-4-(4-morpholino-7-(1H-pyrazol-5-yl)imidazo[1,5-L]pyridazin-2yl)morpholine (example 46);

(R)-4-(7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine (Example 47);

^)-3-methyl-4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (example 48);

^)-3-methyl-4-(4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (example 49);

(3R)-3-methyl-4-(4-(2-methyl-6-(methylsylphinyl)pyridin-3-yl)-7-(lH-pyrazol-5yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 50);

^)-3-methyl-4-(4-(3-methylpyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine (Example 51);

(R)-3-(2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4yl)benzonitrile (Example 52);

(R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine (Example 53);

(R)-4-(7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine (Example 54);

^)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine (Example 55);

(R)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)-3-methylmorpholine (Example 56);

(R)-3-methyl-4-(4-(1-methyl-1H-imidazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)morpholine (Example 57);

(R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5 B]pyridazin-2-yl)-3-methylmorpholine (Example 58);

(R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine (Example 60);

(R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine (Example 61);

(R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5L]pyridazin-2-yl)-3-methylmorpholine (Example 63);

or their stereoisomers, tautomers, isotopically substituted derivatives, or pharmaceutically acceptable salts.

It should be understood that in the present invention A ₁ -A ₆ are selected in such a way that the resulting ring complies with the valence bond theory.

The term hydrogen (H) used in this description includes its isotopes D and T.

The term "alkyl" as used herein refers to alkyl per se or to a straight or branched chain radical of up to and including 10 carbon atoms. Suitable alkyl groups include straight or branched C-C alkyl groups, preferably C-C alkyl groups. In some embodiments, alkyl is C1-C ₄ alkyl. Typical C-C alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups, which may optionally be substituted.

Suitable alkoxy groups include oxygen-substituted C1-C4 alkyl groups as mentioned above, preferably C1-C4 alkyl groups or C1- _C4 alkyl groups; for example, methoxy, ethoxy,

- 15 049140 si and so on. Alkyl in alkoxy groups may optionally be substituted. Substituents for alkoxy groups include, but are not limited to, halogen, morpholino, amino (including alkylamino and dialkylamino) and carboxy (including esters thereof).

Suitable amino groups and optionally substituted amino groups include -NH2, -NHR8 and _-NR8R9 , wherein each of _{R8 and R9} is independently hydrogen, optionally substituted Cj-Cu alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or _R8 and _R9 together with the N to which they are attached form an optionally substituted 4-7-membered cyclic amino group which optionally contains one or more (e.g. 2, 3) additional heteroatoms selected from O, N and S.

The term aryl, as used herein, by itself or as part of another group, refers to monocyclic, bicyclic or tricyclic aromatic groups containing 6-14 carbon atoms. Aryl may be substituted with one or more substituents described herein.

Suitable aryl groups include _C6 - _C14 aryl groups, preferably _C6 - _C10 aryl groups. Typical _C6 - _C14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulyl, biphenyl, biphenylene, and fluorenyl.

The term carbocycle (carbocyclic group) as used herein includes cycloalkyl and partially saturated carbocyclic groups. Suitable cycloalkyl groups are _C3 - _C8 cycloalkyl groups. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The carbocyclic group may be substituted with one or more substituents described herein.

Suitable partially saturated carbocyclic groups include cycloalkenyl groups such as C3-C8cycloalkenyl groups; for example, cyclopentenyl, cycloheptenyl and cyclooctenyl.

Suitable halogen atoms or halogen groups include fluorine, chlorine, bromine, and iodine.

The term heterocycle (heterocyclic group) as used herein refers to a saturated or partially saturated 3-7-membered monocyclic or 7-10-membered bicyclic ring system which consists of carbon atoms and one to four heteroatoms independently selected from O, N and S, wherein the nitrogen and/or sulfur heteroatoms may optionally be oxidized and the nitrogen may optionally be quaternized; this term also includes any bicyclic ring system in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocycle may be substituted at a carbon atom or a nitrogen atom, as long as the resulting compound is stable. The heterocyclic group may be substituted with one or more substituents described in this invention.

Suitable saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl, which may optionally be substituted with one or more substituents described herein.

The term heteroaryl (heteroaromatic ring) as used herein refers to a group having 5-14 ring atoms, wherein 6, 10 or 14 π-electrons are shared in the cyclic structure. The ring atoms are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur atoms. Heteroaryl may optionally be substituted with one or more substituents described herein.

Suitable heteroaryl groups include thienyl (thiophenyl), benzo[L]thienyl, naphtho[2,3-L]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[1,2a]pyrimidin-4-one, tetrahydrocyclopenta[c]pyrazol-3-yl, benzoisoxazolyl such as 1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl or triazolopyrazinyl. If the heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom may be in the form of an N-oxide; for example, in pyridyl-N-oxide, pyrazinyl-N-oxide, and pyrimidinyl-N-oxide.

Some of the compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers, which can be separated according to methods well known to a person of ordinary skill in the art.

- 16 049140

Examples of pharmaceutically acceptable salts include salts of inorganic and organic acids such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and salts of inorganic and organic bases formed by reaction with bases such as sodium hydroxide, tris(hydroxymethyl)aminomethane (tris, tromethamine) and N-methylglucamine.

Examples of prodrugs of the compounds of the invention include ethers of carboxylic acid-containing compounds (e.g., prepared by condensation with a C ₁ -C ₄ alcohol according to methods known in the art); esters of hydroxy-containing compounds (e.g., prepared by condensation with a C 1 -C ₄ carboxylic acid, a C 3 -C 6 acid, or an anhydride thereof such as succinic anhydride and fumaric anhydride according to methods known in the art); imines of amine-containing compounds (e.g., prepared by condensation with a C 1 -C 4 aldehyde or ketone according to methods known in the art); carbamates of amine-containing compounds such as those described by Leu, et al. (J. Med. Chem., 42:3623-3628 (1999)) and Greenwald, et al. (J. Med. Chem., 42:3657-3667 (1999)); and acetals and ketals of alcohol-containing compounds (e.g., obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

The present invention also includes all suitable isotopic variations of the compounds of the present invention or pharmaceutically acceptable salts thereof. Isotopic variations of the compounds of the present invention or pharmaceutically acceptable salts thereof are defined as variations in which at least one atom is replaced by an atom having the same atomic number, but its atomic mass differs from the atomic mass most commonly found in nature. Isotopes that can be included in the compounds of the present invention and their pharmaceutically acceptable salts include, but are not limited to, H, C, N and O; for example, ² H, ³ H, 11 C, ¹³ C, ¹⁴ C, ¹⁵ N, 17 O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Suitable isotopic variations of the compounds or their pharmaceutically acceptable salts of the present invention can be prepared by conventional methods using appropriate isotopic variations ^of suitable reagents.

The compounds of the present invention can be prepared using methods known to those skilled in the art or the novel methods of the present invention. The present invention also provides novel processes for preparing these novel compounds of formula I, II, IIIa, IIIb, or IV, as shown in Schemes 1-7. Specifically, the compounds of the present invention having formula I can be prepared as illustrated by the reaction shown in Scheme 1. 6-Chloro-N-bromimidazo[1,2-diphenylpyridazine, N-iodosuccinimide, and trifluoroacetic acid in chloroform were reacted at room temperature to give 8-bromo-6-chloro-3-iodimidazo[1,2-diphenylpyridazine. 8-bromo-6-chloro-3-iodimidazo[1,2-b]pyridazine and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester were reacted in a solvent mixture of dioxane and water with heating under catalysis using potassium phosphate trihydrate and tetratriphenylphosphine palladium, giving 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-yl)imidazo[1,2-b]pyridazine. 8-Bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-diphenylpyridazine and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester were reacted in a solvent mixture of dioxane and water with heating under catalysis using potassium phosphate trihydrate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, giving 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1-diphenylpyridazine. 6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine and (3R)-3-methylmorpholine were reacted in toluene with heating under sodium tert-butoxide-tris(dibenzylideneacetone)dipalladium catalysis to give (3R)-3-methyl-4(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-(3R)-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine. (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and concentrated hydrochloric acid in ethanol were reacted at room temperature to give the target compound (R)-3methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine.

- 17 049140

Scheme 1.

Other related compounds can be prepared in a similar manner. For example, by replacing 1-methyl-1H-pyrazole-5-boronic acid pinacol ester with 1-methyl-1H-imidazole-5-boronic acid pinacol ester, the title compound ((3-methyl-4-(8-(1-methyl-1H-imidazole-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine was obtained; by replacing 6-chloro-8-bromimidazo-N-pyridazine with 8-bromo-6-chloroimidazo[1,2-a]pyridine, the target compound (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine was obtained; by replacing 1-methyl-1H-pyrazole-5-boronic acid pinacol ester with 6-methylpyridine-3-boronic acid pinacol ester, the target compound (R)-3-methyl-4-(8-(6-methylpyridin-3yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine was obtained; by replacing the pinacol ester of 1-methyl-1H-pyrazole-5-boronic acid with the pinacol ester of 4-(methylsulfonyl)phenylboronic acid, the target compound (3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(III-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine was obtained.

The compounds of the present invention can be prepared as illustrated by the reaction shown in Scheme 2. 8-Bromo-6-chloro-3-iodimidazo[1,2-b]pyridazine, morpholine and diisopropylethylamine (DIEA) were reacted in tetrahydrofuran (THF) with heating to give 4-(6-chloro-3-iodimidazo[1 D-pyridazin-yl)morpholine. 4-(6-chloro-3-iodimidazo[1 D-pyridazin-yl)morpholine, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester, tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ ) and aqueous K ₃ PO ₄ were reacted in dioxane at heating to give 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine. 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine. 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyridazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine, t-BuONa, bis(dibenzylideneacetone)palladium(0) (Pd(dba) ₂ ) and binaphthyldiphenylphosphorus were reacted in toluene with heating to give (3R)-3-methyl-4-(8-morpholine-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine. (3R)-3-methyl-4-(8-morpholine-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and methanolic HCl solution were reacted in methanol at room temperature to give the target compound (3R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine.

Scheme 2.

Other related compounds can be prepared in a similar manner. For example, by replacing morpholine with (2S,6R)-2,6-dimethylmorpholine, the target compound (2S,6R)-2,6-dimethyl-4(6-((R)-3-methylmorpholino)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine was obtained.

The compounds of the present invention can be prepared as illustrated by the reaction shown in Scheme 3. 4-Bromo-1,2-dihydropyridazine-3,6-dione, (1-methyl-1H-pyrazol-5-yl)boronic acid, aqueous potassium phosphate and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf) _Cl2 ) in N,N-dimethylformamide (DMF) were reacted with heating to give 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione. 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione and phosphorus oxychloride were reacted with heating to give 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine. 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine and (S)-3-methylmorpholine were reacted in N-methylpyrrolidone in the presence of (S)-diisopropylethylamine (DIEA) and CuBr with heating to give (S)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine. ^)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine and Zn(CN)2 under [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (DPPF) and tris(dibenzylideneacetone)dipalladium ( _Pd2 (dba) ₃ ) catalysis were reacted in DMF and a small amount of water with heating to give ^)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile. (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile was reacted under hydrogen atmosphere under Raney Ni catalysis at room temperature to give (R)-(4(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazin-3-yl)methylamine. (N)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazin-3-yl)methylamine and 1H-pyrazole-5-carboxylic acid were reacted in DMF in the presence of 2-(7-azabenzotriazole)-N,HN,N-tetramethyluronium hexafluorophosphate (HATU) and DIEA at room temperature to give N-((4-(1-methyl-1H-pyrazol-5-yl)-6-(N)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide. N-((4-(1-methyl-1H-pyrazol-5-yl)-6-(^)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide was reacted with _POCl3 under heating to give the target compound (R)-3-methy-4-(4-(1-methy-1-yrazol-5-ide)-7-(111-11yrazo.1-5-yl)imidazo[1,5-b]11yridazin-2-yl)morpholine.

Scheme 3.

nekton

Other related compounds can be prepared using analogous methods. For example, by replacing morpholine with ((S)-3-methylmorpholine, the target compound 4-(8-(1methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine was obtained; by replacing 1H-pyrazole-5-carboxylic acid with 1H-pyrrole-3-carboxylic acid, the target compound ((S)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5-b]pyridazin-2yl)morpholine was obtained; by replacing 1H-pyrazole-5-carboxylic acid with 1H-imidazole-4-carboxylic acid, the target compound (F)-4-(7-(1H-imidazol-4-yl)-4-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was obtained; by replacing (1-methyl-1H-pyrazol-5-yl)boronic acid with (6-methylpyridin-3-yl)boronic acid, the target compound (F)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine was obtained; by replacing (1-methyl-1H-pyrazol-5-yl)boronic acid with (2-fluorophenyl)boronic acid, the target compound (4-(4-(2-fluorophenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was obtained.

The compounds of the present invention can be prepared as illustrated by the reaction shown in Scheme 4. Reaction of 3,6-dichloropyridazin-4-amine, hexane-2,5-dione, and TsOH-H ₂ O in toluene with heating afforded 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine. Reaction of 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine, (R)3-methylmorpholine, and DIEA in 1-methyl-2-pyrrolidinone (NMP) with heating afforded (R)-4-(6-chloro-5(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine. As a result of the reaction of (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine, Zn(CN) ₂ , 1,1'bis(diphenylphosphino)ferrocene (DPPF), Pd ₂ (dba) ₃ and water in DMF with heating, (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile was obtained. As a result of the reaction of (^)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile, H ₂ and Raney Ni in MeOH at room temperature, (^)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3methylmorpholino)pyridazin-3-yl)methanamine was obtained. (^)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3 methylmorpholino)pyridazin-3-yl)methanamine, 1H-pyrazole-5-carboxylic acid, HATU and DIEA in DMF

- 19 049140 was reacted at room temperature, then K2CO3 was added and the mixture was reacted at room temperature to give (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide. By reacting (R)N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide with POCl ₃ upon heating, (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was obtained. As a result of the reaction of (R)-4-(4-(2,5-dimethyl-1 H-pyrrol-1-yl)-7-(1 H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine with a mixture of trifluoroacetic acid (TFA)/H2O upon heating, (R)-2-(3-methylmorpholino)-7-(1 H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol was obtained. (^)-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-4-ol and triethylamine (TEA) in dry dichloromethane (DCM) were reacted at 0°C, then _Tf2O was added and the mixture was reacted at 0°C to room temperature (RT) to give (^)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate. ^)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate, 1-isopropyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, K2CO3 and Pd(dppf) _Cl2 in dioxane were reacted under heating, then aqueous LiOH solution was added and the mixture was reacted at room temperature to give the target compound ^)-4-(4-(1-isopropyl-1Hpyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.

Scheme 4.

Other related compounds can be prepared using similar methods. For example, by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxaborolane, the title compound ((4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was obtained; by replacing 1-isopropyl-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, the target compound (3)-4-(4-(3-fluoropyridin-4-yl)-7-(1Hpyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was obtained; by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, the target compound (4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine was obtained; by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrrolo[2,3-b]pyridine, the target compound (4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3b]pyridin-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was obtained.

The compounds of the present invention can be prepared as illustrated by the reaction shown in Scheme 5. Reaction of 4,6-dichloro-3-methylpyridazine, (R)-3methylmorpholine and DIEA in methyl 2-pyrrolidinone (NMP) with heating afforded (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine. Reaction of (R)-4-(5-chloro-6-methylpyridazin3-yl)-3-methylmorpholine and SeO ₂ in 1,4-dioxane with heating afforded (R)-4-chloro-6-(3methylmorpholino)pyridazine-3-carbaldehyde. (^)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carbaldehyde, (2,4-dimethoxyphenyl)methanamine and AcOH in 1,1-dichloroethane (DCE) were reacted at room temperature, then NaBH(OAc) ₃ was added and the mixture was reacted at room temperature to obtain (^)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine. As a result of the reaction, (K)-1-(4-chloro-6-(3

- 20 049140 methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine with TFA upon heating was obtained (^)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine. As a result of the reaction of (^)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine and 1H-pyrazole-5-carboxylic acid in the presence of HATU and DIEA in DMF at room temperature was obtained ((4-chloro-6-((1\)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide. As a result of the reaction of X-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide with POCl ₃ upon heating, ^)-4-(4-chloro-7-(R-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)-3-methylmorpholine was obtained. As a result of the interaction of (F)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine, cyclopropylboronic acid, K3PO4-3H2O in the presence of Pd(OAc)2 catalyst and tricyclohexylphosphine in a mixture of solvents of 1,4-dioxane and toluene with heating, the target compound (F)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was obtained.

Scheme 5.

The compounds of the present invention can be prepared as illustrated by the reaction shown in Scheme 6. 1-Tetrahydropyran-2-ylpyrazole-3-carbaldehyde, 6-chloro-3-hydrazinopyridazin-4-amine and PHI(OAc)2 were reacted in DCM at room temperature to give 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine. 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine, HBr and t-BuONO were reacted in CH3CN at 0°C, then CuBr was added and the mixture was reacted at room temperature to give 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)[1,2,4]triazolo[4,3-b]pyridazine. Heating the reaction mixture containing 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine, (2-methylpyrazol-3-yl)boronic acid, Pd( _PPh3 ) ₄ and an aqueous solution of K3PO4 in dioxane under a nitrogen atmosphere gave 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine. Heating the reaction mixture containing 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine and morpholine in sulfolane under nitrogen atmosphere afforded 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine. The reaction of 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine and

HCl/MeOH in MeOH at room temperature gave the target compound 4-[8-(2-methylpyrazol-3-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine.

- 21 049140

Scheme 6.

Other related compounds can be prepared using similar methods. For example, by replacing morpholine with ()-3-methylmorpholine, the target compound ()-3-methyl4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine was obtained.

The compounds of the present invention can be prepared as illustrated by the reaction shown in Scheme 7. By reacting 5,7-dichloropyrazolo[1,5-a]pyrimidine, Pd(dppf)Cl ₂ and an aqueous solution of K ₃ PO ₄ in dioxane with heating, 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine was obtained. Heating the reaction mixture containing 5-chloro-7-(1-methyl-N-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine, sodium tert-butoxide, (±)-2,2'bis(diphenylphosphino)-1,1'-binaphthalene (BINAP) and tris(dibenzylideneacetone)-dipalladium in toluene at room temperature afforded (N)-3-methyl-4-(7-(1-methyl-N-pyrazol-5-yl)pyrazolo[1,5a]pyrimidin-5-yl)morpholine. As a result of the reaction of (^)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine, N-iodosuccinimide (NIS) and trifluoroacetic acid (TFA) in CHCl ₃ at room temperature, (^)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine was obtained. As a result of the reaction of (3R)-4-(3-iodo-7-(1methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III-pyrazole, potassium phosphate trihydrate and Pd(dppf)Cl ₂ in a solvent mixture of dioxane and water with heating, (3R)-3-methyl-4-(7-(1methyl-III-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine was obtained. As a result of the interaction of (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine, a solution of HCl in dioxane and water at room temperature, the target compound (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine was obtained.

Scheme 7.

One of the important aspects of the present invention is the discovery that the compounds of formula I (including the compounds of formulas II, IIIa, IIIb and IV described in this invention) or their stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharmaceutically acceptable salts or mixtures thereof or prodrugs thereof are kinase inhibitors, especially ATR kinase inhibitors. Therefore, the compounds of formula I (including the compounds of formulas II, IIIa, IIIb and IV described in this invention) can be used to treat an ATR kinase-mediated related disease, such as cancer; or used to prepare medicaments for the treatment of an ATR kinase-mediated related disease, such as cancer.

The present invention also relates to methods for treating or preventing kinase-mediated diseases, especially ATR kinase-mediated related diseases, comprising administering to a subject (especially a mammal, more particularly a human) in need thereof, an effective amount of a compound of formula I (including compounds of formulas II, IIIa, IIIb and

- 22 049140

IV, which is described in this invention) or its stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharmaceutically acceptable salts or mixtures thereof, or prodrugs thereof, or a pharmaceutical composition containing an effective amount of a compound of formula I (including compounds of formulas II, IIIa, IIIb and IV, which is described in this invention) or its stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharmaceutically acceptable salts or mixtures thereof, or prodrugs thereof. In this invention, kinase-mediated diseases include cancer, especially ATR kinase-mediated cancer. ATR kinase-mediated diseases that can be treated or prevented by using the methods or pharmaceutical compositions of the present invention include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant islet cell tumor of the pancreas, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tract tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenal cortex carcinoma, skin cancer, and prostate cancer.

The present invention also relates to the use for the treatment or prevention of other diseases caused by excessive or abnormal cell proliferation, including proliferative or hyperproliferative diseases such as myeloproliferative diseases, in particular proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation mediated by ATR kinase. Thus, the present invention also relates to the preparation of medicaments for the treatment or prevention of other diseases caused by excessive or abnormal cell proliferation, in particular proliferative or hyperproliferative disorders caused by excessive or abnormal cell proliferation mediated by ATR kinase, using a compound of formula I (including a compound of formulas II, IIIa, IIIb and IV described in the present invention) or their stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharmaceutically acceptable salts or mixtures thereof or prodrugs thereof.

In practical application of the methods of therapy, effective amounts of pharmaceutical preparations are administered to an individual exhibiting symptoms of one or more of these disorders. The pharmaceutical preparations contain therapeutically effective concentrations of compounds of formula I, II, IIIa, IIIb or IV or their stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharmaceutically acceptable salts or mixtures thereof or prodrugs thereof, on the basis of which preparations for oral, intravenous, local or topical use are prepared for the treatment of cancer and other diseases. These amounts are effective for alleviating or eliminating one or more symptoms of these disorders. An effective amount of a compound for treating a particular disease is an amount sufficient to alleviate or somewhat reduce the intensity of symptoms associated with the disease. Such an amount can be administered as a single dose or can be administered according to an effective regimen. Such an amount can lead to a cure for the disease, but is usually administered to alleviate the symptoms of the disease. Repeated administration is usually necessary to achieve the desired reduction in the intensity of a symptom.

In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I, II, IIIa, IIIb or IV or its stereoisomers, tautomers, isotopically substituted derivatives, or pharmaceutically acceptable salts as an ATR kinase inhibitor and a pharmaceutically acceptable carrier.

Another embodiment of the present invention relates to a pharmaceutical composition effective for treating cancer, comprising a compound of formula I, II, IIIa, IIIb or IV or stereoisomers, tautomers, isotopically substituted derivatives or pharmaceutically acceptable salts thereof, which acts as a kinase inhibitor, in combination with at least one known anticancer agent or a pharmaceutically acceptable salt thereof. In particular, the compound of the present invention can be combined with other anticancer drugs related to the DNA damage and repair mechanism, including PARP inhibitors such as olaparib, niraparib, rucaparib, talazoparib and senaparib; histone deacetylase (HDAC) inhibitors such as volinota, romididesin, papiseta and baylesta; and so on. And the compound of the present invention can be combined with other anticancer drugs that target established cell division sites, including Chk (Chinase Kinase) inhibitors.

- 23 049140 reference point) 1/2, CDK (cyclin-dependent kinase) 4/6 inhibitors such as paposinib, ATM inhibitors, Weel kinase inhibitors, DNA-PK (DNA-dependent protein kinase) inhibitors and so on. Other known anticancer agents that can be used for anticancer combination therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan and topotecan; Topoisomerase II inhibitors such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium and etoposide; RNA/DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine and methotrexate; DNA antimetabolites such as 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, ara-C (cytarabine), pralatrexate, pemetrexed, hydroxyurea and thioguanine; Antimitotic agent such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as the monoclonal antibody (mAb), panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, avastin, herceptin, and mabthera; Kinase inhibitors such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, irbutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, torisel, and everolimus. Other known anticancer agents that may be used for anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (a vaccine for the treatment of prostate cancer).

In practicing the methods of the present invention, a compound of the invention may be administered together with at least one known anticancer agent in a single pharmaceutical composition. Alternatively, a compound of the invention may be administered separately with at least one known anticancer agent. In one embodiment, a compound of the invention and at least one known anticancer agent are administered substantially simultaneously, i.e., all agents are administered at the same time or one after the other, provided that the compounds reach therapeutic levels in the blood at the same time. In another embodiment, a compound of the invention and at least one known anticancer agent are administered according to an individual administration regimen, provided that these compounds reach therapeutic levels in the blood.

The present invention also relates to a bioconjugate acting as a kinase inhibitor, which comprises a compound described in this invention and is effective in suppressing tumor growth. This bioconjugate, which suppresses tumor growth, is composed of a compound described in this application and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or a growth factor, such as epidermal growth factor (EGF) or fibroblast growth factor (FGF), or a cytokine, such as IL-2 (interleukin-2) or IL-4, or any molecule that can bind to a cell surface. Antibodies and other molecules can deliver the compound described in this invention to its targets, making it an effective anticancer agent. Such bioconjugates can also enhance the anticancer effect of therapeutically useful antibodies, such as trastuzumab or rituximab.

The present invention also relates to a pharmaceutical composition effective in suppressing tumor growth, comprising a kinase inhibitor of formula I (including a compound of formulas II, IIIa, IIIb and IV described in this invention) or its stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharmaceutically acceptable salts or mixtures thereof or a prodrug, in combination with radiation therapy; wherein the compound of the invention can be administered at the same time as the radiation therapy or at different times.

The present invention also relates to a pharmaceutical composition effective for post-surgical treatment of cancer, comprising a kinase inhibitor of formula I, II, IIIa, IIIb or IV or its stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharmaceutically acceptable salts or mixtures thereof or a prodrug. The invention also relates to a method for treating cancer by surgically removing a tumor and then treating a mammal with the pharmaceutical composition described in this invention.

The pharmaceutical compositions of this invention include all pharmaceutical preparations that contain the compounds of the present invention in an amount effective to achieve the intended purpose thereof. Although individual needs vary, determining the optimal amounts of each component in pharmaceutical preparations is within the skill of the art. Typically, the compounds or a pharmaceutically acceptable salt thereof can be

- 24 049140 administered orally to mammals at a dose of about 0.0025-50 mg per kg of body weight per day. Preferably, from about 0.01 mg/kg to about 10 mg/kg of body weight is administered orally. If a known anticancer agent is also administered, it is administered in an amount effective to achieve its intended purpose. Optimum amounts of such known anticancer agents are well known to those skilled in the art.

A unit oral dose may contain from about 0.01 to about 50 mg; preferably from about 0.1 to about 10 mg of a compound of the invention. A unit dose may be administered one or more times as one or more tablets per day, each containing from about 0.1 to about 50 mg, suitably about 0.25-10 mg of a compound of the invention or solvates thereof.

In a composition for topical use, the compound of the invention may be present at a concentration of about 0.01-100 mg per gram of carrier.

The compound of the invention may be administered as the crude chemical compound. The compounds of the invention may also be administered as part of a suitable pharmaceutical preparation comprising pharmaceutically acceptable carriers (containing excipients and auxiliaries) that facilitate processing of the compounds to obtain pharmaceutically acceptable preparations. Preferably, pharmaceutical preparations, in particular preparations for oral administration, and preparations used for preferred administration, such as tablets, dragees and capsules, as well as solutions suitable for injection or oral administration, contain from about 0.01% to 99%, preferably from about 0.25% to 75% of the active compound(s), together with the excipient(s).

Also included within the scope of the present invention are non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Base addition salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine, and the like.

The pharmaceutical preparations of the invention may be administered to any mammal, provided that they can experience the therapeutic effect of the compounds of the invention. Primarily such mammals include humans and veterinary animals, although the description is not intended to be limited to them.

The pharmaceutical preparations of the present invention can be administered by any route that allows them to achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively or simultaneously, administration can be by oral route. The dose administered will depend on the age, health and weight of the recipient, the type of concomitant treatment, the frequency of treatment and the nature of the desired effect.

The pharmaceutical preparations of the present invention are prepared in a known manner, for example using conventional mixing, granulation, dragee coating, dissolution or lyophilization methods. Pharmaceutical preparations for oral use can be prepared by combining the active compounds with solid excipients, optionally grinding the resulting mixture, processing this mixture of granules after adding suitable auxiliary substances if desired or necessary, thereby obtaining tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol; cellulose-based preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; as well as binders such as starch paste, including, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Excipients are, in particular, flow-regulating agents and lubricants, for example silicon dioxide, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and/or polyethyleneglycol. The dragee cores are provided with suitable coatings, which, if desired, can be made resistant to gastric juice. For this purpose, concentrated saccharide solutions can be used, which may optionally contain acacia, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium dioxide, varnish solutions and suitable organic solvents or solvent mixtures. In order to obtain coatings resistant to gastric juice,

- 25 049140 juice, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used. Dyes or pigments may be added to the tablet or dragee coatings, for example for identification or to differentiate dose combinations of active compounds.

Other pharmaceutical preparations that can be used orally include hard capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Hard capsules may contain the active compounds in the form of granules, which may be mixed with fillers such as lactose; binders such as starches; and/or lubricants such as talc or magnesium stearate, and stabilizers. In the case of soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids such as fixed liquid oils or liquid paraffin. In addition, stabilizers may be added.

Suitable compositions for parenteral administration include aqueous solutions of the active compounds, for example aqueous solutions and alkaline solutions of water-soluble salts. In addition, suspensions of the active compounds can be administered in the form of appropriate oily injection suspensions. Suitable lipophilic solvents or carriers include fixed liquid oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or polyethyleneglycol-400, or cremophor, or cyclodextrins. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, for example sodium carboxymethylcellulose, sorbitol and/or dextran. Suspension stabilizers may optionally also be contained.

According to one aspect of the present invention, the compounds of the invention are used in topical compositions and parenteral compositions and are used to treat skin cancer.

The topical compositions of the present invention are preferably prepared in the form of oils, creams, lotions, ointments and the like by selecting appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), fats or oils with a branched chain, animal fats and high molecular weight alcohol (greater than C ₁₂ ). Preferred carriers are those in which the active ingredient is soluble. In addition, emulsifiers, stabilizers, wetting agents and antioxidants can be included, as well as, if desired, coloring or flavoring agents. In addition, transdermal permeation enhancers can be used in such topical compositions. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.

Creams are preferably prepared from a mixture of mineral oil, self-emulsifying beeswax and water, into which the active ingredient is mixed, dissolved in a small amount of oil, such as almond oil. A typical example of such a cream is one that includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.

Ointments may be prepared by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one that includes approximately 30% almond oil and approximately 70% white soft paraffin by weight.

The present invention also includes the use of the compounds of the invention for the preparation of medicaments for the treatment of clinical symptoms in response to the effect of inhibiting the activity of kinases (especially ATR kinase). These medicaments may include the above-mentioned pharmaceutical compositions.

The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of a variety of conditions and parameters commonly encountered in clinical therapy and obvious to those skilled in the art are within the spirit and scope of the present invention.

Examples

General Provisions.

All reagents were of commercial grade. Drying and purification of solvents were performed by standard methods. Mass spectrometric analyses were recorded on a Platform II quadrupole mass spectrometer (Agilent 6110) equipped with an electrospray interface. 1H NMR spectra were recorded at 400 MHz on a Brucker Ascend 400 instrument. Chemical shifts were reported as parts per million ( ^ppm ) relative to tetramethylsilane (TMS; 0.00 ^ppm ), and spin–spin coupling constants J were presented in hertz (Hz).

Example 1.

(R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6yl)morpholine.

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a) Preparation of 8-bromo-6-chloro-3-iodimidazo[1,2-a]pyridine. Niodosuccinimide (3.94 g, 17.28 mmol) and trifluoroacetic acid (2.68 ml, 34.6 mmol) were added to a solution of 8-bromo-6-chloroimidazo[1,2a]pyridine (4.0 g, 17.28 mmol) in chloroform (50 ml) at room temperature. The reaction solution was stirred for 2 h at room temperature. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (80 ml). The reaction liquid was extracted with dichloromethane (50 ml x 3). The resulting extraction liquid was washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (silica gel; dichloromethane:ethyl acetate = 1:0-7:3) to give the desired product (5.5 g; yield 89%; yellow solid). Liquid chromatography-mass spectroscopy (LC-MS) (electrospray ionization (ESI)): m / z (M + H) + 356.62.

b) Preparation of 8-bromo-6-chloro-3-(1-methyl-N-pyrazol-5-yl)imidazo[1,2-a]pyridine. Tetratriphenylphosphine palladium (1.28 g; 1.11 mmol) was added to a solution of 8-bromo-6-chloro-3-iodimidazo[1,2-a]pyridine (3 g; 8.4 mmol), 1-(tetrahydro-2H-pyran2-yl)-N-pyrazole-5-boronic acid pinacol ester (2.57 g; 9.24 mmol) and potassium phosphate trihydrate (4.41 g; 16.8 mmol) in a mixture of dioxane (50 ml) and water (5 ml). The reaction solution was stirred for 18 h under nitrogen atmosphere at 80°C. Water (100 mL) was added and the mixture was extracted with dichloromethane (50 mL x 3). The extracted liquid was washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (silica gel; dichloromethane:ethyl acetate = 4:0-7:3) to give the desired product (1.05 g; yield 40.1%; yellow solid). LC-MS (ESI): m/z (M+H) ⁺ 380.8.

c) Preparation of 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1-chloropyrazol-5-yl)imidazo[1,2-a]pyridine. To a solution of 8-bromo-6-chloro-3-(1-methyl-N-pyrazol-5-yl)imidazo[1,2a]pyridine (1 g, 2.62 mmol), 1-methyl-N-pyrazole-5-boronic acid pinacol ester (0.71 g, 3.40 mmol) and potassium phosphate trihydrate (1.4 g, 5.24 mmol) in a mixture of dioxane (30 ml) and water (3 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.38 g, 0.52 mmol). The reaction liquid was stirred for 16 h under nitrogen at 100°C. Water (50 ml) was added and the mixture was extracted with dichloromethane (50 ml x 3). The resulting extracted liquid was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (silica gel; dichloromethane:ethyl acetate = 4:1-0:1) to give the desired product (0.8 g; yield 80.0%; yellow solid). LC-MS (ESI): m/z (M+H) ⁺ 383.0.

d) Preparation of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine. To a solution of ((3-methylmorpholine) (405.81 mg, 4.01 mmol), sodium tert-butoxide (257.05 mg, 2.67 mmol) and methanesulfonato(2-di-tert-butylphosphino2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (53.12 mg, 66.87 mmol) in tert-amyl alcohol (8.00 mL) under nitrogen atmosphere was slowly added 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine (400 mg, 668.68 mmol). After replacing the reaction system atmosphere with nitrogen atmosphere, the reaction solution was stirred at 110°C for 0.5 h, and LC-MS indicated the completion of the reaction. The reaction solution was filtered and then concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by column chromatography (silica gel; ethyl acetate:methanol = 10:1) to give the target product (200 mg; crude product, yellow oil). LC-MS (ESI): m/z (M+H) ⁺ 448.2.

e) Preparation of (R)-3-methyl-4-(8-(1-methyl-1 H-pyrazol-5-yl)-3-(1 H-pyrazol-5-yl)imidazo[1,2-

a]pyridin-6-yl)morpholine. (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3(1-tetrahydro-2H-pyran-2-yl)-3R-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine (200 mg; crude product) was dissolved in methanol (2 mL) at room temperature, and then 4 M hydrochloric acid in dioxane (5 mL) was added dropwise. The reaction liquid was stirred at 10 °C for 0.5 h. LC-MS monitoring showed complete consumption of the starting materials and formation of products. The reaction solution was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by preparative chromatography (silica gel C18 column: 150x25 mm, 5 μm; 13-38% acetonitrile/0.05% ammonia as mobile phase) to give the desired product (9 mg; yield 5.6%; white solid). LC-MS (ESI): m/z (M+H) ⁺ 364.2. ¹ H NMR (400 MHz, DMSO-d ₆ (deuterated dimethyl sulfoxide)): δ 13.15 (s, 1H), 9.03 (d, J=1.8 Hz, 1H),

- 27 049140

8.00 (s, 1H), 7.92 (s, 2H), 7.54 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 3.95-3.88 (m, 1H), 3.85 (s, 3H), 3.80-3.70 (m, 2H), 3.68-3.60 (m, 2H), 3.22-2.95 (m, 2H), 0.99 (d, J=6.8 Hz, 3H).

Example 2.

(R)-3-methyl-4-(8-(1-methyl-III-pyrazol-5-yl)-3-(III-pyrazol-5-yl)imidazo[1,2-L]pyridin-6yl)morpholine.

a) Preparation of 8-bromo-6-chloro-3-iodimidazo[1,2-b]pyridazine. N-iodosuccinimide (7.25 g; 32.25 mmol) and trifluoroacetic acid (3.35 ml; 43 mmol) were added to a solution of 6-chloro-8-bromimidazo[1,2-b]pyridazine (5 g; 21.5 mmol) in chloroform (90 ml) at room temperature. The reaction liquid was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (100 ml) and extracted with dichloromethane (50 ml×3). The resulting extraction liquid was washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (silica gel; dichloromethane:ethyl acetate = 1:0-49:1) to give the desired product (5.2 g; yield 67.7%; yellow solid). LC-MS (ESI): m/z (M+H)+ 357.57.

b) Preparation of 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-

EDpyridazine. To a solution of 8-bromo-6-chloro-3-iodimidazo[1,2-b]pyridazine (4 g, 14.51 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (4.03 g, 14.51 mmol) and potassium phosphate trihydrate (5.94 g, 22.32 mmol) in a mixture of dioxane (50 ml) and water (5 ml) was added tetrakistriphenylphosphine palladium (1.67 g, 1.45 mmol). The reaction solution was stirred for 16 h under nitrogen at 90°C, then water (50 ml) was added and the mixture was extracted with dichloromethane (50 ml×3). The resulting extraction liquid was washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (silica gel; dichloromethane:ethyl acetate = 1:0-4:1) to give the desired product (0.93 g; yield 16.7%; yellow solid). LC-MS (ESI): m/z (M+H)+ 381.80.

c) Obtaining 6-chloro-8-(1-methyl-III-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl-imidazoCD-N-pyridazine. To a solution of 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl-imidazoCD-2-pyridazine (0.93 g, 2.43 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.66 g, 3.16 mmol) and potassium phosphate trihydrate (1.29 g, 4.86 mmol) in a solvent mixture of dioxane (20 ml) and water (2 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.36 g, 0.47 mmol). The reaction liquid was stirred for 16 h under nitrogen at 100°C, then water (30 ml) was added and the mixture was extracted with dichloromethane (50 ml x 3). The resulting extracted liquid was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (silica gel; petroleum ether:ethyl acetate = 10:1-1:1) to give the desired product (0.5 g; yield 53.8%; yellow solid). LCMS (ESI): m/z (M+H)+ 383.80.

d) Preparation of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1Hpyrazol-5-yl)imudazo[1,2-b]pyridazin-6-yl)morpholine. At room temperature, 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine (500 mg, 1.3 mmol) and (1H)-3-methylmorpholine (657.48 mg, 6.5 mmol) were dissolved in toluene (10 ml), and then sodium tert-butoxide (249.86 mg, 2.6 mmol), tris(dibenzylideneacetone)dipalladium (119.04 mg, 0.3 mmol) and 2,2'-bis-(diphenylphosphino)-1,1'-binaphthylene (161.89 mg, 0.26 mmol) were added. Under nitrogen atmosphere, the reaction solution was stirred at reflux temperature for 16 h. The reaction liquid was diluted with toluene (50 mL) and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel; petroleum ether:ethyl acetate = 5:1-0:1) to give the target product (0.12 g; yield 20.6%; yellow solid). LC-MS (ESI): m/z (M+H)+ 449.15.

e) Preparation of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2b]pyridazin-6-yl)morpholine. Concentrated hydrochloric acid (1 ml) was added to a solution of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (120 mg; 0.27 mmol) in ethanol (10 ml) at room temperature. The reaction liquid was stirred at room temperature for 2 h. The reaction liquid was concentrated to give a residue, which was dissolved in methanol (2 mL), and 1 drop of ammonia solution was added. The mixture was purified by preparative liquid chromatography (C18 column; 0-100% acetonitrile/water as a mobile phase) to give the title compound (5.5 mg; yield 5.6%; yellow solid).

The following compounds of Examples 3-8 were prepared using a synthetic procedure similar to that described in Example 2 and using as starting materials 6-chloro-8-bromimidazo[1,2-dipyridazine, N-iodosuccinimide, 1-(tetrahydro-2H-pyran-2-yl)-N-pyrazole-5-boronic acid pinacol ester, the appropriate aryl- or heteroaryl-boronic acid pinacol ester, and (R)-3-methylmorpholine.

- 28 049140

Su

Example Su LC-MS (ESI) ¹ NMR(400 MHz) 2 * N=^ (M+H) ⁺ 365.0 CDCh: δ 7.98 (s, 1H), 7.71 (d, J= 1.9 Hz, 1H), 7.63 (d, J= 1.9 Hz, 1H), 6.84-6.79 (m, 2H), 6.69 (d, J = 1.9 Hz, 1H), 4.17-4.09 (m, 2H), 4.02 (s, 3H), 3.893.88 (m, 1H), 3.78-3.69 (m, 2H), 3.55-3.43 (m, 2H), 1.40 (d, J =6.8 Hz, 3H). 3 (M+H) ⁺ 379.2 CD ₃ OD: δ 7.97 (s, 1H), 7.79 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.20 (s, 2H), 6.66 (d, J = 2.0 Hz, 1H), 4.364.35 (m, 1H), 4.30-4.24 (m, 2H), 4.08-4.05 (m, 1H), 3.90-3.88 (m, 1H), 3.86-3.84 (m, 2H), 3.71-3.70 (m, 1H), 3.43-3.42 (m, 1H), 1.37-1.32 (m, 6H). 4 ΛΑ N=/ (M+H) ⁺ 393.4 CD3OD: δ 7.96 (s, 1H), 7.81 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.22-7.15 (m, 2H), 6.60 (d, J = 1.6 Hz, 1H), 4.60-4.51 (m, 2H), 4.36-4.30 (d, J = 6.4 Hz, 1H), 4.07 (dd, J = 3.6; 11.6 Hz, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.85 (s, 2H), 3.74-3.67 (m, 1H), 3.46-3.39 (m, 1H), 1.47 (d, J = 6.8 Hz, 6H), 1.36 (d, J = 6.8 Hz, 3H). 5 ^=N (M+H) ⁺ 365.3 DMSO-tfc δ 13.08 (s, 1H), 8.27 (s, 1H), 7.96-7.86 (m, 2H), 7.83 (s, 1H), 7.22 (s, 1H), 7.01 (s, 1H), 4.374.35 (m, 1H), 4.03-4.00 (m, 1H), 3.91 (s, 3H), 3.883.84 (m, 1H), 3.81-3.75 (m, 2H), 3.59-3.58 (m, 2H), 1.28 (d, J = 3.2 Hz, 3H). 6 ³ (M+H) ⁺ 376.2 DMSO-tfc δ 13.07 (s, 1H), 9.34 (s, 1H), 8.61 (dd, J = 2.0; 8.0 Hz, 1H), 7.92 (d, J = 36.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 4.46 (d, J = 4.4 Hz, 1H), 4.01 (dd, J = 8.0; 11.6 Hz, 1H), 3.78 (d, J = 6.4 Hz,

- 29 049140

1H), 3.76-3.59 (m, 2H), 3.39-3.37 (m, 1H), 3.31-3.27 (m, 1H), 2.57 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). 7 /=\ /Р *—(\ /)—— (M+N) ⁺ 439.2 DMSO-tfc δ 13.15 (s, 0.5H), 13.11 (s, 0.5H), 8.55 (d, J = 7.6 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 25.6 Hz, 1H), 7.65-7.52 (m, 1H), 7.50-7.47 (m, 1H), 7.12-7.05 (m, 1H), 4.46 (s, 1H),4.O3 (dd, J = 3.2; 11.6 Hz, 1H), 3.98-3.91 (m, 1H), 3.82-3.74 (m, 2H), 3.633.57 (m, 2H), 3.31-3.30 (m, 4H), 1.25 (d, J = 6.4 Hz, 1H). 8 * & (M+N) ⁺ 379.4 CD ₃ OD: δ 7.94 (s, 1H), 7.86-7.74 (m, 2H), 7.58-7.53 (m, 1H), 7.38-7.29 (m, 2H), 7.19 (s, 2H), 4.65-4.52 (m, 1H), 4.30 (dd, J = 6.4; 13.2 Hz, 1H), 4.06 (dd, J = 3.6; 11.6 Hz, 1H), 3.91-3.82 (m, 3H), 3.74-3.67 (m, 1H), 3.46-3.39 (m, 1H), 1.36 (d, J = 6.8 Hz, ZN).

Example 9.

^)-3-methyl-4-(8-morpholino-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine.

a) Preparation of 4-(6-chloro-3-iodimidazo[1,2-b]pyridazin-8-yl)morpholine. After replacing the reaction system atmosphere with nitrogen three times, a mixture of 8-bromo-6-chloro-3-iodimidazo[1,2-b]pyridazine (2.5 g; 6.98 mmol), morpholine (729.32 mg; 8.37 mmol; 736.69 μl) and DIEA (1.98 g; 15.35 mmol; 2.67 ml) in THF (50 ml) was stirred at 80°C under nitrogen atmosphere for 12 hours. The reaction mixture was diluted with ethyl acetate (EA; 100 mL), washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was washed with methyl tert-butyl ether (MTBE; 30 mL) to give the title compound (2.5 g; yellow solid; yield 98.30%). LC-MS (ESI): m/z (M+H)+ 364.9.

b) Preparation of 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5-yl)imidazo[1,2-

[b]pyridazin-8-yl)morpholine. After replacing the reaction system atmosphere with nitrogen three times, a mixture of 4-(6-chloro-3-iodimidazo[1,2-b]pyridazin-8-yl)morpholine (2.5 g; 6.86 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (2.10 g; 7.54 mmol), Pd( _PPh3 ) ₄ (792.41 mg; 685.74 μmol), and an aqueous solution of K3PO4 (3 M; 6.86 ml) in dioxane (35 ml) was stirred at 90°C under nitrogen atmosphere for 8 hours. The reaction mixture was diluted with EA (50 mL), washed with saturated brine (35 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (ISCO®; 40 g Sepa Flash® silica flash chromatography column, gradient elution 0~10% EA/PE (petroleum ether); flow rate 50 mL/min) to give the desired product (0.94 g; white solid; yield 35.25%). LC-MS (ESI): m/z (M+H) ⁺ 389.2.

c) Preparation of (3R)-3-methyl-4-(8-morpholine-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5yl)imidazo[1,2-b]pyridazin-6-yl)morpholine. After replacing the reaction system atmosphere with nitrogen three times, a mixture of 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-5-yl)imidazo[1,2-L]pyridazin-8-yl)morpholine (0.94 g; 2.42 mmol), (N)-3-methylmorpholine (1.22 g; 12.09 mmol), t-BuONa (464.64 mg; 4.83 mmol), Pd(dba) ₂ (278.00 mg; 483.48 μmol) and 1,1'-binaphthyl-2,2'-diphenylphosphine (BINAP; 301.05 mg; 483.48 μmol) in toluene (30 ml) was stirred at 100°C under nitrogen atmosphere for 18 hours. The reaction mixture was diluted with EA (50 mL), washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on

- 30 049140 silica gel (ISCO®; 20 g Sepa Flash® silica flash chromatography column, gradient elution 0~20% EA/PE, flow rate 50 mL/min) to give the desired product (0.18 g; yellow solid; yield 16.42%). LC-MS (ESI): m/z (M+H)+ 454.2.

d) Preparation of (R)-3-methyl-4-(8-morpholino-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine. A solution of HCl in methanol (4 M; 4.41 ml) was added to a solution of (3R)-3-methyl-4-(8-morpholino-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2F]pyridazin-6-yl)morpholine (0.16 g; 352.78 μmol) in methanol (4.5 ml). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in methanol (20 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, and then concentrated under reduced pressure to obtain a crude product, which was purified by preparative high-performance liquid chromatography (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mM _NH4HCO3 ) - ACN (acetonitrile)]; B%: 17%47%; 10 min) to give the title compound (25 mg; off-white solid; yield 19.03%; purity 99.19%). LC-MS (ESI): m/z (M+H) ⁺ 370.1. ¹ H NMR (400 MHz, CD3OD): δ 7.85 (s, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 6.22 (s, 1H), 4.27 (m, 1H), 4.03 (dd, J=3.2; 11.6 Hz, 1H), 3.92-3.90 (m, 4H), 3.82-3.64 (m, 9H), 3.38-3.35 (m, 1H), 1.29 (d, J=2.0 Hz, 3H). Supercritical fluid chromatography (SFC): enantiomeric excess (ee) 100%.

Example 10.

(2S,6R)-2,6-dimethyl-4-(6-((R)-3-methylmorpholino)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8yl)morpholine.

With \^NH id

N

The compound of Example 10 was prepared using a synthetic method similar to that described in Example 9. LC-MS (ESI): m/z (M+H) ⁺ 398.4. 1H NMR (400 MHz, CD ₃ OD): δ 7.82 (s, 1H), 7.80-7.59 (m, 1H), 7.21-7.01 (m, 1H), 6.13 (s, 1H), 4.60 (s, 1H), 4.49-4.39 (m, 2H), 4.27-4.24 (m, 1H), 4.02 (dd, J=3.2; 11.6 Hz, 1H), 3.943.85 (m, 2H), 3.83-3.74 (m, 3H), 3.70-3.64 (m, 1H), 3.36 (dd, J=4.0; 12.8 Hz, 1H), 2.63-2.55 (m, 2H), 1.30-1.25 (m, 9H).

Example 11.

4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine.

The compound of Example 11 was prepared using the synthetic method similar to that described in Example 13. Yellow solid. LC-MS (ESI): m/z (M+H) ⁺ 351.30. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.73 (s, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.44 (s, 1H), 7.14 (d, J=1.3 Hz, 1H), 7.01 (s, 1H), 6.81 (d, J=1.6 Hz, 1H), 3.97 (s, 3H), 3.83-3.74 (m, 4H), 3.63-3.57 (m, 4H).

Example 12.

4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6yl)morpholine.

a) Preparation of 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine. A solution of 1-tetrahydropyran-2-ylpyrazole-3-carbaldehyde (10.16 g; 56.40 mmol) and 6-chloro-3-hydrazinopyridazin-4-amine (9 g; 56.40 mmol) in DCM (120 ml) was stirred at 10-20°C for

- 31 049140 h. Then PhI(OAc)2 (30.88 g, 95.88 mmol) was added to the mixture at 0 °C and stirred at 10-20 °C for 12 h. The reaction mixture was diluted with brine (800 mL) and extracted with DCM (400 mL x 3). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; X g Sepa Flash® silica flash column; eluent: gradient 0~100% ethyl acetate/petroleum ether, PE:EA = 1:3) to give the desired product (8.7 g; yellow solid; yield 16.08%). LC-MS (ESI): m/z (M+H)+ 319.9.

b) Preparation of 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine. To a mixture of 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (0.9 g; 2.81 mmol) in CH ₃ CN (15 mL) were added HBr (69.01 mg; 281.47 μmol; 46.32 μL; purity 33%), t-BuONO (493.43 mg; 4.79 mmol; 569.12 μL) and the mixture was stirred at 0 °C for 0.5 h. Then CuBr (605.65 mg, 4.22 mmol, 128.59 μL) was added. The mixture was stirred at 10-20 °C for 12 h. The reaction mixture was diluted with H ₂ O (80 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ ; petroleum ether/ethyl acetate = 5/1 to 1/1) to give the desired product (380 mg; black solid; yield 7.04%). LC-MS (ESI): m/z (M+H) ⁺ 382.8. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.82 (d, J=2.4 Hz, 1H), 7.44 (s, 1H), 7.44 (d, J=3.2 Hz, 1H), 5.63-5.60 (m, 1H), 4.12-4.09 (m, 1H), 3.78-3.72 (m, 1H), 2.21-2.10 (m, 3H), 1.76-1.61 (m, 3H).

c) Preparation of 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)[1,2,4]triazolo[4,3-b]pyridazine. To a solution of 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)[1,2,4]triazolo[4,3-b]pyridazine (120 mg; 312.80 μmol) and (2-methylpyrazol-3-yl)boronic acid (39.39 mg; 312.80 μmol) in dioxane (6 mL) were added Pd( _PPh3 ) ₄ (36.15 mg; 31.28 μmol) and aqueous _K3PO4 solution (2 M; 469.20 μL) at 10-20°C, then the suspension was degassed under vacuum and purged _with N2 several times and stirred at 100-110°C for 1.5 h. The reaction mixture was diluted with _H2O (30 mL) and extracted with EtOAc (40 mL _x 3). The combined organic layers were washed with brine (40 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (TLC) ( _SiO2 ; PE:EA = 1:3) to give the desired product (90 mg; yellow solid). LC-MS (ESI): m/z (M+H) ⁺ 384.9.

d) Preparation of 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-

[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine. A solution of 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine (20 mg; 51.97 μmol) and morpholine (22.64 mg; 259.86 μmol; 22.87 μL) in sulfolane (0.5 mL) was degassed and purged with N2 ₃ times, and then the mixture was stirred at 120-130 °C for 3 h under N2. The reaction mixture was purified by preparative high-performance liquid chromatography (HPLC) (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 24%-44%; 7 min) to give the target product (97 mg; yellow solid). LC-MS (ESI): m/z (M+H) ⁺ 436.0.

e) Preparation of 4-[8-(2-methylpyrazol-3-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine. To a solution of 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine (40 mg; 91.85 μmol) in MeOH (1.2 ml) was added a solution of HCl in MeOH (4 M; 229.63 μl) at 0°C, and then the mixture was stirred at 25°C for 15 hours. The reaction mixture was filtered and the filter cake was washed with EtOAc (0.5 mL×2) to afford the title compound (57.42 mg; yellow solid; yield 86.91%). LC-MS (ESI): m/z (M+H) ⁺ 352.1. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.94 (d, J=2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.21 (d, J=2.0 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 4.03 (s, 3H), 3.80-3.77 (m, 4H), 3.66-3.64 (m, 4H).

Example 13.

^)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine.

a) Preparation of 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione. 4-bromo-1,2-dihydropyridazine-3,6-dione (4.0 g; 20.94 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (5.23 g; 41.90 mmol) and an aqueous solution of potassium phosphate (aq. K ₃ PO ₄ ; 63 mL; 1 M) were dissolved in N,N-dimethylformamide (DMF; 60 mL). The air in the reaction vessel was replaced with nitrogen and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl ₂ ; 1.67 g; 2.09 mmol) was added under nitrogen atmosphere. After

- 32 049140 After reacting the resulting mixture at 100°C for 16 h, the reaction mixture was concentrated to remove the solvent to give a crude product, which was washed with dichloromethane (DCM; 100 mL) to give the crude target product (15.0 g; black solid). LC-MS (ESI): m/z (M+H)+ 193.25.

b) Preparation of 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine. 4-(1-methyl-1H-pyrazol-5-yl)1,2-dihydropyridazine-3,6-dione (15.0 g; crude product; 20.94 mmol) was dissolved in phosphorus oxychloride (POCl ₃ ; 150 mL), the mixture was heated to 100 °C and stirred for 16 h. Phosphorus oxychloride was removed to give the crude product, which was purified by silica gel column chromatography (EtOAc/PE; 10 to 30%) to give the desired product (2.63 g; white solid; yield 55% over two steps). LC-MS (ESI): m/z (M+H)+ 229.15. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.61 (d, J=1.3 Hz, 1H), 7.51 (s, 1H), 6.49 (d, J=1.3 Hz, 1H), 3.83 (s, 3H).

c) Preparation of (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine. (R)-3-methylmorpholine (1.58 g; 11.53 mmol), CuBr (3.63 g; 25.37 mmol) and N.N-diisopropylethylamine (DIEA; 2.15 g; 15.5 mmol) were added to a solution of 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine (2.63 g; 11.53 mmol) in N-methylpyrrolidone (NMP; 50 ml). The resulting mixture was stirred at 150 °C for 16 h. The reaction was quenched with water (50 ml) and the mixture was diluted with dichloromethane (DCM; 100 ml). The organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (EtOAc/PE; 5-20%) to give the desired product (1.65 g; light red solid; yield 49%). LC-MS (ESI): m/z (M+H)+ 294.25. 1H NMR (400 MHz, CDC13): δ 7.60 (s, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 4.36-4.27 (m, 1H), 4.06 (dd, J=11.4; 3.3 Hz, 1H), 3.97 (dd, J=13.3; 2.0 Hz, 1H), 3.86-3.82 (m, 1H), 3.80 (s, 3H), 3.65 (td, J=12.0; 3.0 Hz, 1H), 3.36 (td, J=12.5; 3.7 Hz, 1H), 1.33 (d, J=6.7 Hz, 3H).

d) Preparation of (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile. Zn(CN) ₂ (0.4 g; 3.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (DPPF; 0.2 g; 0.36 mmol), _Pd2 (dba) ₃ (160 mg; 0.17 mmol) and 3 drops of water were added to a solution of (R)-4-(6-chloro-5-(1-methyl-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine (0.5 g; 1.7 mmol) in DMF (10 ml). The resulting mixture was stirred at 150°C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to give a crude product, which was purified by silica gel column chromatography (EtOAc/PE; 10 to 40%) to give the desired product (0.4 g; light red oil; yield 82%). LC-MS (ESI): m/z (M+H)+ 285.30. 1H NMR (400 MHz, CDCl ₃ ): δ 7.59 (d, J=1.8 Hz, 1H), 6.66 (s, 1H), 6.53 (d, J=1.8 Hz, 1H), 4.54-4.43 (m, 1H), 4.23-4.13 (m, 1H), 4.08 (dd, J=14.8; 5.7 Hz, 1H), 3.89 (s, 3H), 3.84 (brs, 1H), 3.78 (dd, J=12.0; 2.8 Hz, 1H), 3.64 (td, J=12.4; 2.8 Hz, 1H), 3.49-3.38 (m, 1H), 1.38 (d, J=6.8 Hz, 3H).

e) Preparation of (R)-(4-(1-methyl-N-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazine-3-yl)carbonitrile. Raney Ni (approximately 0.3 g) was added to a solution of (R)-4-(1-methyl-N-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile (0.22 g; 0.77 mmol) in MeOH (7 ml). The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After completion of the reaction, the resulting mixture was filtered through diatomaceous earth and the filtrate was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography column (C18; CH3CN/H2O; 5~30% with addition of 0.1% TFA) to give the desired product (0.1 g; colorless oily substance; yield 45%). LC-MS (ESI): m/z (M+H)+ 289.30. 1H NMR (400 MHz, CD3OD): δ 7.61 (s, 1H), 7.32 (s, 1H), 6.51 (s, 1H), 4.47-4.38 (m, 1H), 4.14 (s, 2H), 4.00 (dt, J=16.5; 9.0 Hz, 2H), 3.85-3.72 (m, 4H), 3.63 (dd, J=16.4; 7.3 Hz, 1H), 3.33 (brs, 2H), 1.28 (d, J=6.4 Hz, 3H).

f) Preparation of N-((4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-formamide. 1H-pyrazole-5-carboxylic acid (0.05 g; 0.35 mmol), 2-(7-azabenzotriazole)-N-methylurea hexafluorophosphate (HATU; 200 mg; 0.75 mmol) and DIEA (0.12 g; 0.87 mmol) were added to a solution of N-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methylamine (0.1 g; 0.35 mmol) in DMF (5 ml). The resulting mixture was stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure to remove the solvent to give a crude product, which was purified by preparative thin layer chromatography plate (DCM:MeOH = 20:1) to give the desired product (0.085 g; white solid; yield 64%). LC-MS (ESI): m/z (M+H)+ 383.35. 1H NMR (400 MHz, CDCl ₃ ): δ 10.40 (s, 1H), 8.73 (s, 1H), 7.62-7.52 (m, 2H), 6.82-6.72 (m, 2H), 6.45 (s, 1H), 4.58 (d, J=5.5 Hz, 2H), 4.36-4.25 (m, 1H), 4.02 (ddd, J=22.3; 12.2; 2.6 Hz, 1H), 3.79 (s, 3H), 3.64 (ddd, J=15.7; 12.1; 5.0 Hz, 2H), 3.40-3.30 (m, 1H), 3.163.05 (m, 2H), 1.31 (d, J=6.9 Hz, 3H).

g) Preparation of (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine A solution of N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-formamide (0.085 g; 0.22 mmol) in _POCl3 (5 ml) was stirred at 150°C for 3 h. The reaction mixture was distilled under reduced pressure to remove the solvent to give the crude product, which was purified by column purification

- 33 049140 preparative high-performance liquid chromatography (C18; CH3CN/H2O; 15-45% with addition of 0.1% TFA) to give the title compound (0.02 g; yellow solid; yield 25%). LC-MS (ESI): m/z (M+H)+ 365.25. ¹ H NMR (400 MHz, CD3OD): δ 7.93 (s, 1H), 7.84 (s, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.40 (d, J=1.0 Hz, 1H), 7.27 (s, 1H), 6.80 (d, J=1.7 Hz, 1H), 4.46 (d, J=6.3 Hz, 1H), 4.11-4.02 (m, 2H), 4.00 (s, 3H), 3.87-3.80 (m, 2H), 3.68 (td, J=11.6; 3.0 Hz, 1H), 3.56-3.44 (m, 1H), 1.41 (d, J=6.8 Hz, 3H).

Example 14.

(R)-3-methyl-4-(3-(1H-pyrazol-5-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6yl)morpholine.

The compound of Example 14 was prepared using a synthetic method similar to that described in Example 2.

Example 15.

(R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin6-yl)morpholine.

/^N

V-NH

Υ Ϊ ⁴ Ν νΥ \ /

Example 15 was prepared using a synthetic route similar to that described in Example 12. Off-white solid. LC-MS (ESI): m/z (M+H) ⁺ 366.1. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.88 (br, s, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 6.88 (d, J=1.6 Hz, 1H), 4.42 (d, J=6.4 Hz, 1H), 4.084.05 (m, 1H), 4.03 (s, 3H), 4.00-3.97 (m, 1H), 3.85 (s, 2H), 3.72-3.72 (m, 1H), 3.46-3.41 (m, 1H), 1.39 (d, J=6.8 Hz, 3H).

Example 16.

^)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5yl)morpholine.

N

Ynh % ⁿ ~n

Y

a) Preparation of 5-chloro-7-(1-methyl-N-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine. To a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (5 g; 26.59 mmol) in dioxane (100 ml) were added Pd(dppf)Cl ₂ and an aqueous solution of K ₃ PO ₄ (14.16 g; 53.19 mmol; 10 ml) at room temperature. The mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. Upon completion of the reaction, the reaction liquid was cooled to room temperature and water (100 ml) was added. The mixture was extracted with EtOAc (100 mL x 2), the organic layers were combined, washed with brine, dried using anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (SiO ₂ ; PE/EtOAc = 50/1 to 3/1) to give the desired product (3.35 g; yellow solid; yield 53.91%). LC-MS (ESI): m/z (M+H) ⁺ 234.30.

b) Preparation of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5yl)morpholine. To a solution of 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine (500 mg; 2.14 mmol) in toluene (30 ml) were added sodium tert-butoxide (514.11 mg; 5.35 mmol), (±)-2,2'bis(diphenylphosphino)-1,1'-binaphthalene (BINAP; 133.24 mg; 213.99 mmol) and tris(dibenzylideneacetone)dipalladium (195.95 mg; 213.99 mmol) at room temperature. The reaction liquid was refluxed and stirred for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried using anhydrous sodium sulfate, filtered and concentrated.

- 34 049140 was centrifuged to give a crude product, which was purified by column chromatography (SiO ₂ ; PE/EtOAc = 20/1 to 3/1) to give the desired product (69 mg; yellow solid; yield 10.8%). ^1H NMR (400 MHz, CDC13): δ 7.92 (d, J=2.1 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 6.64 (d, J=1.9 Hz, 1H), 6.33 (s, 1H), 6.22 (d, J=2.2 Hz, 1H), 4.34 (d, J=6.3 Hz, 1H), 4.06 (s, 2H), 3.89 (s, 3H), 3.81 (s, 2H), 3.65-3.58 (m, 1H), 3.39-3.32 (m, 1H), 1.36 (d, J=6.8 Hz, 3H).

c) Preparation of (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine. To a solution of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (59 mg; 197.76 μmol) in CHCl ₃ (5 mL) were added N-iodosuccinimide (NIS; 40 mg; 177.98 μmol) and trifluoroacetic acid (TFA; 22.55 mg; 197.76 μmol) at room temperature. The resulting liquid was stirred at room temperature for 2 h and quenched with saturated sodium bicarbonate solution (5 mL). The reaction liquid was concentrated to obtain a crude product, which was purified by column chromatography ( _SiO2 ; PE/EtOAc = 20/1 to 3/1) to give the target product (59 mg; yellow solid; yield 70.3%). LC-MS (ESI): (M+H)+: 425.4. ¹ H NMR (400 MHz, CDC13): δ 7.90 (s, 1H), 7.62 (d, J=1.9 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 6.33 (s, 1H), 4.38 (s, 1H), 4.22 (d, J=13.4 Hz, 1H), 4.07 (dd, J=11.5; 3.8 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 2H), 3.62 (td, J=11.9; 3.0 Hz, 1H), 3.42-3.34 (m, 1H), 1.25 (d, J=3.7 Hz, 3H).

d) Preparation of (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine. To a solution of (^)-4-(3-iodo-7-(1-methyl-1Hpyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine (33 mg; 77.79 μmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64.91 mg; 233.36 μmol), potassium phosphate trihydrate (41.43 mg; 155.57 μmol) in a solvent mixture of dioxane (8 ml) and water (1.5 ml) was added Pd(dppf)Cl ₂ (5.69 mg; 7.78 μmol). The mixture was stirred at 82°C for 2 hours. After completion of the reaction, the reaction liquid was concentrated to obtain a crude product, which was purified by column chromatography ( _SiO2 ; PE/EtOAc = 20/1 to 3/1) to give the target product (30 mg; yellow solid; yield 86.0%). LC-MS (ESI): m/z (M+H) ⁺ : 449.47.

e) Preparation of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5a]pyrimidin-5-yl)morpholine. A mixture of (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2Hpyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (30 mg; 66.89 μmol), 4 M HCl in dioxane (1 ml) and water (1 ml) was stirred at room temperature for 2 h and then concentrated under reduced pressure. The pH was adjusted to 8 by dropwise addition of ammonium hydroxide. The stirred liquid was purified by preparative HPLC (C18 column; 0-100% acetonitrile/water as mobile phase) to give the title compound (6.5 mg; yellow solid; 26.67%). LC-MS (ESI): m/z (M+H) ⁺ 365.1. 1H NMR (400 MHz, MeOD): δ 8.28 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.63 (br d, J=1.2 Hz, 1H), 6.90-6.83 (m, 1H), 6.80 (s, 1H), 6.76 (d, J=2.0 Hz, 1H), 4.65-4.57 (m, 1H), 4.25 (d, J=12.8 Hz, 1H), 4.05 (dd, J=3.6; 11.6 Hz, 1H), 3.86 (s, 4H), 3.81-3.75 (m, 1H), 3.64 (dt, J=2.8; 12.0 Hz, 1H), 3.42 (dt, J=3.6; 12.8 Hz, 1H), 1.39 (d, J=6.8 Hz, 3H).

Example 17.

(R)-3-methyl-4-(5-(methylsulfonyl)-1-(1 H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-c]pyrimidin3-yl)morpholine.

Example 18.

(R)-3-methyl-4-(1-(methylsulfonyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-c]pyrimidin-7 yl)morpholine.

Example 19.

(R)-3-methyl-4-(6-(methylsulfonyl)-1-(1 H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-a]pyrazin-3 yl)morpholine.

- 35 049140

Example 20.

(X)-3-methyl-4-(3-(methylsulfonyl)-8-(III-pyrrolo[2,3-b]pyridin-4-yl)-[1,2,4]triazolo[4,3a]pyrazin-6-yl)morpholine.

The following compounds of Examples 21-25 were prepared using a synthetic method similar to that described in Example 13.

su

- 36 049140

Example Ri Su LC-MS (ESI) !NMR(400 MHz) 21 r ⁿ * * ^A (M+H) ⁺ 364.25 CD ₃ OD: δ 8.04 (s, 1H), 7.77 (s, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.22 (s, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.96-6.90 (m, 1H), 6.79 (d, J = 1.9 Hz, 1H), 4.524.38 (m, 1H), 4.09-4.01 (m, 2H), 4.00 (s, 3H), 3.88-3.79 (m, 2H), 3.68 (td, J = 11.9; 2.6 Hz, 1H), 3.48 (td, J = 13.0; 3.9 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H). 22 * * A N=, (M+H) ⁺ 364.30 CD ₃ OD: δ 7.79 (s, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 2.1; 1.1 Hz, 1H), 7.22-7.18 (m, 2H), 6.78 (d, J = 1.9 Hz, 1H), 6.43 (t, J = 3.2 Hz, 1H), 4.46 (q, J = 4.9 Hz, 1H), 4.12-4.03 (m, 2H), 4.00 (s, 3H), 3.88-3.78 (m, 2H), 3.67 (td, J = 12.1; 3.2 Hz, 1H), 3.49 (td, J = 13.2; 4.0 Hz 1H), 1.39 (d, J = 6.8 Hz, 3H). 23 _N p ^H * -A (M+H) ⁺ 365.30 CD ₃ OD: δ 8.50 (s, 1H), 8.21 (s, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.60 (s, 1H), 7.07 (s, 1H), 6.79-6.74 (m, 1H), 4.454.38 (m, 1H), 4.06 (dd, J = 11.8; 2.3 Hz, 1H), 3.99 (s, 3H), 3.98-3.94 (m, 1H), 3.84 (s, 2H), 3.68 (td, J = 13.0; 3.2 Hz, 1H), 3.51-3.40 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H). 24 С· y-NH * * 0 (M+H) ⁺ 376.3 DMSO-d ₆ : δ 8.93 (s, 1H), 8.33 (s, 0.12H), 8.18 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.02 (s, 1H), 4.44 (d, J = 5.5 Hz, 1H), 3.98 (dd, J = 21.5; 11.8 Hz, 2H), 3.75 (q, J = 11.0 Hz, 2H), 3.57 (t, J = 11.0 Hz, 1H), 3.30-3.26 (m, 1H), 2.58 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H). 25 С· y-NH * * ά' (M+H) ⁺ 379.15 DMSO-d ₆ : δ 8.37 (s, 0.31H), 7.72 (t, J = 6.8 Hz, 2H), 7.63-7.55 (m, 1H), 7.48-7.36 (m, 2H), 7.27 (s, 1H), 7.11 (s, 1H), 6.97-6.88 (m, 1H), 4.38-4.30 (m, 1H), 3.93 (dd, J = 32.2; 11.1 Hz, 2H), 3.71 (q, J = 11.0 Hz, 2H), 3.593.48 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H).

- 37 049140

Example 26.

(R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine.

a) Preparation of 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine. A solution of 3,6-dichloropyridazin-4-amine (20.0 g, 121.9 mmol), hexane-2,5-dione (16.7 g, 146.3 mmol) and TsOH- _H2O (9.26 g, 48.76 mmol) in toluene (300 ml) was stirred at 140 °C using a Dean-Stark apparatus for 16 h. The mixture was cooled to room temperature and the toluene layer was decanted. The residue was purified by silica gel chromatography (EtOAc/PE; 10 to 20%) to give the title compound (10.2 g, brown solid; yield: 35%). ^1H NMR (400 MHz, CDCl ₃ ): δ 7.47 (s, 1H), 5.96 (s, 2H), 1.99 (s, 6H).

b) Preparation of (3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine. To a solution of 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine (10.2 g, 42.3 mmol) in NMP (100 mL) were added (3-methylmorpholine (5.1 g, 50.8 mmol) and DIEA (16.4 g, 126.9 mmol). The mixture was stirred at 190 °C for 6 h. Upon completion, water (200 mL) was added to the mixture and the mixture was extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (EtOAc/PE; 10 to 30%) to give the title compound (9.25 g; brown solid; yield: 71%). LC-MS (ESI): m/z (M+H)+ 307.10. ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.77 (d, J=4.6 Hz, 1H), 5.94 (d, J=4.6 Hz, 2H), 4.16 (d, J=7.6 Hz, 1H), 4.02 (dd, J=17.8; 13.0 Hz, 2H), 3.80 (d, J=4.5 Hz, 2H), 3.62 (d, J=12.1 Hz, 1H), 3.35 (d, J=12.7 Hz, 1H), 1.99 (s, 6H), 1.28 (d, J=6.2 Hz, 3H).

c) Preparation of (^)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile. To a solution of (^)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3methylmorpholine (9.25 g; 30.2 mmol) in DMF (100 ml) were added Zn(CN) ₂ (7.09 g; 136.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene (DPPF; 7.54 g; 13.6 mmol), _Pd2 (dba) ₃ (0.85 g; 0.93 mmol) and water (2 ml). The mixture was stirred at 150°C for 6 hours. Upon completion, water (200 mL) was added to the mixture and filtered. The filtrate was extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (EtOAc/PE; 20 to 50%) to give the title compound (8.4 g; brown solid; yield: 93%). 1H NMR (400 MHz, CDCl ₃ ): δ 6.58 (s, 1H), 5.97 (s, 2H), 4.35 (s, 1H), 4.20 (d, J=13.8 Hz, 1H), 4.13-4.05 (m, 1H), 3.89-3.75 (m, 2H), 3.70-3.61 (m, 1H), 3.51-3.37 (m, 1H), 2.07 (d, J=5.0 Hz, 6H), 1.36 (d, J=6.8 Hz, 3H).

d) Preparation of (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3yl)methanamine. To a solution of (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile (8.4 g, 28.3 mmol) in MeOH (100 mL) was added Raney Ni (ca. 40 g, w/w). The system was evacuated and filled with _H2 three times and the mixture was stirred at RT for 16 h.

Upon completion, the mixture was filtered through celite and the filter cake was washed with MeOH (90 mL x 10). The filtrate was combined and concentrated to give the title compound (5.6 g; black solid). ¹ H NMR (400 MHz, MeOD): δ 7.43 (s, 1H), 5.95 (s, 2H), 4.36 (s, 1H), 4.03 (d, J=12.2 Hz, 2H), 3.74-3.83 (m, 3H), 3.60 (d, J=11.6 Hz, 1H), 3.35 (s, 2H), 1.96 (s, 6H), 1.27 (d, J=7.0 Hz, 3H).

e) Preparation of (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)-methyl-N-pyrazole-N-carboxamide. To a solution of (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methanamine (5.6 g; 18.6 mmol) in DCM (60 mL) were added 1H-pyrazole-5-carboxylic acid (2.5 g; 22.3 mmol), HATU (4.3 g; 11.2 mmol) and DIEA (7.2 g; 55.8 mmol). The mixture was stirred at RT overnight. Then K2CO3 (5.1 g; 37.2 mmol) was added and the mixture was stirred at RT for for 1 h. Upon completion, water (100 mL) was added to the mixture and the mixture was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (MeOH/DCM; 1 to 3%) to give the title compound (4.3 g; yellow solid; yield: 38%). LC-MS (ESI): m/z (M+H) ⁺ 396.20. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.81 (s, 1H), 7.29 (s, 1H), 6.61 (s, 1H), 5.89 (s, 2H), 4.38 (s, 1H), 4.14-4.00 (m, 3H), 3.99-3.92 (m, 1H), 3.75-3.66 (m, 2H), 3.55-3.48 (m, 1H), 3.20-3.15 (m, 2H), 1.94 (s, 6H), 1.16 (d, J=6.6 Hz, 3H).

f) Preparation of (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-EDpyridazin2-yl)-3-methylmorpholine. A solution of (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpho

- 38 049140 lino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (4.3 g, 10.9 mmol) in _POCl3 (40 mL) was stirred at 120 °C for 4 h. Upon completion, the solvent was removed. Water (5 mL) was added to the mixture, the pH was adjusted to 8 with aqueous ammonium hydroxide (25% (w/w)) and the mixture was extracted with DCM (40 mL×2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (EtOAc/PE; 20 to 100%) to give the title compound (2.7 g, yellow solid; yield: 66%). LC-MS (ESI): m/z (M+H)+ 378.11. ^1H NMR (400 MHz, CDCL3): δ 7.71 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.37 (s, 1H), 5.98 (s, 2H), 4.16-4.03 (m, 2H), 3.95-3.75 (m, 3H), 3.72-3.66 (m, 1H), 3.52-3.41 (m, 1H), 2.11 (s, 6H), 1.37 (d, J=6.7 Hz, 3H).

g) Preparation of (R)-2-(3-methylmorpholino)-7-(1H-pyrrol-5-yl)imidazo[1,5-b]pyridazin-4-ol. A solution of (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine (2.7 g, 7.16 mmol) in TFA/ _H2O (20 ml/2.0 ml) was stirred at 85 °C for 16 h. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (MeOH/DCM; 1 to 10%) to give the title compound (1.5 g, yellow solid; yield: 71%). LC-MS (ESI): m/z (M+H) ⁺ 301.40. ^1H NMR (400 MHz, DMSO- _d6 ): δ 13.33 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 7.03 (s, 1H), 5.93 (s, 1H), 4.06 (s, 1H), 3.92 (d, 7= 11.3 Hz, 1H), 3.67 (s, 3H), 3.48 (s, 1H), 3.183.12 (m, 1H), 1.15 (s, 3H).

h) Preparation of (R)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl-N-imidazoCD-pyridazine-1-yl-trifluoromethanesulfonate. To a solution of (R)-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl-N-imidazoCD-pyridazine-1-ol (1.5 g, 5 mmol) in dry DCM (40 mL) was added TEA (1.5 g, 15.0 mmol) at 0 °C under nitrogen atmosphere and stirred at 0 °C for 10 min. Then Tf ₂ O (4.2 g, 15.0 mmol) was slowly added and the mixture was stirred at 0 °C for 30 min, then warmed to RT. After stirring for 1.5 h, the mixture was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (DCM/PE; 10 to 30%) to give the title compound (1.2 g; yellow solid; yield: 38%). LCMS (ESI): m/z (M+H) ⁺ 565.05. ¹ H NMR (400 MHz, CDCls): δ 8.16 (s, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 6.54 (s, 1H), 4.16-4.03 (m, 2H), 3.83 (m, 3H), 3.73-3.62 (m, 1H), 3.44 (d, J=13.4 Hz, 1H), 1.38 (d, J=6.8 Hz, 3H).

i) Preparation of ^)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-

b]pyridazin-2-yl)-3-methylmorpholine. To a solution of (D)-2-(3-methylmorpholino)-7-(1((trifluoromethyl-sulfonyl-D-pyrazol-N-yl-imidazo-CD-pyridazine-N-yl-trifluoromethanesulfonate (0.3 g, 0.53 mmol), 1-isopropyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150.2 mg, 0.64 mmol) and K2CO3 (219.4 mg, 1.59 mmol) in dioxane (2 mL) was added Pd(dppf) _Cl2 (77.6 mg, 0.11 mmol). The system was evacuated and filled with Ar three times and the mixture was stirred at 90 °C for 16 h. Upon completion, the mixture was cooled to room temperature and 2 N LiOH solution was added (1 mL). After stirring at RT for 0.5 h, the mixture was filtered and the filtrate was concentrated. The residue was purified twice by preparative TLC (MeOH/DCM = 10:1) to afford the title compound (17 mg; yellow solid; yield: 8%). LC-MS (ESI): m/z (M+H) ⁺ 393.15. 1H NMR (400 MHz, MeOD): δ 7.73 (s, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 4.61 (dd, J=12.9; 6.2 Hz, 1H), 4.33 (d, J=7.3 Hz, 1H), 4.07-3.99 (m, 1H), 3.91 (d, J=13.3 Hz, 1H), 3.86-3.75 (m, 2H), 3.67 (t, J=11.9 Hz, 1H), 3.41 (t, J=12.8 Hz, 1H), 1.46 (d, J=6.5 Hz, 6H), 1.35 (d, J=6.7 Hz, 3H).

Example 27 (R)-4-(4,7-di(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.

Example 27 was prepared using a synthetic method similar to that described in Example 26. Example 27 was a yellow solid. LC-MS (ESI): m/z (M+H) ⁺ 351.35. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.22 (t, J=3.2 Hz, 2H), 7.12 (s, 1H), 4.43 (s, 1H), 4.01 (d, J=11.3 Hz, 1H), 3.92 (d, J=13.3 Hz, 1H), 3.78 (t, J=10.1 Hz, 2H), 3.61-3.58 (m, 1H), 3.29-3.26 (m, 1H), 1.24 (d, J=6.8 Hz, 3H).

Example 28.

^)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-2yl)morpholine.

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Example 29.

(R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-3-yl)imidazo[5,1-f][1,2,4]triazin-2yl)morpholine.

Example 30.

^)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(III-pyrazol-5-yl)-[1,2,4]triazolo[3,4f][1,2,4]triazin-6-yl)morpholine.

Example 31.

^)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(III-pyrazol-5-yl)imidazo[1,5-a][1,3,5]triazin-2yl)morpholine.

Example 32.

^)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.

a) Preparation of (D)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine. A solution of 4,6-dichloro-3-methylpyridazine (3.0 g, 18.4 mmol), (D)-3-methylmorpholine (2.8 g, 27.6 mmol) and DIEA (4.8 g, 36.8 mmol) in NMP (30 mL) was stirred at 150 °C for 8 h. Upon completion of the reaction, water (50 mL) was added to the mixture and the mixture was extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/PE, 10% to 30%) to give the title compound (0.55 g; yellow solid; yield: 13%). LC-MS (ESI): m/z (M+H)+ 228.45. ¹ H NMR (400 MHz, _CDCl3 ): δ 6.81 (s, 1H), 4.29-4.15 (m, 1H), 4.04-3.95 (m, 1H), 3.87-3.73 (m, 3H), 3.60 (t, J=11.8 Hz, 1H), 3.27 (m, 1H), 2.58 (s, 3H), 1.24 (d, J=6.8 Hz, 4H).

b) Preparation of (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carbaldehyde. A mixture of (R)-4-(5-(5-methylpyridazin-3-yl)-3-methylmorpholine (510 mg; 2.24 mmol) and SeO ₂ (298 mg; 2.68 mmol) in 1,4-dioxane (10 ml) was stirred at 95°C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography.

- 40 049140 on silica gel (EtOAc/PE; 10 to 30%) to give the title compound (370 mg; yellow solid; yield: 68%). 1H NMR (400 MHz, CDCl ₃ ): δ 10.18 (s, 1H), 6.78 (s, 1H), 4.51 (s, 1H), 4.17 (d, J=13.2 Hz, 1H), 4.08 (d, J=10.8 Hz, 1H), 3.87-3.76 (m, 2H), 3.64 (t, J=11.8 Hz, 1H), 3.54-3.33 (m, 1H), 1.38 (d, J=6.4 Hz, 3H).

c) Preparation of (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-H-(2,4-dimethoxybenzyl)methanamine. AcOH (349 mg; 5.82 mmol) was added to a solution of methyl (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carbaldehyde (470 mg; 1.94 mmol) and (2,4-dimethoxyphenyl)methanamine (390 mg; 2.33 mmol) in DCE (8 ml). The resulting solution was stirred at room temperature for 1 h. NaBH(OAc) ₃ (822 mg; 3.88 mmol; 2.0 equiv) was added portionwise and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH, 100/1 to 50/1) to give the title compound (420 mg; yellow solid; yield: 55%). LC-MS (ESI): m/z (M+H)+ 393.30.

d) Preparation of (R)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine. A solution of (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine (420 mg; 1.07 mmol) in TFA (3 ml) was stirred at 80 °C for 3 h. After removal of the solvent, DCM (5 ml) and aqueous ammonium hydroxide solution (approximately 25% (w/w); 0.5 ml) were added to the residue. The solution was stirred at RT for 5 min and then concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH, 100/1 to 15/1) to give the title compound (210 mg; yellow solid; yield: 81%) as a yellow solid. LC-MS (ESI): m/z (M+H)+ 243.15.

e) Preparation of N-((4-chloro-6-(3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1Hpyrazole-5-carboxamide. To a solution of N-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine (190 mg, 0.78 mmol) in DMF (4 mL) were added N-pyrazole-5-carboxylic acid (88 mg, 0.78 mmol), HATU (593 mg, 1.56 mmol) and DIEA (202 mg, 1.56 mmol). The mixture was stirred at RT overnight. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). All organic layers were combined, washed with brine, dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH, 100/1 to 10/1) to afford the title compound (181 mg; yellow solid; yield: 69%). LC-MS (ESI): m/z (M+H)+ 337.20.

f) Preparation of (P)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine. A solution of N-((4-(1-methyl-1H-pyrazol-5-yl)-6-(N)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)1H-pyrazole-5-carboxamide (181 mg; 0.54 mmol) in _POCl3 (3 ml) was stirred at 120°C for 3 h. After removing the solvent, the residue was diluted with DCM (15 ml), washed with saturated aqueous _NaHCO3 , dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH, 100/1 to 10/1) to give the title compound (88 mg; yellow solid; yield: 51%). LC-MS (ESI): m/z (M+H)+ 319.20. 1H NMR (400 MHz, CDCl ₃ ): δ 7.72 (s, 1H), 7.64 (s, 1H), 7.09 (s, 1H), 6.57 (s, 1H), 4.16-4.00 (m, 2H), 3.86-3.78 (m, 2H), 3.78-3.60 (m, 2H), 3.48-3.36 (m, 1H), 1.36 (d, J=6.4 Hz, 3H).

g) Obtaining ((III)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine. To a mixture of (4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (70 mg, 0.22 mmol), cyclopropylboronic acid (11.38 mg, 0.44 mmol), K3PO4-3H2Q (176 mg, 0.22 mmol) in 1,4-dioxane (1 mL) and toluene (1 mL) were added Pd(OAc) ₂ (5 mg, 0.02 mmol) and tricyclohexylphosphine (11 mg, 0.04 mmol) under _N2 atmosphere. The system was evacuated and filled with _N2 three times. The mixture was stirred at 100 °C for 16 h. Upon completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to give the title compound (15 mg; slightly yellow solid; yield: 21%). LC-MS (ESI): m/z (M+H)+ 325.25. 1H NMR (400 MHz, CDC13): δ 7.70 (s, 1H), 7.61 (s, 1H), 7.08 (s, 1H), 6.07 (s, 1H), 4.16-4.05 (m, 2H), 3.87-3.81 (m, 2H), 3.75-3.63 (m, 2H), 3.46-3.36 (m, 1H), 2.15-2.07 (m, 1H), 1.33 (d, J=5.6 Hz, 3H), 1.20-1.15 (m, 2H), 1.03-0.97 (m, 2H).

The following compounds of Examples 33-63 were prepared using a synthetic method similar to that described in Example 13, Example 26 or Example 32.

- 41 049140

Example Ro Ri r ₂ MW (mol. weight)/bСMS (ESI) Ή NMR (400 MHz) 33 x * 0 An y-NH aS N=^ (M+H) ⁺ 365.4 CD ₃ OD: δ 7.75 (d, J = 2.2 Hz, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.20 (s, 1H), 6.88 (s, 1H), 6.74 (s, 1H), 4.36 (d, J = 6.1 Hz, 1H), 4.05 (d, J = 10.5 Hz, 1H), 3.98 (s, 3H), 3.93 (d, J = 13.9 Hz, 1H), 3.83 (s, 2H), 3.68 (t, J = 11.6 Hz, 1H), 3.42 (t, J = 12.6 Hz, 1H), 1.36 (d, J = 6.5 Hz, ZN). 34 With y-NH N=^ (M+H) ⁺ 379.45 CDCb: δ 7.71 (s, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.46 (s, 1H), 7.12 (s, 1H), 6.61 (s, 1H), 6.44 (s, 1H), 4.02-3.99 (m, 1H), 3.96 (s, 3H), 3.94-3.88 (m, 2H), 3.62 (dt, J = 11.5; 5.9 Hz, 2H), 3.47 (d, J = 6.3 Hz, 1H), 1.28 (s, 3H), 1.27 (s, 3H). 35 /^Ν y-NH (M+H) ⁺ 439.25 DMSO-do: δ 8.13 (s, 4H), 7.73 (s, 1H), 7.59 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 4.44 (s, 1H), 3.98 (dd, J = 22.6; 11.5 Hz, 2H), 3.75 (dd, J = 24.0; 10.9 Hz, 2H), 3.56 (s, 1H), 3.31-3.23 (m, 4H), 1.25 (d, J = 5.9 Hz, ZN). 36 0' y-NH ΐ VJ (M+H) ⁺ 378.15 CDCb: δ 7.71 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 6.37 (s, 1H), 5.98 (s, 2H), 4.09 (dd, J = 14.8; 8.1 Hz, 2H), 3.873.83 (m, 2H), 3.83-3.76 (m, 1H), 3.69 (t, J = 11.4 Hz, 1H), 3.51-3.40 (m, 1H), 2.10 (s, 6H), 1.37 (d, J = 6.6 Hz, ZN). 37 /^Ν y-NH N=^ (M+H) ⁺ 379.4 CDCb: δ 7.73 (s, 1H), 7.67 (s, 1H), 7.44 (s, 1H), 7.12 (s, 1H), 6.57 (s, 1H), 6.44 (s, 1H), 4.25 (q, J = 7.0 Hz, 2H), 4.19-4.08 (m, 2H), 3.87 (s, 2H), 3.81 (d, J = 12.1 Hz, 1H), 3.71 (td, J = 11.6; 3.0 Hz, 1H),

- 42 049140

3.56-3.42 (m, 1H), 1.45 (t, J = 7.3 Hz, 3H), 1.43-1.39 (m, 3H). 38 k/N-* <υ y-NH N-NH (M+H) ⁺ 365.30 CD ₃ OD: δ 8.01 (s, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.15 (s, 1H), 6.64 (s, 1H), 4.31 (d, J = 7.3 Hz, 1H), 4.03 (d, J = 12.0 Hz, 1H), 3.88 (d, J = 13.4 Hz, 1H), 3.82 (s, 2H), 3.67 (t, J = 11.6 Hz, 1H), 3.38 (t, J = 12.3 Hz, 1H), 2.46 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). 39 k' y-NH * (M+H) ⁺ 390.45 CDCb: δ 8.81 (s, 1H), 7.95 (s, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.82 (s, 1H), 6.47 (s, 1H), 4.18 (d, J = 7.3 Hz, 1H), 4.12-4.01 (m, 1H), 3.84 (s, 2H), 3.79 (d, J = 13.3 Hz, lH), 3.68 (t, J = 11.9 Hz, 1H), 3.51-3.37 (m, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H). 40 /^Ν y-NH (M+H) ⁺ 375.35 CD ₃ OD: δ 7.73 (s, 1H), 7.41-7.26 (m, 4H), 7.18 (s, 1H), 6.96 (s, 1H), 6.67 (s, 1H), 4.31 (d, J = 7.4 Hz, 1H), 4.04-3.97 (m, 1H), 3.90 (d, J = 13.4 Hz, 1H), 3.79 (s, 2H), 3.65 (t, J = 12.5 Hz, 1H), 3.39 (t, J = 12.9 Hz, 1H), 2.24 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H). 41 k^N^ /==Ν y-NH '^N^y- N=/ (M+H) ⁺ 379.2 DMSO-d ₆ : δ 7.79-7.58 (m, 1H), 7.47 (s, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 6.93 (s, 1H), 4.37 (s, 1H), 4.00 (d, J = 11.7 Hz, 1H), 3.93 (d, J = 13.4 Hz, 1H), 3.78 (s, 3H), 3.72 (dd, J = 15.8; 4.6 Hz, 2H), 3.57 (t, J = 11.6 Hz, 1H), 3.28 (s, 1H), 2.00 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H).

- 43 049140

42 /^Ν y-NH * (Μ+Η) ⁺ 376.1 CDC1 ₃ : δ 8.64 (d, J = 4.8 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.27 (dd, J = 8.3; 5.3 Hz, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 6.38 (d, J = 2.6 Hz, 1H), 4.19-4.07 (m, 2H), 3.84 (s, 2H), 3.80 (s, 1H), 3.69 (dd, J = 13.2; 10.2 Hz, 1H), 3.50-3.43 (m, 1H), 2.53 (s, 3H), 1.47-1.33 (m, 3H). 43 ΛΝ y-NH sU N (Μ+Η) ⁺ 380.1 DMSO-d ₆ : δ 8.83 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 7.83 (t, J = 5.6 Hz, 1H), 7.73 (s, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 4.37 (d, J = 7.5 Hz, 1H), 4.00 (d, J = 11.4 Hz, 1H), 3.92 (d, J = 13.4 Hz, 1H), 3.74 (q, J = 11.7 Hz, 2H), 3.57 (t, J = 11.7 Hz, 1H), 3.26 (brs, 1H), 1.26 (d, J = 6.6 Hz, 3H). 44 k/ ^N x, Z^N y-NH Ο ¹¹ // —ω—( ^ζ ')—» II \__/ ο —\ (Μ+Η) ⁺ 454.25 DMSO-d ₆ : δ 8.79 (s, 1H), 8.16 (s, 1H), 7.79-7.57 (m, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 6.99 (s, 1H), 4.40-4.31 (m, 1H), 4.05-3.90 (m, 2H), 3.74 (q, J = 11.5 Hz, 2H), 3.57 (t, J = 11.8 Hz, 1H), 3.34-3.24 (m, 4H), 2.44 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H). 45 k/ ^N -, <C' y-NH Ύ^ϊΐ Ν^Ν (Μ+Η) ⁺ 377.1 DMSO-d ₆ : δ 9.20 (s, 1H), 8.82 (s, 1H), 7.70 (s, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 6.99 (s, 1H), 4.40-4.29 (m, 1H), 4.00 (d, J = 11.0 Hz, 1H), 3.92 (d, J = 13.4 Hz, 1H), 3.74 (q, J = 11.3 Hz, 2H), 3.58 (d, J = 12.0 Hz, 1H), 3.29 (s, 1H), 2.48 (s, 3H), 1.26 (d, J = 6.7 Hz, 3H).

- 44 049140

46 Υ^ /^Ν y-NH ό (M+N) ⁺ 370.2 CDCb: δ 7.72 (s, 1H), 7.53 (s, 1H), 7.09 (s, 1H), 5.65 (s, 1H), 4.15-4.06 (m, 2H), 3.95-3.89 (brs, 4H), 3.86-3.75 (brs, 2H), 3.67 (t, J = 12.2 Hz, 2H), 3.49-3.40 (m, 5H), 1.34 (d, J = 6.3 Hz, 3H). 47 Υ ^Ν -* /^Ν Υ·ΝΗ γ (M+N) ⁺ 430.05 CD ₃ OD: δ 8.84 (d, J = 4.6 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.81 (t, J = 6.2 Hz, 1H), 7.74 (s, 1H), 7.20 (s, 1H), 7.03 (s, 1H), 6.79 (s, 1H), 4.32-4.24 (m, 1H), 4.07-4.00 (m, 1H), 3.91 (d, J = 13.4 Hz, 1H), 3.81 (s, 2H), 3.71-3.61 (m, 1H), 3.49-3.34 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H). 48 Υν., An Yνη A o=s=o 1 (M+N) ⁺ 454.25 DMSO-d ₆ : δ 8.19 (d, J = 7.9 Hz, 1H), 8.01 (d, 3 = 7.7 Hz, 1H), 7.68 (s, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 6.97 (s, 1H), 4.31 (s, 1H), 3.97 (d, J = 11.7 Hz, 1H), 3.89 (d, J = 13.3 Hz, 1H), 3.71 (q, J = 11.5 Hz, 3H), 3.55 (d, J = 11.5 Hz, 1H), 3.31-3.25 (m, 3H), 2.54 (s, 3H), 1.22 (d, J = 6.7 Hz, 3H). 49 Υ'. /^Ν Υ-ΝΗ .---ч О / \ ¹¹ * —\\ //— — А // II /— ° (M+N) ⁺ 453.3 DMSO-d ₆ : δ 7.97 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.11 (s, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 4.32 (d, J = 7.2 Hz, 1H), 4.01-3.85 (m, 2H), 3.70 (q, J= 11.5 Hz, 2H), 3.53 (t, J= I.6Hz, 2H), 3.26 (s, 3H), 2.34 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H). 50 Υ ^ν -* Z^N y-NH ★ o=s 1 (M+N) ⁺ 438.25 DMSO-d ₆ : δ 8.18 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.70 (dt, J = 26.3; 13.4 Hz, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 6.97 (s, 1H), 4.36 (s, 1H), 3.97 (dd, J =

- 45 049140

29.9; 12.3 Hz, 2H), 3.74 (q, J = 11.6 Hz, 2H), 3.57 (t, J = 11.9 Hz, 1H), 3.25 (s, 1H), 2.87 (s, 3H), 2.53 (d, J = 4.3 Hz, 3H), 1.26 (d, J = 6.6 Hz, 3H). 51 С· y-NH D (M+H) ⁺ 376.25 DMSO-d ₆ : δ 8.61 (s, 1H), 8.53 (d, J = 4.8 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J = 4.9 Hz, 1H), 7.10 (s, 2H), 6.83 (s, 1H), 4.37-4.29 (m, 1H), 3.92 (dd, J = 31.4; 12.3 Hz, 2H), 3.69 (q, J = 10.7; 9.8 Hz, 2H), 3.55-3.50 (m, 1H), 3.25-3.20 (m, 1H), 2.23 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H). 52 ΛΝ y-NH ..2 (M+H) ⁺ 386.1 DMSO-d ₆ : δ 8.34 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.63 (s, 2H), 7.14 (s, 1H), 7.07 (s, 1H), 4.51-4.40 (m, 1H), 4.063.92 (m, 2H), 3.76 (q, J = 11.2 Hz, 2H), 3.57 (t, J = 11.0 Hz, 2H), 1.26 (d, J = 6.2 Hz, 3H). 53 A/ ⁿ ^* /^N y-NH 0 (M+H) ⁺ 367.25 CDCb: δ 8.84 (d, J = 8.1 Hz, 1H), 7.957.77 (m, 1H), 7.57-7.39 (m, 1H), 6.34 (d, J = 11.5 Hz, 1H), 5.96 (d, J = 17.2 Hz, 1H), 4.32-4.17 (m, 1H), 4.14-3.93 (m, 2H), 3.93-3.78 (m, 3H), 3.77-3.61 (m, 3H), 3.45 (dq, J = 26.3; 14.4; 13.7 Hz, 2H), 2.33-2.13 (m, 1H), 1.84 (dd, J = 37.1; 12.6 Hz, 1H), 1.42-1.33 (m, 3H). 54 /^N y-NH i MW 368,44 / 55 Ad /^N y-NH lA N N (M+H) ⁺ 401.45 DMSO-d ₆ : δ 12.00 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 7.73 (s, 1H), 7.63 (s, 1H),

- 46 049140

7.44 (d, J = 4.8 Hz, lH),7.38(s, 1H),7.16 (s, 1H), 7.04 (s, 1H), 6.51 (s, 1H), 4.424.34 (m, 1H), 4.01 (d, J = 10.6 Hz, 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.76 (t, J = 9.8 Hz, 3H), 3.58 (s, 1H), 1.28 (d, J = 6.6 Hz, 3H). 56 A/N·-.* /^Ν y-NH * N-N (M+H) ⁺ 379.15 CDCb: δ 7.76 (s, 1H), 7.71 (s, 1H), 7.51 (s, 1H), 7.09 (s, 1H), 6.30 (s, 1H), 4.194.08 (m, 2H), 3.91 (s, 3H), 3.86 (s, 2H), 3.79 (d, J = 13.0 Hz, 1H), 3.70 (t, J = 11.9 Hz, 1H), 3.47 (dt, J = 13.3; 6.0 Hz, 1H), 2.43 (s, 3H), 1.38 (d, J = 6.7 Hz, 3H). 57 <C y-NH (M+H) ⁺ 365.4 DMSO-d ₆ : δ 7.95 (s, 1H), 7.71 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 4.42-4.33 (m, 1H), 4.01 (d, J = 11.4 Hz, 1H), 3.90 (d, J = 13.1 Hz, 1H), 3.83 (s, 3H), 3.75 (d, J = 9.9 Hz, 2H), 3.57 (s, 2H), 1.24 (d, J = 7.8 Hz, 3H). 58 С· y-NH N-N (M+H) ⁺ 379.1 DMSO-d ₆ : δ 8.32 (s, 1H), 7.73-7.65 (m, 1H), 7.59 (s, 1H), 7.11 (s, 1H), 6.66 (s, 1H), 4.36-4.27 (m, 1H), 4.02 (q, J = 9.2; 8.3 Hz, 2H), 3.87-3.83 (m, 4H), 3.74 (q, J = 11.6 Hz, 2H), 3.34-3.17 (m, 1H), 2.38 (s, 3H), 1.23 (d, J = 6.7 Hz, 3H). 59 A/N _χ * /^N y-NH V^, ^N NN MW 379.43 / 60 °Α^* ΛΝ y-NH No.* MW 396.43 / 61 A/A* With y-NH Λ N— F (M+H) ⁺ 397.3 CD ₃ OD: δ 8.01 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.15 (d,

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J = 23.4 Hz, 2H), 7.04 (s, 1H), 4.91 (t, J = 4.6 Hz, 1H), 4.79 (t, J = 4.8 Hz, 1H), 4.61 (t, J = 4.7 Hz, 1H), 4.55 (t, J = 4.7 Hz, 1H), 4.44-4.33 (m, 1H), 4.05 (d, J = 11.0 Hz, 1H), 3.92 (d, J = 13.3 Hz, 1H), 3.84 (s, 2H), 3.75-3.64 (m, 1H), 3.49-3.35 (m, 1H), 1.35 (d, J = 6.7 Hz, 3H). 62 /=*N y-NH MW 400,39 / 63 /^N y-NH Λ N— ^{J F} ~< F (M+H) ⁺ 401.15 CD ₃ OD: δ 8.36 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.28 (d, J = 3.0 Hz, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 4.47-4.35 (m, 1H), 4.05 (d, J = 11.4 Hz, 1H), 3.94 (d, J = 13.5 Hz, 1H), 3.84 (s, 2H), 3.69 (t, J = 11.8 Hz, 1H), 3.42 (t, J = 13.2 Hz, 1H), 1.35 (d, J = 6.5 Hz, 3H).

Example 64. Determination of the inhibitory effect of (^)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and its analogs on the activity of the ATR kinase enzyme using an experiment to determine the activity of the ATR kinase enzyme.

ATR kinase enzyme activity was measured using HTRF reagent (Cisbio) in a 384-well plate (Greiner, #784075). The test compound was diluted to 4-fold final concentration in reaction buffer (containing 25 mM 2-hydroxyethyl-piperazine-2-ethanesulfonic acid (HEPES) (pH 8.0), 10 mM _MnCl2 , 1% glycerol, 0.01% Brij-35, 5 mM dithiothreitol (DTT), and 0.1% bovine serum albumin (BSA)). 2.5 μl of the diluted compound solution were added to the appropriate well, followed by 2.5 μl of 80 nM substrate solution (p53; Eurofins, #14952) and 2.5 μl (2 ng/μl) of ATR/ATRIP enzyme solution (Eurofins, 14-953) and finally 2.5 μl of 40 μM ATP solution. The mixture was centrifuged at 1000 rpm for 1 minute and reacted at room temperature, protected from light, for 30 minutes. Then, 5 μl of EDTA (250 mM) stop solution were added to stop the reaction. After 5 μl of detection mixture (containing anti-phospho-p53 (ser15)-K antibody (Cisbio, #61P08KAE; 0.084 ng/μl) and anti-glutathione-S-transferase-2 (GST-d2) antibody (Cisbio, #61GSTDLA; 5.00 ng/μl)) were finally added to each well, fluorescence signals were measured at 665 nm and 615 nm using an Envision 2104 instrument. The relative fluorescence signal ratio was calculated as _{the 665} nm/ _{615 nm} ratio - the _background ratio, and the inhibition rate in % was _calculated as (1 - (relative fluorescence signal ratio in the well with the test compound - relative signal ratio positive control)/(relative fluorescence signal ratio in the blank control well - relative fluorescence signal ratio with the positive control))/100. Data were analyzed using GraphPad Prism 6.0, curve fitted using the equation: Y=Bottom+(Top-Bottom)/(1+10 ^Λ ((LogIC ₅₀ X)*HillSlope)), and IC ₅₀ values were calculated.

Table 1 summarizes the data on the inhibitory effect of compounds on ATR kinase activity (IC ₅₀ ).

Table 2 summarizes the data on the inhibitory effect of compounds at a concentration of 50 nM on ATR kinase activity (% inhibition).

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Table 1

Example 1 2 5 6 13 21 1C ₅ o (nM) >10000 938 58.9 379 4 6.78 Example 22 23 24 25 26 32 1C ₅ o (nM) 2.06 >1000 2 7 6 15 Example 37 39 40 41 42 43 1C ₅ o (nM) 7 3 2 2 2 12 Example 45 46 47 48 49 50 1C ₅ o (nM) 5 12 1 AND 6 16 Example 52 BAY-1895344 1C ₅ o (nM) 9 42*

*: This IC50 value is obtained by comparison with the compound of Example 13.

Table 2

Example 11 33 35 36 38 44 % inhibition 63 27 71 63 90 58

Thus, as established in the experiment on determining the activity of the ATR kinase enzyme, (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine (the compound of Example 13) and analogs have a strong inhibitory effect on the activity of ATR kinase.

Example 65. Determination of the inhibitory effect of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and its analogues on the proliferation of human prostate cancer DU145 cells using the MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.

Thawed DU145 human prostate cancer cells were cultured and passaged until they reached satisfactory growth and a confluency level of approximately 90% and were then used for experiments. The cells were trypsinized and centrifuged at 800 rpm for 5 min, the supernatant was discarded, the residue was resuspended in fresh medium (DMEM + 10% FBS + nonessential amino acids) and counted. The cells were seeded in a 96-well cell culture plate at a density of 2000 cells/well and incubated overnight in an incubator with 5% CO2 at 37°C. Serial dilutions of the concentrated solutions of the test substances (including the test compounds and the reference compound BAY-1895344) in DMSO were performed at ratios of 1:3 and 1:10 to obtain 8 concentrations, respectively. 5 μl of the solutions at each concentration were added to 120 μl of the medium (25-fold dilution) and mixed by shaking. After overnight, the culture medium was removed from the cell plates, 195 μl of fresh medium was added to each well, and 5 μl of the diluted medium containing the test compound at the appropriate concentration were added, respectively (the final concentrations of the compounds are shown in Table 3, the final concentration of DMSO is 1%), and the culture plate was then placed in an incubator with 5% CO2 at 37°C for 4 days. After removing the stock solution, 100 μl of fresh serum-free DMEM containing MTT (0.5 mg/ml) was added to each well and culturing was continued. After 4 h, the stock solution was removed, 100 μl of DMSO was added to each well, the 96-well plates were shaken for 10 min in the dark and placed in a multi-well plate reader to measure absorbance (optical density (OD)) at 552/690 nm. GraphPad Prism 6.0 was used for data analysis. The inhibitory activity of the compounds on cell proliferation was determined based on a plot of cell viability versus the logarithm of compound concentration. Cell viability (%) = (OD^^^a - ODфo _Hа )/(ODD _MS o - ODфo _Hа ) ^χ 100. The IC50 value was obtained using the approximation of the sigmoidal dose-response curve equation Y = 100/(1+10 ^A (LogC - LogIC50)), where C was the concentration of the compound.

Table 3 summarizes the data on the inhibitory effect of the compounds on the proliferation of human prostate cancer DU145 cells.

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Table 3

Example 2 3 4 6 7 8 9 10 1C ₅ o (nM) 1217 1097 1093 913.7 1196 1108 1631 2298 Example 13 16 BAY-1895344 1C ₅ o (nM) 130.9 1374 33.92*

* : This IC50 value is obtained by comparison with the compound of Example 13.

Thus, as found by the MTT assay, (^)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (the compound of Example 2) has an inhibitory effect on the proliferation of DU145 cells. (^)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (the compound of Example 13) has a strong inhibitory effect on the proliferation of DU145 cells.

Example 66.

Determination of the inhibitory effect of (^)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and its analogues on the proliferation of human lung cancer NCIH460 cells using the MTT assay.

Thawed NCI-H460 human lung cancer cells were cultured and passaged until they reached satisfactory growth and a confluency level of approximately 90% and were then used for experiments. The cells were trypsinized and centrifuged at 800 rpm for 5 min, the supernatant was discarded, the residue was resuspended in fresh medium (1640 media + 10% FBS) and counted. The cells were seeded in a 96-well cell culture plate at a density of 2000/4000 cells/well and incubated overnight in a 5% _CO2 incubator at 37°C. Serial dilutions of concentrated solutions of test substances (including test compounds and reference compound BAY-1895344) in DMSO were performed at ratios of 1:3 and 1:10 to obtain 8 concentrations, respectively. 5 μl of solutions at each concentration were added to 120 μl of medium (25-fold dilution) and mixed by shaking. After overnight, the culture medium was removed from the cell plates, 195 μl of fresh medium and, respectively, 5 μl of the diluted medium containing the test compound at the appropriate concentration (the final DMSO concentration is 1% o) were added to each well, and the culture plate was then placed in an incubator with 5% _CO2 at 37°C for 4 days. After removing the stock solution, 100 μl of fresh serum-free DMEM containing MTT (0.5 mg/ml) were added to each well and culturing was continued. After 4 h, the stock solution was removed, 100 μl of DMSO were added to each well, the 96-well plates were shaken for 10 min in the dark and placed in a multi-well plate reader to measure absorbance at 552/690 nm. Cell viability (%) = (OR of _{the compound} - ODφ _ona )/(OD _DM s _O ODφ _ona )×100. GraphPad Prism 6.0 was used for data analysis. The inhibitory activity of the compounds on cell proliferation was determined based on a plot of cell viability versus the logarithm of the compound concentration. The IC ₅₀ value was obtained using the sigmoidal dose-response curve fit Y = 100/(1 + 10 ^A (LogC - LogIC ₅₀ )), where C was the concentration of the compound.

Table 4 summarizes the data on the inhibitory effect (IC ₅₀ ) of the compounds on the proliferation of human lung cancer NCI-H460 cells.

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Table 4

Example 2 3 4 5 6 7 8 9 1C ₅ o (nM) 907.2 1038 531,0 1607 321.9 863,5 409.4 582.8 Example 10 11 12 13 15 16 21 22 1C ₅ o (nM) 1114 158.8 >10000 41.33 1916 526.8 243.8 1149 Example 23 24 25 26 27 32 33 34 1C ₅ o (nM) 1801 27.84 40.36 55.24 286.7 78,58 255.9 1522 Example 35 36 37 38 39 40 41 42 1C ₅ o (nM) 170.7 115.9 58,76 418.7 26.05 17.35 48.75 30.63 Example 43 44 45 46 47 48 49 50 1C ₅ o (nM) 18,19 289.1 78,80 77,81 18,18 155.7 43,02 86,82 Example 51 52 55 61 BAY- 1895344 1C ₅ o (nM) 76.33 26.34 95.31 169.1 21.47*

* : This IC50 value is obtained by comparison with the compound of Example 13.

Thus, as found in the MTT assay, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (the compound of Example 2) has an inhibitory effect on the proliferation of NCI-H460 cells. (R)-3-methyl-4-(4-(1methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (the compound of Example 13) and analogs have a strong inhibitory effect on the proliferation of NCI-H460 cells.

Example 67. Determination of the inhibitory effect of (^)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and its analogues on the proliferation of human colon cancer LoVo cells using an MTT assay.

Thawed LoVo human colon cancer cells were cultured and passaged until they reached satisfactory growth and a confluency level of approximately 90% and then used for experiments. Cells were trypsinized and centrifuged at 800 rpm for 5 min, the supernatant was discarded, the residue was resuspended in fresh medium (1640 media + 10% FBS) and counted. Cells were seeded in 96-well cell culture plates at a density of 2000/4000 cells per well and incubated overnight in a 5% CO2 incubator at 37°C. Serial dilutions of concentrated solutions of test substances (including test compounds and reference compound BAY1895344) in DMSO were performed at ratios of 1:3 and 1:10 to obtain 8 concentrations, respectively. 5 μl of solutions at each concentration were added to 120 μl of medium (25-fold dilution) and mixed by shaking. After overnight, the culture medium was removed from the cell plates, 195 μl of fresh medium and, respectively, 5 μl of the diluted medium containing the test compound at the appropriate concentration (the final DMSO concentration is 1%) were added to each well, and the culture plate was then placed in an incubator with 5% CO2 at 37°C for 4 days. After removing the stock solution, 100 μl of fresh serum-free DMEM containing MTT (0.5 mg/ml) was added to each well and culturing was continued. After 4 h, the stock solution was removed, 100 μl of DMSO was added to each well, the 96-well plates were shaken for 10 min in the dark and placed in a multi-well plate reader to measure absorbance at 552/690 nm. Cell viability (%) = (OD^^^^ ODфo _Hа )/(ODDм _S o - ODфo _Hа ) ^χ 100. GraphPad Prism 6.0 was used for data analysis. The inhibitory activity of the compounds on cell proliferation was determined based on a plot of cell viability versus the logarithm of compound concentration. The IC50 value was obtained using the sigmoidal dose-response curve fit Y = 100/(1 + 10 ^A (LogC LogIC50)), where C was the concentration of the compound.

Table 5 summarizes the data on the inhibitory effect (IC ₅₀ ) of the compounds on the proliferation of human colon cancer LoVo cells.

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Table 5

Example 5 11 12 13 15 21 22 23 1C ₅ o (nM) 557.2 167.7 3226 53.5 597.3 155.1 854.3 1528 Example 24 25 26 27 32 33 34 35 1C ₅ o (nM) 34.39 61,92 68.20 124,0 87.31 230.3 953.3 75.39 Example 36 37 38 39 40 41 42 43 1C ₅ o (nM) 114,0 45,02 127.9 30.74 21.83 49,52 44.69 23.12 Example 44 45 46 47 48 49 50 51 1C ₅ o (nM) 138.2 84.15 72,80 20.73 133.4 32.94 59.87 76,66 Example 52 55 61 BAY-1895344 1C ₅ o (nM) 41.87 51,02 175.3 26.02

* : This IC ₅₀ value is obtained by comparison with the compound of Example 13.

Thus, as found in the MTT assay, (^)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (the compound of Example 2) has an inhibitory effect on the proliferation of LoVo cells. (^)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (the compound of Example 13) and its analogs have a strong inhibitory effect on the proliferation of LoVo cells.

Having now fully described the present invention, it will be apparent to one of ordinary skill in the art that similar actions can be performed under a wide and equivalent range of conditions, compositions and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications and publications cited in this specification are hereby incorporated by reference in their entirety.

Claims (10)

1. Compound of formula I: or its stereoisomer, tautomer, isotopically substituted derivative or pharmaceutically acceptable salt, where: Ri is sulfonyl substituted with C1- _C4 alkyl, or pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1 or 2 substituents selected from the group consisting of _C1C4 alkyl, halogen, hydroxyl, C1- _C4 alkoxy and amino; R2 is _C3 - _C6 cycloalkyl, heterocyclic group, _C6 - _C14 aryl or heteroaryl, wherein each of said _C3 - _C6 cycloalkyl, heterocyclic group, _C6 - _C14 aryl and heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of C1- _C6 alkyl optionally substituted with 1-5 halogens, cyano, halogen, C1- _C4 alkylsulfinyl and C1- _C4 alkylsulfonyl; R ₃ and R4 independently represent hydrogen or C1-C ₆ alkyl; wherein the heterocyclic group is a saturated or partially saturated 3-7 membered monocyclic or 7-10 membered bicyclic ring system that consists of carbon atoms and one to four heteroatoms independently selected from O, N and S; wherein heteroaryl is a group having 5-14 ring atoms consisting of carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein 6, 10 or 14 π-electrons are shared in the cyclic structure; where the penta-fused hexa-heteroaryl containing A1, _A2 , _A3 , A4, A5 and A6 is: - 52 049140 where *1, *2 and *3 denote the places of attachment of this group to morpholinyl, R ₁ and R2 in this compound, respectively; wherein the isotopically substituted derivative is a derivative in which at least one atom is replaced by an atom having the ^same atomic number, but its atomic mass differs from the atomic mass most commonly found in nature, which is selected from ^2H , ^3H , 11C, 13C, ^14C , ^15N , ^17O , 18O, ^35S , ^18F , ^36Cl and ^{125I .} 2. The compound of claim 1, wherein the compound is a compound of formula II, IIIa or IIIb: its stereoisomer, tautomer, isotopically substituted derivative, or pharmaceutically acceptable salt, wherein the penta-fused hexa-heteroaryl containing A1-A6, R1, R2 and R4 are as defined in paragraph 1. 3. A connection according to any of paragraphs 1-2, where R2 is optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl or optionally substituted pyrrolopyridyl; wherein the substituent on R2 is selected from the group consisting of C1- _C6 alkyl, halogen and C1- _C4 alkyl sulfonyl; and/or R4 is C1- _C4 alkyl. 4. The connection according to item 1, where: penta-fused hexa-heteroaryl containing A1-A6 is R ₁ is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C ₁ C ₄ alkyls; R2 is heteroaryl optionally substituted with one or two C 1 -C ₄ alkyls, C ₆ -C ₁₄ aryl optionally substituted with 1-2 substituents selected from the group consisting of C 1 -C ₄ alkylsulfonyl and halogen, or a heterocyclic group optionally substituted with one or two C ₁ -C ₄ alkyls; one of R ₃ and R ₄ is H and the other is C ₁ -C ₄ alkyl; or a penta fused hexa-heteroaryl containing A1 -A6 is R ₁ is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C ₁ C ₄ alkyls; R 2 is heteroaryl optionally substituted with one or two substituents selected from the group consisting of halogen, C 1-C ₄ alkylsulfonyl, C 1-C ₄ alkylsulfinyl, C 1C ₄ alkyl optionally substituted with one to three halogen atoms, C ₆ -C ₁₄ aryl optionally substituted with 1-2 substituents selected from the group consisting of C 1-C ₄ alkyl, -CN, C 1-C ₄ alkylsulfonyl and halogen, or a heterocyclic group optionally substituted with one or two C ₁ -C ₄ alkyls; R ₃ and R ₄ are independently selected from the group consisting of H and C 1-C ₄ alkyl; or - 53 049140 penta-fused hexa-heteroaryl containing A ₁ -A ₆ is *z R1 is pyrazolyl optionally substituted with O-C/alkyl; R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1 _-C4 alkyl substituted with one to three halogen atoms; R3 and _R4 are independently selected from the group consisting of H and C1- _C4 alkyl. 5. The compound according to claim 4, wherein the penta-fused hexa-heteroaryl containing A ₁ -A ₆ is R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C1C4 alkyls; R2 is pyrazolyl, pyridinyl, pyrrolopyridinyl or imidazolyl optionally substituted with one or two C1-C4 alkyls, phenyl optionally substituted with 1-2 substituents selected from the group consisting of _C1 - _C4 alkylsulfonyl and halogen, or morpholinyl optionally substituted with one or two _C1 - _C4 alkyls; one of _R3 and _R4 is H and the other is C1- _C4 alkyl; or a penta-fused hexa-heteroaryl containing _A1 - _A6 is R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted with 1-2 C1C4 alkyls; R2 is pyrazolyl, pyrrolyl, pyridinyl, pyrrolopyridinyl, pyrimidinyl, triazolyl or imidazolyl optionally substituted with one or two substituents selected from the group consisting of halogen, C1- _C4 alkylsulfonyl, C1- _C4 alkylsulfinyl, C1- _C4 alkyl optionally substituted with one to three halogen atoms, phenyl optionally substituted with 1-2 substituents selected from the group consisting of C1- _C4 alkyl, -CN, C1- _C4 alkylsulfonyl and halogen, or morpholinyl, dihydropyranyl or tetrahydropyranyl optionally substituted with one or two _C1 - _C4 alkyls; R ₃ and R ₄ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl; or a penta-fused hexa-heteroaryl containing A ₁ -A ₆ is R1 is pyrazolyl optionally substituted with O-C/alkyl; R2 is pyrazolyl optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1- _C4 alkyl and C1 _-C4 alkyl substituted with one to three halogen atoms; R3 and _R4 are independently selected from the group consisting of H and C1- _C4 alkyl. 6. The compound according to claim 1, wherein the compound is selected from the group consisting of: (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine; (R)-3-methyl-4-(8-(1-ethyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine; ((SH)-3-methyl-4-(8-(1-isopropyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine; (R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine; (R)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine; (R)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6yl)morpholine; (R)-3-methyl-4-(8-(2-fluorophenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; - 54 049140 (R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (2S,6R)-2,6-dimethyl-4-(6-((R)-3-methylmorpholino)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8yl)morpholine; 4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6yl)morpholine; (III)-3-methyl-4-(4-(1-methyl-III-pyrazol-5-yl)-7-(III-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; (K)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4|triazo.to[4,3-b|pyridazin6-yl)morpholine; (III)-3-methyl-4-(7-(1-methyl-III-pyrazol-5-yl)-3-(III-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine; (K)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5-b|pyridazin-2yl)morpholine; (K)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-2-yl)imidazo[1.5-b|pyridazin-2yl)morpholine; (R)-4-(7-(1H-imidazol-4-yl)-4-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3 methylmorpholine; (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; N)-4-(4-(2-fluorophenyl)-7-(N-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; U)-4-(4-(1-isopropyl-III-pyrazol-5-yl)-7-(III-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; U)-4-(4,7-di(1H-pyrazol-5-yl)imidazol[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (III)-3-methyl-4-(4-(1-methyl-III-pyrazol-5-yl)-8-(III-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-2yl)morpholine; (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-3-yl)imidazo[5,1-f][1,2,4]triazin-2yl)morpholine; U)-4-(4-cyclopropyl-7-(III-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (b)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1.5-b|pyridazin-2yl)morpholine; (3R,5R)-3,5-dimethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin2-yl)morpholine; (R)-3-methyl-4-(4-(4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; (R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; (R)-3-methyl-4-(4-(3-methyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; (R)-3-methyl-4-(7-(3-methyl-1H-pyrazol-5-yl)-4-(6-methylpyridin-3-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; (R)-4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; (R)-3-methyl-4-(4-(2-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; (R)-4-(4-(3-fluoropyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3 methylmorpholine; (R)-3-methyl-4-(4-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; (R)-3-methyl-4-(4-morpholino-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; (R)-3-methyl-4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine; U)-3-methyl-4-(4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5b]pyridazin-2-yl)morpholine; (3R)-3-methyl-4-(4-(2-methyl-6-(methylsulfinyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo [1,5- 55 049140 b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(3-methylpyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2yl)morpholine; N)-3-(2-(3-methylmorpholino)-7-(N-pyrazol-5-yl)imidazo[1,5-b]pyrrvdazin-4-yl)benzonitrile; (P)-4-(4-(.3,6-dihydro-2H-pyran-4-yl)-7-(1H-pyrazol-5-yl)imidazo|1,5-b|pyridazin-2-yl)-.3-methylmorpholine; (P)-4-(7-(1H-pyrazol-5-yl)-4-(telrahydro-2H-pyran-4-yl)imidazo|1.5-b|pyridazin-2-yl)-.3methylmorpholine; (P)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo|2..3-b|pyridin-4-yl)imidazo|1.5-b|pyridazin-2-yl)-.3methylmorpholine; (P)-4-(4-(1.5-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo|1.5-b|pyridazin-2-yl)-.3methylmorpholine; (R)-3-methyl-4-(4-(1-methyl-III-imidazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo 11,5-b]pyridazin-2yl)morpholine; (R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3methylmorpholine; or its stereoisomer, tautomer, isotopically substituted derivative, or pharmaceutically acceptable salt. 7. Use of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, isotopically substituted derivative or pharmaceutically acceptable salt thereof in the manufacture of a medicinal product for the treatment or prevention of an ATR (ataxia-telangiectasia and Rad3-related) kinase-mediated disease. 8. The use according to claim 7, wherein the ATR kinase-mediated disease is a cancer selected from liver cancer. melanoma. Hodgkin's disease. non-Hodgkin's lymphomas. acute lymphocytic leukemia. chronic lymphocytic leukemia. multiple myeloma. neuroblastoma. breast carcinoma. ovarian carcinoma. lung carcinoma. Wilms' tumor. cervical carcinoma. testicular carcinoma. soft tissue sarcoma. primary macroglobulinemia. bladder carcinoma. chronic granulocytic leukemia. primary brain carcinoma. malignant melanoma. small cell lung carcinoma. gastric carcinoma. colon carcinoma. malignant insulinoma of the pancreas. malignant carcinoid carcinoma. choriocarcinoma. mycosis fungoides. Head and neck carcinoma. Osteosarcoma. Pancreatic carcinoma. Acute granulocytic leukemia. Hairy cell leukemia. Rhabdomyosarcoma. Kaposi's sarcoma. Genitourinary tract carcinoma. Thyroid carcinoma. Esophageal carcinoma. Malignant hypercalcemia. Cervical hyperplasia. Renal cell carcinoma. Endometrial carcinoma. Polycythemia vera. Essential thrombocytosis. Adrenal cortex carcinoma. Skin cancer or prostate carcinoma. 9. A pharmaceutical composition containing a compound according to any one of claims 1-6 and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition further comprises at least one known anticancer drug or pharmaceutically acceptable salts thereof. selected from the group consisting of: busulfan. melphalan. chlorambucil. cyclophosphamide. ifosfamide. temozolomide. bendamustine. cis-platinum. mitomycin C. bleomycin. carboplatin. camptothecin. irinotecan. topotecan. doxorubicin. epirubicin. aclarubicin. mitoxantrone. methylhydroxyellipticine. etoposide. 5-azacytidine. gemcitabine. 5-fluorouracil. capecitabine. methotrexate. 5-fluoro-2'-deoxyuridine. fludarabine. nelarabine. ara-C. pralatrexate. Pemetrexed. Hydroxyurea. Thioguanine. Colchicine. Vinblastine. Vincristine. Vinorelbine. Paclitaxel. Ixabepilone. Cabazitaxel. Docetaxel. Nivolumab. Pembrolizumab. T-DM1. Olaparib. Niraparib. Rucaparib. Talazoparib and Senaparib.