HK1165418B - Azetidines as histamine h3 receptor antagonists - Google Patents

Description

Azetidines as histamine H3 receptor antagonists

The present invention relates to histamine H3 receptor antagonists, pharmaceutical compositions thereof, the preparation of such compounds, and the production and use as medicaments.

The histamine H3 receptor is a G protein-coupled receptor (GPCR) and is one of four receptors of the histamine receptor family. Histamine receptors have been attractive drug targets as reflected by the development of antihistamines directed at the histamine H1 receptor to treat allergies or the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion. The H3 receptor has been identified as a presynaptic autoreceptor (Arrag et al (1983) Nature: 302; 832-837) that regulates the release of histamine and a heterologous receptor (heteroreceptor) that regulates the release of many other important neurotransmitters (acetylcholine, norepinephrine, dopamine and serotonin). Structurally diverse H3 receptor antagonists/inverse agonists have been developed and demonstrated to be active in a number of cognitive tests performed in mice and rats (e.g., espenshade et al (2006) mol. interactions: 6 (2); 77-88) and in models of sleep disorders and energy balance. From these studies it was concluded that such antagonists are potential therapeutics for a variety of cognitive-affecting diseases (e.g., Alzheimer's disease, Parkinson's disease, attention disorders and hyperactivity disorders, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, Down's syndrome and others) and sleep-affecting diseases (e.g., somnolence and narcolepsy) and energy homeostasis-affecting diseases (e.g., obesity) (Witkin & Nelson (2004) JPET: 103; 1-20; Hancock & Brune (2005) Exp Opin Drugs: 14 (3); 223-.

Accordingly, histamine H3 receptor antagonists are described in the art for use in the treatment of the above-mentioned diseases and disorders.

Cyclohexyl piperazinyl methanone derivatives useful as modulators of the H3 receptor are disclosed in WO-A2007/080140.

Cyclobutyl derivatives are disclosed in WO-A2006/136924 as histamine-3 receptor antagonists.

WO-A2001/66534 and US-A2001/049367 relate to the preparation of cyclic and bicyclic diamino histamine-3 receptor antagonists.

However, there is a continuing need for new compounds that are useful as histamine H3 receptor antagonists.

It is therefore an object of the present invention to provide a new class of compounds which are histamine H3 receptor antagonists, which are effective in the treatment of H3 receptor related diseases and which may exhibit improved drug related properties (including activity), ADME properties and/or reduced side effects.

Accordingly, the present invention provides a compound of formula (I)

Or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein

R¹Is C_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl or T⁰In which C is_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5The alkynyl group is optionally substituted by one or more substituents, which may be the same or different, selected from halogen, OH, OCH₃、OCH₂F、OCHF₂、OCF₃CN and T⁰；

T⁰Is C_3-5Cycloalkyl or a 4-to 5-membered saturated heterocyclyl, wherein T⁰Optionally substituted by one or more substituents, which are the same or different, selected from halogen, C_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl, OH, O-C_1-5Alkyl, O-C_2-5Alkenyl, O-C_2-5Alkynyl and CN, wherein C_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl, O-C_1-5Alkyl, O-C_2-5Alkenyl and O-C_2-5Alkynyl is optionally substituted with one or more, the same or different, halogens;

n is 1 or 2;

X¹is N or CH;

X²is O, S, N-CN, N-OH or N-OC_1-4An alkyl group;

X³is (CH)₂)_n1X⁴(CH₂)_n2R²；

R is F;

m is 0,1, 2,3 or 4;

n1, n2 are independently selected from 0,1 and 2;

X⁴is C (O), C (O) O, OC (O), O, C (O) N (R)^1a)、N(R^1a)C(O)、S(O)₂N(R^1a)、N(R^1a)S(O)₂、S(O)N(R^1a)、N(R^1a)S(O)、S(O)₂、S(O)、N(R^1a)S(O)₂N(R^1b)、S、N(R^1a)、N(R^1a)C(O)N(R^1b)、N(R^1a) C (O) O or OC (O) N (R)^1a)；

R^1a、R^1bIndependently selected from H, C_1-4Alkyl radical, C_2-4Alkenyl and C_2-4Alkynyl, wherein C_1-4Alkyl radical, C_2-4Alkenyl and C_2-4Alkynyl is optionally substituted with one or more, the same or different, halogens;

R²is H, T, C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl is optionally substituted by one or more R, the same or different³Substitution;

R³is halogen, CN, C (O) R⁴、C(O)OR⁴、OR⁴、C(O)N(R⁴R^4a)、S(O)₂N(R⁴R^4a)、S(O)N(R⁴R^4a)、S(O)₂R⁴、S(O)R⁴、N(R⁴)S(O)₂N(R^4aR^4b)、SR⁴、N(R⁴R^4a)、NO₂、OC(O)R⁴、N(R⁴)C(O)R^4a、N(R⁴)SO₂R^4a、N(R⁴)S(O)R^4a、N(R⁴)C(O)N(R^4aR^4b)、N(R⁴)C(O)OR^4a、OC(O)N(R⁴R^4a) Or T;

R⁴、R^4a、R^4bindependently selected from H, T, C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl is optionally substituted by one or more R, the same or different⁵Substitution;

R⁵is halogen, CN, C (O) R⁶、C(O)OR⁶、OR⁶、C(O)N(R⁶R^6a)、S(O)₂N(R⁶R^6a)、S(O)N(R⁶R^6a)、S(O)₂R⁶、S(O)R⁶、N(R⁶)S(O)₂N(R^6aR^6b)、SR⁶、N(R⁶R^6a)、NO₂、OC(O)R⁶、N(R⁶)C(O)R^6a、N(R⁶)SO₂R^6a、N(R⁶)S(O)R^6a、N(R⁶)C(O)N(R^6aR^6b)、N(R⁶)C(O)OR^6a、OC(O)N(R⁶R^6a) Or T;

R⁶、R^6a、R^6bindependently selected from H, T, C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl is optionally substituted with one or more, the same or different, halogens;

t is phenyl, naphthyl, azulenyl, indenyl, indanyl, C_3-7Cycloalkyl, 3-to 7-membered heterocyclyl or 7-to 11-membered heterobicyclic, wherein T is optionally substituted by one or more R which may be the same or different⁷Substitution;

R⁷is halogen, CN, C (O) OR⁸、OR⁸、C(O)R⁸、C(O)N(R⁸R^8a)、S(O)₂N(R⁸R^8a)、S(O)N(R⁸R^8a)、S(O)₂R⁸、S(O)R⁸、N(R⁸)S(O)₂N(R^8aR^8b)、SR⁸、N(R⁸R^8a)、NO₂、OC(O)R⁸、N(R⁸)C(O)R^8a、N(R⁸)S(O)₂R^8a、N(R⁸)S(O)R^8a、N(R⁸)C(O)OR^8a、N(R⁸)C(O)N(R^8aR^8b)、OC(O)N(R⁸R^8a) Oxo (═ O), where the ring is at least partially saturated, T¹、C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl is optionally substituted by one or more R, the same or different⁹Substitution;

R⁸、R^8a、R^8bindependently selected from H, T¹、C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl is optionally substituted by one or more R, the same or different¹⁰Substitution;

R⁹、R¹⁰independently selected from halogen, CN, C (O) R¹¹、C(O)OR¹¹、OR¹¹、C(O)N(R¹¹R^11a)、S(O)₂N(R¹¹R^11a)、S(O)N(R¹¹R^11a)、S(O)₂R¹¹、S(O)R¹¹、N(R¹¹)S(O)₂N(R^11aR^11b)、SR¹¹、N(R¹¹R^11a)、NO₂、OC(O)R¹¹、N(R¹¹)C(O)R^11a、N(R¹¹)SO₂R^11a、N(R¹¹)S(O)R^11a、N(R¹¹)C(O)N(R^11aR^11b)、N(R¹¹)C(O)OR^11a、OC(O)N(R¹¹R^11a) And T¹；

R¹¹、R¹¹、R^11bIndependently selected from H, T¹、C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl is optionally substituted with one or more, the same or different, halogens;

T¹is phenyl, C_3-7Cycloalkyl or 3-to 7-membered heterocyclyl, wherein T¹Optionally substituted by one or more identical or different R¹²Substitution;

R¹²is halogen, CN, C (O) OR¹³、OR¹³、C(O)R¹³、C(O)N(R¹³R^13a)、S(O)₂N(R¹³R^13a)、S(O)N(R¹³R^13a)、S(O)₂R¹³、S(O)R¹³、N(R¹³)S(O)₂N(R^13aR^13b)、SR¹³、N(R¹³R^13a)、NO₂、OC(O)R¹³、N(R¹³)C(O)R^13a、N(R¹³)S(O)₂R^13a、N(R¹³)S(O)R^13a、N(R¹³)C(O)OR^13a、N(R¹³)C(O)N(R¹³R^13b)、OC(O)N(R¹³R^13a) Oxo (═ O), where the ring is at least partially saturated, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_{2- 6}Alkynyl is optionally substituted with one or more, the same or different, halogens;

R¹³、R^13a、R^13bindependently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl, wherein C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl is optionally substituted with one or more, the same or different, halogens.

In the case where a variable or substituent in formula (I) as defined above may be selected from a different set of variables and such variable or substituent occurs more than once, each variable may be the same or different.

Within the meaning of the present invention, the terms apply as follows:

"alkyl" means a straight or branched saturated hydrocarbon chain. Each hydrogen of the alkyl carbon may be substituted with further specified substituents.

"alkenyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be substituted with a further specified substituent.

"alkynyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be substituted with further specified substituents.

“C_1-4Alkyl "means an alkyl chain having 1 to 4 carbon atoms, for example if present at the terminus of the molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or-CH, for example, when two moieties of the molecule are linked through the alkyl group₂-、-CH₂-CH₂-、-CH(CH₃)-、-CH₂-CH₂-CH₂-、-CH(C₂H₅)-、-C(CH₃)₂-。C_1-4Each hydrogen of the alkyl carbon may be substituted with further specified substituents.

“C_1-6Alkyl "means an alkyl chain having 1 to 6 carbon atoms, for example if present at the terminus of the molecule: c_1-4Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or, for example, -CH when two moieties of the molecule are linked via the alkyl group₂-、-CH₂-CH₂-、-CH(CH₃)-、-CH₂-CH₂-CH₂-、-CH(C₂H₅)-、-C(CH₃)₂-。C_1-6Each hydrogen of the alkyl carbon may be substituted with further specified substituents. The term "C_1-5Alkyl "is defined accordingly.

“C_2-6Alkenyl "means an alkenyl chain having 2 to 6 carbon atoms, for example if present at a terminus of the molecule: -CH ═ CH₂、-CH＝CH-CH₃、-CH₂-CH＝CH₂、-CH＝CH-CH₂-CH₃、-CH＝CH-CH＝CH₂or-CH ═ CH-for example when two moieties of the molecule are linked through the alkenyl group. C_2-6Each hydrogen of an alkenyl carbon may be substituted with a further specified substituent. The term "C_{2- 4}Alkenyl "and" C_2-5Alkenyl "is defined accordingly.

“C_2-6Alkynyl "means havingAlkynyl chains with 2 to 6 carbon atoms, for example if present at the end of the molecule: -C ≡ CH, -CH₂-C≡CH、CH₂-CH₂-C≡CH、CH₂-C≡C-CH₃or-C.ident.C-for example when two moieties of the molecule are linked through the alkynyl group. C_2-6Each hydrogen of an alkynyl carbon may be substituted with further specified substituents. The term "C_2-4Alkynyl "and" C_2-5Alkynyl "is defined accordingly.

“C_3-7Cycloalkyl radicals "or" C_3-7Cycloalkyl ring "means a cyclic alkyl chain having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of the cycloalkyl carbon may be substituted with further specified substituents. The term "C_3-5Cycloalkyl "is defined accordingly.

"halogen" means fluorine, chlorine, bromine or iodine. It is generally preferred that the halogen is fluorine or chlorine.

"3-to 7-membered heterocyclyl" or "3-to 7-membered heterocyclic" means a ring having 3,4, 5, 6 or 7 ring atoms and which may contain up to the maximum number of double bonds (fully saturated, partially saturated or unsaturated aromatic or non-aromatic), of which at least one ring atom and up to 4 ring atoms are selected from sulfur (including-S (O) -, -S (O))₂-), oxygen and nitrogen (including ═ n (o) -, and wherein the ring is attached to the remainder of the molecule through a carbon or nitrogen atom. Examples of 3-to 7-membered heterocycles are aziridine (azeridine), azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, pyridine,azole,Oxazoline, heteroOxazole, isoOxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, and,Oxazolidine, isozymeOxazolidines, thiazolidines, isothiazolidines, thiadiazolidines, sulfolanes, pyrans, dihydropyrans, tetrahydropyrans, imidazolidines, pyridines, pyridazines, pyrazines, pyrimidines, piperazines, piperidines, morpholines, tetrazoles, triazoles, triazolanes, tetrazoles, diazepanes (diazepanes), azacycloheptanes(azepine) or homopiperazine. The term "4-to 5-membered heterocyclyl" or "4-to 5-membered heterocycle" is defined accordingly. The term "5-to 6-membered heterocyclyl" or "5-to 6-membered heterocycle" is defined accordingly.

"4 to 5-membered saturated heterocyclic group" or "4 to 5-membered saturated heterocyclic ring" means "4 to 5-membered heterocyclic group" or "4 to 5-membered heterocyclic ring" having no double bond in the ring.

"7-to 11-membered heterobicyclic group" or "7-to 11-membered heterobicyclic" means a heterocyclic ring system of two such rings, said ring system having 7-11 ring atoms, wherein at least one ring atom is shared by both rings, and said rings may contain up to the maximum number of double bonds (fully saturated, partially saturated or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom, up to 6 ring atoms are selected from sulfur (including-S (O) -, -S (O)₂-), oxygen and nitrogen (including ═ n (o) -, and wherein the ring is attached to the remainder of the molecule through a carbon or nitrogen atom. Examples of 7-to 11-membered heterobicyclics are imidazo [1, 5-a]Pyridine, imidazo [2, 1-b ]][1，3]Azole,Imidazo [2, 1-b ]][1，3]Thiazole, 5, 6, 7, 8-tetrahydro-1, 6-naphthyridine, indole, indoline, benzofuran, benzothiopheneAzole, benzisohOxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepinePurine or pteridine. The term 7-to 11-membered heterobicyclic ring also includes two ring spiro structures such as 1, 4-dioxa-8-azaspiro [4.5 ]]Decane or bridged heterocycles, e.g. 8-aza-bicyclo [3.2.1]Octane. The term "8-to 11-membered heterobicyclic group" or "8-to 11-membered heterobicyclic" is defined accordingly.

"5-to 6-membered aromatic heterocyclyl" or "5-to 6-membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene wherein at least one carbon atom is selected from sulfur (including-S (O) -, -S (O))₂-), oxygen and nitrogen (including ═ n (o) -. Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole,Oxazole, isoOxazole, thiazole, isothiazole, thiadiazole, pyran(pyranium), pyridine, pyridazine, pyrimidine, triazole, tetrazole.

Preferred compounds of the formula (I) are those in which one or more of the residues contained therein have the meanings given below, all combinations of definitions of preferred substituents being subject matter of the present invention. For all preferred compounds of formula (I), the invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in any ratio, and their pharmaceutically acceptable salts and also their isotopic derivatives.

In a preferred embodiment of the present invention, substituent R, R of formula (I)¹M, n and X¹To X³Independently have the following meanings. Thus, substituent R, R¹M, n and X¹To X³One or more of these may have the preferred or more preferred meanings given below.

Preferably, R¹Is C_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl, C_3-5Cycloalkyl radical, CH₂-cyclopropyl, CHF-cyclopropyl, CF₂-cyclopropyl, CH₂-cyclobutyl, CHF-cyclobutyl, CF₂-cyclobutyl or a 4-to 5-membered saturated heterocyclyl group, wherein C_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5The alkynyl group is optionally substituted by one or more substituents, which may be the same or different, selected from halogen, OH, OCH₃、OCH-₂F、OCHF₂、OCF₃And CN, and wherein C_3-5Cycloalkyl radical, CH₂-cyclopropyl, CHF-cyclopropyl, CF₂-cyclopropyl, CH₂-cyclobutyl, CHF-cyclobutyl, CF₂-cyclobutyl and 4-to 5-membered saturated heterocyclyl are optionally substituted by one or more substituents, which may be the same or different, selected from halogen, OH, OCH₃、OCH₂F、OCHF₂、OCF₃、CN、CH₃、CH₂F、CHF₂And CF₃。

More preferably, R1 is C_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl, C_3-5Cycloalkyl radical, CH₂-cyclopropyl, CH₂-cyclobutyl or a 4-5 membered saturated heterocyclyl group, wherein C_1-5Alkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl is optionally substituted by one or more substituents which are the sameOr different and selected from halogen, OH, OCH₃、OCH₂F、OCHF₂、OCF₃And CN, and wherein C_3-5Cycloalkyl radical, CH₂-cyclopropyl, CH₂A cyclobutyl group; and 4-to 5-membered saturated heterocyclyl is optionally substituted by one or more substituents which may be the same or different and are selected from halogen, OH, OCH₃、OCH₂F、OCHF₂、OCF₃、CN、CH₃、CH₂F、CHF₂And CF₃。

More preferably, R¹Is C_3-5Cycloalkyl radical, CH₂-cyclopropyl, CHF-cyclopropyl, CF₂-cyclopropyl, CH₂-cyclobutyl, CHF-cyclobutyl, CF₂-cyclobutyl or a 4-to 5-membered saturated heterocyclyl group, wherein C_3-5Cycloalkyl radical, CH₂-cyclopropyl, CHF-cyclopropyl, CF₂-cyclopropyl, CH₂-cyclobutyl, CHF-cyclobutyl, CF₂-cyclobutyl and 4-to 5-membered saturated heterocyclyl are optionally substituted by one or more substituents, which may be the same or different, selected from halogen, OH, OCH₃、OCH₂F、OCHF₂、OCF₃、CN、CH₃、CH₂F、CHF₂And CF₃。

In a more preferred embodiment, R¹Is substituted or unsubstituted C_1-5Alkyl, substituted or unsubstituted C_3-5Cycloalkyl, substituted or unsubstituted CH₂-cyclopropyl or substituted or unsubstituted CH₂-a cyclobutyl group.

In yet another more preferred embodiment, R¹Is substituted or unsubstituted C_3-5Cycloalkyl, substituted or unsubstituted CH₂-cyclopropyl or substituted or unsubstituted CH₂-a cyclobutyl group.

In an even more preferred embodiment, R¹Is isopropyl, cyclobutyl, ethyl, cyclopropyl, CH₂-cyclopropyl or CH₂-a cyclobutyl group.

In yet another even more preferred embodiment, R¹Is isopropyl, cyclobutyl, cyclopropyl, CH₂-cyclopropyl or CH₂-a cyclobutyl group.

In an even more preferred embodiment, R¹Is cyclobutyl, ethyl or cyclopropyl.

In yet another even more preferred embodiment, R¹Is cyclobutyl or cyclopropyl.

Preferably, n is 2.

Preferably, X¹Is N.

Preferably, X²Is O.

Preferably, m is 0.

Preferably, n1, n2 are independently selected from 0 and 1. Even more preferably, n1 is 0 and n2 is 0 or 1.

Preferably, X³Is (CH)₂)_n1C(O)(CH₂)_n2R²、(CH₂)_n1C(O)N(R^1a)(CH₂)_n2R²、(CH₂)_n1C(O)O(CH₂)_n2R²、(CH₂)_n1S(O)₂(CH₂)_n2R²、(CH₂)_n1S(O)₂N(R^1a)(CH₂)_n2R²Or (CH)₂)_n1N(R^1a)S(O)₂(CH₂)_n2R². More preferably, X³Is C (O) N (R)^1a)CH₂T、C(O)OCH₂T、C(O)CH₂T、C(O)CH₂OT、C(O)T、S(O)₂T or S (O)₂CH₂And T. Even more preferably, X³Is C (O) T or C (O) CH₂T。

Preferably, R^1aIs H or CH₃。

Preferably, R²、R³、R⁴、R^4a、R^4b、R⁵、R⁶、R^6a、R^6bOne is T.

Preferably, R²Is T or CH₂OT。

Preferably, T is phenyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, cyclopropyl, cyclopentyl, cyclohexyl or tetrahydroisoquinolinyl, wherein T is optionally substituted by one or more, the same or different, R⁷And (4) substitution.

Preferably, T is unsubstituted or substituted by 1 to 3R⁷Substituted, said R⁷Identical or different and selected from NO₂、CN、C(O)OCH₃、OCH₃、CH₃F and T¹Wherein T is¹Is unsubstituted or substituted by 1 to 3R¹²Substituted, said R¹²Identical or different and selected from NO₂、CN、C(O)OCH₃、OCH₃、CH₃And F.

The compounds of the formula (I) in which some or all of the abovementioned radicals have the preferred or more preferred meanings are also an object of the present invention.

Preferred individual compounds of the invention are selected from the following:

benzyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate;

1-cyclobutyl-4- { [1- (piperidin-1-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (morpholin-4-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (cyclohexylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (tetrahydro-2H-pyran-4-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan;

4- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) benzonitrile;

methyl 5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) pyridine-2-carboxylate;

1-cyclobutyl-4- ({1- [ (2-methylpyrimidin-5-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (5-methylpyrazin-2-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [6- (1H-imidazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [6- (1H-1,2, 4-triazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- { [1- (1H-pyrazol-1-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (piperidin-1-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (morpholin-4-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (1, 1-thiomorpholin) -4-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (3, 3-difluoropyrrolidin-1-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4, 4-difluoropiperidin-1-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [ (6-methylpyridin-3-yl) oxy ] acetyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

4- (2- {3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } -2-oxoethoxy) benzonitrile;

1-cyclobutyl-4- ({1- [ (4-phenyl) sulfonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- { [1- (cyclohexylsulfonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (cyclopentylmethyl) sulfonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- { [1- (phenylsulfonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

4- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } sulfonyl) benzonitrile;

1-cyclobutyl-4- ({1- [ (4-methoxycyclohexyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4, 4-difluorocyclohexyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (3, 5-dimethyl-1H-pyrazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- [ (1- { [4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- { [1- (cyclopropylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (cyclohexylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

4- (2- {3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } -2-oxoethyl) benzonitrile;

1-cyclobutyl-4- [ (1- { [4- (1, 3-thiazol-2-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (2-methyl-1, 3-thiazol-4-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- [ (1- { [4- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1-methylethyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4-phenoxyphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1H-pyrazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (4, 4-dimethyl-4, 5-dihydro-1, 3-)Azol-2-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4-pyridin-3-ylphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4-pyridin-4-ylphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [3- (2-methyl-1, 3-thiazol-4-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1H-benzimidazole;

5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1-methyl-1H-benzimidazole;

5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1-methyl-1H-benzotriazole;

7- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) imidazo [1, 2- α ] pyridine;

1-cyclobutyl-4- { [1- (1H-1,2, 4-triazol-3-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (1-methyl-1H-pyrazol-4-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- { [1- (tetrahydro-2H-pyran-4-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1- ({1- [ (4-chlorophenyl) acetyl ] azetidin-3-yl } carbonyl) -4-cyclobutyl-1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (methylsulfonyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (cyclohexylmethyl) azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (tetrahydro-2H-pyran-4-ylmethyl) azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) azetidine-1-carboxamide;

n- (4-cyanophenyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (cyclohexylmethyl) -N-methylazetidin-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N-methyl-N- (tetrahydro-2H-pyran-4-ylmethyl) azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) -N-methylazetidin-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) -N-methylazetidin-1-carboxamide;

n- (4-cyanobenzyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N-methylazetidin-1-carboxamide;

4-nitrophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-carboxylate;

2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1,2,3, 4-tetrahydroisoquinoline;

n- (4-cyanobenzyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide;

4-chlorophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate;

6-methylpyridin-3-yl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-carboxylate;

4-cyanophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-carboxylate;

1- [ (1-acetylazetidin-3-yl) carbonyl ] -4-cyclobutyl-1, 4-diazepane;

1-cyclobutyl-4- [ (1-propionylazetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1H-imidazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1H-1,2, 4-triazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- [ (1- { [4- (1H-1,2, 4-triazol-1-ylmethyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- ({1- [ (2-methylpyridin-4-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

2- [5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) pyridin-2-yl ] propan-2-ol;

5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -N-methylpyridine-2-carboxamide;

1-cyclobutyl-4- [ (1- { [ 3-fluoro-4- (1H-1,2, 4-triazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1- (1-methylethyl) -4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-ethyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclopentyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclohexyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1- (cyclopropylmethyl) -4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1- (2-methylpropyl) -4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-methyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1-methyl-1H-benzimidazole; and

1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) piperazine.

Prodrugs of the compounds of the invention are also within the scope of the invention.

"prodrug" means a derivative that is converted to a compound of the invention under in vivo physiological conditions by reaction with an enzyme, gastric acid, or the like via, for example, oxidation, reduction, hydrolysis, or the like, each of which is performed enzymatically. Examples of prodrugs are compounds wherein the amino group in the compounds of the invention is acylated, alkylated or phosphorylated to form, for example, eicosamido, alanylamino, pivaloyloxymethylamino, or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted to a boronic ester, for example, acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy, or wherein the carboxyl group is esterified or amidated. These compounds can be produced from the compounds of the present invention according to known methods.

Metabolites of the compounds of formula (I) are also within the scope of the invention.

Where tautomerism (e.g., keto-enol tautomerism) of the compounds of formula (I) may occur, individual forms (e.g., the keto form and the enol form) are included separately or together as a mixture in any proportion. The same holds true for stereoisomers such as enantiomers, cis/trans isomers, conformers, and the like.

In particular, when the compounds of formula (I) have enantiomeric or diastereomeric forms, each pure form is included by formula (I) either alone or in any mixture of at least two pure forms in any ratio, and is a subject of the present invention.

Isotopically labelled compounds of formula (I) are also within the scope of the present invention. Methods for performing isotopic labeling are known in the art. Preferred isotopes are the isotopes of elements H, C, N, O and S.

If desired, the isomers may be separated by methods well known in the art, for example by liquid chromatography. The same is true for enantiomers, separated, for example, by chiral stationary phases. Alternatively, enantiomers may be separated by: they are converted into diastereomers, i.e. coupled with enantiomerically pure auxiliary compounds, followed by separation of the resulting diastereomers and cleavage of the auxiliary residues. Alternatively, any enantiomer of a compound of formula (I) may be obtained by stereoselective synthesis using optically pure starting materials, reagents and/or catalysts.

In case the compounds of formula (I) contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically usable salts. Thus, compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. There may be present compounds of formula (I) containing one or more basic groups, i.e. groups which can be protonated, such compounds being useful according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art. If the compounds of the formula (I) contain both acidic and basic groups in the molecule, the invention also includes internal salts or betaines (zwitterions) in addition to the salt forms described above. The various salts according to formula (I) can be obtained by customary methods known to those skilled in the art, for example by contacting these compounds with organic or inorganic acids or bases in solvents or dispersants, or by anion exchange or cation exchange with other salts. The invention also encompasses all such salts of the compounds of the formula (I), which are not directly suitable for use in medicaments due to their low physiological compatibility, but which can be used, for example, as intermediates for carrying out chemical reactions or for the preparation of pharmaceutically acceptable salts.

The present invention provides compounds of formula (I) which are histamine H3 receptor antagonists.

As previously mentioned, the histamine H3 receptor is a G protein-coupled receptor (GPCR) and is one of four receptors of the histamine receptor family. Histamine receptors have been attractive drug targets as reflected by the development of antihistamines directed at the histamine H1 receptor to treat allergies or the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion. The H3 receptor has been identified as a presynaptic autoreceptor (Arrag et al (1983) Nature: 302; 832-837) that regulates the release of histamine and a heterologous receptor (heteroreceptor) that regulates the release of many other important neurotransmitters (acetylcholine, norepinephrine, dopamine and serotonin). Structurally diverse H3 receptor antagonists/inverse agonists have been developed and demonstrated to be active in a number of cognitive tests performed in mice and rats (e.g., espenshade et al (2006) mol. interactions: 6 (2); 77-88) and in models of sleep disorders and energy balance. From these studies it was concluded that such antagonists are potential therapeutics for a variety of cognitive-affecting diseases (e.g., Alzheimer's disease, Parkinson's disease, attention disorders and hyperactivity disorders, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, Down's syndrome and others) and sleep-affecting diseases (e.g., somnolence and narcolepsy) and energy homeostasis-affecting diseases (e.g., obesity) (Witkin & Nelson (2004) JPET: 103; 1-20; Hancock & Brune (2005) Exp Opin Drugs: 14 (3); 223-.

The pharmacology of the H3 receptor appears to be determined not only by its localization, but also by the modulation of differential splicing. More than 20 splice variants (isoforms) have been described but their function remains to be fully elucidated (Bogers et al (2007) Biochem Pharm: 73; 1195-1204). The H3 receptor is primarily localized to the Central Nervous System (CNS), with the highest expression in rodents being in the cerebral cortex, hippocampus, striatum, and hypothalamus (Drutel et al (2001) mol. Pharmacol: 59; 1-8). Similarly in humans, H3 receptor expression is primarily in the basal ganglia, globus pallidus, hippocampus, and cortex (Martinez-Mir et al (1990) Brain Res: 526; 322327). Notably, many of these brain regions are critical for cognition (cortex and hippocampus) and for sleep and homeostatic regulation (hypothalamus). It has been demonstrated that the H3 receptor is also localized to areas that may be involved in Pain perception or transmission, and thus may provide therapeutic opportunities for different Pain states (Cannon et al (2007) Pain: 129; 76-92).

In addition to agonist-induced signal transduction, the H3 receptor is constitutively active (constitutive active), enabling signal transduction independent of in vitro and in vivo agonists (Morisset et al (2000) Nature: 408, 860-864).

All of these considerations suggest that novel H3 receptor antagonists, such as the series in the present application, may be useful in the treatment of cognitive dysfunction as well as disorders of sleep and energy homeostasis. The term "antagonist" also includes inverse agonists.

Based on the above information and more literature such as WO-A2007/080140 and WO-A2006/136924, the following diseases and disorders are preferably affected.

Neurological disorders:

the major disorders include

-behavioral/cognitive syndromes (e.g. alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorders, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, down's syndrome, epilepsy, convulsions, depression, anxiety);

-an epileptic seizure;

neurodegenerative diseases (e.g. alzheimer's disease, parkinson's disease, multiple sclerosis);

sleep disorders (e.g. somnolence and narcolepsy, excessive daytime sleepiness, daily and seasonal changes in sleep patterns);

-migraine headache

-fatigue;

-stroke;

-tremor.

Diseases affecting energy homeostasis and their associated complications such as obesity, eating disorders associated with excessive food intake, bulimia nervosa, binge eating disorders, their associated complications such as diabetes.

Pain, e.g. neuropathic pain, inflammatory pain, pain sensation.

Cardiovascular diseases, such as acute myocardial infarction, and

other diseases, i.e. gastrointestinal disorders, vestibular dysfunction (e.g. meniere's disease, vertigo due to drug abuse, motion sickness), drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma.

Preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorder, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, disease-related cognitive dysfunction, lewy body dementia, vascular dementia, down's syndrome, epilepsy, convulsions, depression, anxiety, idiopathic somnolence, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, migraine, stroke, tremor, obesity, eating disorders, diabetes, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. meniere's disease), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma. More preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, mild cognitive impairment, disease-related cognitive dysfunction, dementia with lewy bodies, vascular dementia, idiopathic somnolence, narcolepsy, obesity, diabetes, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma.

Even more preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, idiopathic somnolence, narcolepsy, obesity, neuropathic pain.

Preferably, the compounds of the present invention are useful for fatigue and cognitive deficits/disorders associated with multiple sclerosis. Thus, multiple sclerosis is a more preferred disease or disorder of diseases associated with fatigue and cognitive deficits/disorders.

Accordingly, one aspect of the present invention is a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Yet another aspect of the present invention is a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in a method of treatment or prevention of diseases and disorders associated with the H3 receptor.

Yet another aspect of the present invention is a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment or prevention of the following diseases and disorders: neurological disorders such as behavioral/cognitive syndromes (e.g. alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorder, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, down's syndrome, epilepsy, convulsions, depression, anxiety disorders), seizures, neurodegenerative disorders (e.g. alzheimer's disease, parkinson's disease, multiple sclerosis), sleep disorders (e.g. somnolence and narcolepsy, excessive daytime sleepiness, daily and seasonal changes in sleep patterns), migraine, fatigue, stroke, tremor; diseases affecting energy homeostasis and their associated complications, such as obesity, eating disorders associated with excessive food intake, bulimia nervosa, binge eating disorders, their associated complications (e.g., diabetes); pain, such as neuropathic pain, inflammatory pain, pain sensation; cardiovascular diseases, such as acute myocardial infarction; gastrointestinal diseases; vestibular dysfunction (e.g., meniere's disease, vertigo caused by drug abuse, motion sickness); drug abuse; a nasal obstruction; allergic rhinitis (hay fever); or asthma. Preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorder, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, disease-related cognitive dysfunction, lewy body dementia, vascular dementia, down's syndrome, epilepsy, convulsions, depression, anxiety, idiopathic somnolence, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, migraine, stroke, tremor, obesity, eating disorders, diabetes, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. meniere's disease), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma. More preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, mild cognitive impairment, disease-related cognitive dysfunction, dementia with lewy bodies, vascular dementia, idiopathic somnolence, narcolepsy, obesity, diabetes, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma. Even more preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, idiopathic somnolence, narcolepsy, obesity, neuropathic pain.

Yet another aspect of the present invention is the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of diseases and disorders associated with the H3 receptor.

Yet another aspect of the present invention is the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of the following diseases and disorders: neurological disorders such as behavioral/cognitive syndromes (e.g. alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorder, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, down's syndrome, epilepsy, convulsions, depression, anxiety disorders), seizures, neurodegenerative disorders (e.g. alzheimer's disease, parkinson's disease, multiple sclerosis), sleep disorders (e.g. somnolence and narcolepsy, excessive daytime sleepiness, daily and seasonal changes in sleep patterns), migraine, fatigue, stroke, tremor; diseases affecting energy homeostasis and their associated complications, such as obesity, eating disorders associated with excessive food intake, bulimia nervosa, binge eating disorders, their associated complications (e.g., diabetes); pain, such as neuropathic pain, inflammatory pain, pain sensation; cardiovascular diseases, such as acute myocardial infarction; gastrointestinal diseases; vestibular dysfunction (e.g., meniere's disease, vertigo caused by drug abuse, motion sickness); drug abuse; a nasal obstruction; allergic rhinitis (hay fever); or asthma. Preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorder, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, disease-related cognitive dysfunction, lewy body dementia, vascular dementia, down's syndrome, epilepsy, convulsions, depression, anxiety, idiopathic somnolence, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, migraine, stroke, tremor, obesity, eating disorders, diabetes, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. meniere's disease), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma. More preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, mild cognitive impairment, disease-related cognitive dysfunction, dementia with lewy bodies, vascular dementia, idiopathic somnolence, narcolepsy, obesity, diabetes, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma. Even more preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, idiopathic somnolence, narcolepsy, obesity, neuropathic pain.

Yet another aspect of the present invention is a method of treatment, control, delay of progression or prevention in a mammalian patient in need of treatment for one or more conditions selected from diseases and disorders associated with the H3 receptor, wherein the method comprises administering to said patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

Yet another aspect of the invention is a method of treatment, control, delay or prevention in a mammalian patient in need of treatment for one or more conditions selected from the group consisting of: neurological disorders such as behavioral/cognitive syndromes (e.g. alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorder, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, down's syndrome, epilepsy, convulsions, depression, anxiety disorders), seizures, neurodegenerative disorders (e.g. alzheimer's disease, parkinson's disease, multiple sclerosis), sleep disorders (e.g. somnolence and narcolepsy, excessive daytime sleepiness, daily and seasonal changes in sleep patterns), migraine, fatigue, stroke, tremor; diseases affecting energy homeostasis and their associated complications, such as obesity, eating disorders associated with excessive food intake, bulimia nervosa, binge eating disorders, their associated complications (e.g., diabetes); pain, such as neuropathic pain, inflammatory pain, pain sensation; cardiovascular diseases, such as acute myocardial infarction; gastrointestinal diseases; vestibular dysfunction (e.g., meniere's disease, vertigo caused by drug abuse, motion sickness); drug abuse; a nasal obstruction; allergic rhinitis (hay fever); and asthma, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity disorder, schizophrenia, fetal alcohol syndrome, mild cognitive impairment, age-related memory dysfunction, disease-related cognitive dysfunction, lewy body dementia, vascular dementia, down's syndrome, epilepsy, convulsions, depression, anxiety, idiopathic somnolence, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, migraine, stroke, tremor, obesity, eating disorders, diabetes, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. meniere's disease), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma. More preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, mild cognitive impairment, disease-related cognitive dysfunction, dementia with lewy bodies, vascular dementia, idiopathic somnolence, narcolepsy, obesity, diabetes, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma. Even more preferred diseases are alzheimer's disease, parkinson's disease, attention disorders and hyperactivity, schizophrenia, idiopathic somnolence, narcolepsy, obesity, neuropathic pain.

Yet another aspect of the invention is a pharmaceutical composition comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, optionally in combination with one or more other biologically active compounds or pharmaceutical compositions.

Preferably, the one or more bioactive compounds are lipase inhibitors, anorectic agents, selective serotonin uptake inhibitors, neurotransmitter reuptake blockers, dopamine replacement agents, agents that stimulate the metabolism of body fat, antidiabetic agents, lipid lowering agents, anti-stroke agents or histamine H1 receptor antagonists. Combinations of one or more of the histamine H3 receptor antagonists of the present invention with histamine H1 receptor antagonists are preferred, particularly for the treatment of allergic rhinitis, allergic congestion, nasal congestion.

"pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up a carrier, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Thus, the pharmaceutical compositions of the present invention encompass any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may contain one or more additional compounds as active ingredients, such as one or more compounds of formula (I) or other histamine H3 receptor antagonists that are not the first compound in the composition.

The active ingredient may be contained in one or more different pharmaceutical compositions (combinations of pharmaceutical compositions).

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

Compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), intraocular (ophthalmic), pulmonary (nasal or buccal inhalation) or intranasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the active ingredient. They may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

In practice, the compound of formula (I) as active ingredient may be intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as suspensions, elixirs and solutions, and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with solid oral preparations being preferred over liquid preparations.

Tablets and capsules represent the most advantageous oral dosage unit form for ease of administration, in which case solid pharmaceutical carriers are obviously employed. Tablets may be coated, if desired, by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of active compound in these compositions may, of course, vary and may conveniently be between about 2% and about 60% by weight of the unit form. The amount of active compound in such therapeutically useful compositions is that amount which will result in an effective dosage. The active compounds may also be administered intranasally, for example as liquid drops or spray.

Tablets, pills, capsules and the like may also contain binders, such as tragacanth, acacia, corn or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present to act as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

The compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared by appropriate mixing in water with a surfactant, such as hydroxypropyl cellulose. Dispersions can also be prepared in oils of glycerol, liquid polyethylene glycols and mixtures thereof. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or suspensions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and fluid to the extent that it can be readily injected. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed to provide effective dosages of the compounds of the present invention to mammals, particularly humans. For example, oral administration, rectal administration, topical administration, parenteral administration, intraocular administration, pulmonary administration, intranasal administration, and the like may be employed. The dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compound of formula (I) is administered orally.

The effective dose of the active ingredient employed will vary depending upon the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by one skilled in the art.

The starting materials for the synthesis of the preferred embodiments of the present invention are commercially available from sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR, or can be synthesized by methods known to those skilled in the art.

In general, there are several methods that can be used to prepare the compounds of the present invention. In some cases, various policies may be combined. The sequential (sequential) or convergent (convergent) approach may be employed. The following approaches should be considered as examples. Practitioners in the art understand that these approaches can optionally be combined with standard methods and reagents, such as activation of functional groups and protection of functional groups.

An exemplary method for preparing the compounds of the invention, wherein in formula (I), X¹Is N; x²Is O; x⁴To C (O), the method comprises the following steps

(a) Protection of the amino group of the compound of formula (II) by reaction of the amino group with a suitable chloroformate, such as benzyl chloroformate or di-tert-butyl dicarbonate

(b) Reacting the carboxylic acid group of the carbamate compound obtained from step (a) with an amide coupling reagent (e.g., HOBt and HBTU or HOBt and EDCI) or using a reagent (e.g., SOCl)₂) Forming an acid chloride, reacting the active ester or acid chloride with a compound of formula (III)

Wherein n has the above meaning, R^1’Is R as described above¹Or a suitable N-atom protecting group, to form a compound of formula (I), optionally inRemoval of the protecting group R^1’Thereafter, the liberated amino group is reacted with a compound of the formula R¹Reaction of a compound of ═ O, where the oxo group is with R¹Then reducing the resulting imine; or, reacting the liberated amino group with a compound of formula R¹-a halide compound (optionally in the presence of a base), and

(c) deprotecting the azetidino group of the compound obtained in step (b) by hydrogenation (using conditions such as Pd-C and hydrogen) or transfer hydrogenation (using conditions such as ammonium formate and Pd-C) or a strong acid (such as 4M HCl or TFA) to produce a compound represented by formula (IV)

Wherein n and R¹Have the above-mentioned meanings;

(d) reacting the secondary amine obtained in step (c) with a compound of the formula ClC (O) (CH)₂)_n2R²In the presence of a suitable base (e.g. DIPEA or pyridine), typically at a temperature between 0 ℃ and 85 ℃, to give a compound of formula (I) wherein n2, R²As defined above.

In a further embodiment of the above process, the azetidino group of the compound obtained from step (b) may be protected at the orthogonal (orthogonal) protecting group R by the following reaction^1’Is selectively deprotected in the presence of

(e) Hydrogenation (using conditions such as Pd-C and hydrogen) or transfer hydrogenation (using conditions such as ammonium formate and Pd-C) or a strong acid (such as 4MHCl or TFA) to form a compound represented by formula (IVa); and

(f) reacting the azetidinylamino group obtained in (e) with a compound of formula ClC (O) (CH)₂)_n2R²In the presence of acid chloride ofIn the presence of a suitable base (e.g. DIPEA or pyridine), typically at a temperature between 0 ℃ and 85 ℃, wherein n2, R²As defined above; and

(g) removal of the amino protecting group R of the compound obtained in step (f) by hydrogenation (using conditions such as Pd-C and hydrogen) or transfer hydrogenation (using conditions such as ammonium formate and Pd-C) or strong acids (such as 4M HCl or TFA)^1’(ii) a And

(h) reacting the liberated amino group with a compound of the formula R¹Reaction of a compound of ═ O, where the oxo group is with R¹And then reducing the resulting imine to give a compound of formula (I); or, reacting the liberated amino group with a compound of formula R¹-reacting a halide compound (optionally in the presence of a base) to obtain a compound of formula (I).

A further aspect of the invention is therefore a process for preparing the compounds of the invention, in which, in the formula (I), X¹Is N; x²Is O, n1 is 0, X⁴To C (O), the method comprises the following steps

(a) Protecting the amino group of a compound of formula (IIa) by reacting said amino group with a suitable chloroformate, such as benzyl chloroformate or di-tert-butyl dicarbonate

Wherein R, m have the above-mentioned meanings;

(b) reacting the carboxylic acid group of the carbamate obtained in step (a) with a compound of formula (III) -or optionally with an amide coupling reagent (e.g. HOBt and HBTU or HOBt and EDCI) or with a reagent (e.g. SOCl)₂) Forming acyl chloride, and reacting the obtained active ester or acyl chloride with compound of formula (III)

Wherein n has the above meaning, R^1’Is R as described above¹Or a suitable N-atom protecting group, using amide coupling conditions and reagents to produce a compound of formula (I), optionally after removal of the protecting group, and reacting the liberated amino group with a compound of formula R¹Reaction of a compound of ═ O, where the oxo group is with R¹Then reducing the resulting imine; or, reacting the liberated amino group with a compound of formula R¹-a halide compound (optionally in the presence of a base), and

(c) deprotecting the azetidino group of the compound obtained in step (b) to obtain a compound represented by formula (IVb)

(d) Reacting the secondary amine groups obtained in step (c) with a compound of the formula ClC (O) (CH)₂)_n2R²From the acid chloride in the presence of a suitable base to give a compound of formula (I) wherein n2, R²As defined above.

Or, wherein X¹Is N, and X²A compound of formula (I) which is S, may be prepared by a process comprising the steps of

(c ') reacting the amide group obtained in step (b) with Lawesson's reagent (typically between room temperature and 100 ℃ C.)

(d ') deprotecting the azetidino group of the compound obtained in step (C') by hydrogenation (using conditions such as Pd-C and hydrogen) or transfer hydrogenation (using conditions such as ammonium formate and Pd-C) to obtain a compound represented by formula (V)

Wherein n and R¹Have the above-mentioned meanings;

(e ') reacting the secondary amine groups obtained in step (d') with a compound of the formula ClC (O) (CH)₂)_n2R²In the presence of a suitable base, such as DIPEA or pyridine, generally at a temperature between 0 ℃ and 85 ℃, to give compounds of formula (I) wherein n2, R²As defined above.

Or, wherein X¹Is N and X²The compounds of formula (I) which are N-CN may be prepared by a process comprising the steps of

(a) Reacting cyanamide with carbon disulfide, and treating the intermediate with dimethyl sulfate to obtain the compound of formula (VI)

(b) Reacting the amino group of the compound of formula (III) with the compound of formula (VI) (typically between room temperature and 80 ℃);

(c) reacting the compound obtained from step (b) with a compound of formula (VII) wherein X is at an elevated temperature (up to 100 ℃)²Is N-CN, and X^3’Are suitable nitrogen protecting groups (e.g. Boc or Cbz)

(d) When X is present^3’With strong acids (e.g. 4M HCl or TFA) in the case of Boc, or when X is present^3’Removal of X from the compound obtained in step (C) by hydrogenation (using conditions such as Pd-C and hydrogen) or transfer hydrogenation (using conditions such as ammonium formate and Pd-C) for Cbz^3’Nitrogen protecting group to give a compound represented by the formula (VIII)

(e) Will be obtained from step (d)To secondary amine groups with the formula ClC (O) (CH)₂)_n2R²In the presence of a suitable base, such as DIPEA or pyridine, generally at a temperature between 0 ℃ and 85 ℃, to give compounds of formula (I) wherein n2, R²As defined above.

Or, wherein X²Is N-OC_1-4Alkyl and X^3’The compounds of general formula (I) which are Cbz may be prepared from compounds of formula (Ib) by a process comprising the following steps

(a) With oxalyl chloride and then with NH₂-OC_1-4Reaction of alkyl compounds

(b) Deprotection of the azetidinylamino group obtained from step (a) by hydrogenation (using conditions such as Pd-C and hydrogen) or transfer hydrogenation (using conditions such as ammonium formate and Pd-C) to give a compound represented by formula (IX)

(c) Reacting the secondary amine group obtained in step (b) with a compound of the formula ClC (O) (CH)₂)_n2R²In the presence of a suitable base, such as DIPEA or pyridine, generally at a temperature between 0 ℃ and 85 ℃, to give compounds of formula (I) wherein n2, R²As defined above.

Or, wherein X¹Compounds of formula (I) which are CH and n is 1 may be prepared from compounds of formula (X) by a process comprising the following steps

(a) To generate aminoAnd formula R¹Reaction of a compound of ═ O, where the oxo group is with R¹Then reducing the resulting imine;

(b) saponifying the resulting ester group with a base such as LiOH;

(c) reacting the carboxylic acid group obtained in step (b) with a chlorinating agent, such as thionyl chloride or oxalyl chloride, optionally in the presence of a catalyst DMF, reacting the resulting acid chloride with a compound of formula (XI)

Wherein a compound of formula (XI) can be obtained by treating commercially available tert-butyl 3-iodoazetidine-1-carboxylate with zinc;

(d) deprotecting the azetidinyl group obtained in step (c) with a strong acid (e.g., 4M HCl or TFA) to give a compound represented by formula (XII)

(e) Reacting the secondary amine groups obtained in step (d) with a compound of the formula ClC (O) (CH)₂)_n2R²In the presence of a suitable base, such as DIPEA or pyridine, generally at a temperature between 0 ℃ and 85 ℃, to give compounds of formula (I) wherein n2, R²As defined above.

Or, wherein X¹Compounds of formula (I) which are CH and n is 2 can be prepared from compounds of formula (XIII) by a process comprising the following steps

(a) Reacting keto group with sodium azide and MeSO₃Reacting H between room temperature and 80 deg.C, and reducing the resultant product with LAHAmides and esters (typically between room temperature and 80 ℃);

(b) reacting an amino group with a compound of formula R¹Reaction of a compound of ═ O, where the oxo group is with R¹Then reducing the resulting imine;

(c) oxidation of primary alcohols to carboxylic acids with chromic acid (Jones oxidation);

(d) reacting the carboxylic acid group obtained in step (c) with a chlorinating agent, such as thionyl chloride or oxalyl chloride, optionally in the presence of a catalyst DMF, reacting the resulting acid chloride with a compound of formula (XI);

(e) deprotecting the azetidinyl group obtained in step (d) with a strong acid (e.g., 4M HCl or TFA) to give a compound represented by formula (XIV)

(f) Reacting the secondary amine group obtained in step (e) with a compound of the formula ClC (O) (CH)₂)_n2R²In the presence of a suitable base, such as DIPEA or pyridine, generally at a temperature between 0 ℃ and 85 ℃, to give compounds of formula (I) wherein n2, R²As defined above.

Or, wherein X¹Compounds of the general formula (I) in which CH and n is 2 can be prepared from those in which R is^1’Compounds of formula (XIIIa) which are suitable protecting groups (e.g., Cbz or Boc) are prepared by a process comprising the steps of

(a) Reacting a keto group with an alkyl diazoacetate (e.g., ethyl diazoacetate) in the presence of a Lewis acid (e.g., boron trifluoride etherate), typically at a temperature between-80 ℃ and room temperature;

(b) by acid-catalyzed elimination reaction (Alternatively, the alcohol may be converted to a halide (e.g., using a reagent such as PBr)₃Conversion to bromide) or a sulfonate ester (e.g., by reaction with MsCl and TEA to give a mesylate), followed by elimination of the resulting alcohol in the presence of a base (e.g., DBU), typically between room temperature and 100 ℃, to give an α, β -unsaturated ester;

(c) removal of the olefins by hydrogenation (usually with hydrogen or ammonium formate in the presence of a palladium source such as Pd/C);

(d) removal of the protecting group R^1’(for cbz protecting group, H is used₂Pd/C), reacting amino with a compound of the formula R¹Reaction of a compound of ═ O, where the oxo group is with R¹Then reducing the resulting imine;

(e) hydrolyzing the ester with a base such as aqueous LiOH or an acid such as HCl to give a carboxylic acid, reacting the carboxylic acid group with a chlorinating agent such as thionyl chloride or oxalyl chloride, optionally in the presence of a catalyst DMF, reacting the resulting acid chloride with a compound of formula (XI);

(f) deprotecting the azetidino group of the compound obtained in step (d) with a strong acid (e.g., 4M HCl or TFA) to obtain a compound represented by formula (XIV);

(g) reacting the secondary amine groups obtained in step (f) with a compound of the formula ClC (O) (CH)₂)_n2R²In the presence of a suitable base (e.g. DIPEA or pyridine), typically at a temperature of 0 ℃ and 85 ℃, to give a compound of formula (I) wherein n2, R²As defined above.

When independently a compound of formula (IV), (IVb), (V), (VIII), (IX), (XII) or (XIV), wherein the meanings are as described above, the process may comprise a further step of revising by reacting a secondary amine group with any of the following compounds;

(i) firstly, the formula HOC (O) (CH)₂)_n2R²Is converted to the relevant active ester and reacted with an amide coupling reagent (e.g. EDCI/HOBt or HBTU/HOBt in the presence of a base such as DIPEA) to give the compound of formula (I) wherein n1 ═ 0 and X⁴Is C (O);

(ii) and formula R²(CH₂)_n2C(O)OC(O)(CH₂)_n2R²In the presence of a base such as DIPEA to give a compound of formula (I) wherein n1 is 0 and X⁴Is C (O);

(iii) and formula R²(CH₂)_n2Reacting the compound of NCO to obtain the compound of formula (I) wherein n1 is 0 and X⁴Is C (O) NH;

(iv) and formula R²(CH₂)_n2S(O)₂(CH₂)_n1-reacting a halide compound in the presence of a base such as DIPEA to give a compound of formula (I) wherein n1 ═ 0-2 and X⁴Is S (O)₂；

(v) And formula R²(CH₂)_n2(R^1a)NC(O)(CH₂)_n1-reacting a halide compound in the presence of a base such as DIPEA to give a compound of formula (I) wherein n1 ═ 0-2 and X⁴Is C (O) N (R)^1a)；

(vi) And formula R²(CH₂)_n2OC(O)(CH₂)_n1-reacting a halide compound in the presence of a base such as DIPEA to give a compound of formula (I) wherein n1 ═ 0-2 and X⁴Is C (O) O;

(vii) and formula R²(CH₂)_n2(R^1a)NS(O)₂(CH₂)_n1-reacting a halide compound in the presence of a base such as DIPEA to give a compound of formula (I) wherein n1 ═ 0-2 and X⁴Is S (O)₂N(R^1a)；

(viii) Prepared by a three-step method a. -c.;

a. firstly, 2-chloroethanol and sulfonyl chloride isocyanate (isocyanato sulfuryl chloride) are reacted in the presence of alkali to obtain an intermediate compound of a formula (XV)

b. Reacting a compound of formula (XV) with a compound of formula (IV), (IVb), (V), (VIII), (IX), (XII) or (XIV), wherein the meanings are as described above

c. The intermediate from step b. is then reacted with HN (R)^1a)(CH₂)_n2R²In the presence of a base such as TEA at elevated temperature (typically 40-85 ℃) to give a compound of formula (I) wherein n1 is 0 and X is⁴Is S (O)₂N(R^1a)。

(ix) And formula R²(CH₂)_n2C(O)(CH₂)_n1-reacting a halide compound in the presence of a base such as DIPEA at a temperature which is optionally elevated (typically 30 ℃ to 120 ℃) to give a compound of formula (I) wherein n1 ═ 1-2 and X⁴Is C (O);

(x) Prepared by a two-step process d. -e.;

d. formula ClC (O) (CH)₂)_n1-a halide compound with formula R in the presence of a base²(CH₂)_n2X⁴' to give an intermediate compound of formula (XVa), wherein n1 is 1-2 and X^4’Is OH, NH₂Or NHR^1a

e. Reacting a compound of formula (XVa), optionally at elevated temperature (typically 30-120 ℃) in the presence of a base such as DIPEA, with a compound of formula (IV), (IVb), (V), (VIII), (IX), (XII) or (XIV) to give a compound of formula (I), wherein the meaning is as described above; or

(xi) Prepared by a two-step process f. -g;

f. formula ClS (O)₂(CH₂)_n1-a halide compound with formula R in the presence of a base²(CH₂)_n2X⁴' Compound ofTo give an intermediate compound of formula (XVb), wherein n1 is 1-2 and X^4’Is NH₂Or NHR^1a

g. Reacting a compound of formula (XVb) with a compound of formula (IV), (IVb), (V), (VIII), (IX), (XII) or (XIV) in the presence of a base such as DIPEA, optionally at elevated temperature (typically 30-120 ℃), to give a compound of formula (I), wherein the meaning is as described above

Thus, another aspect of the present invention is a process for the preparation of any of the compounds of the present invention, said process comprising the steps of

Reacting a compound of formula (Ia)

Wherein R is¹、n、X¹、X²R, m have the meanings given above, and

(i) formula R²(CH₂)_n2Reaction of an activated ester or anhydride of a compound of c (o) OH in the presence of an amide coupling reagent to give a compound of formula (I) wherein n1 ═ 0 and X⁴Is C (O); or

(ii) Formula R²(CH₂)_n2Reacting the compound of NCO to obtain the compound of formula (I) wherein n1 is 0 and X⁴Is C (O) NH; or

(iii) Formula R²(CH₂)_n2S(O)₂(CH₂)_n1-reacting a halide compound in the presence of a base to give a compound of formula (I) wherein n1 is 0-2 and X⁴Is S (O)₂(ii) a Or

(iv) Formula R²(CH₂)_n2(R^1a)NC(O)(CH₂)_n1-halide compounds in baseIn the presence of a base to give a compound of formula (I) wherein n1 is 0-2 and X⁴Is C (O) N (R)^1a) (ii) a Or

(v) Formula R²(CH₂)_n2OC(O)(CH₂)_n1-reacting a halide compound in the presence of a base to give a compound of formula (I) wherein n1 is 0-2 and X⁴Is C (O) O; or

(vi) Formula R²(CH₂)_n2(R^1a)NS(O)₂(CH₂)_n1-reacting a halide compound in the presence of a base to give a compound of formula (I) wherein n1 is 0-2 and X⁴Is S (O)₂N(R^1a) (ii) a Or

(vii) (aa) reaction of an intermediate compound of formula (XV)

The compound of formula (XV) is obtained from the reaction of 2-chloroethanol with a sulfonyl chloride isocyanate in the presence of a base; then the

(bb) reacting the intermediate from step (aa) with HN (R)^1a)(CH₂)_n2R²In the presence of a base at elevated temperature to give a compound of formula (I) wherein n ═ 0 and X⁴Is S (O)₂N(R^1a) (ii) a Or

(viii) Formula R²(CH₂)_n2C(O)(CH₂)_n1-reacting a halide compound in the presence of a base, optionally at elevated temperature, to give a compound of formula (I) wherein n1 ═ 1-2 and X⁴Is C (O); or

(ix) Reaction of intermediate compounds of formula (XVa)

Of the formula (XVa)The intermediate compound is derived from the formula ClC (O) (CH)₂)_n1-a halide compound with formula R optionally at elevated temperature in the presence of a base²(CH₂)_n2X⁴' reaction of compounds, wherein n1 ═ 1-2 and X^4’Is OH, NH₂Or NHR^1a(ii) a Or

(x) Reaction of an intermediate compound of formula (XVb)

The intermediate compound of formula (XVb) is derived from the formula ClS (O)₂(CH₂)_n1-a halide compound in the presence of a base and of formula R²(CH₂)_n2X⁴' wherein n1 is 1-2 and X^4’Is NH₂Or NHR^1a。

R in the above method^1aWhen H, the method may comprise any further steps of:

(a) reacting the resulting secondary amine with a suitable alkyl halide or active alcohol (e.g., OMs or OTs) in the presence of an organic base (e.g., TEA) or NaH at 0 deg.C and 200 deg.C to provide a compound of formula (I), wherein R is^1aIs an alkyl group; or

(b) Reacting the secondary amine with a suitable alkylaldehyde in the presence of an organic acid (e.g., AcOH) and a reducing agent (e.g., NaBH)₃CN or STAB) at room temperature or elevated temperature (up to 100 ℃) to give compounds of formula (I) wherein R^1aIs an alkyl group.

Furthermore, wherein n1 is 0 and X⁴The compound of formula (I) being C (O) O may comprise a further step;

(a) reacting the carbamate compounds of formula (I) with primary or secondary amines in the presence of a base (e.g., DIPEA) at room temperature or elevated temperature (up to 200 ℃) to give compounds each having a urea group (X)⁴＝C(O)N(R^1a) Compounds of formula (I) according to (1).

When a compound of formula (I) wherein R has the meaning as defined above²With a latent chemically reactive group, the method may include additional steps, modified as follows:

(a) by reacting a suitable alcohol or (hetero) aryl alcohol with a strong base, such as NaH or^tBuOK), the resulting alkoxide or (hetero) arylalkoxide and (generally between room temperature and 180 ℃) R²To obtain the compound of formula (I); or

(b) Using palladium phosphine catalysts (e.g. from Pd) in the Suzuki reaction₂(dba)₃And tricyclohexylphosphine) with R²With a suitable borate or boronic acid (typically at room temperature-150 ℃) in the presence of a base (e.g., K)₃PO₄Or K₂CO₃) In the presence of a catalyst to obtain a compound of formula (I); or

(c) A compound of formula (I) is reacted with a primary or secondary amine, optionally in the presence of a base such as DIPEA or K₂CO₃) In the presence of a catalyst at room temperature or at elevated temperatures up to 200 ℃ to give the compounds of the formula (I).

When a compound of formula (I) wherein R has the meaning as defined above²Where primary or secondary amines are included, the process may include additional steps, modified as follows:

(a) the amines of the compounds of the formula (I) are reacted with (hetero) aromatic halides at elevated temperatures (up to 120 ℃) in palladium-catalyzed coupling reagents (e.g. Pd)₂(dba)₃BINAP and^tBuOK) to obtain the compound of formula (I).

The same reaction types can be used for compounds of the invention in which m in formula (I) is different from 0.

When the compound of formula (I) is represented by formula (XVI), wherein the meaning is as described above, the process further comprises the additional steps, modified as follows;

(a) reacting the ester group with a Grignard reagent (such as MeMgBr), optionally in the presence of lithium chloride, typically at a temperature between-78 ℃ and 150 ℃ to give a compound of formula (I);

(b) saponifying the ester group with an aqueous base (e.g., aqueous lithium hydroxide) and reacting the resulting acid with a coupling reagent (e.g., HOBt and HBTU or HOBt and EDCI) of the formula HN (R)⁴R^4a) The amine of (a) is typically coupled at a temperature between 0 ℃ and 85 ℃ to give the compound of formula (I); or

(c) Reacting said ester group with a compound of formula HN (R)⁴R^4a) In AlMe₃The reaction in the presence of the solution is generally carried out at a temperature between 0 ℃ and 85 ℃ to give the compound of formula (I).

When the compound of formula (I) is represented by formula (XVII), wherein the meaning is as described above, the process may comprise additional steps, modified as follows;

(a) reduction of the ester group (usually with LAH) at a temperature in the range-50 to 100 ℃ gives the compounds of formula (I).

The same reaction types can be used for the compounds of the invention in which m is different from 0 in formula (I).

Examples

Biological evaluation:

cell lines for in vitro characterization of the compounds of the invention CHO-K1 cell lines expressing the human H3 receptor were purchased from Euroscreen (Gosselies, Belgium, Cat: ES-392-C).

Cell lines expressing human H3 receptor were grown in Ham's F12[ Sigma, cat # N6658] supplemented with 10% FBS [ Sigma, cat # F9665], 400. mu.g/ml G418[ Sigma, cat # N1876] and 250. mu.g/ml Zeocin [ Invitrogen, cat # 46-0509]) according to the protocol provided by Euroscreen.

cAMP quantitation protocol for human H3 receptor assay

The assay measures the ability of a test compound to inhibit histamine receptor agonist-induced reduction of intracellular free cAMP (receptor is G)_iCoupled).

Specifically, a quantitative cAMP determination system obtained from Discovex (cAMP XS +; catalog No. 90-0075) was used.

For cAMP assay, confluent cells were detached from the culture vessel with 1 Xtrypsin-EDTA solution (Sigma) and seeded at a density of 10,000 cells/well in 384-well Costar plates (white, clear bottom, catalog No. 3707). Cells were seeded in antibiotic-free medium at a volume of 50. mu.l in 5% CO₂Was incubated at 37 ℃ overnight in a humidified environment.

cAMP determination was performed according to the protocol provided by Discovex.

The cell culture medium was removed and the cells were washed once with PBS (50. mu.l/well). The plate was emptied by inversion, then 7.5. mu.l/well of compound in PBS (containing 1mM IBMX and 0.03% BSA) was added and incubated at 37 ℃ for 30 minutes.

7.5. mu.l/well of a specific agonist solution was then added and the plates were incubated at 37 ℃ for a further 30 minutes.

The following agonist solutions were used for each cell line:

hH 3: 100nM histamine, 10. mu.M forskolin PBS solution (containing 1mM IBMX and 0.03% BSA).

After incubation with agonist, 5. mu.l/well of cAMP XS antibody solution was added followed by 20. mu.l/well of Gal/EII/lysine (1: 5: 19) + ED (1: 1). The plates were incubated at room temperature for 1 hour, then 20. mu.l/well of EA reagent was added. Luminescence was allowed to develop at room temperature for approximately 3 hours, and the plates were then read using a 'BMGNoostar' plate reader.

Determination of Compounds

The test compound was measured at 8 concentrations and the measurement was repeated three times. At concentrations 100-fold higher than the final concentration, serial 10-fold dilutions were made in 100% DMSO, followed by dilutions in assay buffer using a 2-step protocol to reach the desired assay concentration and 1% DMSO.

The specific compounds exemplified below are shown below in potency range (IC)₅₀Value) to classify:

A：＜50nM；B：＞50nM-100nM；C：＞100nM-5000nM

synthesis of the Compounds:

analytical method

NMR spectrometer used

Bruker DRX 500MHz NMR

Bruker AVANCE 400MHz NMR

Bruker DPX 250MHz NMR

Bruker DPX 360MHz NMR

Configuration of Bruker DRX 500MHz NMR

The high-performance digital NMR spectrometer comprises a 2-channel microbay console, a Windows XP host workstation and a Topspin version 1.3.

Equipped with:

● Oxford Instruments magnet 11.74 Tesla (500MHz proton resonance frequency)

● B-VT 3000 temperature controller

● GRASP II gradient spectroscopy assembly for fast acquisition of 2D pulse sequences

● deuterium locking switch for gradient shimming

● 5mm broadband reverse geometry dual resonance probe with self-containedDynamic tuning and matching (BBIATMA). Can be used²H-lock and shielded z-gradient coil, in the frequency range¹⁵N and³¹pulsing/decoupling nuclei in P, by¹And H, observing.

Configuration of Bruker DPX 250MHz NMR

A high performance one bay Bruker 250MHz digital two channel NMR spectrometer console, Windows XP mainframe workstation, running XwinNMR version 3.5.

Equipped with:

● Oxford Instruments magnet 5.87 Tesla (250MHz proton resonance frequency)

● B-VT 3300 variable temperature controller unit

● switched Probe with four nuclei (QNP) for use with²H lock observation¹H、¹³C、¹⁹F and³¹P。

configuration of Bruker AVANCE 400MHz NMR

High-performance one bay Bruker AVANCE 400MHz digital two-channel NMR spectrometer console

Equipped with:

● Bruker magnet 9.40 Tesla (400MHz proton resonance frequency)

● B-VT 3200 variable temperature controller unit

● GRASP II gradient spectroscopy assembly for producing a one field gradient of up to 50 Gauss/cm

● switched Probe with four nuclei (QNP) for use with²H lock observation¹H、¹³C、¹⁹F and³¹p is the reaction of²The H-lock is provided with a z-gradient coil for gradient spectroscopy.

LCMS method used

The example compounds and their intermediates were analyzed by HPLC-MS using the following combination of methods.

LCMS method A (2 min method)

LCMS method B (3 min method)

LCMS method C (7 min method)

LCMS method D (7 min method)

LCMS method E (10 min method)

LCMS method F (15 min method)

Preparative HPLC method used:

as noted, the example compounds and their intermediates were purified by one or any combination of the following methods.

Preparation method 1 (Low pH)

Preparation method 2(FTE high pH)

Preparation method 3 (Low pH)

Preparation method 4(FTE preparation)

Preparation method 5 (neutral)

Nomenclature of Compounds

All compounds were named using ACD Labs 10.0 naming software according to IUPAC nomenclature. Some compounds were isolated as TFA, formic acid or fumarate salts, which the chemical name does not reflect. Within the meaning of the present invention, the chemical name stands for the neutral form of the compound as well as its TFA, formic acid or fumarate salt or any other salt, in particular a pharmaceutically acceptable salt, if applicable.

List of abbreviations

Route 1

General procedure a:

preparation of 4-cyclobutyl-1, 4-diazepan-1-carboxylic acid tert-butyl ester

To [1, 4 ] stirred at 20 to 25 ℃]A solution of tert-butyl diazepane-1-carboxylate (5g, 24.97mmol) in DCE (70ml) was added dropwise cyclobutanone (1.75g, 24.97mmol) followed by acetic acid (1.5g, 24.97 mmol). The resulting mixture was stirred at 20 to 25 ℃ for about 2 h. Sodium triacetoxyborohydride (7.94g, 37.46mmol) was added in 9 portions and the temperature was maintained in the range of 20 to 25 ℃. The resulting suspension was stirred at 20 to 25 ℃ overnight. Is divided into4 portions of saturated NaHCO are added₃(80ml) of an aqueous solution and the resulting biphasic mixture was stirred at 20 to 25 ℃ for about 0.5 h. The organic layer was separated, washed with water (20ml) and the aqueous layer back-extracted with DCM (20ml) at pH 9. The combined organic phases were dried (Na)₂SO₄) Filtration and concentration under reduced pressure gave the title compound as a yellow oil (6.1g, 96% yield).

LCMS data: calculated value MH⁺(255) (ii) a Found value 100% [2(M-Boc)]H⁺m/z(307)，Rt＝1.4min。

NMR data:¹H NMR(400MHz，MeOD)ppm 3.38-3.52(4H，m)，2.86-2.98(1H，m)，2.40-2.54(4H，m)，2.02-2.12(2H，m)，1.77-1.92(4H，m)，1.61-1.75(2H，m)，1.46(9H，s)。

general procedure B：

Preparation of 1-cyclobutyl-1, 4-diazepanes

To a stirred solution of tert-butyl 4-cyclobutyl-1, 4-diazepan-1-carboxylate (6.1g, 23.98mmol) in DCM (70ml) at 20 to 25 ℃ was added dropwise a solution of 4M HCl in dioxane (30ml, 120 mmol). The resulting mixture was stirred at 20 to 25 ℃ for about 2 h. MeOH (6ml) was added and the resulting mixture was stirred at 20 to 25 ℃ for 1 to 2 days. The solvent was removed under reduced pressure and the resulting gum residue slurried in diethyl ether (100ml) for 0.5 h. The solvent was evaporated and the residue slurried in diethyl ether/MeOH (10: 1, 66 ml). The resulting white solid was collected by filtration, suspended in DCM (150ml) and treated with 2M NaOH. The aqueous phase was extracted with DCM until complete transfer of the product into the organic layer was achieved, which was analyzed by TLC (developing solution, DCM/MeOH/concentrated NH₃(90: 10: 1); color developing solution, PMA). The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated under reduced pressure to give the title compound as an orange oil (2.67g, 73% yield).

LCMS data: calculated value MH⁺(155) (ii) a Found 100% (MH)⁺)m/z 155，Rt＝0.44min。

NMR data:¹h NMR (400MHz, chloroform-d) ppm 2.85-2.97(5H, m), 2.43-2.53(4H, m), 1.97-2.08(2H, m), 1.52-1.91(7H, m).

Route 2

Preparation of benzyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate

To a stirred solution of 3-azetidinecarboxylic acid (500mg, 4.95mmol) at 0 ℃ in 2M K₂CO₃Water (5ml) and IITo a solution of alkane (5ml), benzyl chloroformate (929mg/0.78ml, 5.45mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 15 hours. The reaction was monitored by TLC. After completion of the reaction mixture was quenched with piperazine (42mg, 0.50mmol), concentrated under reduced pressure and treated with 2M HCl in water (10 ml). The aqueous layer was extracted with EtOAc (5X 10mL), the organic phase was separated and dried (MgSO)₄) Filtering, and concentrating under reduced pressure. The crude orange oil was purified by FCC on silica gel to give the title compound (760mg, 65% yield) as a white solid.

LCMS data (reaction IPC): calculated value MH⁺(236) (ii) a Found 7% (MH)⁺)m/z 236，Rt＝1.09min。

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.49(1H, br.s.), 7.30-7.42(5H, m), 5.10-5.15(2H, m), 4.18-4.27(4H，m)，3.43(1H，m)。

Example 1-preparation of benzyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate. Potency Range A

To a stirred 1- [ (benzyloxy) carbonyl group]To a solution of azetidine-3-carboxylic acid (500mg, 2.13mmol) in DMF/DCM (1: 10) (11ml) were added HOBt (287mg, 2.13mmol) and EDCI (490mg, 2.56 mmol). The resulting suspension was stirred at room temperature for 10 minutes, then a solution of 1-cyclobutyl-1, 4-diazepane (328mg, 2.13mmol) in DCM (3ml) was added dropwise. After stirring at room temperature for 16 h, TLC showed the reaction was complete and the solvent was evaporated under pressure. The residue was taken up in saturated NaHCO₃Aqueous (10ml) and the resulting aqueous layer extracted with EtOAc (3 × 7.5 ml). The combined organic phases were dried (MgSO)₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (with 99: 1 to 97: 3 DCM/2M NH)₃Gradient eluted in MeOH) to give the title compound (475mg, 60% yield) as a yellow oil.

LCMS data: calculated value MH⁺(372) (ii) a Found 97% (MH)⁺) m/z 372, Rt 2.51min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.29-7.41(5H, m), 5.10(2H, s), 4.19-4.47(2H, m), 4.07-4.18(2H, m), 3.59-3.71(2H, m), 3.48-3.58(1H, m), 3.33(2H, m), 2.85(1H, m), 2.45-2.56(2H, m), 2.34-2.45(2H, m), 1.97-2.10(2H, m), 1.73-1.92(4H, m), 1.58-1.73(2H, m).

Preparation of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepanes

To 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl]Benzyl azetidine-1-carboxylate (420mg, 1.13mmol) in EtOH (10ml) was added 5% Pd-C (42mg, 10% wt/wt). The flask was evacuated and the vacuum was adjusted to N₂And (5) gas purification. The flask was again evacuated and evacuated with H₂And (5) gas purification.¹H NMR showed the reaction was complete after 16 hours. Through CeliteThe suspension was filtered, washed with MeOH (3X 5ml), dried (MgSO)₄) The combined filtrates were filtered and concentrated under reduced pressure to give the title compound (248mg, 93% yield) as a viscous pale yellow oil.

LCMS data: calculated value MH⁺(238) (ii) a Measured value (MH)⁺) m/z 238Rt 2.91-3.02min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 4.01-4.08(2H, m), 3.72-3.80(1H, m), 3.67-3.72(2H, m), 3.60-3.67(2H, m), 3.33-3.38(2H, m), 2.86(1H, m), 2.48(2H, td, J ═ 10.3, 5.0Hz), 2.35-2.44(3H, m), 1.99-2.09(2H, m), 1.75-1.90(4H, m), 1.57-1.72(2H, m).

General procedure C：

Example 2-preparation of 1-cyclobutyl-4- { [1- (piperidin-1-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

To a stirred 0 ℃ solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (20mg, 0.084mmol) in DCM (1ml) and TEA (0.023ml, 0.17mmol) was added piperidine-1-carbonyl chloride (14.9mg, 0.013ml, 0.10mmol) dropwise. Will reactStir for 1 hour, then warm to room temperature and monitor progress with LCMS. After 1h, the reaction was quenched with water (5ml), extracted with DCM (2 × 10ml) and dried (MgSO)₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (with 99: 1 to 96: 4 DCM/2M NH)₃Gradient over MeOH) to give the impure title compound (22mg, 78%) as a brown oil. HPLC was again purified by preparative HPLC to give the title compound (3mg, 10% yield) as a colourless oil.

LCMS data: calculated value MH⁺(348) (ii) a Found 95% (MH)⁺) m/z 348, Rt 2.19min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 4.08-4.20(2H, m), 3.97-4.06(2H, m), 3.56(2H, m), 3.36-3.48(1H, m), 3.24-3.31(2H, m), 3.16-3.22(4H, m), 2.72-2.83(1H, m), 2.42(2H, m), 2.34(2H, m), 1.96(2H, m), 1.77(4H, m), 1.49-1.66(10H, m), 1.38-1.48(4H, m).

The following compounds were prepared according to the procedures described in route 2, general procedure C, above.

Example 3-1-cyclobutyl-4- { [1- (morpholin-4-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan preparation. Potency Range A

In a similar manner (route 2, GP C), with 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.126mmol) and morpholine-4-carbonyl chloride (23mg, 0.151mmol), FCC purification on silica gel (using 99: 1 to 96: 4 DCM/2M NH)₃Gradient of MeOH) to give the title compound (6.6mg, 15% yield) as a colorless oil.

LCMS data: calculated value MH⁺(351) (ii) a Found 95% (MH)⁺)m/z 351，Rt＝3.15min (method D).

NMR data: 1H NMR (250MHz, chloroform-d) ppm 4.13-4.23(2H, m), 4.04(2H, m), 3.54-3.63(6H, m), 3.36-3.52(1H, m), 3.27(6H, m), 2.71-2.85(1H, m), 2.42(2H, m), 2.29-2.38(2H, m), 1.90-2.04(2H, m), 1.43-1.87(10H, m).

Route 3

General procedure D：

Example 4-preparation of 1-cyclobutyl-4- { [1- (cyclohexylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

To a stirred solution of cyclohexanecarboxylic acid (10.8mg, 0.084mmol) in DCM/DMF (1.1ml) were added HOBt (11.4mg, 0.084mmol) and EDCI (16.1mg, 0.084 mmol). After 10min, a solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (20mg, 0.084mmol) in DCM (1ml) and DIPEA (0.01ml, 0.084mmol) was added dropwise. After 15 hours, the solvent is evaporated under reduced pressure and purified by silica gel FCC (using 99: 1 to 95: 5 DCM/2M NH)₃Gradient over MeOH) to give the title compound (24mg, 82% yield) as a brown oil.

LCMS data: calculated value MH⁺(348) (ii) a Found 100% (MH)⁺) m/z 348 and (MNa)⁺)370.1, Rt ═ 2.19min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 4.57(1H, m), 4.13-4.23(2H, m), 4.05(1H, m), 3.56-3.74(2H, m), 3.52(1H, m), 3.29-3.41(2H, m), 2.81-2.90(1H, m),2.49-2.57(1H，m)，2.43-2.49(2H，m)，2.34-2.42(1H，m)，2.15(1H，m)，2.03(2H，m)，1.89(2H，m)，1.75-1.85(4H，m)，1.57-1.72(4H，m)，1.38-1.54(2H，m)，1.15-1.32(4H，m)。

the following compounds were prepared according to the procedures described in pathway 3, general procedure D, above.

Example 5-preparation of 1-cyclobutyl-4- { [1- (tetrahydro-2H-pyran-4-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

In a similar manner (route 3, GP D), using tetrahydro-2H-pyran-4-carboxylic acid (16.4mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol), the title compound was obtained (15mg, 34% yield) as a colorless oil.

LCMS data: calculated value MH⁺(349) (ii) a Found 99% (MH)⁺) m/z 349, Rt 3.14min (method C).

NMR data: 1H NMR (500MHz, chloroform-d) ppm 4.59-4.65(1H, m), 4.14-4.27(2H, m), 3.96-4.10(3H, m), 3.49-3.76(3H, m), 3.29-3.46(4H, m), 2.81-2.91(1H, m), 2.34-2.58(5H, m), 1.99-2.08(2H, m), 1.74-1.93(7H, m), 1.53-1.74(3H, m).

Example 6 preparation of 4- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) benzonitrile. Potency Range A

In a similar manner (route 3, GP D), using 4-cyanobenzoic acid (18.5mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol) gave the title compound (15mg, 34% yield) as a viscous orange-brown oil.

LCMS data: calculated value MH⁺(366) (ii) a Found 99% (MH)⁺) m/z 366, Rt 3.58min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.71-7.77(4H, m), 4.72(1H, m), 4.38-4.47(1H, m), 4.32(2H, m), 3.58-3.75(3H, m), 3.35-3.40(2H, m), 2.83-2.91(1H, m), 2.34-2.58(4H, m), 2.04(2H, m), 1.74-1.94(5H, m), 1.56-1.73(2H, m).

Example 7 preparation of methyl 5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) pyridine-2-carboxylate. Potency Range A

In a similar manner (route 3, GP D), using 6- (methoxycarbonyl) pyridine-3-carboxylic acid (200mg, 1.10mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (262mg, 1.10mmol) gives the title compound (173mg, 39% yield) as a white solid.

LCMS data: calculated value MH⁺(401) (ii) a Found 100% (MH)⁺) m/z 401, Rt 3.31min (method D).

NMR data: 1H NMR (500MHz, chloroform-d) ppm 8.96(1H, m), 8.18-8.27(1H, m), 8.09-8.18(1H, m), 4.74(1H, m), 4.27-4.50(3H, m), 4.03(3H, s), 3.57-3.75(3H, m), 3.32-3.43(2H, m), 2.87(1H, s), 2.47-2.57(2H, m), 2.42(2H, m), 1.98-2.10(2H, m), 1.76-1.93(4H, m), 1.57-1.72(2H, m).

Pathway 4

General procedure E：

Example 8 preparation of 1-cyclobutyl-4- ({1- [ (2-methylpyrimidin-5-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

To a stirred solution of 2-methylpyrimidine-5-carboxylic acid (23mg, 0.17mmol) in DCM (3ml) were added HOBt (23mg, 0.17mmol) and HBTU (64mg, 0.17 mmol). After 3 hours, a solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (48mg, 0.17mmol) in DCM (1ml) was added and the yellow suspension gradually dissolved to give a yellow solution. The reaction mixture was washed with saturated NaHCO₃(1ml) quench and extract the aqueous layer with DCM (3X 5 ml). Drying (MgSO)₄) The combined organic layers were filtered and concentrated under reduced pressure. FCC purification on silica gel (with 99: 1-95: 5 DCM/2M NH)₃Gradient eluted in MeOH) to give the title compound (17.4mg, 29% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(358) (ii) a Found 99% (MH)⁺) m/z 358, Rt 3.05min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.89(2H, m), 4.77(1H, m), 4.36-4.44(2H, m), 4.27-4.34(1H, m), 3.58-3.72(3H, m), 3.33-3.38(2H, m), 2.85(1H, m), 2.77(3H, s), 2.46-2.52(2H, m), 2.37-2.43(2H, m), 2.02(2H, m), 1.87(1H, m), 1.74-1.84(3H, m), 1.58-1.70(2H, m).

The following compounds were prepared according to the procedures described in route 4, general procedure E, above.

Example 9 preparation of 1-cyclobutyl-4- ({1- [ (5-methylpyrazin-2-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 4, GP E), using 5-methylpyrazine-2-carboxylic acid (23mg, 0.17mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (40mg, 0.17mmol) gives the title compound (22mg, 34% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(358) (ii) a Found 98% (MH)⁺) m/z 358, Rt 2.05min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 9.15(1H, s), 8.37(1H, s), 4.92(1H, m), 4.82(1H, m), 4.32-4.45(2H, m), 3.57-3.75(3H, m), 3.33-3.42(2H, m), 2.86(1H, m), 2.60(3H, s), 2.33-2.57(4H, m), 2.11-2.31(1H, m), 1.97-2.08(2H, m), 1.87-1.94(1H, m), 1.74-1.87(3H, m), 1.61(2H, m).

Example 10 preparation of 1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 4, GP E), using 6-methylpyridine-3-carboxylic acid (200mg, 1.46mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (0.346mg, 1.46mmol) gave the title compound (219mg, 42% yield) as a white solid.

LCMS data: calculated value MH⁺(357) (ii) a Found 100% (MH)⁺) m/z 357, RT 3.34min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.76(1H, d, J ═ 1.8Hz), 7.90(1H, dd, J ═ 8.1, 2.0Hz), 7.23(1H, d, J ═ 8.1Hz), 4.75(1H, m), 4.35-4.46(2H, m), 4.28-4.36(1H, m), 3.59-3.74(3H, m), 3.33-3.42(2H, m), 2.82-2.92(1H, m), 2.61(3H, s), 2.48-2.54(2H, m), 2.39-2.46(2H, m), 2.00-2.10(2H, m), 1.74-1.93(4H, m), 1.58-1.74(2H, m).

Example 11-preparation of 1-cyclobutyl-4- [ (1- { [4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 4, GP E), using 4- (tetrahydropyran-4-yloxy) benzoic acid (50mg, 0.23mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (53mg, 0.23mmol), the title compound was obtained (57mg, 57%).

LCMS data: calculated value MH⁺(442) (ii) a Found 97% (MH)⁺) m/z 442, Rt 2.79min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.63(2H, d, J ═ 8.7Hz), 6.92(2H, d, J ═ 8.9Hz), 4.70-4.85(1H, m), 4.50-4.64(1H, m), 4.20-4.47(3H, m), 3.93-4.06(2H, m), 3.54-3.78(5H, m), 3.30-3.44(2H, m), 2.80-2.95(1H, m), 2.32-2.62(4H, m), 1.97-2.12(4H, m), 1.74-1.96(6H, m), 1.60-1.74(2H, m).

Example 12 preparation of 1-cyclobutyl-4- [ (1- { [6- (1H-imidazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (pathway 4GP E), using 6- (1H-imidazol-1-yl) nicotinic acid (26mg, 0.14mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol), the title compound was obtained (16mg, 31%).

LCMS data: calculated value MH⁺(409) (ii) a Found 100% (MH)⁺) m/z 409, Rt 3.38min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.75(1H, d, J ═ 1.7Hz), 8.41(1H, s), 8.17(1H, dd, J ═ 8.5, 1.2Hz), 7.68(1H, s), 7.43(1H, d, J ═ 8.5Hz), 7.23(1H, s), 4.83(1H, m.), 4.40-4.51(2H, m), 4.27-4.39(1H, m), 3.56-3.79(3H, m), 3.40(2H, m.), 2.82-2.96(1H, m), 2.53(4H, m.), 2.04-2.11(2H, m), 1.49-1.99(6H, m).

Example 13 preparation of 1-cyclobutyl-4- [ (1- { [6- (1H-1,2, 4-triazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 4, GP E), with 6- (1H-1,2, 4-triazol-1-yl) nicotinic acid (26mg, 0.14mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol), the title compound was obtained (16mg, 31%).

LCMS data: calculated value MH⁺(410) (ii) a Found 100% (MH)⁺) m/z 410, Rt 3.46min (method D).

¹H NMR(500MHz，MeOD)ppm 9.42(1H，s)，8.81(1H，d，J＝2.0Hz)，8.31(1H，dd，J＝8.5，2.2Hz)，8.24(1H，s)，8.05(1H，d，J＝8.5Hz)，4.62(2H，m)，4.38-4.52(1H，m)，4.23-4.38(1H，m)，3.85-4.02(1H，m)，3.60-3.75(2H，m)，3.40-3.57(2H，m)，2.84-3.02(1H，m)，2.52-2.71(2H，m)，2.39-2.51(2H，m)，2.01-2.16(2H，m)，1.77-1.96(4H，m)，1.56-1.77(2H，m)。

Example 14 preparation of 1-cyclobutyl-4- [ (1- { [6- (1H-pyrazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 4GP E), using 6- (1H-pyrazol-1-yl) nicotinic acid (50mg, 0.26mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (57mg, 0.24mmol) gives the title compound (4.7mg, 5%) after preparative HPLC (method 2).

LCMS data: calculated value MH⁺(409) (ii) a Found 98% (MH)⁺) m/z 409, Rt 4.02min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.74(1H，d，J＝1.8Hz)，8.66(1H，d，J＝2.7Hz)，8.21(1H，dd，J＝8.5，2.3Hz)，8.04(1H，d，J＝8.7Hz)，7.80(1H，s)，6.50-6.63(1H，m)，4.62(2H，d，J＝7.3Hz)，4.37-4.48(1H，m)，4.28-4.37(1H，m)，3.83-3.99(1H，m)，3.60-3.74(2H，m)，3.43-3.55(2H，m)，2.84-3.03(1H，m)，2.41-2.63(4H，m)，2.01-2.13(2H，m)，1.79-1.97(4H，m)，1.57-1.76(2H，m)。

pathway 5

Preparation of 1- { [1- (chloroacetyl) azetidin-3-yl ] carbonyl } -4-cyclobutyl-1, 4-diazepane

To 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (330mg, 1.39mmol) and Na at 0 deg.C₂CO₃To a solution of (590mg, 5.56mmol) in dichloromethane (10ml) was added chloroacetyl chloride (107. mu.l, 1.39 mmol). After 10 minutes the reaction temperature was raised to room temperature and stirred for an additional 1 hour. The reaction was then filtered and concentrated under reduced pressure to give the title compound as a colorless oil (411mg, 91% yield), which was used without further purification.

LCMS data: calculated value MH⁺(314) (ii) a Found 81% (MH)⁺)m/z 314，Rt＝3.38min。

NMR data:¹H NMR(500MHz，CDCl₃)ppm 4.54-4.65(1H，m)，4.25-4.37(1H，m)，4.06-4.24(2H，m)，3.77-3.89(2H，m)，3.47-3.76(3H，m)，3.20-3.37(2H，m)，2.74-2.89(1H，m)，2.28-2.59(4H，m)，1.70-2.04(6H，m)，1.49-1.68(2H，m)。

general procedure F：

Example 15-preparation of 1-cyclobutyl-4- { [1- (1H-pyrazol-1-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

1- { [1- (chloroacetyl) nitrogenHeterocyclic but-3-yl]Carbonyl } -4-cyclobutyl-1, 4-diazepane (40mg, 0.13mol), K₂CO₃A solution of (20mg, 0,14mmol) and pyrazole (9mg, 0.13mmol) was heated in DMF (2ml) at 120 ℃ for 16 h in a sealed tube. The solvent was evaporated under reduced pressure and purified by silica gel FCC (eluent gradient; DCM/MeOH/NH)₃99: 1-92: 8: 1) to give the title compound (18mg, 40% yield) as a light brown oil.

LCMS data: calculated value MH⁺(346) (ii) a Found 79% (MH)⁺) m/z 346, Rt 3.23min (method D).

NMR data-estimated-90% purity:¹H NMR(500MHz，CDCl₃)ppm 7.49-7.58(2H，m)，6.32(1H，m)，4.70-4.88(2H，m)，4.29-4.39(1H，m)，4.11-4.28(2H，m)，3.95-4.09(1H，m)，3.45-3.72(3H，m)，3.25-3.38(2H，m)，2.79-2.92(1H，m)，2.30-2.57(4H，m)，2.03(2H，m)，1.72-1.96(4H，m)，1.54-1.72(2H，m)。

pathway 6

General procedure N：

Example 16-preparation of 1-cyclobutyl-4- { [1- (piperidin-1-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

1- { [1- (chloroacetyl) azetidin-3-yl]A solution of carbonyl } -4-cyclobutyl-1, 4-diazepane (40mg, 0.13mmol) and piperidine (38. mu.l, 0.38mmol) in toluene (2ml) was heated at 80 ℃ for 4h in a sealed tube and then cooled to room temperature. The reaction was diluted with DCM (30ml) and saturated NaHCO₃(2X 15ml) aqueous solution, dried (MgSO₄) Filtering, and concentrating under reduced pressure. The residue was purified by FCC on silica gel (eluent gradient; DCM/MeOH/NH)₃99: 1 to 92: 8: 1) to give the title compound (25mg, 53% yield) as a colourless oil.

LCMS data: calculated value MH⁺(363) (ii) a Found 85% (MH)⁺) m/z 363, Rt 3.74min (method D).

NMR data:¹H NMR(500MHz，CDCl₃)ppm 4.55-4.65(1H，m)，4.30-4.40(1H，m)，4.06-4.24(2H，m)，3.47-3.73(3H，m)，3.28-3.40(2H，m)，2.92-3.06(2H，m)，2.80-2.90(1H，m)，2.30-2.58(8H，m)，1.98-2.08(2H，m)，1.73-1.93(4H，m)，1.50-1.73(6H，m)，1.34-1.46(2H，m)。

the following compounds were prepared according to the procedure described in pathway 6, general procedure N, above.

Example 17-preparation of 1-cyclobutyl-4- { [1- (morpholin-4-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

In a similar manner (route 6, GP N), using 1- { [1- (chloroacetyl) azetidin-3-yl ] carbonyl } -4-cyclobutyl-1, 4-diazepan (100mg, 0.32mmol) and morpholine (83mg, 0.95mmol), after purification by preparative HPLC (method 2) gives the title compound (8.8mg, 8%) as a colourless oil.

LCMS data: calculated value MH⁺(365) (ii) a Found 99% (MH)⁺) m/z 365, Rt 3.06min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.43-4.51(2H，m)，4.15-4.23(1H，m)，4.06-4.15(1H，m)，3.77-3.87(1H，m)，3.67-3.73(4H，m)，3.58-3.67(2H，m)，3.41-3.51(2H，m)，3.07(2H，s)，2.87-3.00(1H，m)，2.41-2.63(8H，m)，2.02-2.13(2H，m)，1.78-1.95(4H，m)，1.61-1.76(2H，m)。

example 18 preparation of 1-cyclobutyl-4- ({1- [ (1, 1-thiomorpholin-4-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepan. Potency Range A

In a similar manner (route 6, GP N), after purification by preparative HPLC (method 2) using 1- { [1- (chloroacetyl) azetidin-3-yl ] carbonyl } -4-cyclobutyl-1, 4-diazepane (150mg, 0.47mmol) and thiomorpholine-1, 1-dioxide (130mg, 0.75mmol), the title compound was obtained (7.9mg, 3%) as a colourless oil.

LCMS data: calculated value MH⁺(413) (ii) a Found 100% (MH)⁺) m/z 413, Rt 3.00min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.37-4.54(2H，m)，4.16-4.27(1H，m)，4.07-4.15(1H，m)，3.69-3.89(2H，m)，2.67-3.69(18H，m)，2.16-2.32(2H，m)，1.89-2.16(4H，m)，1.67-1.87(2H，m)。

example 19-preparation of 1-cyclobutyl-4- ({1- [ (3, 3-difluoropyrrolidin-1-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepan. Potency Range A

In a similar manner (route 6, GP N), using 1- { [1- (chloroacetyl) azetidin-3-yl ] carbonyl } -4-cyclobutyl-1, 4-diazepane (150mg, 0.47mmol) and 3, 3-difluoropyrrolidine hydrochloride (111mg, 0.75mmol), after purification by preparative HPLC (method 2) gave the title compound (6.3mg, 3%) as a colorless oil.

LCMS data: calculated value MH⁺(385) (ii) a Found 100% (MH)⁺) m/z 385, Rt 3.56min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.37-4.52(2H，m)，4.04-4.30(3H，m)，3.65-3.91(3H，m)，3.37-3.65(4H，m)，3.28-3.37(2H，m)，2.83-3.19(6H，m)，2.08-2.43(8H，m)，1.69-1.93(2H，m)。

example 20-preparation of 1-cyclobutyl-4- ({1- [ (4, 4-difluoropiperidin-1-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 6, GP N), using 1- { [1- (chloroacetyl) azetidin-3-yl ] carbonyl } -4-cyclobutyl-1, 4-diazepane (150mg, 0.47mmol) and 4, 4-difluoropiperidine hydrochloride (90mg, 0.57mmol), after purification by preparative HPLC (method 2) gave the title compound (7.3mg, 4%) as a colorless oil (method 2).

LCMS data: calculated value MH⁺(399) (ii) a Found 90% (MH)⁺) m/z 399, Rt 3.68min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 4.63(1H, m), 4.17-4.34(2H, m), 4.06-4.17(1H, m), 3.51-3.77(3H，m)，3.29-3.43(2H，m)，3.04-3.13(2H，m)，2.81-2.93(1H，m)，2.35-2.77(8H，m)，1.75-2.14(10H，m)，1.55-1.75(2H，m)。

Pathway 7

General procedure G：

Example preparation of 1-cyclobutyl-4- [ (1- { [ (6-methylpyridin-3-yl) oxy ] acetyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane. Potency Range A

To a stirred solution of 3-hydroxy-6-methylpyridine (28mg, 0.26mmol) in EtOH (1ml) was added NaH (8mg, 60% dispersion in mineral oil, 0.19 mmol). When the evolution of gas has ceased, the solution is added to 1- { [1- (chloroacetyl) azetidin-3-yl radical at room temperature]Carbonyl } -4-cyclobutyl-1, 4-diazepane (40mg, 0.13mmol) in EtOH (1ml) and the reaction was heated in a sealed tube at 80 ℃ for 4 h. After cooling to room temperature, quench with water (1ml) and the resulting mixture was diluted with DCM (30ml) and saturated NaHCO₃(2X 15ml) solution washed and dried (MgSO₄) Filtering, and concentrating under reduced pressure. The residue was purified by FCC on silica gel (eluent gradient; DCM/MeOH/NH)₃99: 1-90: 10: 1) to give the title compound (18mg, 36% yield) as a colorless oil.

LCMS data: calculated value MH⁺(387) (ii) a Found 94% (MH)⁺) m/z 387, Rt 3.50min (method D).

NMR data:¹H NMR(500MHz，CDCl₃)ppm 8.19(1H，d，J＝2.7Hz)，7.04-7.16(2H，m)，4.64-4.74(1H，m)，4.52-4.63(2H，m)，4.35-4.43(1H，m)，4.14-4.29(2H，m)，3.53-3.72(3H，m)，3.24-3.40(2H，m)，2.77-2.90(1H，m)，2.29-2.57(7H，m)，1.95-2.08(2H，m)，1.71-1.94(4H，m)，1.52-1.71(2H，m)。

the following compounds were prepared according to the procedures described in pathway 7, general procedure G, above.

Example 22-preparation of 4- (2- {3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } -2-oxoethoxy) benzonitrile. Potency Range A

In a similar manner (route 7, GP G), after purification by preparative HPLC using 4-cyanophenol (30mg, 0.26mmol) and 1- { [1- (chloroacetyl) azetidin-3-yl ] carbonyl } -4-cyclobutyl-1, 4-diazepan (40mg, 0.13mmol), the title compound was obtained (5mg, 10% yield) as a colorless oil.

LCMS data: calculated value MH⁺(397) (ii) a Found 99% (MH)⁺) m/z 397, Rt 3.82min (method D).

NMR data:¹H NMR(500MHz，CDCl₃)ppm 7.69(2H，d，J＝8.9Hz)，7.11(2H，d，J＝8.9Hz)，4.74(2H，s)，4.45-4.56(2H，m)，4.20-4.29(1H，m)，4.14-4.20(1H，m)，3.81-3.91(1H，m)，3.56-3.76(2H，m)，3.42-3.52(2H，m)，2.97-3.21(1H，m)，2.48-2.82(4H，m)，2.06-2.21(2H，m)，1.82-2.02(4H，m)，1.62-1.80(2H，m)。

pathway 8

General procedureH：

Example 23-preparation of 1-cyclobutyl-4- ({1- [ (4-methoxyphenyl) sulfonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range B

To a stirred solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (40mg, 0.169mmol) in DCM (4ml) was added DIPEA (0.056ml, 0.34mmol) and 4-methoxybenzenesulfonyl chloride (38mg, 0.185mmol) at room temperature. After stirring at room temperature for 16 h, the reaction was quenched by addition of MeOH (0.5ml) and the solvent was evaporated under reduced pressure. Purification by preparative HPLC (method 1) gave TFA salt,¹h NMR check 90% purity. Repurification on silica FCC (eluent gradient; DCM/MeOH/NH)₃98: 2: 0.5-95: 5: 0.5) to give the title compound (25mg, 36% yield) as a colorless oil.

LCMS data: calculated value MH⁺(408) (ii) a Found 99% (MH)⁺) m/z 408, Rt 4.20min (method D).

¹H NMR(500MHz，MeOD)ppm 7.69-7.91(2H，m)，7.17(2H，d，J＝8.9Hz)，3.82-3.99(7H，m)，3.55-3.68(1H，m)，3.45-3.53(2H，m)，3.32(3H，s)，2.89(1H，m)，2.48-2.54(1H，m)，2.43-2.47(1H，m)，2.37-2.43(2H，m)，1.99-2.13(2H，m)，1.77-1.89(3H，m)，1.75(1H，dt，J＝11.6，5.8Hz)，1.59-1.71(2H，m)。

The following compounds were prepared according to the procedures described in pathway 8, general procedure H, above.

Example 24-1-cyclobutyl-4- { [1- (cyclohexylsulfonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

In a similar manner (route 8, GP H), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol) and cyclohexanesulfonyl chloride (42.3mg, 0.23mmol), the title compound was obtained (32mg, 40% yield) as a colorless oil.

LCMS data: calculated value MH⁺(384) (ii) a Found 99% (MH)⁺) m/z 384, Rt 4.44min (method D).

¹H NMR(500MHz，MeOD)ppm 4.17(2H，m)，4.03(2H，m)，3.74-3.82(1H，m)，3.58-3.67(2H，m)，3.39-3.47(2H，m)，2.87-3.00(2H，m)，2.55(2H，m)，2.47(2H，m)，2.02-2.18(4H，m)，1.78-1.94(6H，m)，1.60-1.76(3H，m)，1.40-1.52(2H，m)，1.34(2H，m)，1.17-1.26(1H，m)。

Example 25 preparation of 1-cyclobutyl-4- ({1- [ (cyclopentylmethyl) sulfonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 8, GP H), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol) and cyclopentylmethanesulfonyl chloride (42.3mg, 0.23mmol) gave the title compound (26mg, 32% yield) as a colorless oil.

LCMS data: calculated value MH⁺(384) (ii) a Found 98% (MH)⁺) m/z 384, Rt 4.47min (method D).

¹H NMR(500MHz，MeOD)ppm 4.15(2H，m)，4.05(2H，m)，3.75-3.82(1H，m)，3.59-3.65(2H，m)，3.41-3.46(2H，m)，3.11(2H，m)，2.93(1H，m)，2.52-2.58(2H，m)，2.44-2.50(2H，m)，2.27-2.37(1H，m)，2.04-2.12(2H，m)，1.93-2.01(2H，m)，1.81-1.91(4H，m)，1.65-1.74(4H，m)，1.55-1.64(2H，m)。

Example 26-preparation of 1-cyclobutyl-4- { [1- (phenylsulfonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane. Potency Range A

In a similar manner (route 8, GP H), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol) and benzenesulfonyl chloride (40.9mg, 0.23mmol), the title compound was obtained (18mg, 23% yield) as a colorless oil.

LCMS data: calculated value MH⁺(378) (ii) a Found 98% (MH)⁺) m/z 378, Rt 4.15min (method D).

¹H NMR(500MHz，MeOD)ppm 7.83-7.91(2H，m)，7.71-7.78(1H，m)，7.65-7.70(2H，m)，3.95-4.01(2H，m)，3.92(2H，m)，3.57-3.66(1H，m)，3.45-3.51(2H，m)，3.33-3.35(1H，m)，3.32(2H，m)，2.83-2.95(1H，m)，2.48-2.51(1H，m)，2.42-2.46(1H，m)，2.40(2H，m)，2.01-2.10(2H，m)，1.78-1.87(3H，m)，1.60-1.76(3H，m)。

Example 27-preparation of 4- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } sulfonyl) benzonitrile. Potency Range A

In a similar manner (route 8, GP H), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol) and 4-cyanobenzenesulfonyl chloride (46.7mg, 0.23mmol) gives the title compound (45mg, 53% yield) as a colorless oil.

LCMS data: calculated value MH⁺(403) (ii) a Found 100% (MH)⁺) m/z 403, Rt 4.17min (method D).

¹H NMR(500MHz，MeOD)ppm 7.99-8.08(4H，m)，4.01-4.08(2H，m)，3.95(2H，m)，3.66(1H，m)，3.45-3.51(2H，m)，3.33-3.38(2H，m)，2.84-2.96(1H，m)，2.48-2.53(1H，m)，2.43-2.46(1H，m)，2.38-2.43(2H，m)，2.02-2.11(2H，m)，1.78-1.87(3H，m)，1.75(1H，m)，1.60-1.71(2H，m)。

Pathway 9

General procedure I：

Example 28 preparation of 1-cyclobutyl-4- ({1- [ (4-methoxycyclohexyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

To a stirred solution of 4-methoxycyclohexanecarboxylic acid (20mg, 0.13mmol) in DMF/DCM (1: 1) (2ml) were added HOBt (38mg, 0.28mmol) and HBTU (96mg, 0.25mmol), and the reaction mixture was stirred at room temperature for 15 min. A solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol) in DCM (1ml) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and purified by silica gel FCC (using DCM/MeOH/NH)₃(ii) a 95: 5: 0.5-90: 10: 1 as eluent) to give the titleThe compound is a colorless oil obtained by¹H NMR spectroscopy detected a 1: 1 mixture of diastereomers (5.2mg, 11% yield).

LCMS data: diastereomer A-calculated MH⁺(378) (ii) a Found 43% (MH)⁺) m/z 378, Rt 3.50 min. Method D.

Diastereomer B-calculated MH⁺(378) (ii) a Found 55% (MH)⁺) m/z 378, Rt 3.68min, method D.

NMR data:¹H NMR(500MHz，MeOD)ppm 4.34-4.49(2H，m)，4.11-4.20(1H，m)，4.00-4.09(1H，m)，3.79(1H，m)，3.56-3.68(2H，m)，3.40-3.52(3H，m)，3.35(1H，s)，3.29(2H，s)，2.93(1H，m)，2.42-2.63(4H，m)，2.19-2.39(1H，m)，2.03-2.16(3H，m)，1.94-2.02(1H，m)，1.60-1.93(8H，m)，1.41-1.56(3H，m)，1.13-1.28(1H，m)。

the following compounds were prepared according to the procedures described in pathway 9, general procedure I, above.

Example 29-preparation of 1-cyclobutyl-4- ({1- [ (4, 4-difluorocyclohexyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 9, GP I), using 4, 4-difluorocyclohexanecarboxylic acid (21mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol), the title compound was obtained as a colorless oil (5.7mg, 12% yield).

LCMS data: calculated value MH⁺(384) (ii) a Found 90% (MH)⁺) m/z 384, Rt 3.87min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.36-4.49(2H，m)，4.13-4.20(1H，m)，4.06(1H，m)，3.74-3.86(1H，m)，3.56-3.72(2H，m)，3.37-3.53(2H，m)，2.78-3.05(1H，m)，2.36-2.64(5H，m)，2.03-2.17(4H，m)，1.59-1.99(12H，m)。

example 30-preparation of 1-cyclobutyl-4- [ (1- { [4- (3, 5-dimethyl-1H-pyrazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I), using 4- (3, 5-dimethyl [1H ] -pyrazol-1-yl) benzoic acid (27mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (30mg, 0.13mmol), after purification by preparative HPLC, the title compound was obtained as a colorless oil (7.1mg, 13% yield).

LCMS data: calculated value MH⁺(436) (ii) a Found 91% (MH)⁺) m/z 436, Rt 2.65min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 7.82(2H，d，J＝8.5Hz)，7.58(2H，d，J＝8.5Hz)，6.13(1H，s)，4.62(2H，d)，4.13-4.50(3H，m)，3.90(1H，d)，3.66-3.83(2H，m)，3.46-3.65(5H，m)，2.87-3.16(2H，m)，2.35-2.44(2H，m)，2.34(3H，s)，2.27(3H，s)，2.18-2.26(2H，m)，2.03-2.18(1H，m)，1.74-1.93(2H，m)。

example 31-1-cyclobutyl-4- [ (1- { [4- (5-methyl-1, 3,4-Oxadiazol-2-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]Preparation of 1, 4-diazepane. Potency Range A

In a similar manner (pathway 9, GP I), with 4- (5-dimethyl-1, 3,4-Oxadiazol-2-yl) benzoic acid (26mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol) to give the title compound (5.6mg, 10% yield) as a colourless oil.

LCMS data: calculated value MH⁺(424) (ii) a Found 98% (MH)⁺) m/z 424, Rt 3.57min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.15(2H，d，J＝8.4Hz)，7.86(2H，d，J＝8.4Hz)，4.52-4.64(2H，m)，4.38-4.47(1H，m)，4.29-4.37(1H，m)，3.86-3.95(1H，m)，3.60-3.72(2H，m)，3.44-3.54(2H，m)，2.95(1H，m)，2.66(3H，s)，2.54-2.62(2H，m)，2.38-2.54(2H，m)，2.04-2.19(2H，m)，1.81-1.96(4H，m)，1.60-1.76(2H，m)。

example 32-preparation of 1-cyclobutyl-4- { [1- (cyclopropylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I), using cyclopropylacetic acid (13mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol) gives the title compound (5.3mg, 13% yield) as a colourless oil.

LCMS data: calculated value MH⁺(320) (ii) a Found 93% (MH)⁺)m/z 320，Rt 2.07min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.32-4.41(2H，m)，4.14-4.21(1H，m)，4.06-4.12(1H，m)，3.74-3.84(1H，m)，3.58-3.70(2H，m)，3.43-3.52(2H，m)，2.93-3.08(1H，m)，2.55-2.69(3H，m)，2.47-2.55(1H，m)，2.10-2.16(2H，m)，2.08(2H，d，J＝7.0Hz)，1.81-1.98(4H，m)，1.62-1.78(2H，m)，0.94-1.05(1H，m)，0.49-0.57(2H，m)，0.18(2H，m)。

example 33-preparation of 1-cyclobutyl-4- { [1- (cyclohexylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I), after purification by preparative HPLC using cyclohexylacetic acid (18mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol), the title compound was obtained as a colourless oil (11.5mg, 25% yield).

LCMS data: calculated value MH⁺(362) (ii) a Found 99% (MH)⁺) m/z 362, Rt 2.68min (method C).

NMR data: 1H NMR (500MHz, MeOD) ppm 4.32-4.47(2H, m), 4.14-4.27(2H, m), 4.03-4.13(1H, m), 3.66-3.86(3H, m), 3.41-3.63(4H, m), 2.89-3.13(2H, m), 2.35(2H, m), 2.20-2.30(3H, m), 2.06-2.17(1H, m), 2.02(2H, m), 1.62-1.93(8H, m), 1.12-1.37(3H, m), 0.91-1.06(2H, m).

Example 34-preparation of 4- (2- {3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } -2-oxoethyl) benzonitrile. Potency Range A

In a similar manner (route 9, GP I), after purification by preparative HPLC using 4-cyanophenylacetic acid (20mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol), the title compound was obtained as a colourless oil (3.9mg, 8% yield).

LCMS data: calculated value MH⁺(381) (ii) a Found 92% (MH)⁺) m/z 381, Rt 2.36min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 7.69(2H，d，J＝8.2Hz)，7.46(2H，d，J＝8.2Hz)，4.36-4.57(2H，m)，4.16-4.30(2H，m)，4.08-4.15(1H，m)，3.66-3.88(3H，m)，3.62(2H，s)，3.46-3.60(4H，m)，2.89-3.13(2H，m)，2.32-2.42(2H，m)，2.18-2.30(3H，m)，2.01-2.18(1H，m)，1.73-1.93(2H，m)。

example preparation of 35-1-cyclobutyl-4- [ (1- { [4- (1, 3-thiazol-2-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I), after purification by preparative HPLC (method 2) using 4- (1, 3-thiazol-4-yl) benzoic acid (46mg, 0.22mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol), the title compound was obtained (5mg, 6% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(425) (ii) a Found 100% (MH)⁺) m/z 425, Rt 4.08min (LCMS method D).

¹H NMR(500MHz，MeOD)ppm 8.01-8.09(2H，m)，7.92(1H，d，J＝3.2Hz)，7.77(2H，d，J＝8.2Hz)，7.68(1H，d，J＝3.2Hz)，4.51-4.62(2H，m)，4.26-4.45(2H，m)，3.83-3.93(1H，m)，3.59-3.71(2H，m)，3.42-3.52(2H，m)，2.91-3.09(1H，m)，2.45-2.69(4H，m)，2.01-2.16(2H，m)，1.79-1.98(4H，m)，1.59-1.77(2H，m)。

Example 36 preparation of 1-cyclobutyl-4- [ (1- { [4- (2-methyl-1, 3-thiazol-4-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I), using 4- (2-methyl-1, 3-thiazol-4-yl) benzoic acid (250mg, 1.15mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (210mg, 0.89mmol), after purification by preparative HPLC (method 2) gave the title compound (30mg, 8% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(439) (ii) a Found 97% (MH)⁺) m/z 439, Rt 4.24min (LCMS method D).

¹H NMR(500MHz，MeOD)ppm 7.99(2H，d，J＝8.4Hz)，7.78(1H，s)，7.71(2H，d，J＝8.4Hz)，4.52-4.61(2H，m)，4.25-4.42(2H，m)，3.88(1H，m)，3.59-3.76(2H，m)，3.43-3.55(2H，m)，3.01-3.27(1H，m)，2.73-2.83(5H，m)，2.55-2.72(2H，m)，2.07-2.21(2H，m)，1.81-2.06(4H，m)，1.60-1.81(2H，m)。

Example 37-1-cyclobutyl-4- [ (1- { [4- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]Preparation of 1, 4-diazepane. Potency Range A

In a similar manner (pathway 9, GP I), with 4- (5-methyl-1, 2,4-Oxadiazol-3-yl) benzoic acid (100mg, 0.49mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (140mg, 0.59mmol) gave, after purification by preparative HPLC (method 2), the title compound (3.6mg, 1.5% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(424) (ii) a Found 100% (MH)⁺) m/z 424, Rt 2.50min (LCMS method C).

¹H NMR(500MHz，MeOD)ppm 8.14(2H，m)，7.80(2H，d，J＝8.2Hz)，4.49-4.62(2H，m)，4.25-4.44(2H，m)，3.78-3.94(1H，m)，3.55-3.73(2H，m)，3.41-3.54(2H，m)，2.90-3.04(1H，m)，2.67(3H，s)，2.42-2.65(4H，m)，2.04-2.14(2H，m)，1.77-1.97(4H，m)，1.60-1.76(2H，m)。

Example 38 preparation of 1-cyclobutyl-4- [ (1- { [4- (1-methylethyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I), after purification by preparative HPLC (method 2) using 4- (1-methylethyl) benzoic acid (86mg, 0.52mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (125mg, 0.52mmol), the title compound was obtained (24mg, 12% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(384) (ii) a Found 98% (MH)⁺) m/z 384, Rt 4.50min (LCMS method D).

¹H NMR (500MHz, chloroform-d) ppm 7.57(2H, d, J ═ 8.2Hz), 7.26(2H, m), 4.63-4.81(1H, m), 4.18-4.47(3H, m), 3.52-3.81(3H, m), 3.29-3.44(2H, m), 2.77-2.99(2H, m), 2.30-2.63(4H, m), 1.97-2.10(2H, m), 1.73-1.95(4H, m), 1.51-1.73(2H, m), 1.25(6H, d, J ═ 7.0 Hz).

Example 39-preparation of 1-cyclobutyl-4- ({1- [ (4-phenoxyphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 9, GP I), after purification by preparative HPLC (method 2) using 4-phenoxybenzoic acid (112mg, 0.52mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (125mg, 0.53mmol), the title compound was obtained (34mg, 15% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(434) (ii) a Found 100% (MH)⁺) m/z 434, Rt 4.57min (LCMS method D).

¹H NMR (500MHz, chloroform-d) ppm 7.59-7.68(2H, m), 7.34-7.42(2H, m), 7.13-7.21(1H, m), 7.02-7.08(2H, m), 6.95-7.01(2H, m), 4.63-4.83(1H, m), 4.17-4.50(3H, m), 3.53-3.81(3H, m), 3.27-3.46(2H, m), 2.79-2.99(1H, m), 2.29-2.68(4H, m), 1.99-2.12(2H, m), 1.52-1.99(6H, m).

Example 40 preparation of 1-cyclobutyl-4- [ (1- { [4- (1H-pyrazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I), purification using preparative HPLC (method 2) using 4- (1H-pyrazol-1-yl) benzoic acid (100mg, 0.52mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (125mg, 0.52mmol) gave the title compound (31mg, 14% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(408) (ii) a Found 93% (MH)⁺) m/z 408, Rt 3.84min (LCMS method D).

¹H NMR (500MHz, chloroform-d) ppm 7.98(1H, d, J ═ 2.6Hz), 7.68-7.82(5H, m), 6.49(1H, m), 4.75(1H, m), 4.21-4.48(3H, m), 3.56-3.77(3H, m), 3.28-3.44(2H, m), 2.85(1H, m), 2.31-2.59(4H, m), 1.96-2.31(2H, m), 1.73-1.96(4H, m), 1.52-1.73(2H, m).

Example 41-1-cyclobutyl-4- [ (1- { [4- (3-methyl-1, 2,4-Oxadiazol-5-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]Preparation of 1, 4-diazepane. Potency Range A

In a similar manner (pathway 9, GP I), with 4- (3-methyl-1, 2,4-Oxadiazol-5-yl) benzoic acid (100mg, 0.49mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (diazepane)119mg, 0.50mmol) to give, after purification by preparative HPLC (method 2), the title compound (8mg, 4% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(424) (ii) a Found 92% (MH)⁺) m/z 424, Rt 3.90min (LCMS method D).

¹H NMR (500MHz, chloroform-d) ppm 8.17(2H, d, J ═ 8.5Hz), 7.80(2H, d, J ═ 8.2Hz), 4.71-4.80(1H, m), 4.27-4.48(3H, m), 3.58-3.84(3H, m), 3.40(2H, m), 2.88(1H, m), 2.33-2.65(7H, m), 2.01-2.11(2H, m), 1.87(2H, m), 1.55-1.77(4H, m).

Example 42-1-cyclobutyl-4- [ (1- { [4- (4, 4-dimethyl-4, 5-dihydro-1, 3-)Azol-2-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]Preparation of 1, 4-diazepane. Potency Range A

In a similar manner (pathway 9, GP I), with 4- (4, 4-dimethyl-4, 5-dihydro-1, 3-)Oxazol-2-yl) benzoic acid (12mg, 0.05mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (20mg, 0.09mmol) to give the title compound (3mg, 13% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(439) (ii) a Found 95% (MH)⁺) m/z 439, Rt 2.36min (LCMS method C).

¹H NMR(500MHz，MeOD)ppm 8.00(2H，d，J＝8.4Hz)，7.74(2H，d，J＝8.2Hz)，4.53(2H，d，J＝7.6Hz)，4.27-4.41(2H，m)，4.23(2H，s)，3.84-3.92(1H，m)，3.60-3.66(2H，m)，3.44-3.48(2H，m)，2.88-2.97(1H，m)，2.52-2.59(2H，m)，2.43-2.49(2H，m)，2.04-2.11(2H，m)，1.82-1.90(4H，m)，1.62-1.73(2H，m)，1.39(6H，s)。

Example 43-preparation of 1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 9, GP I), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (137mg, 0.57mmol) and (6-methylpyridin-3-yl) acetic acid (73mg, 0.48mmol), after purification by preparative HPLC (method 2) gave the title compound (16mg, 9%) as a colourless oil.

LCMS data: calculated value MH⁺(371) (ii) a Found 100% (MH)⁺) m/z 371, Rt 3.41min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.31(1H，d，J＝1.7Hz)，7.65(1H，dd，J＝8.0，2.1Hz)，7.27(1H，d，J＝8.1Hz)，4.39-4.51(2H，m)，4.15-4.23(1H，m)，4.05-4.15(1H，m)，3.75-3.88(1H，m)，3.56-3.69(2H，m)，3.53(2H，s)，3.41-3.50(2H，m)，2.88-3.01(1H，m)，2.39-2.61(7H，m)，2.04-2.13(2H，m)，1.77-1.96(4H，m)，1.59-1.76(2H，m)。

example 44 preparation of 1-cyclobutyl-4- ({1- [ (4-pyridin-3-ylphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 9, GP I), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (118mg, 0.50mmol) and 4-pyridine-3-benzoic acid (100mg, 0.50mmol), after purification by preparative HPLC (method 2) gives the title compound (39mg, 19%).

LCMS data: calculated value MH⁺(419) (ii) a Found 100% (MH)⁺) m/z 419, Rt 3.82min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.86(1H, d, J ═ 2.0Hz), 8.63(1H, dd, J ═ 4.8, 1.4Hz), 7.90(1H, dt, J ═ 7.9, 2.0Hz), 7.77(2H, d, J ═ 8.4Hz), 7.63(2H, d, J ═ 8.2Hz), 7.40(1H, dd, J ═ 7.9, 4.8Hz), 4.71-4.84(1H, m), 4.35-4.49(2H, m), 4.26-4.35(1H, m), 3.57-3.80(3H, m), 3.31-3.45(2H, m), 2.81-2.95(1H, m), 2.34-2.63 (1H, m), 1.99-3.75 (1H, 1.75H, m), 1.75-4.75H, 1H, m).

Example 45 preparation of 1-cyclobutyl-4- ({1- [ (4-pyridin-4-ylphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 9, GP I), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (118mg, 0.50mmol) and 4-pyridine-4-benzoic acid (100mg, 0.50mmol), the title compound was obtained (25mg, 12%).

LCMS data: calculated value MH⁺(419) (ii) a Found 100% (MH)⁺) m/z 419, Rt 3.82min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.68(2H, d, J ═ 5.0Hz), 7.75(2H, d, J ═ 8.1Hz), 7.68(2H, d, J ═ 8.1H), andz)，7.51(2H，d，J＝5.3Hz)，4.75(1H，m)，4.34-4.50(2H，m)，4.24-4.33(1H，m)，3.57-3.96(3H，m)，3.34-3.52(2H，m)，3.04-3.13(1H，m)，2.69(4H，m)，2.04-2.26(5H，m)，1.91-2.01(1H，m)，1.59-1.77(2H，m)。

example 46 preparation of 1-cyclobutyl-4- [ (1- { [3- (2-methyl-1, 3-thiazol-4-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 9, GP I) with 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (100mg, 0.42mmol) and 3- (2-methyl-1, 3-thiazol-4-yl) benzoic acid (92mg, 0.42mmol) gave the title compound (55mg, 34%).

LCMS data: calculated value MH⁺(439) (ii) a Found 99% (MH)⁺) m/z 439, Rt 2.58min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.10(1H, s), 7.97(1H, d, J ═ 7.9Hz), 7.54(1H, d, J ═ 7.8Hz), 7.40-7.46(1H, m), 7.36(1H, s), 4.69(1H, d, J ═ 8.1Hz), 4.25-4.43(3H, m), 3.56-3.74(3H, m), 3.31-3.38(2H, m), 2.87(1H, s), 2.74(3H, s), 2.33-2.61(4H, m), 1.97-2.06(2H, m), 1.74-1.94(4H, m), 1.59(2H, s).

Example 47 preparation of 2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1H-benzimidazole.

In a similar manner (route 9, GP I), after purification by preparative HPLC (method 1) using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (100mg, 0.42mmol) and 1H-1, 3-benzimidazole-2-carboxylic acid (69mg, 0.42mmol), the TFA salt of the title compound was obtained (26mg, 10%).

LCMS data: calculated value MH⁺(382) (ii) a Found 100% (MH)⁺) m/z 382, Rt 2.42min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 7.63-7.72(2H，m)，7.29-7.43(2H，m)，4.86-5.08(2H，m)，4.33-4.53(2H，m)，4.13-4.30(1H，m)，3.42-4.01，(8H，m)，2.86-3.15(2H，m)，2.07-2.43(6H，m)，1.72-1.93(2H，m)。

example 48 preparation of 5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1-methyl-1H-benzimidazole.

In a similar manner (route 9, GP I), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (100mg, 0.42mmol) and 1-methyl-benzimidazole-5-carboxylic acid (76mg, 0.42mmol) gives the title compound (35mg, 21%) after purification by preparative HPLC (method 2).

LCMS data: calculated value MH⁺(396) (ii) a Measured value (MH)⁺) m/z 396, Rt 3.51min (method D).

NMR data: NMR purity > 95%.¹H NMR(500MHz，MeOD)ppm 8.21(1H，s)，7.95(1H，s)，7.55-7.69(2H，m)，4.54(2H，m)，4.36(1H，m)，4.24-4.32(1H，m)，3.89(3H，s)，3.80-3.88(1H，m)，3.54-3.66(2H，m)，3.39-3.47(2H，m)，2.88(1H，m)，2.47-2.56(2H，m)，2.36-2.46(2H，m)，2.01-2.08(2H，m)，1.75-1.89(4H，m)，1.57-1.70(2H，m)。

Example 49 preparation of 5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1-methyl-1H-benzotriazole.

In a similar manner (route 9, GP I), after purification by preparative HPLC (method 2) using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (100mg, 0.42mmol) and 1-methyl-1, 2, 3-benzotriazole-5-carboxylic acid (75mg, 0.42mmol), the title compound was obtained (40mg, 24%).

LCMS data: calculated value MH⁺(397) (ii) a Found 98% (MH)⁺) m/z 397, Rt 3.49min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.27(1H，s)，7.84(2H，s)，4.53-4.64(2H，m)，4.28-4.47(5H，m)，3.82-3.96(1H，m)，3.55-3.73(2H，m)，3.39-3.53(2H，m)，2.82-2.97(1H，m)，2.50-2.61(2H，m)，2.39-2.50(2H，m)，2.00-2.12(2H，m)，1.76-1.93(4H，m)，1.57-1.75(2H，m)。

example 50 preparation of 7- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) imidazo [1, 2-a ] pyridine

In a similar manner (route 9, GP I), after purification by preparative HPLC (method 2) using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (175mg, 0.74mmol) and imidazo [1, 2-a ] pyridine-7-carboxylic acid (120mg, 0.74mmol), the title compound is obtained (34mg, 9%).

LCMS data: calculated value MH⁺(382) (ii) a Found 100% (MH)⁺) m/z 382, Rt 3.37min (method D).

NMR data:¹H NM[R(500MHz，MeOD)ppm 8.53(1H，d，J＝7.0Hz)，7.97(1H，s)，7.85(1H，s)，7.72(1H，s)，7.18(1H，d，J＝7.0Hz)，4.55-4.70(2H，m)，4.24-4.46(2H，m)，3.83-3.97(1H，m)，3.58-3.68(2H，m)，3.41-3.53(2H，m)，2.86-2.99(1H，m)，2.42-2.63(4H，m)，2.01-2.13(2H，m)，1.77-1.98(4H，m)，1.56-1.76(2H，m)

example 51-preparation of 1-cyclobutyl-4- { [1- (1H-1,2, 4-triazol-3-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan.

In a similar manner (route 9, GP I), after purification by preparative HPLC (method 2) using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (100mg, 0.42mmol) and 1,2, 4-triazole-3-carboxylic acid (47mg, 0.42mmol), the title compound was obtained (45mg, 32%).

LCMS data: calculated value MH⁺(333) (ii) a Found 100% (MH)⁺) m/z 333, Rt 2.24min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.44(1H，s)，4.74-4.87(2H，m)，4.26-4.42(2H，m)，3.84-3.97(1H，m)，3.56-3.73(2H，m)，3.46-3.53(2H，m)，2.88-3.04(1H，m)，2.56-2.66(2H，m)，2.43-2.56(2H，m)，2.02-2.16(2H，m)，1.80-1.99(4H，m)，1.59-1.79(2H，m)

example 52 preparation of 1-cyclobutyl-4- ({1- [ (1-methyl-1H-pyrazol-4-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane.

In a similar manner (route 9, GP I), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (25mg, 0.11mmol) and 1-methyl-pyrazole-4-carboxylic acid (13mg, 0.11mmol) gives the title compound (10mg, 26%) after purification by preparative HPLC (method 2).

LCMS data: calculated value MH⁺(346) (ii) a Found 100% (MH)⁺) m/z 346, Rt 1.83min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.03(1H，s)，7.78(1H，s)，4.52-4.63(2H，m)，4.24-4.33(1H，m)，4.14-4.23(1H，m)，3.90(3H，s)，3.82-3.89(1H，m)，3.56-3.67(2H，m)，3.42-3.51(2H，m)，2.84-2.96(1H，m)，2.49-2.59(2H，m)，2.39-2.49(2H，m)，2.02-2.12(2H，m)，1.77-1.93(4H，m)，1.58-1.72(2H，m)。

pathway 10

General procedure J：

Example 53-preparation of 1-cyclobutyl-4- { [1- (tetrahydro-2H-pyran-4-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan. Potency Range C

To a stirred mixture of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol)) And DIPEA (42. mu.l, 0.25mmol) in DCM (1ml) was added a solution of tetrahydropyran-4-yl acetyl chloride (21mg, 0.13mmol) in DCM (1 ml). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water and 1M HCl were added and the reaction mixture was washed with DCM (3 × 5 ml). Drying (MgSO)₄) The combined organic layers were filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a colourless oil (1.2mg, 3% yield).

LCMS data: calculated value MH⁺(364) (ii) a Found 95% (MH)⁺) m/z 364, Rt 3.33min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.31-4.49(2H，m)，4.14-4.29(2H，m)，4.10(1H，m)，3.92(3H，m)，3.67-3.86(2H，m)，3.56(1H，m)，3.46-3.53(1H，m)，3.39-3.46(3H，m)，3.23(1H，m)，3.01-3.15(1H，m)，2.88-3.01(1H，m)，2.32-2.45(1H，m)，2.17-2.32(2H，m)，2.14(1H，m)，2.08-2.11(1H，m)，1.94-2.06(2H，m)，1.74-1.92(1H，m)，1.65(2H，m)，1.25-1.46(5H，m)。

the following compounds were prepared according to the procedures described in pathway 10, general procedure J, above.

Example 54 preparation of 1- ({1- [ (4-chlorophenyl) acetyl ] azetidin-3-yl } carbonyl) -4-cyclobutyl-1, 4-diazepane. Potency Range A

In a similar manner (route 10, GP J), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (100mg, 0.42mmol) and 4-chlorobenzeneacetyl chloride (88mg, 0.46mmol), the title compound was obtained (55mg, 34%).

LCMS data: calculated value MH⁺(390) (ii) a Found 100% (MH)⁺) m/z 390, Rt 2.54min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.26-7.34(2H, m), 7.22(2H, d, J ═ 8.2Hz), 4.52-4.60(1H, m), 4.15-4.24(2H, m), 4.04-4.14(1H, m), 3.75-3.82(1H, m), 3.65-3.74(1H, m), 3.51-3.62(1H, m), 3.29-3.47(4H, m), 2.87-3.01(1H, m), 2.41-2.77(4H, m), 1.96-2.13(4H, m), 1.84-1.91(2H, m), 1.59-1.77(2H, m).

Example 55-1-cyclobutyl-4- [ (1- { [4- (methylsulfonyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 10, GP J), 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol) and 4- (methylsulfonyl) benzoyl chloride (51mg, 0.23mmol) were purified by silica gel FCC (96: 3.6: 0.4 DCM/MeOH/NH)₃Elution) followed by purification by preparative HPLC (method 1) gave the TFA salt of the title compound (22.7mg, 20%).

LCMS data: calculated value MH⁺(420) (ii) a Found 100% (MH)⁺) m/z 420, Rt 2.11min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.04(2H, d, J ═ 8.2Hz), 7.84(2H, d, J ═ 7.6Hz), 4.61-4.80(1H, m), 4.23-4.55(4H, m), 3.51-3.77(5H, m), 3.27-3.48(2H, m), 3.11(3H, s), 2.14-2.90(8H, m), 1.88-2.00(1H, m), 1.68-1.84(1H, m).

Pathway 11

General procedure K：

Example 56-preparation of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (cyclohexylmethyl) azetidine-1-carboxamide. Potency Range A

To a stirred solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol) in DCM (1ml) was added cyclohexylmethyl isocyanate (18. mu.l, 0.13mmol) in DCM (1ml) and then. The reaction mixture was stirred at room temperature for 16 hours and then evaporated under reduced pressure, and the resulting crude material was purified by FCC on silica gel (using a gradient eluent; 99: 1-90: 10: 1 DCM: MeOH: 7MNH₃in MeOH) to give the title compound as a colorless oil (39mg, 82% yield).

LCMS data: calculated value MH⁺(377) (ii) a Found 96% (MH)⁺) m/z 377, Rt 4.18min (method D).

NMR data:¹h NMR (250MHz, chloroform-d) ppm 4.12-4.25(3H, m), 3.98-4.11(2H, m), 3.58-3.72(2H, m), 3.44-3.58(2H, m), 3.26-3.43(2H, m), 3.03(2H, t, J ═ 6.4Hz), 2.75-2.94(1H, m), 2.29-2.62(4H, m), 1.97-2.17(2H, m), 1.78-1.96(3H, m), 1.53-1.78(6H, m), 1.43(1H, m), 1.03-1.34(4H, m), 0.71-1.02(2H, m).

The following compounds were prepared using the methods described in pathway 11, general procedure K, above.

Example 57-preparation of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (tetrahydro-2H-pyran-4-ylmethyl) azetidine-1-carboxamide. Potency Range A

In a similar manner (route 11, GP K), using 4- (isocyanatomethyl) tetrahydropyran (18mg, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol) gives the title compound (36mg, 74% yield) as a colorless oil.

LCMS data: calculated value MH⁺(379) (ii) a Found 90% (MH)⁺) m/z 379, Rt 1.91min (method C).

NMR data: 1H NMR (500MHz, chloroform-d) ppm 4.14-4.27(3H, m), 4.02-4.13(2H, m), 3.97(2H, m), 3.60-3.71(2H, m), 3.54(1H, m), 3.29-3.43(4H, m), 3.10(2H, m), 2.79-2.94(1H, m), 2.46-2.55(2H, m), 2.36-2.46(2H, m), 2.04(2H, m), 1.77-1.95(4H, m), 1.50-1.77(5H, m), 1.22-1.38(2H, m).

Example 58 preparation of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) azetidine-1-carboxamide. Potency Range A

In a similar manner (route 11, GP K), using 4-fluorobenzyl isocyanate (16.1. mu.l, 0.13mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (30mg, 0.13mmol), the title compound (25.5mg, 52% yield) was obtained as a colorless oil.

LCMS data: calculated value MH⁺(389) (ii) a Found 92% (MH)⁺) m/z 389, Rt 2.48min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.23-7.30(2H, m), 6.98-7.05(2H, m), 4.40-4.46(1H, m), 4.34-4.38(2H, m), 4.19-4.28(2H, m),4.04-4.11(2H，m)，3.61-3.68(2H，m)，3.50-3.59(1H，m)，3.31-3.38(2H，m)，2.80-2.91(1H，m)，2.46-2.52(2H，m)，2.37-2.45(2H，m)，1.99-2.09(2H，m)，1.75-1.92(4H，m)，1.56-1.74(2H，m)。

example 59 preparation of N- (4-cyanophenyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide. Potency Range A

In a similar manner (route 11, GP K), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (150mg, 0.63mmol) and 4-cyanophenylisocyanate (136mg, 0.95mmol), after purification by preparative HPLC (method 2) gives the title compound (20mg, 8%) as a colourless oil.

LCMS data: calculated value MH⁺(382) (ii) a Found 99% (MH)⁺) m/z 382, Rt 3.84min (method D).

NMR data:¹h NMR (500MHz, chloroform-d)ppm 7.48-7.62(4H，m)，6.36(1H，s)，4.30-4.42(2H，m)，4.15-4.28(2H，m)，3.54-3.73(3H，m)，3.32-3.43(2H，m)，2.88(1H，m)，2.37-2.60(4H，m)，2.01-2.10(2H，m)，1.75-1.99(4H，m)，1.51-1.76(2H，m)。

Pathway 12

General procedure L：

Example 60-preparation of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (cyclohexylmethyl) -N-methylazetidine-1-carboxamide. Potency Range A

Stirring of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl at 0 ℃ under nitrogen]To a solution of (E) -N- (cyclohexylmethyl) azetidine-1-carboxamide (26mg, 0.069mmol) in anhydrous DMF (1ml) was added sodium hydride (4.1mg, 60% dispersion in mineral oil, 0.103 mmol). The resulting suspension was stirred at 0 ℃ for 30 minutes. Methyl iodide (4.3. mu.l, 0.069mmol) was added and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into ice water, extracted with EtOAc (3 × 5ml), the combined organic layers were washed with brine (5ml), dried (MgSO)₄) Filtering, and concentrating under reduced pressure. Purification by preparative HPLC gave the title compound (5.6mg, 21% yield) as a colourless oil.

LCMS data: calculated value MH⁺(391) (ii) a Found 94% (MH)⁺) m/z 391, Rt 2.97min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.16(4H，m)，3.93-4.11(1H，m)，3.64-3.86(3H，m)，3.41-3.63(4H，m)，3.10(2H，m)，3.00-3.08(1H，m)，2.90-3.00(1H，m)，2.87(3H，s)，2.31-2.43(2H，m)，2.17-2.30(3H，m)，1.98-2.17(1H，m)，1.79-1.93(2H，m)，1.58-1.78(6H，m)，1.12-1.35(3H，m)，0.84-1.04(2H，m)。

the following compounds were prepared according to the procedures described in pathway 12, general procedure L, above.

Example 61-preparation of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N-methyl-N- (tetrahydro-2H-pyran-4-ylmethyl) azetidine-1-carboxamide. Potency Range A

In a similar manner (route 12, GP L), using 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (tetrahydro-2H-pyran-4-ylmethyl) azetidine-1-carboxamide (24.9mg, 0.066mmol), sodium hydride (3.9mg, 60% dispersion in mineral oil, 0.099mmol) and iodomethane (4.1 μ L, 0.066mmol), the title compound was obtained (4.2mg, 16% yield) as a colorless oil.

LCMS data: calculated value MH⁺(393) (ii) a Found 94% (MH)⁺) m/z 393, Rt 2.20min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.12-4.29(4H，m)，3.97-4.12(1H，m)，3.94(2H，m)，3.66-3.87(3H，m)，3.46-3.63(4H，m)，3.36-3.43(2H，m)，3.14-3.22(2H，m)，2.93-3.12(2H，m)，2.91(3H，s)，2.32-2.46(2H，m)，2.17-2.31(3H，m)，2.00-2.16(1H，m)，1.75-1.99(3H，m)，1.50-1.68(2H，m)，1.19-1.35(2H，m)。

example 62-preparation of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) -N-methylazetidine-1-carboxamide. Potency Range A

In a similar manner (route 12, GP L), using 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) azetidine-1-carboxamide (18mg, 0.046mmol), sodium hydride (2.8mg, 60% dispersion in mineral oil, 0.070mmol) and iodomethane (2.9. mu.l, 0.046mmol), the title compound was obtained (4.3mg, 23% yield) as a colourless oil.

LCMS data: calculated value MH⁺(403) (ii) a Found 90% (MH)⁺) m/z 403, Rt 2.72min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 7.19-7.41(2H，m)，6.93-7.16(2H，m)，4.44(2H，s)，4.14-4.25(4H，m)，3.64-3.95(3H，m)，3.40-3.62(5H，m)，3.05(1H，m)，2.90-3.01(1H，m)，2.83(3H，s)，2.31-2.54(2H，m)，2.18-2.31(3H，m)，1.98-2.17(1H，m)，1.68-1.93(2H，m)。

example 63-preparation of 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) -N-methylazetidine-1-carboxamide. Potency Range A

In a similar manner (route 12, GP L), after purification by preparative HPLC (method 2) using N- (4-cyanophenyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide (80mg, 0.21mmol) and iodomethane (16 μ L, 0.25mmol), the title compound was obtained (2.7mg, 3%) as a colourless oil.

LCMS data: calculated value MH⁺(396) (ii) a Found 100% (MH)⁺) m/z 396, Rt 3.77min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.65(2H, d, J ═ 8.4Hz), 7.33(2H, d, J ═ 8.5Hz), 3.90-4.02(2H, m), 3.51-3.83(4H, m), 3.20-3.45(6H, m), 2.79-2.99(1H, m), 2.26-2.66(4H, m), 2.02(2H, m), 1.45-1.97(6H, m).

Example 64 preparation of N- (4-cyanobenzyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N-methylazetidine-1-carboxamide. Potency Range A

In a similar manner (route 12, GP L), purification using preparative HPLC (method 2) with N- (4-cyanobenzyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide (35mg, 88 μmol) and iodomethane (68 μ L, 105 μmol) gave the title compound (1.1mg, 0.3%) as a colorless oil.

LCMS data: calculated value MH⁺(410) (ii) a Found 100% (MH)⁺) m/z 410, Rt 2.53min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 7.72(2H，d，J＝8.1Hz)，7.45(2H，d，J＝8.1Hz)，4.50-4.62(2H，m)，4.14-4.26(4H，m)，3.71-3.80(1H，m)，3.59-3.71(2H，m)，3.42-3.52(2H，m)，3.31-3.39(2H，m)，2.86(3H，s)，2.48-2.75(3H，m)，2.05-2.19(2H，m)，1.81-2.00(4H，m)，1.62-1.79(2H，m)。

pathway 13

Preparation of 4-nitrophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate

To a solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (208mg, 0.88mmol) and TEA (146. mu.l, 1.05mmol) in dichloromethane (5ml) was added 4-nitrophenyl chloroformate (176mg, 0.88mmol) at 0 ℃. After 10 minutes, the reaction temperature was raised to room temperature, and after 1 hour of further reaction, the mixture was diluted with dichloromethane (30ml) and 1M aq.K₂CO₃Washed (2X 15ml) and dried (MgSO₄) Filtering, and concentrating under reduced pressure. The residue was purified by FCC on silica gel (99: 1-92: 8: 1 DCM/MeOH/2M NH eluent with a gradient₃MeOH solution) to give the title compound (206mg, 58% yield) as a yellow oil.

LCMS data: calculated value MH⁺(403) (ii) a Found 99% (MH)⁺)m/z 403，Rt＝4.36min。

NMR data:¹H NMR(500MHz，CDCl₃)ppm 8.20-8.31(2H，m)，7.29-7.37(2H，m)，4.51-4.65(1H，m)，4.19-4.42(3H，m)，3.56-3.77(3H，m)，3.29-3.43(2H，m)，2.80-2.94(1H，m)，2.35-2.62(4H，m)，1.99-2.09(2H，m)，1.75-1.95(4H，m)，1.52-1.75(2H，m)。

general procedure M

Example 65-preparation of 2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1,2,3, 4-tetrahydroisoquinoline. Potency Range A

Reacting 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl]Azetidine-1-carboxylic acid 4-nitrophenyl ester (50mg, 0.12mmol), 1,2,3, 4-tetrahydroisoquinoline (25. mu.l, 0.19mmol) and DIPEA (42. mu.l, 0.24mmol) were stirred in 1, 2-dichloroethane (2ml) and isopropanol (1ml) at 120 ℃ for 16 h in a sealed tube. The mixture was then cooled to room temperature, diluted with dichloromethane (30ml) and washed with 1Maq.K₂CO₃Washed (2X 15ml) and dried (MgSO₄) Filtering, and concentrating under reduced pressure. The residue was purified by FCC on silica gel (99: 1 to 92: 8: 1 DCM/MeOH/2M NH)₃Gradient elution in MeOH) to give the title compound (9mg, 19% yield) as a colorless oil.

LCMS data: calculated value MH⁺(397) (ii) a Found 88%(MH⁺) m/z 397, Rt 4.26min (method D).

NMR data:¹H NMR(500MHz，CDCl₃)ppm 7.05-7.23(4H，m)，4.50(2H，s)，4.23-4.35(2H，m)，4.11-4.23(2H，m)，3.61-3.72(2H，m)，3.46-3.61(3H，m)，3.31-3.39(2H，m)，2.80-2.92(3H，m)，2.34-2.57(4H，m)，1.98-2.10(2H，m)，1.53-1.96(6H，m)。

the following compounds were prepared according to the procedures described in pathway 13, general procedure M, above.

Example 66 preparation of N- (4-cyanobenzyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide. Potency Range A

In a similar manner (route 13, GP M), after purification by preparative HPLC (method 2) using 4-nitrophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate (100mg, 0.25mmol) and 4-cyanobenzylamine hydrochloride (46mg, 0.27mmol), the title compound was obtained (7mg, 7% yield) as a colorless oil.

LCMS data: calculated value MH⁺(396) (ii) a Found 96% (MH)⁺) m/z 396, Rt 3.75min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 7.64-7.71(2H，m)，7.47(2H，d，J＝8.4Hz)，4.38(2H，s)，4.08-4.20(4H，m)，3.74-3.84(1H，m)，3.57-3.70(2H，m)，3.40-3.52(2H，m)，2.87-3.00(1H，m)，2.52-2.62(2H，m)，2.42-2.52(2H，m)，2.02-2.14(2H，m)，1.79-1.94(4H，m)，1.58-1.78(2H，m)。

pathway 14

General procedure O:

example 67-preparation of 4-chlorophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate. Potency Range A

A stirred solution of 4-chlorophenol (200mg, 1.56mmol) and triphosgene (460mg, 1.56mmol) in DCE (5ml) was cooled to 0 deg.C and DIPEA (2.16ml, 12.4mmol) was added. The resulting solution was stirred at 0 ℃ for 90 minutes, then a solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (367mg, 1.56mmol) in DCE (2ml) was added. The resulting mixture was heated at 100 ℃ for 12 h, then cooled to room temperature and diluted with DCM (25ml) and water (30 ml). The organic phase was separated and the aqueous phase was extracted with DCM (3 × 25 ml). The combined organic phases were dried (MgSO)₄) Filtering, and concentrating under reduced pressure. The residue was purified by FCC (98: 2: 1 DCM: MeOH: NH)₃) And then purified by preparative HPLC (method 2) to give the title compound (1.4mg, 0.2% yield).

LCMS data: calculated value MH⁺(392) (ii) a Found 100% (MH)⁺) m/z 392, Rt 2.86min (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 7.30-7.40(2H，m)，6.99-7.19(2H，m)，4.35(2H，m)，4.19(2H，m)，3.80-3.88(1H，m)，3.59-3.67(2H，m)，3.43-3.48(2H，m)，2.94(1H，m)，2.56(2H，m)，2.45-2.50(2H，m)，2.04-2.10(2H，m)，1.81-1.92(4H，m)，1.62-1.72(2H，m)。

the following compounds were prepared according to the procedures described in pathway 14, general procedure O, above.

Example 68-preparation of 6-methylpyridin-3-yl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate. Potency Range A

In a similar manner (route 14, GP O), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (430mg, 1.83mmol) and 3-hydroxy-6-methylpyridine (200mg, 1.83mmol), after purification by preparative HPLC (method 2) gives the title compound (0.6mg, 0.1%) as a colourless oil.

LCMS data: calculated value MH⁺(373) (ii) a Measured value (MH)⁺) m/z 373. The product was eluted at the solvent front (method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.22(1H，d，J＝2.6Hz)，7.51(1H，dd，J＝8.5，2.7Hz)，7.30(1H，d，J＝8.4Hz)，4.31-4.48(2H，m)，4.21(2H，m)，3.86(1H，m)，3.57-3.71(2H，m)，3.43-3.49(2H，m)，2.94(1H，m)，2.54-2.65(2H，m)，2.50(3H，s)，2.43-2.48(2H，m)，2.03-2.12(2H，m)，1.77-1.95(4H，m)，1.56-1.73(2H，m)。

example 69 preparation of 4-cyanophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate. Potency Range A

In a similar manner (route 14, GP O), using 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (200mg, 1.26mmol) and 4-cyanophenol (150mg, 1.26mmol), the title compound was obtained after purification by preparative HPLC (method 2) (6mg, 1%).

LCMS data: calculated value MH⁺(383) (ii) a Measured value (MH)⁺) m/z 383. The product was unstable to LCMS conditions that produced several UV peaks (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.64-7.69(2H, m), 7.24-7.29(2H, m), 4.56(1H, m), 4.20-4.39(3H, m), 3.60-3.81(3H, m), 3.39(3H, m), 2.81-2.96(1H, m), 2.34-2.66(4H, m), 2.01-2.13(2H, m), 1.762.01(3H, m), 1.53-1.76(3H, m).

Pathway 15

Example 70-preparation of 1- [ (1-acetylazetidin-3-yl) carbonyl ] -4-cyclobutyl-1, 4-diazepane. Potency Range A

To a stirred solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepan (100mg, 0.42mmol) in dichloromethane (10mL) cooled to 0 deg.C was added diisopropylethylamine (160mg, 1.26mmol) and acetic anhydride (45mg, 0.51 mmol). The resulting mixture was stirred at room temperature for 3 hours, then quenched by the addition of water (10 ml). The aqueous layer was extracted with dichloromethane (3X 10ml) and the combined organic layers were extracted with saturated NaHCO₃(10ml) washed with aqueous solution and dried (Na)₂SO₄) Filtering, and concentrating. FCC purification on silica gel (using a gradient eluent; 100: 0-99: 1 DCM: 2M NH)₃MeOH solution) was added to the crude product, which was then purified by preparative HPLC (method 2) to give the title compound (35mg, 30% yield) as a colorless oil.

LCMS data: calculated value MH⁺(280) (ii) a Found 99% (MH)⁺) m/z 280, Rt 3.10min (method D).

¹H NMR (500MHz, chloroform-d) ppm 4.55(1H, m), 4.14-4.24(2H, m), 4.02-4.13(1H, m), 3.47-3.81(3H, m), 3.29-3.45(2H, m), 2.83-2.96(1H, m), 2.34-2.68(4H, m), 1.91-2.12(4H, m), 1.78-1.91(5H, m), 1.55-1.77(2H, m).

Pathway 16

Example 71-preparation of 1-cyclobutyl-4- [ (1-propionylazetidin-3-yl) carbonyl ] -1, 4-diazepane. Potency Range A

To a stirred solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (125mg, 0.53mmol) in dichloromethane (5ml) was added sodium carbonate (167mg, 1.58mmol) and propionyl chloride (58mg, 0.63mmol) at 0 ℃. The resulting mixture was stirred at room temperature for 13 hours, and then the volatiles were removed under reduced pressure. FCC purification on silica gel (using a gradient eluent; 100: 0 to 98: 2 DCM: 2MNH₃in MeOH) was then purified by preparative HPLC (method 2) to give the title compound (18mg, 12% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(294) (ii) a Found 86% (MH)⁺) m/z 294, Rt 3.18min (method D).

¹H NMR (500MHz, chloroform-d) ppm 4.47-4.57(1H, m), 4.12-4.23(2H, m), 4.00-4.12(1H, m), 3.46-3.74(3H, m), 3.27-3.42(2H, m), 2.79-2.91(1H, m), 2.30-2.57(4H, m), 1.95-2.19(4H, m), 1.72-1.93(4H, m), 1.52-1.72(2H, m), 1.10(3H, t, J ═ 7.6Hz)。

Pathway 17

Example 72-preparation of 1-cyclobutyl-4- [ (1- { [4- (1H-imidazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

To 4- (1H-imidazol-1-yl) benzoic acid (150mg, 0.80mmol) cooled to 0 ℃ in dichloromethane (10mL) was then added oxalyl chloride (1 mL). DMF (2 drops) was added and the mixture was stirred at 0 ℃ for 45min, then the volatiles were removed under reduced pressure. The residue was diluted with dichloromethane (20mL), cooled to 0 deg.C and triethylamine (201mg, 2.0mmol) was added followed by 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (187mg, 0.79 mmol). The resulting mixture was stirred at room temperature for 16 h, then diluted with more dichloromethane (50mL) and quenched by addition of water (50 mL). Then saturated NaHCO₃The organic layer was washed with aqueous solution (50mL) and dried (Na)₂SO₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (using a gradient eluent; 97: 3-95: 5 DCM/2M NH)₃MeOH solution) was added to the reaction solution, and then purified by preparative HPLC (method 2) to give the title compound (14mg, 4% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(408) (ii) a Found 100% (MH)⁺) m/z 408, Rt 3.38min (method D).

¹H NMR(500MHz，MeOD)ppm 8.26(1H，s)，7.84(2H，d，J＝8.5Hz)，7.72(2H，d，J＝8.7Hz)，7.68(1H，s)，7.19(1H，s)，4.50-4.64(2H，m)，4.35-4.45(1H，m)，4.24-4.35(1H，m)，3.84-3.94(1H，m)，3.57-3.70(2H，m)，3.42-3.53(2H，m)，2.86-2.99(1H，m)，2.42-2.63(4H，m)，2.01-2.13(2H，m)，1.78-1.95(4H，m)，1.59-1.75(2H，m)。

The following compounds were prepared according to the procedures described in pathway 17, general procedure P, above.

Example 73-preparation of 1-cyclobutyl-4- [ (1- { [4- (1H-1,2, 4-triazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 17, GP P), purification with 4- (1H-1,2, 4-triazol-1-yl) benzoic acid (100mg, 0.53mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (125mg, 0.53mmol) by preparative HPLC (method 1) gave the TFA salt of the title compound (32mg, 12% yield) as a yellow oil.

LCMS data: calculated value MH⁺(409) (ii) a Found 100% (MH)⁺) m/z 409, Rt 2.14min (method C).

¹H NMR(500MHz，MeOD)ppm 9.22(1H，s)，8.22(1H，s)，7.97(2H，d，J＝8.5Hz)，7.85(2H，d，J＝8.5Hz)，4.51-4.68(2H，m)，4.27-4.50(2H，m)，4.13-4.27(1H，m)，3.84-3.95(1H，m)，3.66-3.84(2H，m)，3.40-3.66(4H，m)，2.87-3.15(2H，m)，2.05-2.41(6H，m)，1.72-1.92(2H，m).

Example 74-preparation of 1-cyclobutyl-4- [ (1- { [4- (1H-1,2, 4-triazol-1-ylmethyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 17GP P), after purification by preparative HPLC (method 2) using 4- (1H-1,2, 4-triazol-1-ylmethyl) benzoic acid (60mg, 0.29mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (62mg, 0.261mmol), the title compound (1.2mg, 1%) was obtained as an oil.

LCMS data: calculated value MH⁺(423) (ii) a Found 95% (MH)⁺) m/z 423, Rt 3.52min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.61(1H，s)，8.02(1H，s)，7.66(2H，d，J＝8.2Hz)，7.41(2H，d，J＝8.1Hz)，5.51(2H，s)，4.46-4.60(2H，m)，4.31-4.43(1H，m)，4.23-4.31(1H，m)，3.81-3.94(1H，m)，3.56-3.70(2H，m)，3.41-3.52(2H，m)，2.83-3.01(1H，m)，2.52-2.60(2H，m)，2.41-2.53(2H，m)，2.05-2.12(2H，m)，1.78-1.94(4H，m)，1.59-1.77(2H，m)。

example preparation of 75-1-cyclobutyl-4- ({1- [ (2-methylpyridin-4-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (pathway 17GP P), 2-methylpyridine-4-carboxylic acid (100mg, 0.73mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol) were purified by silica gel FCC (90: 9: 1Et₂O/MeOH/NH₃) After this time, the title compound was obtained.

NMR data: (¹Purity 96% by H NMR).¹H NMR(500MHz，MeOD)ppm 8.54(1H，d，J＝5.2Hz)，7.50(1H，s)，7.42(1H，d，J＝5.2Hz)，4.46-4.56(2H，m)，4.34-4.42(1H，m)，4.34-4.42(1H，m)，4.25-4.34(1H，m)，3.84-3.94(1H，m)，3.59-3.71(2H，m)，3.43-3.50(2H，m)，2.95(1H，m)，2.54-2.63(5H，m)，2.45-2.53(2H，m)，2.08(2H，q，J＝8.0Hz)，1.80-1.97(4H，m)，1.61-1.76(2H，m)。

Pathway 18

Preparation of methyl 4- [ (2-hydroxy-1, 1-dimethylethyl) carbamoyl ] benzoate

In N₂1, 1' -carbonyldiimidazole (422mg, 2.6mmol) was added in one portion to a suspension of monomethyl terephthalate (360mg, 2.0mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 18 hours. A solution of 2-amino-2-methyl-1-propanol (232mg, 2.6mmol) in dichloromethane (1mL) was added and stirring continued for an additional 3 hours. The reaction was poured into saturated NaHCO₃The reaction was quenched in aqueous solution (50 mL). After extraction with dichloromethane (3X 50mL), the combined organic extracts were washed with brine (50mL) and dried (MgSO)₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (using a gradient eluent; 7: 3-1: 1 heptane: EtOAc) afforded the title compound (100mg, 20% yield) as a white solid.

LCMS data: calculated value MH⁺(252) (ii) a Found 100% (MH)⁺) m/z 252, Rt 1.08min (method A).

¹H NMR (500MHz, chloroform-d) ppm 8.10(2H, d, J ═ 8.4Hz), 7.80(2H, d, J ═ 8.4Hz), 6.23(1H, br.s.), 3.95(3H, s), 3.72(2H, s), 1.44(6H, s).

4- (4, 4-dimethyl-4, 5-dihydro-1, 3-)Preparation of oxazol-2-yl) benzoic acid methyl ester

To 4- [ (2-hydroxy-1, 1-dimethylethyl) carbamoyl group]Methyl benzoate (100mg, 0.40mmol) in CDCl₃To the solution (2mL) was added thionyl chloride (57mg, 0.48 mmol). The mixture was heated to 60 ℃ in a sealed tube and reacted for 4 hours. After cooling, the reaction was poured into saturated NaHCO₃Quench in aqueous solution (20 mL). After extraction with dichloromethane (3X 20mL), the combined organic extracts were washed with brine (20mL) and dried (MgSO)₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (eluted with 20: 80 heptane/EtOAc) afforded the title compound (78mg, 84% yield) as a colorless oil.

LCMS data: calculated value MH⁺(234) (ii) a Found 81% (MH)⁺) m/z 234, Rt 1.19min (method a).

¹H NMR (500MHz, chloroform-d) ppm 8.48(2H, d, J ═ 8.4Hz), 8.19(2H, d, J ═ 8.4Hz), 4.80(2H, s), 3.94(3H, s), 1.77(6H, s).

4- (4, 4-dimethyl-4, 5-dihydro-1, 3-)Preparation of oxazol-2-yl) benzoic acid

To 4- (4, 4-dimethyl-4, 5-dihydro-1, 3-Oxazol-2-yl) benzoic acid methyl ester (78mg, 0.33mmol) in THF (1mL) and H₂To the O (1mL) solution was added LiOH (23mg, 1 mmol). The mixture was stirred at room temperatureAfter stirring for 4h, it was diluted with EtOAc (5mL), quenched by addition of aqueous HCl (5mL, 0.5M aq, 2.5mmol), extracted with EtOAc (3X 10mL), and the combined organic extracts washed with brine (10mL) and dried (MgSO. RTM.)₄) Filtering, and concentrating under reduced pressure. The crude residue was obtained (12mg, 16% yield) as a colorless oil and used without further purification.

LCMS data: calculated value MH⁺(220) (ii) a Found 44% (MH)⁺) m/z 220, Rt 0.90min (method A).

¹H NMR (500MHz, chloroform-d) ppm 8.16(2H, d, J ═ 8.1Hz), 8.09(2H, d, J ═ 8.2Hz), 4.22(2H, s), 1.47(6H, m).

Pathway 19

Preparation of 2- (diazoidene) 1- (6-methylpyridin-3-yl) ethanone

To a stirred solution of 6-methylnicotinic acid (200mg, 1.46mmol) in DCM (10ml) was added oxalyl chloride (1.25ml, 14.6mmol) and DMF (2 drops) at 0 deg.C and the resulting solution was stirred at room temperature for 2 hours. The reaction was then concentrated under reduced pressure, then redissolved in DCM (10ml) and cooled to 0 ℃. TMS diazomethane (1.45ml, 2M in THF, 2.9mmol) and NEt were added slowly₃(0.38ml, 2.9mmol), and the resulting solution was kept at 5 ℃ for reaction for 12 hours. The reaction was then filtered and concentrated under reduced pressure to give the title compound (180mg, 76%) as a black oil, which was used without further purification.

Preparation of methyl (6-methylpyridin-3-yl) acetate

To a stirred solution of 2- (diazoidene)) -1- (6-methylpyridin-3-yl) ethanone (100mg, 0.62mmol) in methanol (5ml) was added AgO (39mg, 0.36mmol) and the resulting solution was heated at 65 ℃ for 2 h. The reaction was then cooled to room temperature and passed through CeliteFiltration and concentration under reduced pressure gave the title product (60mg, 58%) as an orange oil, which was used without further purification.

LCMS data: calculated value MH⁺(166) (ii) a Found 100% (MH)⁺) m/z 166, Rt 0.79min (method C).

Preparation of (6-methylpyridin-3-yl) acetic acid

To a stirred solution of methyl (6-methylpyridin-3-yl) acetate (60mg, 0.36mmol) in methanol (5ml) was added NaOH (1.0ml, 2M in water, 2.0mmol) and the resulting solution was heated at 65 ℃ for 2 h. The solvent was then removed under reduced pressure and the residue was dissolved in methanolic HCl (methanolic HCl) (5ml) and then concentrated again to give the title product (54mg, quantitative yield) which was used without further purification.

LCMS data: calculated value MH⁺(152) (ii) a Found 100% (MH)⁺) m/z 152, Rt 0.79min, method C.

Pathway 20

Preparation of methyl 6- (methylcarbamoyl) pyridine-3-carboxylate

MeNH stirred at 0 deg.C₂AlMe was added to a solution of HCl (173mg, 5.12mmol) in toluene (5mL)₃(2M in hexane, 1.28mL, 2.56 mmol). After 30 minutes, the solution was introduced via a catheter into a stirred solution of dimethyl pyridine-2, 5-dicarboxylate (500mg, 2.56mmol) in DCM (5mL) at 0 ℃ and then stirred at room temperature overnight. NMR analysis of a small aliquot showed a ratio of 0.8: 1 product to starting material. Adding MeNH₂HCl (173mg, 5.124mmol) and AlMe₃(2M in hexane, 1.28mL, 2.56mmol) and the reaction stirred for 12 h. Addition of H₂The reaction was quenched with O (2mL) and extracted with EtOAc (2X 10 mL). The combined organic layers were dried (MgSO)₄) Filtration and concentration under reduced pressure gave the title compound (520mg, quantitative yield), which was used without further purification.

NMR data:¹h NMR (250MHz, chloroform-d) ppm 9.14(1H, d, J ═ 1.8Hz), 8.45(1H, dd, J ═ 8.1, 2.1Hz), 8.29(1H, d, J ═ 8.1Hz), 8.06(1H, br.s.), 3.99(3H, s), 3.07(3H, d).

Pathway 21

Preparation of methyl 6- (1-hydroxy-1-methylethyl) pyridine-3-carboxylate

To a stirred solution of dimethyl pyridine-2, 5-dicarboxylate (2.0g, 10.25mmol) in THF (40mL) at-78 deg.C was added MeMgCl (3M sol in THF, 6.83mL, 20.49 mmol). After 2 hours, a second portion of MeMgCl (3.4mL, 10.25mmol) was added and after 45 minutes a third portion was addedPortion (1.8mL, 5.4 mmol). Confirm completion of reaction by TLC, add saturated NH₄Aqueous Cl (1mL) was quenched and concentrated under reduced pressure. FCC purification on silica gel (eluted with 80: 20 heptane/EtOAc) afforded the title compound (539mg, 27% yield) as an oil.

LCMS data: calculated value MH⁺(196) (ii) a Found 100% (MH)⁺) m/z 196, Rt 1.24min (method B).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 9.12(1H, d, J ═ 1.2Hz), 8.30(1H, dd, J ═ 8.2, 2.1Hz), 7.48(1H, d, J ═ 8.4Hz), 4.73(1H, br.s.), 3.96(3H, s), 1.56(6H, s).

Pathway 22

General procedure Q

Preparation of lithium 6- (1-hydroxy-1-methylethyl) pyridine-3-carboxylate

To a stirred solution of methyl 6- (1-hydroxy-1-methylethyl) pyridine-3-carboxylate (479mg, 2.45mmol) in THF (10mL) was added LiOH (2M in water, 1.35mL, 2.70 mmol). After 4 hours, the solvent was removed under reduced pressure to give the title compound (458mg, 100%) which was used without further purification.

NMR data:¹H NMR(500MHz，MeOD)ppm 9.00(1H，d，J＝1.4Hz)，8.27(1H，dd，J＝8.2，2.1Hz)，7.68(1H，d，J＝8.2Hz)，1.55(6H，s)。

the following compounds were prepared according to the procedures described in pathway 22, general procedure Q, above.

Preparation of lithium 6- (methylcarbamoyl) pyridine-3-carboxylate

In a similar manner (route 24, GP Q), using methyl 6- (methylcarbamoyl) pyridine-3-carboxylate (520mg, 2.68mmol) and LiOH (2M in water, 1.47mL, 2.95mmol) in THF (10mL) gave the title compound (498mg, 100%) which was used without further purification.

NMR data:¹H NMR(250M[Hz，MeOD)ppm 9.09(1H，dd，J＝2.0，0.8Hz)，8.37(1H，dd，J＝8.0，2.1Hz)，8.06(1H，dd，J＝8.0，0.8Hz)，2.97(3H，s)。

preparation of lithium 3-fluoro-4- (1H-1,2, 4-triazol-1-yl) benzoate

In a similar manner (route 24, GP Q), using a solution of methyl 3-fluoro-4- (1H-1,2, 4-triazol-1-yl) benzoate (100mg, 0.45mmol) and LiOH (11.4mg, 0.48mmol) in THF (1mL) and water (1mL) gave the title compound (96mg, 100%) as a white solid which was used without further purification.

General procedure R

Example preparation of 76-2- [5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) pyridin-2-yl ] propan-2-ol. Potency Range A

To a stirred mixture of lithium 6- (1-hydroxy-1-methylethyl) pyridine-3-carboxylate (50mg, 0.28mmol) and HOBt (42mg, 0.30mmol)HBTU, (117mg, 0.30mmol) and 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (46mg, 0.30mmol) were added to a solution of DMF (2 mL). After 20 hours, the reaction was adsorbed onto a SCX column and the product was washed with 7M NH₃And (4) eluting. Volatiles were removed under reduced pressure and silica FCC purified (using 90: 9: 1 Et)₂O/MeOH/NH₃Elution) gave the title compound (1.4mg, 1.2%).

LCMS data: calculated value MH⁺(401) (ii) a Found 100% (MH)⁺) m/z 401, Rt 3.44min (method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.77(1H，d，J＝1.5Hz)，8.06(1H，dd，J＝8.3，2.1Hz)，7.79(1H，d，J＝8.2Hz)，4.57(2H，d，J＝7.2Hz)，4.36-4.43(1H，m)，4.27-4.35(1H，m)，3.89(1H，m)，3.59-3.69(2H，m)，3.44-3.50(2H，m)，3.35(1H，s)，2.96(1H，m)，2.58(2H，d，J＝4.4Hz)，2.45-2.53(2H，m)，2.04-2.12(2H，m)，1.79-1.95(4H，m)，1.62-1.75(2H，m)，1.52-1.58(6H，m)。

the following compounds were prepared according to the procedures described in pathway 22, general procedure R, above.

Example 77-5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -N-methylpyridine-2-carboxamide. Potency Range A

In a similar manner (route 24, GP R), using lithium 6- (methylcarbamoyl) pyridine-3-carboxylate (50mg, 0.28mmol) and a solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (46mg, 0.30mmol) in DMF (2mL) gave the title compound (35mg, 21%).

LCMS data: calculated value MH⁺(400) (ii) a Found 100% (MH)⁺)m/z 400，Rt＝194min (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.79(1H, s), 8.23(1H, d, J ═ 7.9Hz), 8.08(1H, dd, J ═ 8.0, 1.8Hz), 8.01(1H, br.s.), 4.67-4.82(1H, m), 4.24-4.50(3H, m), 3.57-3.77(3H, m), 3.30-3.42(2H, m), 2.98-3.10(3H, m), 2.78-2.93(1H, m), 2.32-2.60(4H, m), 1.49-2.11(8H, m).

Example preparation of 78-1-cyclobutyl-4- [ (1- { [ 3-fluoro-4- (1H-1,2, 4-triazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan. Potency Range A

In a similar manner (route 24, GP R), after purification by preparative HPLC (method 2) using lithium 3-fluoro-4- (1H-1,2, 4-triazol-1-yl) benzoate (49mg, 0.23mmol) and a solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutyl-1, 4-diazepane (50mg, 0.21mmol) in DMF (2mL) and DIPEA (104 μ L, 0.63mmol), the title compound was obtained (16mg, 17%).

LCMS data: calculated value MH⁺(427) (ii) a Found 100% (MH)⁺) m/z 427, Rt 3.52min (method D).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.76(1H, d, J ═ 2.6Hz), 8.15(1H, s), 8.03(1H, t, J ═ 7.9Hz), 7.65(1H, dd, J ═ 11.8, 1.4Hz), 7.60(1H, dd, J ═ 8.4, 1.2Hz), 4.80(1H, m), 4.35-4.58(2H, m), 4.31(1H, m), 3.56-3.82(3H, m), 3.39(2H, m), 2.76-2.96(1H, m), 2.50(4H, m), 2.03-2.13(2H, m), 1.86(4H, m), 1.52-1.75(2H, m).

Pathway 23

Preparation of 4- (methylsulfonyl) benzoyl chloride

To a stirred solution of 4-methylsulfonylbenzoic acid (100mg, 0.48mmol) in DCM (2mL) was added SOCl₂(52. mu.L, 0.73mmol) and toluene (2mL), and the resulting solution was stirred at 60 ℃ for 20 hours. Then adding a portion of SOCl₂(100. mu.L, 1.45mmol) and the reaction heated at 80 ℃ for an additional 24 hours. Volatiles were removed under reduced pressure and the crude product was used in the subsequent step without further purification.

Pathway 24

Preparation of tert-butyl 4- ({1- [ (benzyloxy) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepan-1-carboxylate

To the stirred 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl group]Benzyl azetidine-1-carboxylate (1.0g, 4.25mmol) in DCM (20mL) was added SOCl₂(0.754g, 0.460mL, 6.38mmol) and the resulting mixture was stirred at room temperature for 2 hours. LCMS analysis showed incomplete conversion, so 1.0eq of SOCl was added₂(501mg, 305. mu.L) and the reaction was stirred for an additional 19 hours. The volatiles were removed under reduced pressure and the crude acid chloride was dissolved in DCM (10mL) and added dropwise to a solution of 1, 4-diazepane-1-carboxylic acid tert-butyl ester (0.658g, 5.10mmol, 1.2eq) and DIPEA (1.67g, 12.75mmol, 3.0eq) in DCM (10mL) at 0 ℃. The resulting solution was stirred at room temperature for 17 hours, then NaHCO was added₃(5mL)And (6) quenching. The reaction was diluted with DCM (10mL) and the phases separated. The organic phase was washed with brine (5mL) and dried (MgSO)₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (with DCM/MeOH/NH 98: 1.2: 0.8-97: 2.7: 0.3₃Gradient elution) to give the title compound (1.54g, 86%).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.28-7.40(5H, m), 5.04-5.15(2H, m), 4.18-4.39(2H, m), 4.13(2H, q, J ═ 8.3Hz), 3.22-3.74(9H, m), 1.75-1.91(2H, m), 1.37-1.51(9H, m).

Preparation of 4- (azetidin-3-ylcarbonyl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester

Stirring of 4- ({1- [ (benzyloxy) carbonyl]Azetidin-3-yl } carbonyl) -1, 4-diazepan-1-carboxylic acid tert-butyl ester (1.54g, 3.69mmol) in EtOH (10mL) with N₂Purge, 10% Pd/C (154mg, 10% wt/wt) was added. Using (N) for flask₂Vacuum cycle x 3) purification followed by H₂(H₂Vacuum cycle x 3) purge. After 24 hours, NMR analysis showed the reaction was not complete. Through CeliteThe mixture was filtered, fresh catalyst (154mg, 10% wt/wt) was added, hydrogenation was continued, and the process was repeated after additional 24 hours and 48 hours. NMR analysis confirmed the consumption of the starting material, which was obtained by CeliteThe reaction was filtered and concentrated under reduced pressure to give the title compound (1.02g, 98%).

NMR data:¹H NMR(500MHz，MeOD)ppm 4.10-4.26(3H，m)，3.95-4.09(1H，m)，3.65-3.72(1H，m)，3.46-3.58(4H，m)，3.36-3.46(4H，m)，1.69-1.86(2H，m)，1.39-1.53(9H，m)。

preparation of tert-butyl 4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepan-1-carboxylate

To a stirred solution of tert-butyl 4- (azetidin-3-ylcarbonyl) -1, 4-diazepan-1-carboxylate (1.02g, 3.6mmol) and DIPEA (1.41g, 10.8mmol) in DCM (20mL) at 0 deg.C was added a solution of 6-methylpyridine-3-carbonyl chloride (420mg, 4.32mmol) in DCM (5 mL). After 3h, the reaction was diluted with DCM (10mL) and saturated NaHCO₃Washed with aqueous solution (10mL), brine (5mL), and dried (MgSO)₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (with DCM/MeOH/NH: 100: 0-95: 4.5: 0.5₃Gradient elution) to give the title compound (527mg, 36%) as an orange-brown oil.

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.72(1H, br.s.), 7.87(1H, m), 7.18-7.25(1H, m), 4.58-4.80(1H, m), 4.36(2H, m), 4.23-4.33(1H, m), 3.53-3.81(4H, m), 3.17-3.44(4H, m), 2.59(3H, d, J ═ 2.0Hz), 1.71-2.00(3H, m), 1.36-1.62(9H, m).

Preparation of 1- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane

To a stirred solution of tert-butyl 4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepan-1-carboxylate (455mg, 1.13mmol) in DCM (10mL) was added TFA (440. mu.L, 5.65mmol) and stirred at room temperature for 24 h. TFA (0.5mL, 6.5mmol) was added to the reaction and the reaction was stirred for an additional 5 hours until consumption of starting material was observed by TLC. Volatiles were removed under reduced pressure and the crude product was shaken with Ambersep 900-OH resin in DCM (20ml) for 2 h. The resin was removed by filtration, and the washings were concentrated under reduced pressure to give the title compound (302mg, 89%).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.66(1H，d，J＝1.7Hz)，7.95(1H，dd，J＝8.1，2.1Hz)，7.38(1H，d，J＝8.1Hz)，4.51-4.58(2H，m)，4.32-4.40(1H，m)，4.24-4.32(1H，m)，3.86(1H，dt，J＝15.0，7.4Hz)，3.77-3.81(1H，m)，3.61-3.70(1H，m)，3.50(1H，m)，3.20-3.30(6H，m)，2.55(3H，s)，1.93-2.10(2H，m)。

general procedure S

Example 79 preparation of 1- (1-methylethyl) -4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range C

To the stirred 1- ({1- [ (6-methylpyridin-3-yl) carbonyl group]Azetidin-3-yl } carbonyl) -1, 4-diazepane (60mg, 0.194mmol) in EtOH (3mL) was added Pd/C (10% wt/wt, 6mg) and acetone (143. mu.L, 1.95 mmol). Using N for flask₂(N₂Vacuum cycle x 3), then with H₂(H₂Vacuum cycle x 3) purge. After 24 hours, pass through CeliteThe reaction was filtered and concentrated under reduced pressure. Silica gel FCC purification (90: 9: 1 Et)₂O/MeOH/NH₃) Capture and release (capture and release) (SCX-2, washed with MeOH, then 7M NH₃MeOH solution released) to give the title compound (18.4mg, 27%).

LCMS data: calculated value MH⁺(345) (ii) a Found 100% (MH +) m/z 345. The product is eluted in a solvent (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.74(1H, s), 7.88(1H, d, J ═ 8.1Hz), 7.22(1H, d, J ═ 8.1Hz), 4.74(1H, m), 4.34-4.44(2H, m), 4.27-4.33(1H, m), 3.59-3.71(3H, m), 3.36(1H, m), 3.32(1H, m), 2.85-2.99(1H, m), 2.64-2.74(2H, m), 2.55-2.63(5H, m), 1.74-1.89(2H, m), 0.99(6H, m).

The following compounds were prepared according to the procedures described in pathway 24, general procedure S, above.

Example 80-preparation of 1-ethyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 24GP S), using 1- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane (70mg, 0.23mmol) and acetaldehyde (127. mu.L, 2.27mmol), the title compound was obtained (13.9mg, 18%).

LCMS data: calculated value MH⁺(331) (ii) a Found 100% (MH)⁺) m/z 331. the product was eluted at the solvent front (method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.72-8.79(1H, m), 7.89(1H, dt, J ═ 8.0, 1.9Hz), 7.22(1H, d, J ═ 7.9Hz), 4.74(1H, m), 4.35-4.45(2H, m), 4.26-4.34(1H, m), 3.60-3.76(3H, m), 3.33-3.43(2H, m), 2.67(2H, m), 2.60(5H, m), 2.51-2.57(2H, m), 1.81-1.95(2H, m), 1.06(3H, t, J ═ 7.1 Hz).

Example 81-preparation of 1-cyclopentyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 24GP S), using 1- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane (60mg, 0.194mmol) and cyclopentanone (207. mu.L, 1.95mmol), the title compound was obtained (39.7mg, 55%).

LCMS data: calculated value MH⁺(371) (ii) a Found 100% (MH)⁺) m/z 371. the product was eluted at the solvent front (LCMS method C).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.69(1H，s)，7.99(1H，dt，J＝8.1，1.1Hz)，7.41(1H，d，J＝8.2Hz)，4.52-4.60(2H，m)，4.35-4.42(1H，m)，4.25-4.33(1H，m)，3.85-3.95(1H，m)，3.59-3.71(2H，m)，3.43-3.51(2H，m)，2.89-3.00(1H，m)，2.82(2H，m)，2.68-2.76(2H，m)，2.59(3H，s)，1.80-1.96(4H，m)，1.69(2H，m)，1.53-1.63(2H，m)，1.36-1.48(2H，m)。

example 82 preparation of 1-cyclohexyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range A

In a similar manner (route 24GP S), using 1- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane (60mg, 0.194mmol) and cyclohexanone (201. mu.L, 1.95mmol), the title compound was obtained (26.7mg, 36%).

LCMS data: calculated value MH⁺(386) (ii) a Found 100% (MH)⁺) m/z 386, Rt 2.04(LCMS method C).

NMR data:¹h NMR (500MHz, chloroform-d) ppm 8.76(1H, d, J ═ 1.7Hz), 7.85-7.93(1H, m), 7.21-7.26(1H, m), 4.70-4.78(1H, m), 4.35-4.49(2H, m), 4.22-4.35(1H, m), 3.57-3.79(2H, m), 3.43(2H, m), 2.65-3.26(4H, m), 2.61(3H, s), 1.77-2.13(5H, m), 1.53-1.76(4H, m), 1.19-1.44(4H, m), 1.04-1.18(1H, m).

Pathway 25

General procedure T

Example 83-preparation of 1- (cyclopropylmethyl) -4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range C

To the stirred 1- ({1- [ (6-methylpyridin-3-yl) carbonyl group]Azetidin-3-yl } carbonyl) -1, 4-diazepan (100mg, 0.33mmol) and 1- (bromomethyl) cyclopropane (53mg, 0.39mmol) in ACN (5mL) was added potassium carbonate (91mg, 0.66 mmol). The mixture was heated to 70 ℃ in a sealed tube for 20 hours and then concentrated under reduced pressure. The crude residue was purified by FCC on silica gel (97: 3: 1 DCM/MeOH/NH)₃Eluted), then purified by preparative HPLC (method 2) to give the title compound (45mg, 38% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(357) (ii) a Found 93% (MH)⁺) m/z 357, Rt 3.45min method D.

NMR data:¹H NMR(500MHz，MeOD)ppm 8.70(1H，d，J＝1.1Hz)，7.99(1H，dd，J＝8.1，2.3Hz)，7.41(1H，d，J＝8.1Hz)，4.57(2H，m)，4.22-4.46(2H，m)，3.83-3.97(1H，m)，3.57-3.75(2H，m)，3.40-3.56(2H，m)，2.65-2.89(4H，m)，2.59(3H，s)，2.35-2.45(2H，m)，1.78-2.01(2H，m)，0.80-0.96(1H，m)，0.46-0.63(2H，m)，0.05-0.20(2H，m)。

the following compounds were prepared according to the procedures described in pathway 25, general procedure T, above.

Example 84 preparation of 1- (2-methylpropyl) -4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane. Potency Range C

In a similar manner (route 25, GP T), using 1- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepan (100mg, 0.33mmol) and 1-bromo-2-methylpropane (54mg, 0.39mmol), after purification by preparative HPLC (method 2) gave the title compound (25mg, 21% yield) as a light yellow oil.

LCMS data: calculated value MH⁺(359) (ii) a Found 89% (MH)⁺) m/z 359, Rt 3.98min method D.

NMR data:¹H NMR(500MHz，MeOD)ppm 8.70(1H，s)，7.99(1H，dt，J＝8.2，1.9Hz)，7.41(1H，d，J＝8.1Hz)，4.49-4.62(2H，m)，4.23-4.45(2H，m)，3.83-3.94(1H，m)，3.56-3.69(2H，m)，3.40-3.51(2H，m)，2.67-2.76(2H，m)，2.54-2.67(5H，m)，2.21-2.30(2H，m)，1.68-1.96(3H，m)，0.85-0.95(6H，m)。

pathway 26

Example 85-1-methyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane preparation. Potency Range D

To the stirred 1- ({1- [ (6-methylpyridin-3-yl) carbonyl group]Azetidin-3-yl } carbonyl) -1, 4-diazepane (50mg, 0.162mmol) in formic acid (0.25mL) formaldehyde (37% aq. sol., 0.097mL, 1.296mmol) was added and the reaction mixture was heated at 100 ℃ for 5 hours. The volatiles were then removed under reduced pressure and silica FCC purified (95: 4.5: 0.5-92.5: 7.25: 0.75 DCM/MeOH/NH)₃Gradient elution) to give the title compound (38mg, 75%).

LCMS data: calculated value MH⁺(317) (ii) a Found 90% (MH)⁺) m/z 317, Rt 2.94min (LCMS method D).

NMR data:¹H NMR(500MHz，MeOD)ppm 8.70(1H，d，J＝1.8Hz)，7.99(1H，m)，7.41(1H，d，J＝8.1Hz)，4.52-4.60(2H，m)，4.34-4.43(1H，m)，4.26-4.33(1H，m)，3.89(1H，m)，3.66-3.70(1H，m)，3.63(1H，m)，3.49(1H，m)，3.44-3.47(1H，m)，2.66-2.73(2H，m)，2.60-2.65(2H，m)，2.59(3H，s)，2.38(3H，m)，2.36-2.36(1H，m)，1.92-1.99(1H，m)，1.85-1.92(1H，m)。

pathway 27

Example 86 preparation of 2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1-methyl-1H-benzimidazole

To the stirred 2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl group]To a solution of azetidin-1-yl } carbonyl) -1H-benzimidazole (170mg, 0.45mmol) in THF (10ml) was added NaOH (1.12ml, 2.5M in water, 2.8 mmol). After 5min, dimethyl sulfate (0.2ml, 2.1mmol) was added and the reaction stirred at room temperature for 16 h. The reaction was then concentrated under reduced pressure and purified directly by FCC (using a gradient eluent; 98: 2-95: 5 DCM: 2M NH)₃MeOH solution) to give the title compound (45mg, 25% yield) as a yellow oil.

NMR data:¹h NMR (300MHz, chloroform-d) ppm 7.70-7.80(1H, m), 7.20-7.45(3H, m), 5.00(1H, m), 4.86(1H, m), 4.55(1H, m), 4.35(1H, m), 4.15(3H, s), 3.55-3.80(3H, m), 3.30-3.45(2H, m), 2.85(1H, m), 2.30-2.60(4H, m), 2.00-2.15(2H, m), 1.50-1.95(6H, m).

Pathway 28

3- [ (4-Cyclobutylpiperazin-1-yl) carbonyl ] azetidine-1-carboxylic acid benzyl ester

To a stirred 1- [ (benzyloxy) carbonyl group at room temperature]To a solution of azetidine-3-carboxylic acid (250mg, 1.06mmol) in dichloromethane (2mL) was added SOCl₂(115. mu.L, 1.59 mmol). The mixture was stirred for 18 hours, then the volatiles were removed under reduced pressure. The residue was then dissolved in dichloromethane (3mL), 1-cyclobutylpiperazine (115mg, 1.28mmol) was added, followed by DIPEA (940. mu.L, 5.31 mmol). The mixture was stirred at room temperatureStirred for 4 hours and then saturated NaHCO₃Aqueous solution (1mL) was quenched. The aqueous phase was extracted with dichloromethane (2X 5mL), the organic phases were combined, washed with brine (2mL), dried (MgSO 5)₄) Filtered, concentrated under reduced pressure, and FCC purified on silica gel (97.5: 2.25: 0.25 DCM/MeOH/NH)₃) After that, the title compound (130mg, 34%) was obtained.

NMR data:¹h NMR (500MHz, chloroform-d) ppm 7.30-7.44(5H, m), 5.09(2H, s), 4.21-4.39(2H, m), 4.08-4.19(2H, m), 3.57-3.79(2H, m), 3.44-3.57(1H, m), 3.16-3.38(2H, m), 2.54-2.83(1H, m), 2.20-2.40(4H, m), 1.98-2.15(2H, m), 1.80-1.97(2H, m), 1.65-1.80(2H, m)

Preparation of 1- (azetidin-3-ylcarbonyl) -4-cyclobutylpiperazine

To the stirred 3- [ (4-cyclobutylpiperazin-1-yl) carbonyl group]Benzyl azetidine-1-carboxylate (130mg, 0.36mmol) in EtOH (10mL) was added 10% Pd/C (13mg, 10% wt/wt). The flask was evacuated and the vacuum was adjusted to N₂And (5) gas purification. The flask was again evacuated and evacuated with H₂And (5) gas purification. After 16 hours, the reaction mixture was passed through CeliteFiltration and addition of 10% Pd/C (13mg, 10% wt/wt). The flask was evacuated and the vacuum was adjusted to N₂And (5) gas purification. The flask was again evacuated and evacuated with H₂And (5) gas purification. After 23 hours, the reaction mixture was passed through CeliteFiltration and concentration of the filtrate under reduced pressure gave the final compound (60mg, 74%) which was used without further purification.

Example 87-1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) piperazine. Potency Range C

To a stirred solution of 1- (azetidin-3-ylcarbonyl) -4-cyclobutylpiperazine (60mg, 0.27mmol) in dichloromethane (1mL) was added 6-methylpyridine-3-carbonyl chloride (31mg, 0.32mmol) and DIPEA (142 μ L, 0.81mmol) at 0 ℃. After 4 hours, saturated NaHCO was added₃The reaction was quenched with aqueous solution (1mL), the aqueous layer extracted with dichloromethane (2X 5mL), dried (MgSO 5)₄) Filtering, and concentrating under reduced pressure. FCC purification on silica gel (using 90: 9: 1Et₂O/MeOH/NH₃Elution) followed by capture and release on SCX-2 column (washing with MEOH, 7M NH₃Released in MeOH) to give the title compound (17.8mg, 19%)

LCMS data: calculated value MH⁺(343) (ii) a Found 97% (MH)⁺) m/z 343, Rt 3.47min (method D).

¹H NMR(500MHz，MeOD)ppm 8.69(1H，d，J＝2.0Hz)，7.98(1H，dd，J＝8.2，2.2Hz)，7.41(1H，d，J＝8.1Hz)，4.49-4.66(2H，m)，4.32-4.50(1H，m)，4.22-4.32(1H，m)，3.79-3.96(1H，m)，3.53-3.75(2H，m)，3.36-3.50(2H，m)，2.72-2.98(1H，m)，2.59(3H，s)，2.27-2.47(4H，m)，2.01-2.21(2H，m)，1.84-2.02(2H，m)，1.58-1.84(2H，m)

Pathway 29

Preparation of 6-methylpyridine-3-carbonyl chloride

To a stirred solution of 6-methylpyridine-3-carboxylic acid (100mg, 0.73mmol) in DCM (2mL) were added oxalyl chloride (120. mu.L, 1.46mmol) and DMF (2 drops). After 2 hours, the reaction mixture was concentrated under reduced pressure and the crude product was used in the subsequent step without further purification.

Claims (7)

1. A compound selected from the group consisting of

Benzyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate;

1-cyclobutyl-4- { [1- (piperidin-1-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (morpholin-4-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (cyclohexylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (tetrahydro-2H-pyran-4-ylcarbonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepan;

4- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) benzonitrile;

methyl 5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) pyridine-2-carboxylate;

1-cyclobutyl-4- ({1- [ (2-methylpyrimidin-5-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (5-methylpyrazin-2-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [6- (1H-imidazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [6- (1H-1,2, 4-triazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- { [1- (1H-pyrazol-1-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (piperidin-1-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (morpholin-4-ylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (1, 1-thiomorpholin-4-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (3, 3-difluoropyrrolidin-1-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4, 4-difluoropiperidin-1-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [ (6-methylpyridin-3-yl) oxy ] acetyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

4- (2- {3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } -2-oxoethoxy) benzonitrile;

1-cyclobutyl-4- { [1- (cyclohexylsulfonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (cyclopentylmethyl) sulfonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- { [1- (phenylsulfonyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

4- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } sulfonyl) benzonitrile;

1-cyclobutyl-4- ({1- [ (4-methoxycyclohexyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4, 4-difluorocyclohexyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (3, 5-dimethyl-1H-pyrazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- [ (1- { [4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- { [1- (cyclopropylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

1-cyclobutyl-4- { [1- (cyclohexylacetyl) azetidin-3-yl ] carbonyl } -1, 4-diazepane;

4- (2- {3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } -2-oxoethyl) benzonitrile;

1-cyclobutyl-4- [ (1- { [4- (1, 3-thiazol-2-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (2-methyl-1, 3-thiazol-4-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- [ (1- { [4- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1-methylethyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4-phenoxyphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1H-pyrazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (4, 4-dimethyl-4, 5-dihydro-1, 3-)Azol-2-yl) phenyl]Carbonyl } azetidin-3-yl) carbonyl]-1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (6-methylpyridin-3-yl) acetyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4-pyridin-3-ylphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- ({1- [ (4-pyridin-4-ylphenyl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [3- (2-methyl-1, 3-thiazol-4-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1- ({1- [ (4-chlorophenyl) acetyl ] azetidin-3-yl } carbonyl) -4-cyclobutyl-1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (methylsulfonyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (cyclohexylmethyl) azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (tetrahydro-2H-pyran-4-ylmethyl) azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) azetidine-1-carboxamide;

n- (4-cyanophenyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (cyclohexylmethyl) -N-methylazetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N-methyl-N- (tetrahydro-2H-pyran-4-ylmethyl) azetidine-1-carboxamide;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N- (4-fluorobenzyl) -N-methylazetidine-1-carboxamide;

n- (4-cyanobenzyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] -N-methylazetidine-1-carboxamide;

2- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -1,2,3, 4-tetrahydroisoquinoline;

n- (4-cyanobenzyl) -3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxamide;

4-chlorophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate;

3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylic acid 6-methylpyridin-3-yl ester;

4-cyanophenyl 3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidine-1-carboxylate;

1- [ (1-acetylazetidin-3-yl) carbonyl ] -4-cyclobutyl-1, 4-diazepane;

1-cyclobutyl-4- [ (1-propionylazetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1H-imidazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclobutyl-4- [ (1- { [4- (1H-1,2, 4-triazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- [ (1- { [4- (1H-1,2, 4-triazol-1-ylmethyl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan;

1-cyclobutyl-4- ({1- [ (2-methylpyridin-4-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane;

2- [5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) pyridin-2-yl ] propan-2-ol;

5- ({3- [ (4-cyclobutyl-1, 4-diazepan-1-yl) carbonyl ] azetidin-1-yl } carbonyl) -N-methylpyridine-2-carboxamide;

1-cyclobutyl-4- [ (1- { [ 3-fluoro-4- (1H-1,2, 4-triazol-1-yl) phenyl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepane;

1-cyclopentyl-4- ({1- [ (6-methylpyridin-3-yl) carbonyl ] azetidin-3-yl } carbonyl) -1, 4-diazepane; and

1-cyclobutyl-4- [ (1- { [6- (1H-pyrazol-1-yl) pyridin-3-yl ] carbonyl } azetidin-3-yl) carbonyl ] -1, 4-diazepan.

2. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, optionally in combination with one or more other biologically active compounds or pharmaceutical compositions.

3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, for use as a medicament.

4. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use in a method of treatment or prevention of diseases and disorders associated with the H3 receptor.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment or prevention of the following diseases and disorders: neurological disorders; diseases affecting energy homeostasis and their associated complications; pain; cardiovascular diseases; gastrointestinal diseases; vestibular dysfunction; drug abuse; a nasal obstruction; allergic rhinitis; or asthma.

6. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of diseases and disorders associated with the H3 receptor.

7. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of the following diseases and disorders: neurological disorders; diseases affecting energy homeostasis and their associated complications; pain; cardiovascular diseases; gastrointestinal diseases; vestibular dysfunction; drug abuse; a nasal obstruction; allergic rhinitis; or asthma.