Muscarinic acetylcholine M1 receptor antagonists

Abstract

Provided herein are compounds useful as antagonists of muscarinic acetylcholine receptor M1 (mAChR M1); synthetic methods of making the compounds; pharmaceutical compositions comprising such compounds; and methods of using the compounds and compositions to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980057628.6 and invention name “Muscarinic acetylcholine M1 receptor antagonist”. Background Art

[0002] Human muscarinic acetylcholine receptor M 1 (mAChR M 1 ) is a 479 amino acid protein encoded by the CHRM1 gene. mAChR M 1 There are five members of the muscarinic acetylcholine receptor family (M 1 -M 5 ) that are widely expressed throughout the body, where they play diverse roles in cognitive, sensory, motor, and autonomic functions. 1 mAChRs are present in the central and peripheral nervous systems, particularly in the cerebral cortex and sympathetic ganglia. 1 Potential role of highly selective mAChR M in epileptic seizure activity and motor control 1 Antagonists may have potential utility in the treatment of some epileptic disorders as well as certain movement disorders including Parkinson's disease, dystonia, and fragile X syndrome. Summary of the invention

[0003] The present disclosure provides, for example, muscarinic acetylcholine M 1 Receptor (mAChR M 1 ) and their use as medicaments, methods for their preparation, and pharmaceutical compositions comprising the disclosed compounds as at least one active ingredient. The present disclosure also provides the use of the disclosed compounds as a medicament for inhibiting the activity of muscarinic acetylcholine M1 receptors in patients and / or in the preparation of a medicament for inhibiting the activity of muscarinic acetylcholine M1 receptors in patients.

[0004] In one aspect, a compound of formula (IA) is provided:

[0005]

[0006] Where: E is -CH 2 -、-CH 2 CH 2 -、-O-CH 2 -or-CH 2 -O-; X is a bond, -C≡C-, -C(=O)--CH 2 O-、-CH 2 CH 2O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-; Y is a bond, -O- or -N(R 8 )-;R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 Alkyl; each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 Alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; each R 6 are independently selected from hydrogen, deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 Alkyl; R 8 is hydrogen or C 1-6 Alkyl; R 9 is hydrogen or C1-6 Alkyl; each R 10 Independently selected from H and C 1-6 Alkyl; R 11 It is C 1-6 Alkyl; each R 12 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 Alkyl; each R 13 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; a is 1, 2, 3, 4 or 5; m is 0, 1, 2 or 3; n is 1, 2, 3, 4 or 5; p is 0, 1, 2 or 3; and each q is independently 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt or solvate thereof.

[0007] In some embodiments are compounds of Formula (IA), wherein R 4 yes

[0008] In one aspect, a compound of formula (I) is provided:

[0009]

[0010] in:

[0011] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-;

[0012] Y is a bond, -O- or -N(R 8 )-;

[0013] R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution;

[0014] Each R 2 Independently selected from H and C1-6 alkyl;

[0015] Each R 3 Independently selected from H and C 1-6 alkyl;

[0016] R 4 yes

[0017] Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy;

[0018] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0019] R 7 is hydrogen or C 1-6 alkyl;

[0020] R 8 is hydrogen or C 1-6 alkyl;

[0021] R 9 It is C 1-6 alkyl;

[0022] Each R 10 Independently selected from H and C 1-6 alkyl;

[0023] R 11 It is C 1-6 alkyl;

[0024] m is 0, 1, 2, or 3;

[0025] n is 1, 2, 3, 4, or 5;

[0026] p is 0, 1, 2 or 3; and

[0027] q is 0, 1, 2, 3, or 4;

[0028] or a pharmaceutically acceptable salt or solvate thereof.

[0029] In some embodiments are compounds of formula (I), a pharmaceutically acceptable salt or solvate thereof, compounds having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof;

[0030]

[0031] In some embodiments are compounds of formula (I), a pharmaceutically acceptable salt or solvate thereof, compounds having the structure of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof;

[0032]

[0033] In some embodiments are compounds of formula (I), a pharmaceutically acceptable salt or solvate thereof, compounds having the structure of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof;

[0034]

[0035] In some embodiments are compounds of formula (I), a pharmaceutically acceptable salt or solvate thereof, a compound having the structure of formula (Id), or a pharmaceutically acceptable salt or solvate thereof;

[0036]

[0037] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is a 5- or 6-membered heteroaryl ring. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is a 5- or 6-membered heterocycloalkyl ring or a 4-, 5- or 6-membered cycloalkyl ring. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, m is 0. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, q is 0.

[0038] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, X is a bond and Y is a bond. In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, X is a bond and Y is -O-. In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, X is a bond and Y is -N(H)-. In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, X is -CH 2 N(H)- and Y is a bond. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt or solvate thereof, X is -S(O) 2 - and Y is a bond. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, each R 2 and each R 3are all H. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, n is 1, 2 or 3. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, n is 3. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, n is 2. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, n is 1. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 4 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 4 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 4 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 4 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 and -S(O) 2 R 11 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts or solvates thereof, each R 6is independently selected from halogen and -CN. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, p is 1 or 2. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, p is 2. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, p is 1. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, p is 0.

[0039] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0040] Another aspect is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0041] Another aspect is a method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt or solvate thereof.

[0042] Another aspect is a method of treating neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy. In some embodiments, a method of treating neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy.

[0043] On the other hand is a method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the central nervous system. In some embodiments, a method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is multiple sclerosis. In some embodiments, a method of treating a demyelinating disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0044] In some embodiments of the methods described herein, the methods further comprise taking one or more immunomodulators. In some embodiments, the one or more immunomodulators are selected from: IFN-β1 molecules; corticosteroids; polymers of glutamate, lysine, alanine and tyrosine or glatiramer; antibodies or fragments thereof or natalizumab directed against α-4 integrin; anthracenedione molecules or mitoxantrone; fingolimod or FTY720 or other SIPl functional modulators; dimethyl fumarate; antibodies or daclizumab directed against the α subunit (CD25) of the IL-2 receptor of T cells; antibodies or alemtuzumab directed against CD52; antibodies directed against CD20; and dihydroorotate dehydrogenase inhibitors or teriflunomide.

[0045] Another aspect is to modulate the muscarinic acetylcholine receptor M 1 A method of treating a subject with M1-positive leukemia comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, acts as a selective M1 antagonist. DETAILED DESCRIPTION

[0046] The present disclosure relates, at least in part, to compounds capable of inhibiting the muscarinic acetylcholine M1 receptor.

[0047] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "agent" includes a plurality of such agents, and reference to "cell" includes reference to one or more cells (or reference to a plurality of cells) and the like expression of effects. When ranges are used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to a number or a numerical range, the term "about" means that the number or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the number or numerical range. The term "comprising" (and related terms, such as "having" or "including") is not intended to exclude that in certain other embodiments, for example, embodiments of any material composition, composition, method or process, etc. described herein may be "consisting of" or "essentially consisting of" the features.

[0048] definition

[0049] As used in the specification and the appended claims, the following terms have the following indicated meanings unless indicated to the contrary.

[0050] As used herein, C 1 -C x Including C 1 -C 2 、 C 1 -C 3 ...C 1 -C x . C 1 -C x refers to the number of carbon atoms that make up the designated moiety (excluding optional substituents).

[0051] "Amino" refers to -NH 2 Group.

[0052] "Cyano" refers to a -CN group.

[0053] "Nitro" refers to -NO 2 Group.

[0054] "Oxa" refers to an -O- group.

[0055] "Oxo" refers to a =0 group.

[0056] "Thio" refers to a =S group.

[0057] "Imino" refers to a =NH group.

[0058] "Oximo" refers to a =N-OH group.

[0059] "Alkyl" or "alkylene" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 In certain embodiments, an alkyl group contains from one to thirteen carbon atoms (e.g., C 1 -C 13 In certain embodiments, an alkyl group contains from one to eight carbon atoms (e.g., C 1 -C 8 In other embodiments, the alkyl group contains from one to six carbon atoms (e.g., C 1 -C 6 In other embodiments, the alkyl group contains one to five carbon atoms (e.g., C 1 -C 5 In other embodiments, the alkyl group contains one to four carbon atoms (e.g., C 1 -C 4 In other embodiments, the alkyl group contains one to three carbon atoms (e.g., C 1 -C 3 In other embodiments, the alkyl group contains one to two carbon atoms (e.g., C 1 -C 2 In other embodiments, the alkyl group contains one carbon atom (e.g., C 1 In other embodiments, the alkyl group contains five to fifteen carbon atoms (e.g., C 5 -C 15 In other embodiments, the alkyl group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkyl group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkyl group contains three to five carbon atoms (e.g., C 3 -C 5 Alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl) and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SRa 、-OC(O)R a 、-N(R a ) 2 、-C(O)R a、 -C(O)OR a、 -C(O)N(R a ) 2 、-N(R a )C(O)OR f、 -OC(O)-NR a R f 、-N(R a )C(O)R f 、-N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), S(O) t R f (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0060] "Alkoxy" refers to a radical of the formula -O-alkyl bonded through an oxygen atom wherein alkyl is an alkyl chain as defined above.

[0061] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In certain embodiments, alkenyl comprises two to eight carbon atoms. In other embodiments, alkenyl comprises two to four carbon atoms. Alkenyl is connected to the rest of the molecule by a single bond, such as vinyl (i.e., ethenyl or vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R f 、-N(R a ) 2 、-C(O)R a、-C(O)OR a 、-C(O)N(R a ) 2 、-N(R a )C(O)OR f 、-OC(O)-NR a R f 、-N(R a )C(O)R f 、-N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0062] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. In certain embodiments, the alkynyl group contains two to eight carbon atoms. In other embodiments, the alkynyl group has two to four carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)R a 、-N(R a ) 2 、-C(O)R a、 -C(O)OR a、 -C(O)N(R a ) 2 、-N(R a )C(O)OR f、 -OC(O)-NR a R f 、-N(R a )C(O)R f 、-N(R a )S(O)t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), S(O) t R f (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0063] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbons of six to eighteen carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., according to the Hückel theory, it contains a cyclic, delocalized (4n+2)π-electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (as in "aralkyl") is intended to include aryl groups optionally substituted with one or more of the following substituents, the substituents being independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaralkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -Rb -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R A (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c It is a straight or branched alkylene or alkenylene chain.

[0064] "Aryloxy" refers to a radical of the formula -O-aryl bonded through an oxygen atom wherein aryl is as defined above.

[0065] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain part of the aralkyl is optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl is optionally substituted as described above for the aryl group.

[0066] "Aralkyloxy" refers to a radical of the formula -O-aralkyl bonded through an oxygen atom, wherein aralkyl is as defined above.

[0067] "Aralkenyl" refers to a group of the formula -R d -aryl radical, wherein R d is an alkenylene chain as defined above. The aryl part of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain part of the aralkenyl group is optionally substituted as defined above for alkenylene.

[0068] "Arylalkynyl" refers to a group of the formula -R e -aryl radical, wherein R eis an alkynylene chain as defined above. The aryl part of the aralkyne group is optionally substituted as described above for aryl. The alkynylene chain part of the aralkyne group is optionally substituted as defined above for an alkynylene chain.

[0069] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including condensed rings or bridged ring systems, with three to fifteen carbon atoms. In certain embodiments, cycloalkyl contains three to ten carbon atoms. In other embodiments, cycloalkyl contains five to seven carbon atoms. Cycloalkyl is connected to the rest of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only a single C-C bond) or partially unsaturated (i.e., contains one or more double bonds or triple bonds). Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, cycloalkyl contains three to eight carbon atoms (e.g., C-C bond). 3 -C 8 In other embodiments, the cycloalkyl group contains three to seven carbon atoms (e.g., C 3 -C 7 In other embodiments, the cycloalkyl group contains three to six carbon atoms (e.g., C 3 -C 6 In other embodiments, the cycloalkyl group contains three to five carbon atoms (e.g., C 3 -C 5 In other embodiments, the cycloalkyl group contains three to four carbon atoms (e.g., C 3 -C 4 Cycloalkyl). Partially unsaturated cycloalkyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic cycloalkyl includes, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "cycloalkyl" is intended to include cycloalkyl optionally substituted with one or more of the following substituents, the substituents being independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaralkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a )2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c It is a straight or branched alkylene or alkenylene chain.

[0070] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0071] "Haloalkyl" means an alkyl group, as defined above, substituted with one or more halo groups, as defined above.

[0072] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluorine groups, for example trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0073] "Haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halo groups.

[0074] "Heterocycloalkyl" refers to a stable 3 to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, heterocycloalkyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which includes a condensed ring, a spirocyclic or a bridged ring system. The heteroatoms in heterocycloalkyl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Heterocycloalkyl is partially or completely saturated. In certain embodiments, heterocycloalkyl is connected to the rest of the molecule by any atom of the ring. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocycloalkyl" is intended to include heterocycloalkyl as defined above optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaralkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)ORa , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain.

[0075] "Heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing one to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is connected to the rest of the molecule through any atom of the ring. Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaralkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a )2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain.

[0076] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0077] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. C-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0078] "Heteroaryloxy" refers to a radical of the formula -O-heteroaryl bonded through an oxygen atom wherein heteroaryl is as defined above.

[0079] "Heteroarylalkyl" refers to a group of the formula -Rc -heteroaryl radical, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl is optionally substituted as defined above for the heteroaryl group.

[0080] "Heteroarylalkoxy" refers to a group of the formula -OR c - a heteroaryl group bonded through an oxygen atom, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy is optionally substituted as defined above for the heteroaryl group.

[0081] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and that the description includes substituted aryl groups and unsubstituted aryl groups.

[0082] "Tautomers" refer to molecules in which a proton transfer from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds provided herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0083]

[0084] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. Pharmaceutically acceptable salts of any pyrazole compound described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0085] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are amino acid salts such as argininate, gluconate and galacturonate (see, e.g., Berge SM et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66: 1-19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0086] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding inorganic or organic bases to the free acids. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydroxylamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0087] "Prodrug" refers to a compound that is converted into a biologically active compound described herein under physiological conditions or by solvolysis in some embodiments. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs are generally inactive when administered to a subject, but are converted into active compounds in vivo, for example, by hydrolysis. Prodrug compounds generally provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., "Design of Prodrugs" (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).

[0088] A discussion of prodrugs is provided in Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0089] The term "prodrug" is also intended to include any covalently bonded carriers that release the active compound in vivo when such prodrugs are administered to a mammalian subject. Prodrugs of active compounds as described herein are prepared by modifying functional groups present in the active compound in a manner that allows the modification to be cleaved into the parent active compound in routine operations or in vivo. Prodrugs include compounds in which hydroxyl, amino or sulfhydryl groups are bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form free hydroxyl, free amino or free sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compound, and the like.

[0090] "Pharmaceutically acceptable solvate" refers to a composition of matter in the form of a solvent addition. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of a solvent and is formed during the preparation process with a pharmaceutically acceptable solvent (such as water, ethanol, etc.). A "hydrate" is formed when the solvent is water, or an alcoholate is formed when the solvent is ethanol. Solvates of the compounds described herein are conveniently prepared or formed in the methods described herein. The compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0091] The terms "allosteric site" and allosteric binding site refer to a ligand binding site that is topologically different from the positive binding site.

[0092] The term "ligand" refers to a natural or synthetic molecule that is capable of binding or associating with a receptor to form a complex and mediate, prevent or alter a biological effect. The term "ligand" is intended to encompass allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogs of natural substrates.

[0093] The terms "natural ligand" and "endogenous ligand" refer to a naturally occurring ligand that binds a receptor.

[0094] The terms "positive site" and "positive binding site" refer to the primary binding site on a receptor that is recognized by the receptor's endogenous ligand or agonist. For example, the positive site on the muscarinic acetylcholine M1 receptor is the site where acetylcholine binds.

[0095] The term “mAChR M 1 A receptor antagonist is a drug that partially or completely inhibits or reverses the effect of an agonist (e.g., acetylcholine) on mAChR M 1 Any exogenously administered compound or agent that modulates the action of a receptor. The term includes compounds or agents characterized as (or described as) antagonists, partial antagonists, and negative allosteric modulators. For example, mAChRM 1Receptor antagonists may mediate their effects by binding to either the positive or allosteric site, or they may interact at a unique binding site not normally involved in the biological regulation of the receptor's activity. Thus, in animals, particularly mammals (e.g., humans), mAChR M is activated in the presence or absence of acetylcholine or another agonist. 1 Receptor antagonists directly or indirectly inhibit mAChR M 1 In various aspects, mAChR M 1 Receptor antagonists reduce the expression of mAChR M in cells in the presence of extracellular acetylcholine. 1 In some embodiments, the activity of a mAChR 1 Compounds that are "mAChR M 1 Receptor competitive antagonists," "mAChR M 1 Receptor noncompetitive antagonists," "mAChRM 1 Partial antagonists of mAChR 1 Compounds that are "negative allosteric modulators of β-actin receptors".

[0096] The term “mAChR M 1 A receptor competitive antagonist is a receptor that binds to mAChR M 1 A competitive antagonist is a compound or agent that blocks the positive site of the mAChR receptor without activating the receptor. 1 The receptors interact and compete with the endogenous ligand acetylcholine for binding to the receptor and reduce the ability of the receptor to transduce intracellular signals in response to endogenous ligand binding.

[0097] The term “mAChR M 1 A noncompetitive antagonist is a receptor antagonist that is not a mAChR 1 The positive binding site of the receptor binds to the site and can partially or completely inhibit or reverse the action of agonists (such as acetylcholine) on mAChR M 1 Thus, noncompetitive antagonists can be used with mAChR M 1 receptor interaction and reduce the binding of the endogenous ligand acetylcholine to the receptor and / or reduce the ability of the receptor to transduce intracellular signals in response to the binding of the endogenous ligand.

[0098] The term “mAChR M 1 A "partial antagonist" is one that binds to the positive or allosteric site but only partially blocks mAChR M. 1Any exogenously administered compound or agent that inhibits the response of a mAChR receptor to an agonist, such as acetylcholine. 1 receptor interaction, but not complete inhibition of mAChR M 1 The response of a receptor to an agonist such as acetylcholine.

[0099] The term “mAChR M 1 A "negative allosteric modulator" is a molecule that binds directly or indirectly to mAChR M in the presence of acetylcholine or another agonist in animals (particularly mammals, such as humans). 1 Any exogenously administered compound or agent that targets an allosteric site of receptor activity. For example, although not intended to limit the present disclosure, a selective muscarinic M 1 Negative allosteric modulators can preferentially bind to muscarinic M 1 receptors and reduces muscarinic M by acting as a noncompetitive antagonist 1 Signaling. In one aspect, a mAChR M1 receptor negative allosteric modulator decreases the activity of a mAChR M1 receptor in a cell in the presence of extracellular acetylcholine.

[0100] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, e.g., rats, mice and guinea pigs, etc. In one aspect, the subject is a human.

[0101] As used herein, "treat," "treat," or "alleviate," or "ameliorate," are used interchangeably herein. These terms refer to an approach to obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" refers to eradication or amelioration of the underlying disease being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient still suffers from the underlying condition. For a prophylactic benefit, the composition is administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0102] As used herein, “EC 50 ” is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% activation or enhancement of a biological process or component of a process (including proteins, subunits, organelles, ribonucleoproteins, etc.). For example, EC 50Can refer to the concentration of agonist that elicits a response halfway between baseline and maximal response in an in vitro assay.In some embodiments, in vitro assay systems utilize cell lines that either endogenously express the target of interest or have been transfected with an appropriate expression vector directing expression of a recombinant form of the target.

[0103] As used herein, “IC 50 ” is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process or component of a process (including proteins, subunits, organelles, ribonucleoproteins, etc.). For example, IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in an appropriate assay. 1 IC of receptor 50 Can be measured in an in vitro test system.

[0104] Compound

[0105] The present disclosure provides a muscarinic acetylcholine M 1 Receptor (mAChR M 1 ). These compounds and compositions comprising these compounds can be used to treat or prevent neurological disorders. In some embodiments, the compounds described herein can be used to treat Parkinson's disease.

[0106] In some embodiments, provided herein are compounds having the structure of Formula (I):

[0107]

[0108] in:

[0109] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-;

[0110] Y is a bond, -O- or -N(R 8 )-;

[0111] R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution;

[0112] Each R 2 Independently selected from H and C 1-6 alkyl;

[0113] Each R 3 Independently selected from H and C 1-6 alkyl;

[0114] R 4 yes

[0115] Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy;

[0116] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0117] R 7 is hydrogen or C 1-6 alkyl;

[0118] R 8 is hydrogen or C 1-6 alkyl;

[0119] R 9 It is C 1-6 alkyl;

[0120] Each R 10 Independently selected from H and C 1-6 alkyl;

[0121] R 11 It is C 1-6 alkyl;

[0122] m is 0, 1, 2, or 3;

[0123] n is 1, 2, 3, 4, or 5;

[0124] p is 0, 1, 2 or 3; and

[0125] q is 0, 1, 2, 3, or 4;

[0126] or a pharmaceutically acceptable salt or solvate thereof.

[0127] In some embodiments, provided herein are compounds having the structure of Formula (Ia):

[0128]

[0129] in:

[0130] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-;

[0131] Y is a bond, -O- or -N(R 8 )-;

[0132] R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution;

[0133] Each R 2 Independently selected from H and C 1-6 alkyl;

[0134] Each R 3 Independently selected from H and C 1-6 alkyl;

[0135] R 4 yes

[0136] Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkyl and C 1-6 Haloalkoxy;

[0137] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0138] R 7 is hydrogen or C 1-6 alkyl;

[0139] R 8 is hydrogen or C 1-6 alkyl;

[0140] R 9 It is C 1-6 alkyl;

[0141] Each R 10 Independently selected from H and C 1-6 alkyl;

[0142] R 11 It is C 1-6 alkyl;

[0143] m is 0, 1, 2, or 3;

[0144] n is 1, 2, 3, 4, or 5;

[0145] p is 0, 1, 2 or 3; and

[0146] q is 0, 1, 2, 3, or 4;

[0147] or a pharmaceutically acceptable salt or solvate thereof.

[0148] In some embodiments, provided herein are compounds having the structure of Formula (Ib):

[0149]

[0150] in:

[0151] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH2 CH 2 N(R 7 )-;

[0152] Y is a bond, -O- or -N(R 8 )-;

[0153] R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution;

[0154] Each R 2 Independently selected from H and C 1-6 alkyl;

[0155] Each R 3 Independently selected from H and C 1-6 alkyl;

[0156] R 4 yes

[0157] Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy;

[0158] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0159] R 7 is hydrogen or C 1-6 alkyl;

[0160] R 8 is hydrogen or C 1-6 alkyl;

[0161] R 9 It is C1-6 alkyl;

[0162] Each R 10 Independently selected from H and C 1-6 alkyl;

[0163] R 11 It is C 1-6 alkyl;

[0164] m is 0, 1, 2, or 3;

[0165] n is 1, 2, 3, 4, or 5;

[0166] p is 0, 1, 2 or 3; and

[0167] q is 0, 1, 2, 3, or 4;

[0168] or a pharmaceutically acceptable salt or solvate thereof.

[0169] In some embodiments, provided herein are compounds having the structure of Formula (Ic):

[0170]

[0171] in:

[0172] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-;

[0173] Y is a bond, -O- or -N(R 8 )-;

[0174] R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution;

[0175] Each R 2 Independently selected from H and C1-6 alkyl;

[0176] Each R 3 Independently selected from H and C 1-6 alkyl;

[0177] R 4 yes

[0178] Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy;

[0179] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0180] R 7 is hydrogen or C 1-6 alkyl;

[0181] R 8 is hydrogen or C 1-6 alkyl;

[0182] R 9 It is C 1-6 alkyl;

[0183] Each R 10 Independently selected from H and C 1-6 alkyl;

[0184] R 11 It is C 1-6 alkyl;

[0185] m is 0, 1, 2, or 3;

[0186] n is 1, 2, 3, 4, or 5;

[0187] p is 0, 1, 2 or 3; and

[0188] q is 0, 1, 2, 3, or 4;

[0189] or a pharmaceutically acceptable salt or solvate thereof.

[0190] In some embodiments, provided herein are compounds having the structure of Formula (Id):

[0191]

[0192] in:

[0193] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-;

[0194] Y is a bond, -O- or -N(R 8 )-;

[0195] R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution;

[0196] Each R 2 Independently selected from H and C 1-6 alkyl;

[0197] Each R 3 Independently selected from H and C 1-6 alkyl;

[0198] R 4 yes

[0199] Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy;

[0200] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0201] R 7 is hydrogen or C 1-6 alkyl;

[0202] R 8 is hydrogen or C 1-6 alkyl;

[0203] R 9 It is C 1-6 alkyl;

[0204] Each R 10 Independently selected from H and C 1-6 alkyl;

[0205] R 11 It is C 1-6 alkyl;

[0206] m is 0, 1, 2, or 3;

[0207] n is 1, 2, 3, 4, or 5;

[0208] p is 0, 1, 2 or 3; and

[0209] q is 0, 1, 2, 3, or 4;

[0210] or a pharmaceutically acceptable salt or solvate thereof.

[0211] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes

[0212] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6In some embodiments, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A heteroaryl ring substituted with a haloalkoxy radical, wherein the heteroaryl ring is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A heteroaryl ring substituted with a haloalkoxy radical, wherein the heteroaryl ring is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. In some embodiments, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, ring A is optionally substituted with halogen, -CN, -N(R) or -N(R) 10 )2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, ring A is optionally substituted with halogen, -CN, -N(R) or -N(R) or -N(R) substituted with halogen, -CN, -N(R) or -N(R) 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2, C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments, Ring A is optionally substituted with -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH or C 1-6 In some embodiments, Ring A is optionally substituted with -NH 2 , methyl, -CH 2 In some embodiments, Ring A is unsubstituted.

[0213] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0214] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts or solvates thereof, Ring A is In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is an unsubstituted 5- or 6-membered heterocycloalkyl ring. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is an unsubstituted 5-membered heterocycloalkyl ring. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is an unsubstituted 6-membered heterocycloalkyl ring.

[0215] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id) or pharmaceutically acceptable salts or solvates thereof, Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is an unsubstituted 4, 5 or 6 membered cycloalkyl ring. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is an unsubstituted 4, 5 or 6 membered cycloalkyl ring. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is

[0216] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, each R 5are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 In some embodiments, each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl and C 1-6 Alkoxy.

[0217] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), or (Id), or pharmaceutically acceptable salts or solvates thereof, m is 0, 1, 2, or 3. In some embodiments, m is 0 to 1, 0 to 2, 0 to 3, 1 to 2, 1 to 3, or 2 to 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0218] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0219] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (Id), or pharmaceutically acceptable salts or solvates thereof, Ring A is

[0220] In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0221]

[0222] X is a bond, -CH2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-;

[0223] Y is a bond, -O- or -N(R 8 )-;

[0224] Each R 2 Independently selected from H and C 1-6 alkyl;

[0225] Each R 3 Independently selected from H and C 1-6 alkyl;

[0226] R 4 yes

[0227] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0228] R 7 is hydrogen or C 1-6 alkyl;

[0229] R 8 is hydrogen or C 1-6 alkyl;

[0230] n is 1, 2, 3, 4, or 5; and

[0231] p is 0, 1, 2 or 3.

[0232] In some embodiments, is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:

[0233]

[0234] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-;

[0235] Y is a bond, -O- or -N(R 8 )-;

[0236] Each R 2 Independently selected from H and C 1-6 alkyl;

[0237] Each R 3 Independently selected from H and C 1-6 alkyl;

[0238] R 4 yes

[0239] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0240] R 7 is hydrogen or C 1-6 alkyl;

[0241] R 8 is hydrogen or C 1-6 alkyl;

[0242] n is 1, 2, 3, 4, or 5; and

[0243] p is 0, 1, 2 or 3.

[0244] In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof:

[0245]

[0246] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R7 )-or-CH 2 CH 2 N(R 7 )-;

[0247] Y is a bond, -O- or -N(R 8 )-;

[0248] Each R 2 Independently selected from H and C 1-6 alkyl;

[0249] Each R 3 Independently selected from H and C 1-6 alkyl;

[0250] R 4 yes

[0251] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0252] R 7 is hydrogen or C 1-6 alkyl;

[0253] R 8 is hydrogen or C 1-6 alkyl;

[0254] n is 1, 2, 3, 4, or 5; and

[0255] p is 0, 1, 2 or 3.

[0256] In some embodiments, is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:

[0257]

[0258] X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R7 )-;

[0259] Y is a bond, -O- or -N(R 8 )-;

[0260] Each R 2 Independently selected from H and C 1-6 alkyl;

[0261] Each R 3 Independently selected from H and C 1-6 alkyl;

[0262] R 4 yes

[0263] Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;

[0264] R 7 is hydrogen or C 1-6 alkyl;

[0265] R 8 is hydrogen or C 1-6 alkyl;

[0266] n is 1, 2, 3, 4, or 5; and

[0267] p is 0, 1, 2 or 3.

[0268] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0269] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes

[0270] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 independently selected from -F, -Cl, -Br, -CN, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 Yes-NH 2 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 6 Yes-S(O) 2 CH 3 .

[0271] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, p is 0, 1, 2 or 3. In some embodiments, p is 0 to 1, 0 to 2, 0 to 3, 1 to 2, 1 to 3 or 2 to 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0272] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0273] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes p is 1, and R 6 Selected from halogen, -CN, -N(R 10 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O)2 R 11 In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes p is 1, and R 6 Selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes And each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0274] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes p is 2, and each R 6 are independently selected from halogen, -CN, -N(R 10 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes p is 2, and each R 6 are independently selected from halogen, -CN, -N(R 10 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes p is 2, and each R 6 are independently selected from halogen, -CN, -N(R 10 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 .

[0275] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes p is 1, and R 6 Selected from halogen, -CN, -N(R 10 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, R 4 yes p is 2, and R 6 Selected from halogen, -CN, -N(R 10 2. C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 In some embodiments, R 4 yes In some embodiments, R4 yes

[0276] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 2 Independently selected from H and C 1-4 In some embodiments, each R 2 is independently selected from H and methyl. In some embodiments, each R 2 is H. In some embodiments, each R 2 It is C 1-4 In some embodiments, each R 2 It's methyl.

[0277] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 3 Independently selected from H and C 1-4 In some embodiments, each R 3 is independently selected from H and methyl. In some embodiments, each R 3 is H. In some embodiments, each R 3 It is C 1-4 In some embodiments, each R 3 It's methyl.

[0278] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, each R 2 and R 3 It's H.

[0279] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), or (IIIa), or pharmaceutically acceptable salts or solvates thereof, X is a bond. In some embodiments, X is -CH 2 In some embodiments, X is -CH 2 CH 2 In some embodiments, X is -O-. In some embodiments, X is -N(R 7 )-. In some embodiments, X is S(O) 2 In some embodiments, X is -CH 2 N(R 7)-. In some embodiments, X is -CH 2 CH 2 N(R 7 )-. In some embodiments, X is -NH-. In some embodiments, X is -CH 2 NH-. In some embodiments, X is -CH 2 CH 2 NH-. In some embodiments, X is -N(CH 3 )-. In some embodiments, X is -CH 2 N(CH 3 )-. In some embodiments, X is -CH 2 CH 2 N(CH 3 )-.

[0280] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, Y is a bond. In some embodiments, Y is -N(R 8 )-. In some embodiments, Y is or -NH-. In some embodiments, Y is or -N(CH 3 )-.

[0281] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, n is 1, 2, 3, 4 or 5. In some embodiments, n is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5 or 4 to 5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0282] In some embodiments of the compound of Formula (I), (la), (lb), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, X is a bond and Y is a bond.

[0283] In some embodiments of the compound of Formula (I), (la), (lb), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, X is a bond and Y is -O-.

[0284] In some embodiments of the compound of Formula (I), (la), (lb), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, X is a bond and Y is -N(H)-.

[0285] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, X is -CH 2 O- and Y is a bond.

[0286] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, X is -CH 2 CH 2 N(H)- and Y is a bond.

[0287] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, X is -CH 2 N(H)- and Y is a bond.

[0288] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or pharmaceutically acceptable salts or solvates thereof, X is S(O) 2 And Y is a bond.

[0289] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein yes

[0290] In some embodiments, yes

[0291] In some embodiments, yes

[0292] In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes In some embodiments, yes

[0293] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof may be selected to provide stable moieties and compounds.

[0294] In some embodiments is a compound selected from the group consisting of:

[0295]

[0296]

[0297] or a pharmaceutically acceptable salt or solvate thereof.

[0298] In some embodiments is a compound selected from the group consisting of:

[0299]

[0300] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is selected from the following:

[0301]

[0302]

[0303] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is selected from the following:

[0304]

[0305] or a pharmaceutically acceptable salt or solvate thereof.

[0306] In some embodiments is a compound selected from the group consisting of:

[0307]

[0308] or a pharmaceutically acceptable salt or solvate thereof.

[0309] In some embodiments is a compound selected from the group consisting of:

[0310]

[0311] or a pharmaceutically acceptable salt or solvate thereof.

[0312] Preparation of compounds

[0313] The compounds used in the reactions described herein are prepared according to known organic synthesis techniques, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” were obtained from standard commercial sources, including Acros rganics (Heil, Belgium), Aldrich Chemical (Milwaukee, Wisconsin, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, United Kingdom), Ark Pharm, Inc. (Libertyville, Illinois), Avocado Research (Lancashire, United Kingdom), BDH Inc. (Toronto, Canada), Bionet (Cornwall, United Kingdom), Chemservice Inc. (West Westchester, Pennsylvania), Combi-blocks (San Diego, California), Crescent Chemical Co. (Hopaugh, New York), eMolecules (San Diego, California), FisherScientific Co. (Pittsburgh, Pennsylvania), Fisons Chemicals (Leicestershire, United Kingdom), FrontierScientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics (Cornwall, United Kingdom), Lancaster Synthesis (Windham, New Hampshire), Matrix Scientific (Columbia County, South Carolina), Maybridge Chemical Co. Ltd. (Cornwall, England), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganix (Houston, Texas), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hannover, Germany), Ryan Scientific, Inc. (Mount Pleasant, South Carolina), Spectrum Chemicals (Gardena, California), Sundia Meditech (Shanghai, China), TCI America (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland) and WuXi (Shanghai, China).

[0314] Suitable reference books and papers detailing the synthesis of reactants that can be used to prepare the compounds described herein, or providing references to articles describing the preparations, include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York; SR Sandler et al., Organic Functional Group Preparations, 2nd ed., Academic Press, New York, 1983; H. O. House, Modern Synthetic Reactions, 2nd ed., WA Benjamin, Inc. Menlo Park, California 1972; T. L. Gilchrist, Heterocyclic Chemistry, 2nd ed., John Wiley & Sons, New York, 1992; J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th ed., Wiley-Interscience, New York, 1992. Other suitable reference books and papers that detail the synthesis of reactants that can be used to prepare the compounds described herein or provide references to articles describing the preparations include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, 2nd Revised and Expanded Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (ed.), Modern Carbonyl Chemistry (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., Patai's 1992 Guide to the Chemistry of Functional Groups (1992), Interscience ISBN: 0-471-93022-9; Solomons, TWG, Organic Chemistry, 7th edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, Intermediate Organic Chemistry, 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; Organic Reactions (1942-2000) John Wiley & Sons, more than 55 volumes; and Chemistry of Functional Groups John Wiley & Sons, 73 volumes. .

[0315] Specific and similar reactants are also known through the index of known chemicals produced by the Chemical Abstract Service of the American Chemical Society and through online databases (American Chemical Society, Washington, D.C., can be contacted for more details). Chemicals known but not commercially available in the catalog are optionally prepared by custom chemical synthesis companies, many of which provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth, Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0316] Other forms of compounds

[0317] Isomers

[0318] The compounds described herein include all possible tautomers within the formulas described herein.

[0319] In addition, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), entgegen (E, opposite side, trans) and zusammen (Z, same side, cis) isomers and their corresponding mixtures. In some cases, the compounds exist as tautomers.

[0320] In some cases, the compounds described herein have one or more chiral centers and each center exists in (R)-configuration or (S)-configuration. The compounds described herein include all diastereomers, enantiomers and epimer forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the mixture of enantiomers and / or diastereomers produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatography of racemic mixtures. In some embodiments, the compounds described herein are prepared as single stereoisomers by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating diastereomers and recovering optically pure enantiomers. In some embodiments, dissociable complexes (e.g., crystalline diastereomeric salts) are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent by any practical means that will not result in racemization.

[0321] The term "geometric isomer" refers to E or Z geometric isomers (eg, cis or trans) of an olefin double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0322] Labeled compounds

[0323] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, e.g., 2 H. 3 H. 11 C, 13 C and / or 14 C content. In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the methods described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby extending the duration of drug action.

[0324] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having the disclosed structures but with the replacement of hydrogen by deuterium or tritium or with the replacement of carbon by 13 C or 14C-enriched carbon-substituted compounds are within the scope of the present disclosure.

[0325] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be modified with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), to mark. 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 17 O. 18 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br, 125 Isotopic substitutions of I. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0326] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2H atom substitution. Methods for the synthesis of deuterium-containing compounds are known in the art. In some embodiments, deuterium-substituted compounds are synthesized using various methods described in the following literature: Dean, Dennis C.; (ed.) "Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development" [In: Curr., Pharm. Des, 2000; 6 (10)] 2000, 110 pp; George W.; Varma, Rajender S. "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", Tetrahedron, 1989, 45 (21), 6601-21; and Evans, E. Anthony. "Synthesis of radiolabeled compounds", Journal of Radioanalytical Chemistry (J. Radioanal. Chem.), 1981, 64 (1-2), 9-32.

[0327] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0328] Pharmaceutically acceptable salts

[0329] In some embodiments, the compounds described herein are present in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0330] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the purified compound in its free form with a suitable acid or base separately and isolating the salt thus formed.

[0331] Solvate

[0332] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0333] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed during crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed in the methods described herein. As an example only, organic solvents including but not limited to dioxane, tetrahydrofuran or methanol are used to conveniently prepare hydrates of the compounds described herein by recrystallization from a water / organic solvent mixture. In addition, the compounds provided herein exist in non-solvated forms as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0334] Prodrug

[0335] In some embodiments, the compounds described herein exist in the form of prodrugs. The present invention provides methods of treating diseases by administering such prodrugs. The present invention also provides methods of treating diseases by administering such prodrugs as pharmaceutical compositions.

[0336] In some embodiments, prodrugs include amino acid residues or polypeptide chains of two or more (e.g., two, three or four) amino acid residues, covalently linked to the free amino group, hydroxyl or carboxylic acid group of the compounds of the invention by amide or ester bonds. Amino acid residues include, but are not limited to, 20 naturally occurring amino acids, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. In other embodiments, prodrugs include nucleic acid residues or oligonucleotides of two or more (e.g., two, three or four) nucleic acid residues covalently linked to the compounds of the compounds of the invention.

[0337] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphates, metal salts, and sulfonates. In some embodiments, compounds with free amino, acylamino, hydroxyl, or carboxyl groups are converted into prodrugs. For example, free carboxyl groups are derived as amides or alkyl esters. In some cases, all of these prodrug moieties are incorporated into groups including, but not limited to, ethers, amines, and carboxylic acid functional groups.

[0338] Hydroxy prodrugs include esters such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphates, sulfonates, sulfates, and disulfide-containing esters; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, and phosphoryloxymethoxycarbonyl, as described in Advanced Drug Delivery Reviews, 1996, 19, 115.

[0339] Amine-derived prodrugs include, but are not limited to, the following groups and combinations of groups:

[0340]

[0341] and sulfonamides and phosphonamides.

[0342] In some cases, sites on any aromatic ring moiety are susceptible to various metabolic reactions, and thus appropriate substituents are introduced on the aromatic ring structure to reduce, minimize or eliminate this metabolic pathway.

[0343] Pharmaceutical composition

[0344] In certain embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa) as described herein is administered as a pure chemical. In some instances, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa) as described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient or a physiologically suitable (or acceptable) carrier) based on the selected route of administration and as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, Pa. (2005)).

[0345] Thus, provided herein are pharmaceutical compositions comprising at least one compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa) as described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and is not deleterious to the recipient (i.e., subject) of the composition.

[0346] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0347] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.

[0348] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ib) or a pharmaceutically acceptable salt thereof.

[0349] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (Ic) or a pharmaceutically acceptable salt thereof.

[0350] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Id) or a pharmaceutically acceptable salt thereof.

[0351] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0352] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (IIa) or a pharmaceutically acceptable salt thereof.

[0353] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0354] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof.

[0355] In certain instances, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa) as described herein is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or by-products produced in one or more steps of the synthetic method.

[0356] Such pharmaceutical compositions include those suitable for oral, rectal, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal or intravenous), vaginal, ophthalmic or aerosol administration.

[0357] Exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, which include one or more disclosed compounds as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. In some examples, the active ingredients are mixed with generally non-toxic pharmaceutically acceptable carriers such as for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0358] In some embodiments for preparing solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums and other pharmaceutical diluents (such as water) to form a solid preformulation composition containing a uniform mixture of the disclosed compound or its non-toxic pharmaceutically acceptable salt. When referring to these preformulation compositions as uniform, it is meant that the active ingredient is uniformly dispersed throughout the composition, making the composition easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules.

[0359] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethyl cellulose, hydroxypropyl methyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) ) Wetting agents, such as glycerol; (4) disintegrants, such as crospovidone, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, sodium docusate, cetyl alcohol, and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, in some embodiments, the composition comprises a buffer. In some embodiments, solid compositions of similar types are also used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols.

[0360] In certain embodiments, tablet is prepared by compression or molding optionally with one or more auxiliary components.In some instances, binder (for example gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersant are used to prepare compressed tablets.In certain embodiments, molded tablet is prepared by molding the mixture of the subject composition moistened with inert liquid diluent in a suitable machine.In certain embodiments, tablet and other solid dosage forms such as dragee, capsule, pill and granule are scored or prepared with coating and shell, such as enteric coating and other coatings.

[0361] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some instances, the liquid dosage form contains an inert diluent such as, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0362] In some instances, suspensions contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0363] In some instances, formulations for rectal or vaginal administration are in the form of suppositories, which are prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent.

[0364] Dosage forms for the subject compositions for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions and with any preservatives, buffers or propellants as needed.

[0365] In some embodiments, ointments, pastes, creams and gels contain, in addition to the subject compositions, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0366] In some embodiments, in addition to the subject composition, powders and sprays also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0367] In some embodiments, the compounds described herein are formulated as eye drops for ocular administration.

[0368] Compositions and compounds disclosed herein are optionally administered by aerosol. This is achieved by preparing an aqueous aerosol, liposome preparation or solid powder containing the compound. In certain embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In certain embodiments, a sonic nebulizer is used because they minimize exposure of the drug to shear, which can cause degradation of the compound contained in the subject composition. Typically, aqueous aerosols are prepared by preparing an aqueous solution or suspension of the subject composition with a conventional pharmaceutically acceptable carrier and stabilizer. Carriers and stabilizers vary with the needs of the specific subject composition, but typically include nonionic surfactants (tweens, pluronics or polyethylene glycol), harmless proteins (e.g., serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (e.g., glycine), buffers, salts, sugars or sugar alcohols. Aerosols are typically prepared by isotonic solutions.

[0369] Pharmaceutical compositions suitable for parenteral administration comprise a combination of the subject composition and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes or suspending agents or thickening agents which render the formulation isotonic with the blood of the intended recipient.

[0370] Examples of suitable aqueous and nonaqueous carriers for pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0371] Also contemplated are enteral pharmaceutical preparations comprising a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. An enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluid at a specific pH value. The small intestine is a portion of the gastrointestinal tract (intestine) between the stomach and the large intestine, including the duodenum, jejunum, and ileum. The pH value of the duodenum is about 5.5, the pH value of the jejunum is about 6.5, and the pH value of the distal ileum is about 7.5. Thus, the enteric material is insoluble until, for example, a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, hexahydrocellulose acetate phthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, methyl acrylate, copolymers of methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric and Aquateric). The solubility of each of the above materials is known or easily determined in vitro.

[0372] The dosage of the composition comprising at least one compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa) as described herein varies depending on the condition of the patient (e.g., human), i.e., the stage of the disease, general health, age and other factors.

[0373] The pharmaceutical composition is given in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. Typically, suitable dosage and treatment regimen provide compositions in an amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or mitigation of symptom severity). Optimal dose is typically determined using experimental models and / or clinical trials. In certain embodiments, optimal dose depends on the patient's body mass, body weight or blood volume.

[0374] The oral dosage is generally about 1.0 mg to about 1000 mg per day, one to four or more times.

[0375] The disclosed compounds are administered to subjects or patients (animals and humans) in need of such treatment at a dosage that will provide the best drug efficacy. It should be understood that the dosage required for any particular application will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, the concurrent medications or special diets followed by the patient, and other factors, wherein the appropriate dosage is ultimately determined by the attending physician. In order to treat the above-mentioned clinical conditions and diseases, the expected compounds disclosed herein are administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectum in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration includes subcutaneous injection, intravenous or intramuscular injection or infusion techniques.

[0376] Methods of using the compounds and compositions

[0377] Antagonists of MAChR M1

[0378] Muscarinic acetylcholine receptor M 1 (mAChR M 1 ) are present in the central and peripheral nervous systems, particularly in the cerebral cortex and sympathetic ganglia. Notably, M1 is expressed on oligodendrocyte progenitor cells (OPCs) in the central nervous system. Over time, OPCs will differentiate into oligodendrocytes that produce myelin. Myelin is essential for the conduction of action potentials along axons, and its loss has been attributed to neurodegenerative diseases, particularly multiple sclerosis. In some embodiments, non-selective mAChR antagonists accelerate the differentiation of OPCs into oligodendrocytes. In some embodiments, selective mAChR M 1Antagonists can be used to treat demyelinating disorders, such as multiple sclerosis. In some embodiments, M1 antagonists can be used to treat epileptic disorders and certain movement disorders, including Parkinson's disease, dystonia, and fragile X syndrome. In one aspect, the compounds disclosed herein are muscarinic acetylcholine M 1 Receptor (mAChR M 1 In some embodiments, the compounds disclosed herein are antagonists of muscarinic acetylcholine M 2 Receptor (mAChR M 2 In some embodiments, the compounds disclosed herein are antagonists of muscarinic acetylcholine M 3 Receptor (mAChR M 3 In some embodiments, the compounds disclosed herein are antagonists of muscarinic acetylcholine M 4 Receptor (mAChR M 4 In some embodiments, the compounds disclosed herein are antagonists of muscarinic acetylcholine M 5 Receptor (mAChR M 5 In some embodiments, the compounds disclosed herein are mAChR M 1 、mAChR M 2 、mAChR M 3 、mAChR M 4 or mAChR M 5 In some embodiments, the compounds disclosed herein are muscarinic acetylcholine M 1 Receptor (mAChR M 1 ) relative to mAChR M 2 、M 3 、M 4 or M 5 In some embodiments, the compounds disclosed herein exhibit selective antagonists for mAChR M 1 Responsive IC 50 Alignment of mAChR M 2 IC 50 In some embodiments, the compounds disclosed herein exhibit a 5-fold lower, a 10-fold lower, a 20-fold lower, a 30-fold lower, a 50-fold lower, a 100-fold lower, or a >100-fold lower effect on mAChR M. 1 Responsive IC 50 Alignment of mAChR M 3 IC 50 In some embodiments, the compounds disclosed herein exhibit a 5-fold lower, a 10-fold lower, a 20-fold lower, a 30-fold lower, a 50-fold lower, a 100-fold lower, or a >100-fold lower effect on mAChR M.1 Responsive IC 50 Alignment of mAChR M 4 IC 50 In some embodiments, the compounds disclosed herein exhibit a 5-fold lower, a 10-fold lower, a 20-fold lower, a 30-fold lower, a 50-fold lower, a 100-fold lower, or a >100-fold lower effect on mAChR M. 1 Responsive IC 50 Alignment of mAChR M 5 IC 50 In some embodiments, the compounds disclosed herein exhibit a 5-fold lower, a 10-fold lower, a 20-fold lower, a 30-fold lower, a 50-fold lower, a 100-fold lower, or a >100-fold lower effect on mAChR M. 1 Responsive IC 50 Alignment of mAChR M 2 、M 3 、M 4 or M 5 or a combination of ICs 50 About 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, or >100-fold lower.

[0379] Treatment

[0380] The compounds disclosed herein are useful for treating, preventing, ameliorating, managing, or reducing the risk of a variety of conditions where the patient or subject would benefit from the administration of muscarinic acetylcholine. 1 Receptor antagonism.

[0381] In one aspect, treatment may include selective M 1 Receptor antagonism to the extent that it effectively affects cholinergic activity. Therefore, the compounds disclosed herein can be used for conditions that are associated with cholinergic activity, such as cholinergic hyperfunction. In some embodiments, provided herein is a method for treating or preventing a condition in a subject, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, at a dose and amount effective to treat the condition in the subject.

[0382] Provided herein are methods for treating one or more conditions in a subject for which muscarinic acetylcholine receptor inhibition is predicted to be beneficial, comprising the steps of administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, at a dosage and in an amount effective to treat the condition in the subject.

[0383] In some embodiments, provided herein are methods of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof.

[0384] In some embodiments, provided herein is a method of treating a neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy. In some embodiments, a method of treating a neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy.

[0385] In some embodiments, a method of treating a demyelinating disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a demyelinating disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the central nervous system. In some embodiments, a method of treating a demyelinating disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is multiple sclerosis. In some embodiments, a method of treating a demyelinating disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa) or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0386] In some embodiments, a subject's muscarinic acetylcholine receptor M is modulated 1 A method of treating a subject with M1-positive leukemia comprising administering to the subject a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, acts as a selective M1 antagonist.

[0387] Combination therapy

[0388] Combination therapy is also contemplated herein, such as co-administration of the disclosed compounds and additional active agents as part of a specific treatment regimen intended to provide beneficial effects from the combined action of these therapeutic agents. In some embodiments, the compounds described herein are administered in combination with one or more immunomodulators. In some embodiments, the compounds described herein are administered in combination with one or more immunomodulators, wherein the immunomodulator is selected from IFN-β1 molecules; corticosteroids; polymers of glutamate, lysine, alanine and tyrosine or glatiramer; antibodies or fragments thereof or natalizumab for α-4 integrins; anthracene dione molecules or mitoxantrone; fingolimod or FTY720 or other SIPl functional regulators; dimethyl fumarate; antibodies or daclizumab for the α subunit (CD25) of the IL-2 receptor for T cells; antibodies or alemtuzumab for CD52; antibodies for CD20; and dihydroorotate dehydrogenase inhibitors or teriflunomide. In some embodiments, the immunomodulator is an IFN-β1 molecule. In some embodiments, the immunomodulator is a corticosteroid. In some embodiments, the immunomodulator is a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer. In some embodiments, the immunomodulator is an antibody or fragment thereof or natalizumab to alpha-4 integrin. In some embodiments, the immunomodulator is an anthracenedione molecule or mitoxantrone. In some embodiments, the immunomodulator is fingolimod or FTY720 or other SIP1 functional regulators. In some embodiments, the immunomodulator is dimethyl fumarate. In some embodiments, the immunomodulator is an antibody or daclizumab to the alpha subunit (CD25) of the T cell IL-2 receptor. In some embodiments, the immunomodulator is an antibody or alemtuzumab to CD52. In some embodiments, the immunomodulator is an antibody to CD20. In some embodiments, the immunomodulator is an inhibitor of dihydroorotate dehydrogenase or teriflunomide.

[0389] The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic synergies resulting from the combination of therapeutic agents. The combined administration of these therapeutic agents is typically performed over a defined period of time (typically weeks, months, or years, depending on the combination selected). Combination therapy is intended to include administration of multiple therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at different times, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0390] Substantially simultaneous administration is achieved, for example, by administering to the subject a single formulation or composition (e.g., tablets or capsules of each therapeutic agent with a fixed ratio) or multiple single formulations of each therapeutic agent (e.g., capsules). Sequential or substantially simultaneous administration of each therapeutic agent is achieved by any suitable route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0391] Combination therapy also includes further combination administration of therapeutic agents as described above with other biologically active ingredients and non-drug therapies. When combination therapy further includes non-drug therapy, the non-drug therapy is performed at any appropriate time, as long as the beneficial effects of the combined action of the therapeutic agent and the non-drug therapy are achieved. For example, in appropriate cases, when the non-drug therapy is temporarily (perhaps for several days or even weeks) removed and does not participate in the administration of the therapeutic agent, a beneficial effect is still achieved.

[0392] The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that the components are present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms that are administered simultaneously or sequentially.

[0393] The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[0394] Examples

[0395] List of abbreviations

[0396] As used above and throughout the description of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0397] ACN or MeCN Acetonitrile

[0398] Bn Benzyl

[0399] BOC or Boc tert-butyl carbamate

[0400] CDI 1,1'-Carbonyldiimidazole

[0401] Cy Cyclohexyl

[0402] DCE Dichloroethane (ClCH 2 CH 2 Cl)

[0403] DCM Dichloromethane (CH 2 Cl 2 )

[0404] DIPEA or DIEA diisopropylethylamine

[0405] DMAP 4-(N,N-dimethylamino)pyridine

[0406] DMF Dimethylformamide

[0407] DMA N,N-Dimethylacetamide

[0408] DMSO Dimethyl sulfoxide

[0409] equiv equivalent

[0410] Et Ethyl

[0411] EtOH

[0412] EtOAc Ethyl acetate

[0413] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0415] HFIP 1,1,1,3,3,3-Hexafluoropropane-2-ol

[0416] HPLC High Performance Liquid Chromatography

[0417] LAH Lithium Aluminum Hydride

[0418] LCMS liquid chromatography-mass spectrometry

[0419] Me Methyl

[0420] MeOH Methanol

[0421] MS mass spectrometry

[0422] NMM N-Methylmorpholine

[0423] NMR Nuclear Magnetic Resonance

[0424] PMB p-Methoxybenzyl

[0425] rt room temperature

[0426] TEA Triethylamine

[0427] TFA Trifluoroacetic acid

[0428] THF Tetrahydrofuran

[0429] TLC Thin layer chromatography

[0430] I. Chemical Synthesis

[0431] Unless otherwise stated, the reagents and solvents used were from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations that were sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times were approximate and not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise stated.

[0432] Examples 1 and 2: Synthesis of (7R,8aS)-7-(3-(Benzo[d]thiazol-7-yl)propyl)-2-(3-fluoropyridin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (Example 1) and (7S,8aS)-7-(3-(Benzo[d]thiazol-7-yl)propyl)-2-(3-fluoropyridin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (Example 2)

[0433]

[0434] Step 1: Place (8aS)-octahydropyrrolo[1,2-a]pyrazin-6-one hydrochloride (1000 mg, 5.66 mmol, 1 equivalent) and DCM (10 mL) in a 25 mL round-bottom flask. Stir the resulting solution at room temperature. Then add Boc 2 O (2471mg, 11.32mmol, 2 equivalents), and stirring continuously while dropping. TEA (1718mg, 16.98mmol, 3 equivalents) was added dropwise at 0°C within 3 minutes, and stirring continuously while dropping. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The resulting solution was extracted with 2x350 mL ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The solid was filtered out. The resulting mixture was concentrated. The residue was chromatographed on a silica gel column to obtain (8aS)-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (850mg, 62%) as a yellow semi-solid.

[0435] Step 2: A 250mL three-necked round-bottom flask was purged and maintained with a nitrogen inert atmosphere, and THF (40mL) was placed therein. The solution was stirred in a liquid nitrogen bath at -70°C for 5 minutes. Then LDA (568mg, 5.30mmol, 1.5 equivalents) was added dropwise at -70°C, stirring continuously while dropping. The resulting solution was stirred in a liquid nitrogen bath at -70°C under a nitrogen atmosphere for 10 minutes. A solution of (8aS)-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester solution (850mg, 3.53mmol, 1 equivalent) in THF (10mL) was added dropwise at -70°C within 15 minutes, stirring continuously while dropping. The resulting solution was stirred in a liquid nitrogen bath at -70°C under a nitrogen atmosphere for 1 hour. 3-Bromoprop-1-yne (547 mg, 4.6 mmol, 1.3 eq.) was added dropwise to the mixture at -70°C over 25 minutes with constant stirring. The resulting solution was stirred in a liquid nitrogen bath at -40°C under a nitrogen atmosphere for 1 hour. Then, NH 4 Cl solution quenched the reaction. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The solid was filtered out. The resulting mixture was concentrated. The residue was chromatographed on a silica gel column to give (8aS)-6-oxo-7-(prop-2-yn-1-yl)-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (650 mg, 66%) as a yellow semi-solid.

[0436] Step 3: In a 20 mL sealed tube, (8aS)-6-oxo-7-(prop-2-yn-1-yl)-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (320 mg, 1.15 mmol, 1 equivalent), 7-bromo-1,3-benzothiazole (295.3 mg, 1.38 mmol, 1.2 equivalents), Pd(PPh 3 ) 4 (66.4 mg, 0.057 mmol, 0.05 equivalent), DEA (857.8 mg, 5.74 mmol, 5 equivalent), CuI (11 mg, 0.057 mmol, 0.05 equivalent), PPh 3 (60.3 mg, 0.230 mmol, 0.2 equiv), N,N- dimethylformamide (5 mL). The resulting solution was stirred at 80 ° C for 2 hours. The solid was filtered off and the filtrate was concentrated. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column to give (8aS)-7-[3-(1,3-benzothiazol-7-yl)prop-2-yn-1-yl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (380 mg, 80%) as a yellow semi-solid.

[0437] Step 4: A 25 mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and (8aS)-7-[3-(1,3-benzothiazol-7-yl)prop-2-yn-1-yl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (380 mg, 0.92 mmol, 1 eq.), Pd / C (500 mg, 4.7 mmol, 5.09 eq.), and MeOH (8 mL) were placed therein. The resulting solution was stirred at room temperature under hydrogen for 3 hours. The solid was filtered off. The resulting mixture was concentrated. The residue was chromatographed on a silica gel column to give (7R, 8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (300 mg, 78%) as a brown semi-solid.

[0438] Step 5: Place (7R,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (300 mg, 0.72 mmol, 1 equivalent) and DCM (5 mL) in a 25 mL round-bottom flask. Stir the resulting solution at room temperature. Then add TFA (4 mL) dropwise at 0°C with constant stirring. Stir the resulting solution at room temperature for 40 minutes. Concentrate the resulting mixture. Use NH 3 -MeOH (7M) was added to adjust the pH value of the solution to 8-9. The resulting solution was stirred at room temperature for 60 minutes. The resulting mixture was concentrated. The residue was purified by HPLC to give (8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-octahydropyrrolo[1,2-a]pyrazin-6-one (135 mg, 59%) as a yellow semi-solid.

[0439] Step 6: A 20 mL sealed tube was purged and maintained with a nitrogen inert atmosphere, and (8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-octahydropyrrolo[1,2-a]pyrazin-6-one (135 mg, 0.43 mmol, 1 eq.), 3-fluoro-4-iodopyridine (115 mg, 0.52 mmol, 1.21 eq.), Pd 2 (dba) 3 (176 mg, 0.19 mmol, 0.45 equiv), Xantphos (198 mg, 0.34 mmol, 0.80 equiv), Cs 2 CO 3(404 mg, 1.24 mmol, 2.90 equiv), dioxane (4 mL). The resulting solution was stirred in a 110 ° C oil bath for 2 hours. The solid was filtered off. The resulting mixture was concentrated. The crude product was purified by preparative HPLC. 80 mg of the racemate was obtained as a white solid. The racemate was separated by chiral preparative HPLC. This gave 32.8 mg of Example 1 and 19.4 mg of Example 2.

[0440] Example 1: LCMS: m / z=410.8[M+1] + , 1 H NMR (300 MHz, methanol-d 4 )δ9.25 (s, 1H), 8.18 (d, J = 3.0Hz, 1H), 8.10 (d, J = 2.85Hz, 1H), 7.92 (d, J = 3.75Hz, 1H), 7.5 1 (t, J=8.2, 7.3Hz, 1H), 7.35 (d, J=7.3Hz, 1H), 7.02 (m, J=8.2, 5.7Hz, 1H), 4.03 (d, J=6.0Hz 1H), 3.92–3.75(m, 3H), 3.20–2.80(m, 4H), 2.79–2.50(m, 2H), 2.02–1.72(m, 5H), 1.60–1.40(m, 1H).

[0441] Example 2: LCMS: m / z=410.8[M+1]+, 1 H NMR (300 MHz, methanol-d 4 )δ9.25 (s, 1H), 8.18 (d, J = 3.0Hz, 1H), 8.10 (d, J = 2.85Hz, 1H), 7.92 (d, J = 3.75 Hz, 1H), 7.51 (t, J=8.2, 7.3Hz, 1H), 7.35 (d, J=7.3Hz, 1H), 7.02 (m, J=8.2, 5.7 Hz, 1H), 4.03 (d, J=6.0Hz, 2H), 3.84 (d, J=6.15Hz, 1H), 3.72 (d, J=4.35Hz, 1H) , 3.03-2.80(m, 4H), 2.79-2.40(m, 3H), 2.15-1.75(m, 3H), 1.60-1.20(m, 2H).

[0442] Example 3: Synthesis of (7S,8aS)-2-(3-fluoropyridin-4-yl)-7-(3-(imidazo[1,2-a]pyridin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0443]

[0444] Step 1: In a 30 mL sealed tube, tert-butyl (8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (340 mg, 1.22 mmol, 1 equivalent), DMF (5 mL), 5-bromoimidazo[1,2-a]pyridine (288 mg, 1.47 mmol, 1.2 equivalents), Pd(PPh 3 ) 4 (70.6 mg, 0.06 mmol, 0.05 equiv), DEA (911.4 mg, 6.11 mmol, 5 equiv), CuI (11.6 mg, 0.06 mmol, 0.05 equiv), PPh 3 (64.1 mg, 0.24 mmol, 0.2 equiv.). The resulting solution was stirred in an 80°C oil bath for 2 hours. The solid was filtered off. The resulting solution was extracted with ethoxyethane. The residue was chromatographed on a silica gel column to give (8aS)-7-(3-[imidazo[1,2-a]pyridin-5-yl]prop-2-yn-1-yl)-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (300 mg, 62%) as a yellow oil. LCMS: m / z=395.2[M+H] + .

[0445] Step 2: In a 25 mL round-bottom flask, (8aS)-7-(3-[imidazo[1,2-a]pyridin-5-yl]prop-2-yn-1-yl)-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (280 mg, 0.71 mmol, 1 eq), MeOH (4 mL), and Pd / C (280 mg, 2.63 mmol, 3.71 eq) were placed. The resulting solution was stirred under H 2 The mixture was stirred at room temperature for 3 hours. The solid was filtered off. The resulting mixture was concentrated. The residue was chromatographed on a silica gel column to give (7R,8aS)-7-(3-[imidazo[1,2-a]pyridin-5-yl]propyl)-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (230 mg, 81%) as a yellow oil. LCMS: m / z=399.2[M+H] + .

[0446] Step 3: In a 25 mL round-bottom flask was placed (7R,8aS)-7-(3-[imidazo[1,2-a]pyridin-5-yl]propyl)-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (220 mg, 0.55 mmol, 1 eq), DCM (6 mL), and TFA (3 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The residue was purified by flash preparative HPLC to give (8aS)-7-(3-[imidazo[1,2-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazine-6-one (150 mg, 92%) as a yellow oil. LCMS: m / z=299.1[M+H] + .

[0447] Step 4: A 10 mL sealed tube was purged and maintained with a nitrogen inert atmosphere, and (8aS)-7-(3-[imidazo[1,2-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one (70 mg, 0.235 mmol, 1 eq.), dioxane (2 mL), 3-fluoro-4-iodopyridine (62.77 mg, 0.282 mmol, 1.2 eq.), Pd 2 (dba) 3 (43 mg, 0.047 mmol, 0.2 eq.), Xantphos (54.3 mg, 0.094 mmol, 0.4 eq.), Cs 2 CO 3 (229 mg, 0.704 mmol, 3 equiv.). The resulting solution was stirred in a 110 °C oil bath for 2 hours. The solid was filtered off. The resulting mixture was concentrated. The residue was purified by preparative HPLC to give (8aS)-2-(3-fluoropyridin-4-yl)-7-(3-[imidazo[1,2-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one (36 mg, 21%) as a white solid. The product was purified by chiral preparative HPLC to give the title compound (Example 3) (6 mg). LCMS: m / z=394.2[M+H] + ; 1 H NMR (300 MHz, methanol-d 4)δ8.52 (d, J=8.7Hz, 1H), 8.37 (d, J=2.2Hz, 1H), 8.22 (d, J=7.0Hz, 1H), 8.14 (d, J=2.3Hz, 1H), 7.98 (m, J=9.0 , 7.2Hz, 1H), 7.86 (d, J=9.0Hz, 1H), 7.44 (m, J=6.2Hz, 2H), 4.50 (d, J=13.0Hz, 1H), 4.38 (d, J=13.6Hz, 1H), 4. 08 (d, J=13.2Hz, 1H), 3.81 (d, J=7.5Hz, 1H), 3.35 (s, 1H), 3.32-3.15 (m, 3H), 3.13 (s, 1H), 3.07 (d, J=12.0Hz , 1H), 2.67 (d, J=9.6Hz, 1H), 2.55 (m, J=12.1, 7.4Hz, 1H), 2.07-1.96 (m, 2H), 1.63 (s, 1H), 1.55-1.38 (m, 1H).

[0448] Example 4: Synthesis of 6-((7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)nicotinonitrile

[0449]

[0450] Step 1: A 100 mL three-necked round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and dry THF (10 mL) was placed therein. Then LiHMDS (2N) (5.5 mL, 11 mmol, 1.5 eq) was added at -78°C. (S)-2-(tert-butoxycarbonylamino)pentanedioic acid dimethyl ester (2 g, 7.3 mmol, 1 eq) dissolved in dry THF (30 mL) was added thereto at -78°C within 10 minutes. The resulting solution was stirred at -78°C for 1 hour. 3-bromoprop-1-yne (1.3 g, 11 mmol, 1.5 eq) was added to the mixture within 10 minutes. The resulting solution was stirred for another 2 hours while the temperature was maintained at -65°C. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with aqueous Cl solution. The resulting mixture was concentrated. The resulting solution was extracted with dichloromethane (100 mL). The residue was chromatographed on a silica gel column to give dimethyl (2S, 4S)-2-(tert-butoxycarbonylamino)-4-(prop-2-ynyl)pentanedioate (1.2 g, 53%) as a yellow solid. LCMS (m / z) 314.1 [M+H] + .

[0451] Step 2: To dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(prop-2-ynyl)pentanedioate (1.2 g, 3.8 mmol) was added to CH 2 Cl 2 To the solution in 4% paraformaldehyde (10 mL) was added TFA (5 mL), and the solution was stirred at room temperature until no starting material remained. After the solution was concentrated in vacuo, the resulting oil was dissolved in toluene (20 mL) and heated under reflux for 1.5 hours. The solution was concentrated in vacuo to give 1.1 g of the corresponding crude lactam. The crude product was chromatographed on a silica gel column to give (2S, 4S)-5-oxo-4-(prop-2-ynyl)pyrrolidine-2-carboxylic acid methyl ester (0.7 g, 100%) as a yellow oil. LCMS (m / z) 182.3 [M+H] + .

[0452] Step 3: To a solution of (2S,4S)-5-oxo-4-(prop-2-ynyl)pyrrolidine-2-carboxylic acid methyl ester (0.7 g, 3.8 mmol) in 15 mL of anhydrous ethanol was added NaBH 4 (289 mg, 7.6 mmol). After 20 hours at room temperature, acetic acid (2 mL) was slowly added and the mixture was stirred for 30 minutes. Water (1.5 mL) was added and the mixture was stirred for 10 minutes at room temperature. The pH was adjusted to 7 by adding 2N NaOH and the solvent was evaporated under reduced pressure. The residue was extracted with hot ethyl acetate (5 x 30 mL) and a colorless solid was obtained after evaporation, which was chromatographed on a silica gel column to give (3S, 5S)-5-(hydroxymethyl)-3-(prop-2-ynyl)pyrrolidin-2-one (0.42 g, 72%) as a colorless solid. LCMS (m / z) 154.5 [M+H] + .

[0453] Step 4: (3S,5S)-5-(hydroxymethyl)-3-(prop-2-ynyl)pyrrolidin-2-one (0.42 g, 2.73 mmol, 1 eq.) was reacted with CH 2 Cl 2 TEA (0.55 g, 5.46 mmol, 2 eq) and MsCl (0.47 g, 4.1 mmol, 1.5 eq) were added dropwise to a solution of 4% NaHCO (15 mL). The mixture was stirred at room temperature for 2 h, then diluted with DCM (60 mL) and washed with saturated NaHCO 3 (3×30 mL) aqueous solution. Dry (Na 2 SO 4 ), the solvent was removed under reduced pressure, and the residue was washed with NH 4 HCO 3 (water / CH 3CN solution (40%)) to give ((2S,4S)-5-oxo-4-(prop-2-ynyl)pyrrolidin-2-yl)methanesulfonic acid methyl ester as a yellow oil (0.43 g, 68% yield). LCMS (m / z) 232.5 [M+H] + .

[0454] Step 5: A mixture of methyl ((2S,4S)-5-oxo-4-(prop-2-ynyl)pyrrolidin-2-yl)methanesulfonate (430 mg, 1.85 mmol, 1 eq) and 2-(benzylamino)ethanol (1.12 g, 7.4 mmol, 4 eq) was heated in a microwave oven (Personal Chemistry Optimizer) at 130°C for 40 minutes. The residue was partitioned between water and DCM, the organic phase was washed with brine, dried (Na 2 SO 4 ) and evaporated in vacuo. The residue was chromatographed on a silica gel column to give (3S,5S)-5-((benzyl(2-hydroxyethyl)amino)methyl)-3-(prop-2-ynyl)pyrrolidin-2-one (320 mg, 60% yield) as a yellow oil. LCMS (m / z) 287 [M+H] + .

[0455] Step 6: To a solution of (3S,5S)-5-((benzyl(2-hydroxyethyl)amino)methyl)-3-(prop-2-ynyl)pyrrolidin-2-one (0.32 g, 1.1 mmol, 1 eq) in DCM (15 mL) was added TEA (222 mg, 2.2 mmol, 2 eq) and MsCl (190 mg, 1.65 mmol, 1.5 eq) at 0°C. The mixture was warmed to room temperature and stirred for 20 h, then it was diluted with DCM (60 mL) and washed with saturated NaHCO 3 (3×30 mL) aqueous solution. Dry (Na 2 SO 4 ) and after removing the solvent, the crude product (0.31 g) was used directly in the next step. LCMS (m / z) 365 [M+H] + .

[0456] Step 7: The crude product of step 6 (0.31 g) was dissolved in CH 3 In a mixture of CN / THF (1 / 1, 10 mL), 60% NaH (66 mg, 1.65 mmol, 1.5 eq.) was then added in portions at room temperature under nitrogen atmosphere. After stirring for 16 hours, the solvent was removed under vacuum and the residue was taken up in water and extracted with DCM. The organic phase was washed with brine and dried (Na 2 SO4 ) and concentrated. 4 HCO 3 (water / CH 3 CN solution (45%)) to give (7S,8aS)-2-benzyl-7-(prop-2-ynyl)-hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (90 mg, 30% yield) as a colorless solid. LCMS (m / z) 269 [M+H] + . 1 H NMR (400MHz, MeOD): δ7.36-7.28 (m, 5H), 3.90-3.86 (m, 1H), 3.61-3.53 (m, 3H), 3.06-3.03 (m, 1H), 2.90-2.87 (m, 2H), 2.71-2. 69 (m, 1H), 2.51-2.48 (m, 2H), 2.34-2.30 (m, 1H), 2.28.-2.26 (m, 1H), 1.98-1.96 (m, 1H), 1.82-1.77 (m, 1H), 1.59-1.56 (m, 1H).

[0457] Step 8: 1-Chloroethyl chloroformate (6.4 mL, 59.6 mmol, 8 equiv) was added to a solution of (7S,8aS)-2-benzyl-7-(prop-2-ynyl)-hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (2 g, 7.45 mmol, 1 equiv), DIEA (10.4 mL, 59.6 mmol, 8 equiv) in toluene (40 mL). The reaction mixture was stirred at 100 °C for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in methanol (40 mL) and heated to 65 °C for 30 minutes. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (40 mL). 6-Fluoronicotinonitrile (910 mg, 7.45 mmol, 1 equiv) and cesium carbonate (7.3 g, 22.4 mmol, 3 equiv) were added. The reaction mixture was stirred at 80 °C for 8 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl and purified by MgSO 4 Dry, filter and concentrate. The residue was chromatographed on a silica gel column to give 6-((7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile (1.3 g). LCMS (m / z) 281 [M+H] + .

[0458] Step 9: DIEA (0.27 mL, 1.52 mmol, 5 eq), CuI (3 mg, 0.015 mmol, 5 mol%) and PPh3 6-((7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile (85 mg, 0.304 mmol, 1 eq) and 5-bromo-[1,2,4]triazolo[1,5-a]pyridine (72 mg, 0.365 mmol, 1.2 eq) in DMF (1 mL) were added to a sealed tube. The resulting mixture was bubbled with nitrogen. Pd(PPh 3 ) 4 (18 mg, 0.015 mmol, 5 mol%). The container was capped and heated to 80 ° C for 23 hours. The reaction mixture was directly loaded onto a preparative HPLC column and eluted with 0.1% formic acid / water / acetonitrile (5-100% gradient). The fractions containing the product were combined and concentrated to give 6-((7S, 8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-yn-1-yl)-6-oxohexahydroxypyrrolo[1,2-a]pyrazine-2(1H)-yl)nicotinonitrile (67 mg). The substance was dissolved in MeOH and Pd / C (5 wt%, 50 mg) was added. The reactants were heated in H 2 Stir for 2 hours under atmosphere. The reactant was filtered through celite, concentrated, and purified by preparative HPLC to give 6-((7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)nicotinonitrile (35 mg). LCMS (m / z) 402 [M+H] + .

[0459] Example 5: Synthesis of 6-((7R,8aS)-7-((([1,2,4]triazolo[1,5-a]pyridin-5-ylmethyl)amino)methyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)nicotinonitrile

[0460]

[0461] Step 1: To a sealed tube containing a solution of 6-((7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile (819 mg, 2.92 mmol, 1.0 equiv) in MeOH (10 mL) was added bis(trifluoroacetic acid)phenyliodide (PIFA, 4.4 g, 10.2 mmol, 3.5 equiv). The vessel was capped and heated to 60 °C for 56 hours. The reaction mixture was concentrated and then purified on silica gel to give methyl 2-((7R,8aS)-2-(5-cyanopyridin-2-yl)-6-oxooctahhydropyrrolo[1,2-a]pyrazin-7-yl)acetate (173 mg, 19% yield). The material was dissolved in MeOH (2 mL) and THF (2 mL), 1 M NaOH (1.7 mL, 1.65 mmol, 3.0 equiv) was added, and the reaction was stirred at ambient temperature for 1.5 hours. The reaction was acidified with 1 M HCl (1.8 mL) and extracted with ethyl acetate. The organic phase was washed with brine and purified by MgSO 4 Dry, filter and concentrate to give 2-((7R,8aS)-2-(5-cyanopyridin-2-yl)-6-oxooctahhydropyrrolo[1,2-a]pyrazin-7-yl)acetic acid (135 mg, 82% yield). LCMS (m / z) 301 [M+H] + .

[0462] Step 2: To a sealed tube containing a solution of 2-((7R,8aS)-2-(5-cyanopyridin-2-yl)-6-oxooctahhydropyrrolo[1,2-a]pyrazin-7-yl)acetic acid (135 mg, 0.450 mmol, 1.0 equiv) in THF (4.5 mL) was added NaN 3 (102 mg, 1.57 mmol, 3.5 eq), Bu 4 NBr (22 mg, 0.067 mmol, 15 mol%) and Boc 2 O (108 mg, 0.494 mmol, 1.1 equiv). The vessel was capped and heated to 80 °C for 45 h. The reaction was heated with 10% Na 2 S 2 O 3 The mixture was quenched and then heated to ethyl acetate and NH 4 The organic layer was washed with brine and concentrated with MgSO 4 Dry, filter and concentrate. The crude residue was purified on silica gel to give tert-butyl (((7R,8aS)-2-(5-cyanopyridin-2-yl)-6-oxooctahedralpyrrolo[1,2-a]pyrazin-7-yl)methyl)carbamate (22 mg, 13% yield). LCMS (m / z) 272 [M-Boc+H]+ .

[0463] Step 3: To tert-butyl (((7R,8aS)-2-(5-cyanopyridin-2-yl)-6-oxooctahedralopyrrolo[1,2-a]pyrazin-7-yl)methyl)carbamate (22 mg, 0.06 mmol, 1.0 equiv) was added to CH 2 Cl 2 To the solution in 4% paraformaldehyde (1 mL) was added 4M HCl in dioxane (150 μL, 0.60 mmol, 10 equiv). The reaction was stirred for 30 min and then concentrated. To the resulting residue was added MeOH (2 mL), NaOAc (10 mg, 0.12 mmol, 2.0 equiv), [1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde (11 mg, 0.072 mmol, 1.2 equiv) and NaBH 3 CN (6 mg, 0.09 mmol, 1.5 eq). The reaction was stirred at ambient temperature for 16 h, then concentrated and purified by preparative HPLC to give 6-((7R,8aS)-7-((([1,2,4]triazolo[1,5-a]pyridin-5-ylmethyl)amino)methyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile (15 mg, 54% yield) as a formate salt. LCMS (m / z) 403 [M+H] + .

[0464] Examples 6-9 were prepared in a similar manner as described in Examples 1-5.

[0465] Example 6: Synthesis of 7-(3-(benzo[d]thiazol-7-yl)propyl)-2-(3-fluoropyridin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0466]

[0467] The title compound was obtained as a racemic mixture of diastereoisomers from racemic tert-butyl 6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in a manner similar to that described in Examples 1 and 2. LCMS: m / z=411.1 [M+H] +

[0468] Examples 7 and 8: Synthesis of (7S,8aR)-7-(3-(Benzo[d]thiazol-7-yl)propyl)-2-(3-fluoropyridin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (Example 7) and (7R,8aR)-7-(3-(Benzo[d]thiazol-7-yl)propyl)-2-(3-fluoropyridin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (Example 8)

[0469]

[0470] The title compound was prepared from (R)-tert-butyl 6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in a manner similar to that described in Examples 1 and 2. LCMS Example 7: m / z = 410.8 [M+H]+; LCMS Example 8: m / z = 410.8 [M+H]+.

[0471] Example 9: Synthesis of (8aS)-7-(3-(benzo[d]thiazol-7-yl)propyl)-2-(3-fluoropyridin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0472]

[0473] Prior to the chiral HPLC separation performed in Step 6 of Examples 1 and 2, the title compound was isolated as a mixture of diastereomers.

[0474] Example 10: Synthesis of 6-((7S,8aS)-7-(3-(benzo[d]thiazol-7-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile

[0475]

[0476] Step 1: To a solution of (7S,8aS)-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (100 mg, 0.56 mmol, 1.0 equiv) in DCM (10 mL) was added Boc 2 O (610 mg, 2.8 mmol, 5.0 equiv) and Et 3 N (283 mg, 2.8 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using NH 4 HCO 3 (water / CH 3 CN solution (45%)) to obtain (7S,8aS)-6-oxo-7-(prop-2-ynyl)-hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a white solid. LCMS: m / z = 279.1 [M+H] + .

[0477] Step 2: A 30 mL sealed tube was purged and maintained with a nitrogen inert atmosphere, and (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (110 mg, 0.395 mmol, 1.0 eq.), DMF (3 mL), 7-bromo-1,3-benzothiazole (101 mg, 0.474 mmol, 1.2 eq.), Pd(PPh 3 ) 4 (23 mg, 0.020 mmol, 0.05 equiv), CuI (3.8 mg, 0.020 mmol, 0.05 equiv), PPh 3 (21 mg, 0.079 mmol, 0.2 equiv), DIEA (294 mg, 1.98 mmol, 5.0 equiv). The resulting solution was stirred in an 80 °C oil bath for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)prop-2-yn-1-yl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as a light yellow oil. LCMS: m / z=412.1[M+H] + .

[0478] Step 3: In a 100 mL round-bottom flask, (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)prop-2-yn-1-yl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (140 mg, 0.341 mmol, 1.0 equiv), MeOH (5 mL) and 10% Pd / C (73 mg) were placed. The mixture was stirred at room temperature under H 2 Stir for 3 hours under atmosphere. The mixture was filtered through celite and concentrated in vacuo. Purification by silica gel chromatography gave (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as a light yellow oil. LCMS: m / z=416.1[M+H] + .

[0479] Step 4: Into a 25 mL round-bottom flask was placed (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (130 mg, 0.313 mmol, 1.0 equiv), DCM (3 mL) and TFA (2 mL). The resulting solution was stirred at room temperature for 1 hour and then concentrated in vacuo. Purification by silica gel chromatography gave (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-octahydropyrrolo[1,2-a]pyrazine-6-one as a light yellow oil. LCMS: m / z=316.1[M+H] + .

[0480] Step 5: In a 30 mL sealed tube, (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-octahydropyrrolo[1,2-a]pyrazin-6-one (90 mg, 0.29 mmol, 1.0 eq), ACN (3 mL), 6-fluoropyridine-3-carbonitrile (62 mg, 0.34 mmol, 1.2 eq) and Cs 2 CO 3 (280 mg, 0.858 mmol, 3.0 equiv.). The resulting solution was stirred in an 80 °C oil bath for 2 hours. The mixture was cooled to room temperature, filtered and concentrated. Purification by silica gel chromatography followed by further purification by reverse phase HPLC gave the title compound 6-[(7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-6-oxo-octahydropyrrolo[1,2-a]pyrazine-2-yl]pyridine-3-carbonitrile as an off-white solid. LCMS: m / z=418.1[M+H] + .

[0481] The following example was prepared from (7S,8aS)-7-(3-(benzo[d]thiazol-7-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and the appropriate corresponding heteroaryl halide using the same procedure as described for Example 10, Step 5.

[0482]

[0483]

[0484] The following example was prepared from 6-((7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile and the appropriate corresponding aryl bromide using the same procedure as described for Example 4, Step 9.

[0485]

[0486] Example 26: Synthesis of (7S,8aS)-7-(3-(benzo[d]thiazol-7-yl)propyl)-2-(pyridin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one.

[0487]

[0488] A 30 mL sealed tube was purged and maintained with a nitrogen inert atmosphere, and (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-octahydropyrrolo[1,2-a]pyrazin-6-one (40 mg, 0.13 mmol, 1.0 eq.), dioxane (2 mL), 3-bromopyridine (30 mg, 0.190 mmol, 1.5 eq.), Pd 2 (dba) 3 (23 mg, 0.025 mmol, 0.2 eq.), Xantphos (29 mg, 0.051 mmol, 0.4 eq.), Cs 2 CO 3 (124 mg, 0.380 mmol, 3.0 equiv.). The resulting mixture was stirred in a 110 °C oil bath for 3 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. Purification by silica gel chromatography followed by further purification by reverse phase HPLC gave the title compound (7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-2-(pyridin-3-yl)-octahydropyrrolo[1,2-a]pyrazin-6-one as a white solid. LCMS: m / z=393.1[M+H] + .

[0489] The following examples were prepared from (7S,8aS)-7-(3-(benzo[d]thiazol-7-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and the appropriate corresponding heteroaryl bromide using the same procedure as described for Example 26.

[0490]

[0491] Example 30: Synthesis of (7S,8aS)-2-(2-aminopyridin-4-yl)-7-(3-(benzo[d]thiazol-7-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one.

[0492]

[0493] Step 1: A 10 mL sealed tube was purged and maintained with a nitrogen inert atmosphere, and (7S, 8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-2-(2-chloropyridin-4-yl)-octahydropyrrolo[1,2-a]pyrazin-6-one (30 mg, 0.070 mmol, 1.0 equiv), dioxane (2 mL), tert-butyl carbamate (247 mg, 2.11 mmol, 3.0 equiv), Pd 2 (dba) 3 (13 mg, 0.014 mmol, 0.2 eq), Brettphos (15 mg, 0.028 mmol, 0.4 eq) and Cs 2 CO 3 (69 mg, 0.21 mmol, 3.0 equiv.). The mixture was stirred in a 90 °C oil bath for 3 h. The solid was filtered off and the filtrate was concentrated. The crude product was purified by flash preparative HPLC to give tert-butyl N-[4-[(7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-6-oxo-octahydropyrrolo[1,2-a]pyrazin-2-yl]pyridin-2-yl]carbamate as a white solid. LCMS: m / z=508.1[M+H] + .

[0494] Step 2: Into an 8 mL vial was placed tert-butyl N-[4-[(7S,8aS)-7-[3-(1,3-benzothiazol-7-yl)propyl]-6-oxo-octahydropyrrolo[1,2-a]pyrazin-2-yl]pyridin-2-yl]carbamate (10 mg, 0.020 mmol, 1.0 equiv), DCM (1 mL) and TFA (0.5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated and purified by reverse phase HPLC to give the title compound (7S,8aS)-2-(2-aminopyridin-4-yl)-7-[3-(1,3-benzothiazol-7-yl)propyl]-octahydropyrrolo[1,2-a]pyrazin-6-one as a white solid. LCMS: m / z=408.1[M+H] + .

[0495] Example 31: Synthesis of (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-2-(6-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0496]

[0497] Step 1: A 30 mL sealed tube was purged and maintained with nitrogen, and 5-bromo-[1,2,4]triazolo[1,5-a]pyridine (1.00 g, 5.05 mmol, 1.0 equiv), DMF (10 mL), (7S,8aS)-2-benzyl-7-(prop-2-yn-1-yl)-octahydropyrrolo[1,2-a]pyrazin-6-one (1.36 g, 5.05 mmol, 1.0 equiv), Pd(PPh 3 ) 4 (292 mg, 0.252 mmol, 0.05 eq.), CuI (48 mg, 0.25 mmol, 0.05 eq.), PPh 3 (265 mg, 1.01 mmol, 0.2 equiv), DEA (3.77 g, 25.3 mmol, 5.0 equiv). The mixture was stirred in a 90 °C oil bath for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc, filtered and concentrated in vacuo. Purification by silica gel chromatography gave (7S,8aS)-2-benzyl-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-yn-1-yl)-octahydropyrrolo[1,2-a]pyrazin-6-one as a yellow oil. LCMS: m / z=386.1[M+H] +

[0498] Step 2: In a 100 mL round-bottom flask, (7S,8aS)-2-benzyl-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-yn-1-yl)-octahydropyrrolo[1,2-a]pyrazin-6-one (700 mg, 1.82 mmol, 1.0 equiv), MeOH (10 mL) and 10% Pd / C (193 mg) were placed. The mixture was heated in an oil bath at 50 °C under H 2 Stir overnight under atmosphere. The mixture was cooled to room temperature, filtered through celite and concentrated. Purification by silica gel chromatography gave (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one as a yellow oil. LCMS: m / z=300.1[M+H] +

[0499] Step 3: In a 10 mL sealed tube was placed (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one (40 mg, 0.13 mmol, 1.0 eq), NMP (0.5 mL), 2-fluoro-6-(trifluoromethyl)pyridine (33 mg, 0.20 mmol, 1.5 eq) and DIEA (0.5 mL). The resulting solution was stirred in an oil bath at 100 °C for 2 h. The crude product was purified by reverse phase HPLC to give the title compound (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-2-[6-(trifluoromethyl)pyridin-2-yl]-octahydropyrrolo[1,2-a]pyrazin-6-one as a white solid. LCMS: m / z = 445.1 [M+H] + .

[0500] The following example was prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and the appropriate corresponding heteroaryl halide using the same procedure as described for Example 31, Step 3.

[0501]

[0502] Example 37: Synthesis of (7S,8aS)-2-(2-methoxypyridin-4-yl)-7-(3-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one

[0503]

[0504] A 10 mL sealed tube was purged with nitrogen and maintained, and (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one (40 mg, 0.13 mmol, 1.0 eq), PhMe (2 mL), 4-bromo-2-methoxypyridine (28 mg, 0.15 mmol, 1.1 eq), Pd 2 (dba) 3(15 mg, 0.016 mmol, 0.12 equiv), BINAP (100 mg, 0.16 mmol, 1.2 equiv), t-BuOK (45 mg, 0.40 mmol, 3.0 equiv). The resulting solution was stirred in a 100 °C oil bath for 2 hours. The solid was filtered off and the filtrate was concentrated. Purification by silica gel chromatography gave the title compound (7S,8aS)-2-(2-methoxypyridin-4-yl)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one as a yellow solid. LCMS: m / z=407.2[M+H] + .

[0505] The following examples were prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and the appropriate corresponding aryl or heteroaryl bromide using the same procedure as described for Example 37. Examples 41, 42, 43, 44 and 46 were obtained as mixtures of diastereomers.

[0506]

[0507]

[0508] Examples 50 and 51: Synthesis of (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and (7R,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one.

[0509]

[0510] Example 41 was purified by chiral chromatography (chiralpak IF-3) to give Example 51, LCMS: m / z=417.4 [M+Na] + ; then 50, LCMS: m / z=395.1[M+H] + .

[0511] Example 52: Synthesis of 5-((7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-fluorobenzonitrile

[0512]

[0513] A 10 mL sealed tube was purged with nitrogen and maintained, and (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one (30 mg, 0.100 mmol, 1.0 eq), dioxane (2 mL), 5-bromo-2-fluorobenzonitrile (24 mg, 0.12 mmol, 1.2 eq), Pd 2 (dba) 3 (18 mg, 0.02 mmol, 0.2 eq.), Xantphos (23 mg, 0.04 mmol, 0.4 eq.), Cs 2 CO 3 (98 mg, 0.30 mmol, 3.0 equiv.). The resulting solution was stirred in a 110 °C oil bath for 2 hours. The mixture was filtered, concentrated, and purified by silica gel chromatography. Further purification by reverse phase HPLC gave the title compound 5-((7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)-2-fluorobenzonitrile as a white solid. LCMS: m / z=419.1[M+H] + .

[0514] Example 53: Synthesis of (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-2-(5-(hydroxymethyl)pyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0515]

[0516] Step 1: (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)-2-(5-((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one was prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (99 mg, 0.33 mmol, 1.0 equiv) and 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine as described in the synthesis of Example 37. LCMS: m / z = 521.2 [M+H] + .

[0517] Step 2: In a 25 mL round-bottom flask was placed (7S,8aS)-2-(5-[[(tert-butyldimethylsilyl)oxy]methyl]pyridin-2-yl)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-hexahydropyrrolo[1,2-a]pyrazin-6-one (70 mg, 0.13 mmol, 1.0 eq), THF (3 mL), TBAF (53 mg, 0.20 mmol, 1.5 eq). The resulting solution was stirred at room temperature for 1 hour and concentrated in vacuo. The crude product was purified by silica gel chromatography and then by reverse phase HPLC to give (7S,8aS)-2-[5-(hydroxymethyl)pyridin-2-yl]-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-5-yl]propyl)-hexahydropyrrolo[1,2-a]pyrazin-6-one as a white solid. LCMS: m / z=407.2[M+H] + .

[0518] Example 54: Synthesis of 6-((7S,8aS)-7-(3-(1-methyl-1H-benzo[d]imidazol-7-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile.

[0519]

[0520] 6-((7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile (132 mg, 0.47 mmol, 1 eq), 7-bromo-1-methyl-1H-benzo[d]imidazole (100 mg, 0.47 mmol, 1 eq), Cs 2 CO 3 (307 mg, 0.942 mmol, 2 eq.) and Pd(Amphos)Cl 2 A mixture of 2-nitropropene (4.0 mg, 0.047 mmol, 0.1 eq.) in ACN (1.0 mL) was stirred for 2 h under N 2 The mixture was heated to 80 °C in a purged sealed vial for 6 h. The mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated. The organics were purified by MgSO 4 The mixture was dried, filtered and concentrated. The material was dissolved in MeOH (1.0 ml) and EtOAc (1.0 mL). 10% Pd / C (50 mg) was added. The reaction was stirred at 4 °C for 2 h. 2 Stir under atmosphere for 23 hours. The reaction was filtered through celite, concentrated, and purified by silica gel chromatography (gradient from 0% MeOH in DCM to 10% MeOH in DCM) to give the title compound. LCMS: m / z=415.1 [M+H]+ . 1 H NMR (400 MHz, d 6 -DSMO): δ8.50 (dd, J=2.0, 0.4Hz, 1H), 8.07 (s, 1H), 7.88 (dd, J=7.6, 2.0Hz, 1H), 7.46 (dd, J=6.4, 1.2Hz, 1H ), 7.08 (appt, J=5.6Hz, 1H), 7.03-7.00 (m, 2H), 4.67 (m, 1H), 4.51 (m, 1H), 4.03 (s, 3H), 3.83 (dd, J=10.4, 1. 6Hz, 1H), 3.43 (m, 1H), 3.06-3.02 (m, 2H), 2.91 (td, J=10.0, 2.8Hz, 1H), 2.78 (td, J=9.6, 2.0Hz, 1H), 2.65 (d d, J=10.4, 8.8Hz, 1H), 2.42 (m, 1H), 2.34 (m, 1H), 1.89 (m, 1H), 1.73-1.67 (m, 2H), 1.41 (m, 1H), 1.26 (m, 1H).

[0521] The following examples were prepared from 6-((7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile and the appropriate corresponding aryl or heteroaryl bromide using the same procedure as described for Example 54.

[0522]

[0523] Example 61: Synthesis of 6-((7S,8aS)-6-oxo-7-(3-(1,2,3,4-tetrahydroquinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile.

[0524]

[0525] The title compound was isolated as a minor product from the synthesis of Example 60. LCMS: m / z = 417.2 [M+H] + .

[0526] Example 62: Synthesis of (7S,8aS)-2-(5-fluoropyridin-2-yl)-7-(3-{[1,2,4]triazolo[1,5-a]pyridin-8-yl}propyl)-octahydropyrrolo[1,2-a]pyrazin-6-one

[0527]

[0528] Step 1: A 3000 mL 3-neck RBF equipped with a mechanical stirrer, JKem thermocouple and reflux condenser was charged with (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (129.0 g, 95 wt% purity and 90% diastereomeric excess, 439 mmol, 1.0 equiv) and 8-bromo-[1,2,4]triazolo[1,5-a]pyridine (86.8 g, 439 mmol, 1.0 equiv). The solid was dissolved in a 1:1 v / v mixture of triethylamine / THF (1200 mL). Copper iodide (2.78 g, 8.77 mmol, 0.02 equiv) was added, followed by bis(triphenylphosphine)palladium(II) chloride (6.16 g, 8.77 mmol, 0.02 equiv). The mixture was heated (using a heating mantle) to 70°C and mechanically stirred for 5 minutes, at which point the heating mantle was turned off. As the reaction cooled, a brown precipitate appeared. As cooling continued, the precipitate became larger, eventually turning the mixture into a solid brown precipitate. The precipitate was diluted with water (1 L) and gently stirred with a stirring rod. The liquid was poured out and filtered. The process was repeated with another 500 mL of water. The remaining solid was set aside. The filtrate was concentrated to remove volatiles (triethylamine and THF). The resulting aqueous brown precipitate was diluted with brine and extracted with EtOAc (2×). The reaction flask containing the precipitate was distributed between EtOAc and brine. The layers were separated, all EtOAc extracts were combined, and washed with saturated NH4Cl (2×) aqueous solution and brine in turn. The organics were dried over MgSO4, filtered and concentrated. The concentrate was treated with MTBE / MeOH (10:1, 750 mL) and gently heated with a heat gun to promote solvation of impurities. The dark brown liquid was filtered through a coarse filter and all remaining solids were washed with MTBE (2×). The remaining solids were vacuum oven dried overnight to give (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)prop-2-yn-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a light brown solid. LCMS: m / z=396.2[M+H] + .

[0529] Step 2: To a solution of tert-butyl (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)prop-2-yn-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (163 g, 95 wt% pure material, 390 mmol) in MeOH / EtOAc (4:1, 800 mL) was added a slurry of 10% Pd / C (50 wt% H2O, 30 g) and MeOH / EtOAc (2:1, 500 mL). Hydrogen was bubbled through the reaction mixture via a balloon and the balloon was refilled as needed. At 26 hours, additional 10% Pd / C (50 wt% H2O, 25 g) was added and the hydrogen bubbling process was continued. Additional 10% Pd / C (50 wt% H2O) was added at 74 hours (25 g) and 126 hours (10 g) respectively until the reaction was complete at 168 hours as determined by LCMS. Nitrogen was bubbled through the reaction mixture for 20 minutes, and the mixture was diluted with DCM (500 mL). The mixture was filtered through diatomaceous earth and the filter cake was rinsed with DCM. The filtrate was concentrated in vacuo to give (7S, 8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-6-oxohexahydroxypyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a brown viscous oil. LCMS: m / z=400.2[M+H] + . The concentrated oil was dissolved in MeOH / dioxane (1:1, 500 mL) and transferred to a 2000 mL RBF. The flask was placed in an ice bath and 4N HCl / dioxane (300 mL) was added via an addition funnel over 2 hours. After the addition was complete, the cooling bath was removed and the mixture was stirred for a total of 22 hours. The mixture containing the off-white precipitate was filtered. The filtrate was washed with EtOAc and all filtrates were set aside. The solid was placed in a dish and dried under vacuum to give 115.4 g of off-white powder. The dried solid was dissolved / suspended in 600 mL of water and 600 mL of DCM. 3N NaOH aqueous solution (400 mL) (pH>11) was added, followed by brine (200 mL). The layers were separated and the aqueous phase was extracted with additional DCM (5×500 mL). The combined organics were dried over MgSO4, filtered and concentrated to afford ((7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one as a light orange oil.

[0530] Step 3: A mixture containing (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (3.27 g, 10.9 mmol, 1.0 equiv), 2-bromo-5-fluoropyridine (2.88 g, 16.4 mmol, 1.5 equiv), Ruphos Pd G2 (505 mg, 0.65 mmol, 0.06 equiv) and cesium carbonate (7.11 g, 21.8 mmol, 2.0 equiv) in dioxane (25 mL) was stirred at 80 °C in a thick-walled sealed container for 24 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The concentrate was added to saturated NH 4 Partition between Cl and EtOAc. The organics were washed with additional saturated NH 4 Cl, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0% MeOH in EtOAc to 10% MeOH in EtOAc gradient) gave (7S,8aS)-2-(5-fluoropyridin-2-yl)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-hexahydropyrrolo[1,2-a]pyrazin-6-one as a white solid. LCMS: m / z=395.1[M+H] +1 H NMR (300 MHz, methanol-d 4 )δ8.66 (dd, J=6.9, 1.2Hz, 1H), 8.41 (s, 1H), 8.02 (d, J=3.1Hz, 1H), 7.54 (dd, J=7.1, 1.1H z, 1H), 7.46-7.38 (m, 1H), 7.17 (t, J=7.0Hz, 1H), 6.91 (dd, J=9.2, 3.4Hz, 1H), 4.54-4.43 (m, 1H), 4.34-4.24 (m, 1H), 4.01-3.90 (m, 1H), 3.63 (m, 1H), 3.07 (t, J=7.2Hz, 3H), 3.01- 2.89 (m, 1H), 2.87-2.75 (m, 2H), 2.63-2.40 (m, 2H), 2.05-1.82 (m, 3H), 1.56-1.30 (m, 1H).

[0531] Example 63: Synthesis of (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0532]

[0533] A 10 mL sealed tube was purged and maintained with nitrogen, and (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (60 mg, 0.20 mmol, 1.0 eq), NMP (1 mL), 2-chloro-5-fluoropyrimidine (32 mg, 0.24 mmol, 1.2 eq), and DIEA (1 mL) were placed in the tube. The resulting solution was stirred in an oil bath at 130° C. for 2 hours. The mixture was cooled to room temperature and purified by silica gel chromatography and then further purified by reverse phase HPLC to give (7S,8aS)-2-(5-fluoropyrimidin-2-yl)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-hexahydropyrrolo[1,2-a]pyrazin-6-one as an off-white solid. LCMS: m / z=396.1 [M+H] + . 1 H NMR (300 MHz, methanol-d 4 )δ8.66 (m, 1H), 8.41 (s, 1H), 8.32 (s, 2H), 7.54 (dd, J=7.2, 0.9Hz, 1H), 7.17 (t, J=7.2Hz, 1H), 4.92 (m, 1H), 4.87 (m, 1H), 3 .96 (m, 1H), 3.56 (m, 1H), 3.10-3.05 (m, 2H), 2.90-2.84 (m, 2H), 2.66-2.44 (m, 3H), 1.96-1.89 (m, 3H), 1.43-1.36 (m, 2H).

[0534] The following examples were prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and the appropriate corresponding heteroaryl halide using the same procedure as described for Example 63.

[0535]

[0536] Example 70: Synthesis of (7S,8aS)-7-(3-{7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}propyl)-2-(5-fluoropyridin-2-yl)-octahydropyrrolo[1,2-a]pyrazin-6-one

[0537]

[0538] Step 1: A 10 mL sealed tube was purged and maintained with nitrogen, and 2-bromo-5-iodopyridine (180 mg, 0.634 mmol, 1 eq.), toluene (3.00 mL), trifluoro(3,3,3-trifluoropropyl)borane (126 mg, 0.761 mmol, 1.2 eq.), Pd(OAc) were placed in it. 2 (29 mg, 0.12 mmol, 0.2 eq), Cs 2 CO 3 (517 mg, 1.56 mmol, 2.5 eq), H 2 O (1.5 mL). The resulting solution was stirred in a 100°C oil bath for 2 hours. The mixture was cooled to room temperature, filtered and concentrated. Purification by silica gel chromatography gave 2-bromo-5-(3,3,3-trifluoropropyl)pyridine as a yellow oil. LCMS: m / z = 254.1 [M+H] + .

[0539] Step 2: A 10 mL sealed tube was purged and maintained with nitrogen, and (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (20 mg, 0.067 mmol, 1.0 eq), PhMe (1 mL), 2-bromo-5-(3,3,3-trifluoropropyl)pyridine (21 mg, 0.08 mmol, 1.2 eq), Pd 2 (dba) 3 (12 mg, 0.013 mmol, 0.2 equiv), BINAP (17 mg, 0.027 mmol, 0.4 equiv), t-BuOK (23 mg, 0.20 mmol, 3.0 equiv). The mixture was stirred in a 100 °C oil bath for 2 hours. The mixture was cooled to room temperature, filtered and concentrated. Purification by silica gel chromatography gave (7S,8aS)-7-(3-[[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-2-[5-(3,3,3-trifluoropropyl)pyridin-2-yl]-hexahydropyrrolo[1,2-a]pyrazin-6-one as an off-white solid. LCMS: m / z=473.1[M+H] + .

[0540] The following examples were prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and the appropriate corresponding aryl or heteroaryl bromide using the same procedure as described for Example 70, Step 2. Examples 72, 73 and 74 were obtained as mixtures of diastereomers.

[0541]

[0542] Example 77: Synthesis of (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-(hydroxymethyl)pyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0543]

[0544] Step 1: (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one was prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (90 mg, 0.30 mmol, 1.0 equiv) and 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine as described in the synthesis of Example 37. LCMS: m / z=521.1 [M+H] + .

[0545] Step 2: The title compound was prepared from: (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one as described for the synthesis of Example 53, Step 2. LCMS: m / z = 407.2 [M+H] + .

[0546] Example 78: Synthesis of (7S,8aS)-7-(3-{7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}propyl)-2-(5-fluoropyridin-2-yl)-octahydropyrrolo[1,2-a]pyrazin-6-one

[0547]

[0548] Step 1: A 100 mL round-bottom flask was purged and maintained with nitrogen and charged with 3-bromo-4-fluoropyridin-2-amine (900 mg, 4.71 mmol, 1.0 eq), IPA (15 mL), N,N-dimethylformamide dimethyl acetal (730 mg, 6.13 mmol, 1.3 eq). The resulting solution was stirred in an 85° C. oil bath for 2 hours, at which time the mixture was cooled to 50° C. and NH 2OH.HCl (426 mg, 6.13 mmol, 1.3 equiv). The resulting solution was stirred in a 50 °C oil bath for another 2 hours. The mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to give (E)-N-(3-bromo-4-fluoropyridin-2-yl)-N-hydroxycarboximidamide as an off-white solid. LCMS: m / z=234.1 [M+H] +

[0549] Step 2: Into a 100 mL round-bottom flask was placed (E)-N-(3-bromo-4-fluoropyridin-2-yl)-N-hydroxycarboximidamide (1.00 g, 4.27 mmol, 1.0 equiv) and THF (15 mL). The solution was cooled to 0 °C and TFAA (2.69 g, 13 mmol, 3.0 equiv) was added. The mixture was slowly warmed to room temperature and stirred for 5 hours. The pH value of the solution was adjusted to pH ~ 7 by adding aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel chromatography to give 8-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine as a yellow oil. LCMS: m / z=216.1[M+H] + .

[0550] Step 3: A 30 mL sealed tube was purged and maintained with nitrogen, and 8-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.926 mmol, 1.0 equiv), DMF (4 mL), (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (258 mg, 0.926 mmol, 1.0 equiv), Pd(PPh 3 ) 4 (54 mg, 0.046 mmol, 0.05 equiv), CuI (9 mg, 0.046 mmol, 0.05 equiv), PPh 3 (49 mg, 0.19 mmol, 0.2 equiv) and DIEA (691 mg, 4.63 mmol, 5.0 equiv). The resulting solution was stirred in a 60 ° C oil bath for 2 hours. The resulting solution was partitioned between water and ethyl acetate. The layers were separated, the organics were concentrated, and purified by silica gel chromatography to give (7S, 8aS)-7-(3-[7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl]prop-2-yn-1-yl)-6-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as a yellow oil. LCMS: m / z=414.1[M+H] + .

[0551] Step 4: Into a 25 mL round-bottom flask were placed (7S,8aS)-7-(3-[7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl]prop-2-yn-1-yl)-6-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (180 mg, 0.435 mmol, 1.0 equiv), MeOH (5 mL) and 10% Pd / C (93 mg). The mixture was heated at room temperature under H 2 Stir overnight under atmosphere. The mixture was filtered through celite, concentrated, and purified by silica gel chromatography to give (7S,8aS)-7-(3-[7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-6-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester as a yellow oil. LCMS: m / z=418.2[M+H] +

[0552] Step 5: Into a 25 mL round-bottom flask was placed (7S,8aS)-7-(3-[7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-6-oxo-hexahydropyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (150 mg, 0.359 mmol, 1.0 equiv), DCM (3 mL) and TFA (2 mL). The resulting solution was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 7. The crude product was purified by silica gel chromatography to give (7S,8aS)-7-(3-[7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazine-6-one as a yellow oil. LCMS: m / z=318.2[M+H] + .

[0553] Step 6: A 10 mL sealed tube was purged and maintained with nitrogen, and (7S,8aS)-7-(3-[7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (50 mg, 0.16 mmol, 1.0 eq), PhMe (3 mL), 2-bromo-5-fluoropyridine (33 mg, 0.19 mmol, 1.2 eq), Pd 2 (dba) 3(29 mg, 0.032 mmol, 0.2 equiv), BINAP (39 mg, 0.063 mmol, 0.4 equiv) and t-BuOK (53 mg, 0.47 mmol, 3.0 equiv). The mixture was stirred in a 100 °C oil bath for 2 hours. The solid was filtered and the resulting mixture was concentrated. The residue was purified by silica gel chromatography and then further purified by reverse phase HPLC to give the title compound (7S,8aS)-7-(3-[7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl]propyl)-2-(5-fluoropyridin-2-yl)-hexahydropyrrolo[1,2-a]pyrazin-6-one as a white solid. LCMS: m / z=413.2[M+H] + .

[0554] Example 79: Synthesis of (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-5-d)propyl-2,2,3,3-d4)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0555]

[0556] Step 1: (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl-5-d)propyl-2,2,3,3-d4)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one was prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)prop-2-yn-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (180 mg, 0.455 mmol, 1.0 equiv) in a manner similar to that described for the synthesis of Steps 4 and 5 of Example 78, except that D 2 Gas replaces H 2 Gas. LCMS: m / z=305[M+H] + .

[0557] Step 2: The title compound was prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl-5-d)propyl-2,2,3,3-d4)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (40 mg, 0.13 mmol, 1.0 equiv) in a manner similar to that described for the synthesis of Example 62, Step 3, except that Ruphos Pd G4 was used as the catalyst. LCMS: m / z=399.2 [M] + .

[0558] Example 80: Synthesis of 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0559]

[0560] Step 1: tert-Butyl 6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate was prepared from hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one (1.59 g, 11.3 mmol, 1.0 equiv) in two steps in a manner similar to that described for the synthesis of (8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in Steps 1 and 2 of Examples 1 and 2.

[0561] Step 2: 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from tert-butyl 6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (330 mg, 1.19 mmol, 1.0 equiv) and 8-bromo-[1,2,4]triazolo[1,5-a]pyridine as described in the synthesis of Example 31, Step 1-2. LCMS: m / z=300.1 [M+H] + .

[0562] Step 3: As described in the synthesis of Example 78, Step 6, 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-onecarboxylate (158 mg, 0.53 mmol, 1.0 equiv) and 2-bromo-5-fluoropyridine were obtained as a stereoisomer mixture to obtain 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one. LCMS: m / z=395.2 [M+H] + .

[0563] Examples 81, 82 and 83: (7S,8aR)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, (7R,8aR)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one Synthesis of (7R,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one and (7R,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one.

[0564]

[0565] The title compound was prepared as a pure stereoisomer from 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (Example 80) via chiral chromatography (chiralpak IF-3). LCMS: m / z=395.2; 395.2; 395.2 [M+H] + .

[0566] Example 84: Synthesis of 6-(7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-6-oxooctahhydro-2H-pyrido[1,2-a]pyrazin-2-yl)nicotinonitrile.

[0567]

[0568] Step 1: 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)octahydro-6H-pyrido[1,2-a]pyrazin-6-one was obtained from octahydro-6H-pyrido[1,2-a]pyrazin-6-one (404 mg, 2.62 mmol, 1.0 equiv) as a mixture of stereoisomers in 5 steps in a similar manner as described for the synthesis of Example 80 Steps 1 and 2. LCMS: m / z=312.4 [M+H] + .

[0569] Step 2: The title compound was prepared as a mixture of stereoisomers from 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)octahydro-6H-pyrido[1,2-a]pyrazin-6-one (60 mg, 0.19 mmol, 1.0 equiv) and 6-fluoronicotinonitrile in a manner similar to that described for the synthesis of Example 63. LCMS: m / z = 416.2 [M+H] +.

[0570] Example 85: Synthesis of 6-(3-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)-4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)nicotinonitrile.

[0571]

[0572] Step 1: Into a 250 mL round-bottom flask was placed tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (5.00 g mg, 23.1 mmol, 1.0 equiv.), DCM (50 mL). Then DIEA (7.47 g, 57.8 mmol, 2.5 equiv.) was added. The flask was cooled to 0 ° C and a solution of chloroacetyl chloride (3.14 g, 27.7 mmol, 1.2 equiv.) in DCM (10 mL) was added dropwise. The resulting solution was stirred while warming to room temperature over 1 hour. The mixture was diluted with DCM and washed with water (3×). The organic phase was dried over MgSO4, filtered and concentrated to give tert-butyl 4-(2-chloroacetyl)-3-(hydroxymethyl)piperazine-1-carboxylate as a brown oil. LCMS: m / z=293.1[M+H] + .

[0573] Step 2: A 250 mL 3-neck round bottom flask was purged and maintained with an inert atmosphere of nitrogen and a solution of tert-butyl 4-(2-chloroacetyl)-3-(hydroxymethyl)piperazine-1-carboxylate (6.00 g, 20.47 mmol, 1.0 eq) in THF (60 mL) was added. The mixture was cooled to 0 ° C and NaH (1.48 g, 61.5 mmol, 3.0 eq) was added. The ice bath was removed and the resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water. The resulting solution was extracted with 500 mL DCM. The organics were washed with water (2X) and purified by Na 2 SO 4 Dry, filter and concentrate. Purify by silica gel chromatography (15% MeOH in DCM) to give tert-butyl 4-oxo-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate as a yellow solid. LCMS: m / z = 257.1 [M+H]+

[0574] Step 3: 3-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one, as a mixture of stereoisomers, was obtained from tert-butyl 4-oxo-3-(prop-2-yn-1-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (280 mg, 0.951 mmol, 1.0 equiv) and 8-bromo-[1,2,4]triazolo[1,5-a]pyridine in a similar manner to that described for the synthesis of Example 80, Step 2. LCMS: m / z=316.1 [M+H] + .

[0575] Step 4: The title compound was prepared as a mixture of stereoisomers from 3-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)propyl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (60 mg, 0.19 mmol, 1.0 equiv) and 6-fluoronicotinonitrile in a manner similar to that described for the synthesis of Example 63. LCMS: m / z = 418.1 [M+H] + .

[0576] Example 86: Synthesis of (7S,8aS)-7-((Z)-3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)allyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0577]

[0578] Step 1: To a solution of (7S,8aS)-tert-butyl 7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)prop-2-yn-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (250 mg, 0.632 mmol, 1.0 eq) and quinoline (12 mg, 0.095 mmol, 0.15 eq) in EtOAc / MeOH (3:1, 6 mL) was added 5 wt% Lindlar catalyst (50 mg). The mixture was stirred at 4 ℃ for 1 h. 2 Stir for 16 hours under atmosphere and filter through celite. Purify by reverse phase HPLC to obtain (7S,8aS)-7-((Z)-3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)allyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester. LCMS: m / z=398.2[M+H] + .

[0579] Step 2: To a solution of tert-butyl (7S,8aS)-7-((Z)-3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)allyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (37 mg, 0.093 mmol, 1.0 equiv) in MeOH (1.0 mL) was added a solution of 4N HCl in dioxane (2.0 mL). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo to give the amine (7S,8aS)-7-((Z)-3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)allyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one as the HCl salt. LCMS: m / z = 298.2 [M+H] + .

[0580] Step 3: A mixture of (7S,8aS)-7-((Z)-3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)allyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one HCl salt (from above), 2-chloro-5-fluoropyrimidine (19 mg, 0.15 mmol, 1.5 equiv) and DIEA (24 mg, 0.19 mmol, 2.0 equiv) in NMP (1.5 mL) was heated to 130 °C by microwave irradiation for 1 hour. The mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous phase was back extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (gradient of 0% MeOH in EtOAc to 10% MeOH in EtOAc) gave the title compound as a white solid. LCMS: m / z=395.1[M+H] + .

[0581] Example 87: Synthesis of (7S,8aS)-2-(5-fluoropyridin-2-yl)-7-(3-(pyrazolo[1,5-a]pyridin-4-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0582]

[0583] Step 1: (7S,8aS)-7-(3-(pyrazolo[1,5-a]pyridin-4-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one was prepared from (7S,8aS)-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (99 mg, 0.56 mmol, 1.0 equiv) and 4-bromopyrazolo[1,5-a]pyridine as described in the synthesis of Example 31, Step 1-2. LCMS: m / z=299.1 [M+H] + .

[0584] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(pyrazolo[1,5-a]pyridin-4-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (30 mg, 0.10 mmol, 1.0 equiv) and 2-bromo-5-fluoropyridine as described in the synthesis of Example 78, Step 6. LCMS: m / z=394.1 [M+H] + .

[0585] Example 88: (7S,8aS)-2-(5-fluoropyrimidin-2-yl)-7-(3-(pyrazolo[1,5-a]pyridin-4-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0586]

[0587] The title compound was prepared from (7S,8aS)-7-(3-(pyrazolo[1,5-a]pyridin-4-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (70 mg, 0.24 mmol, 1.0 equiv) and 2-chloro-5-fluoropyrimidine in a manner similar to that described for Example 63. LCMS: m / z = 395.4 [M+H] + .

[0588] Example 89: Synthesis of (8aS)-7-(3-(6-fluoroimidazo[1,2-a]pyridin-5-yl)propyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0589]

[0590] Step 1: (7S,8aS)-7-(3-(6-fluoroimidazo[1,2-a]pyridin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (136 mg, 0.488 mmol, 1.0 equiv) and 5-bromo-6-fluoroimidazo[1,2-a]pyridine in a manner similar to that described for the synthesis of Example 78, Steps 3-5. LCMS: m / z=317.2 [M+H] + .

[0591] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(6-fluoroimidazo[1,2-a]pyridin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (38 mg, 0.12 mmol, 1.0 equiv) and 2-bromo-5-fluoropyridine as described in the synthesis of Example 78, Step 6. LCMS: m / z=412.1 [M+H] + .

[0592] Example 90: Synthesis of (7S,8aS)-2-(5-fluoropyridin-2-yl)-7-(3-(pyridazin-3-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0593]

[0594] Step 1: (7S,8aS)-7-(3-(pyridazin-3-yl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (335 mg, 1.20 mmol, 1.0 equiv) and 3,6-dibromopyridazine in a manner similar to that described for the synthesis of Example 78, Step 3-5. LCMS: m / z=317.2 [M+H] + .

[0595] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(pyridazin-3-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (50 mg, 0.19 mmol, 1.0 equiv) and 2-bromo-5-fluoropyridine as described in the synthesis of Example 62, Step 3, except that RuPhos Pd G4 was used as the catalyst. LCMS: m / z=356.1 [M+H] + .

[0596] Example 91: Synthesis of (7S,8aS)-2-(5-methylpyridin-2-yl)-7-(3-(pyridazin-3-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0597]

[0598] The title compound was prepared from (7S,8aS)-7-(3-(pyridazin-3-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (50 mg, 0.19 mmol, 1.0 equiv) and 2-bromo-5-methylpyridine as described in the synthesis of Example 90. LCMS: m / z=352.2 [M+H] + .

[0599] Example 92: Synthesis of (7S,8aS)-2-(5-fluoropyrimidin-2-yl)-7-(3-(quinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0600]

[0601] Step 1: (7S,8aS)-7-(3-(quinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one was prepared from (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (250 mg, 0.898 mmol, 1.0 equiv) and 5-bromoquinoxaline in a manner similar to that described for the synthesis of Example 77, Steps 3-5. LCMS: m / z=311.1 [M+H] + .

[0602] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(quinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (60 mg, 0.193 mmol, 1.0 equiv) and 2-chloro-5-fluoropyrimidine in a manner similar to that described for Example 63. LCMS: m / z = 407.1 [M+H] + .

[0603] Example 93: Synthesis of (7S,8aS)-2-(5-fluoropyridin-2-yl)-7-(3-(quinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0604]

[0605] The title compound was prepared from (7S,8aS)-7-(3-(quinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (38 mg, 0.122 mmol, 1.0 equiv) and 2-bromo-5-fluoropyridine as described in the synthesis of Example 78, Step 6. LCMS: m / z=406.1 [M+H] + .

[0606] Example 94: Synthesis of (7S,8aS)-2-(6-methylpyridazin-3-yl)-7-(3-(quinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0607]

[0608] The title compound was prepared from (7S,8aS)-7-(3-(quinoxalin-5-yl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (60 mg, 0.19 mmol, 1.0 equiv) and 3-bromo-6-methylpyridazine as described in the synthesis of Example 78, Step 6. LCMS: m / z=403.1 [M+H] + .

[0609] Example 95: Synthesis of (7S,8aS)-7-(3-(2-cyclopropyl-3-fluorophenyl)propyl)-2-(6-methylpyridazin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0610]

[0611] Step 1: (7S,8aS)-7-(3-(2-cyclopropyl-3-fluorophenyl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (582 mg, 2.09 mmol, 1.0 equiv) and 1-bromo-2-cyclopropyl-3-fluorobenzene in a manner similar to that described for the synthesis of Example 78, Steps 3-5. LCMS: m / z=317.1 [M+H] + .

[0612] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(2-cyclopropyl-3-fluorophenyl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (60 mg, 0.19 mmol, 1.0 equiv) and 3-bromo-6-methylpyridazine in a similar manner to that described for Example 78, Step 6. LCMS: m / z=409.1 [M+H] + .

[0613] Example 96: Synthesis of (7S,8aS)-7-(3-(3-fluoro-2-methylphenyl)propyl)-2-(6-methylpyridazin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0614]

[0615] Step 1: (7S,8aS)-7-(3-(3-fluoro-2-methylphenyl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (300 mg, 1.08 mmol, 1.0 equiv) and 1-bromo-3-fluoro-2-methylbenzene in a manner similar to that described for the synthesis of Example 78, Steps 3-5. LCMS: m / z=307.1 [M+H] + .

[0616] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(3-fluoro-2-methylphenyl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (60 mg, 0.21 mmol, 1.0 equiv) and 3-bromo-6-methylpyridazine in a manner similar to that described for Example 78, Step 6. LCMS: m / z=383.1 [M+H] + .

[0617] Example 97: Synthesis of (7S,8aS)-7-(3-(3-fluoro-2-methylphenyl)propyl)-2-(6-methylpyridazin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0618]

[0619] Step 1: (7S,8aS)-7-(3-(3-fluoro-2-methoxyphenyl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (300 mg, 1.08 mmol, 1.0 equiv) and 1-bromo-3-fluoro-2-methoxybenzene in a manner similar to that described for the synthesis of Example 78, Steps 3-5. LCMS: m / z=307.1 [M+H] + .

[0620] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(3-fluoro-2-methoxyphenyl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (60 mg, 0.19 mmol, 1.0 equiv) and 3-bromo-6-methylpyridazine in a manner similar to that described for Example 78, Step 6. LCMS: m / z=399.1 [M+H] + .

[0621] Example 98: Synthesis of (7S,8aS)-7-(3-(4-fluoro-3-methoxyphenyl)propyl)-2-(6-methylpyridazin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0622]

[0623] Step 1: (7S,8aS)-7-(3-(4-fluoro-3-methoxyphenyl)propyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (300 mg, 1.08 mmol, 1.0 equiv) and 4-bromo-1-fluoro-2-methoxybenzene in a manner similar to that described for the synthesis of Example 78, Steps 3-5. LCMS: m / z=307.1 [M+H] + .

[0624] Step 2: The title compound was prepared from (7S,8aS)-7-(3-(4-fluoro-3-methoxyphenyl)propyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one 60 mg, 0.19 mmol, 1.0 equiv) and 3-bromo-6-methylpyridazine in a manner similar to that described for Example 78, Step 6. LCMS: m / z=399.1 [M+H] + .

[0625] Example 99: Synthesis of (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)allyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0626]

[0627] Step 1: To a solution of (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (2.00 g, 7.19 mmol, 1 eq.) in EtOAc / MeOH (1:1, 20 mL) containing quinoline (186 mg, 1.44 mmol, 0.2 eq.) was added 5 wt% of Lindlar catalyst. The mixture was placed under an H2 atmosphere and stirred at room temperature for 2.5 hours. The mixture was filtered through celite and concentrated. Purification by silica gel chromatography (30% EtOAc in hexane to 85% EtOAc in hexane gradient) gave (7S,8aS)-7-allyl-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a yellow solid. LCMS: m / z = 281.2 [M+H]+ .

[0628] Step 2: A mixture of (7S,8aS)-tert-butyl 7-allyl-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (150 mg, 0.54 mmol, 1.0 equiv), 1,2-difluoro-4-vinylbenzene (150 mg, 1.07 mmol, 2.0 equiv) and the second generation Grubbs-Hoveyda catalyst (16.8 mg, 0.027 mmol, 0.05 equiv) in DCE (2.5 mL) was stirred in a sealed vial at 70 °C for 4 h, at which time more catalyst (16.8 mg, 0.027 mmol, 0.05 equiv) was added. Stirring was continued for an additional 14 h, and the mixture was warmed to room temperature and concentrated. Purification by silica gel chromatography (gradient of 30% EtOAc in hexanes to 90% EtOAc in hexanes) gave tert-butyl (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)allyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate as a dark red oil. LCMS: m / z = 393.1 [M+H] + .

[0629] Step 3: To a solution of tert-butyl (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)allyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (125 mg, 0.319 mmol, 2.0 equiv) in MeOH (1.0 mL) was added a solution of 4N HCl in dioxane (2.0 mL). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The resulting solid was dissolved in MeOH and loaded into a column containing a strong cation exchange resin. The column was eluted with MeOH (2 column volumes) and the eluent was discarded. Elution with 2N NH3 in MeOH gave the product (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)allyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one as the free base after concentration. LCMS: m / z = 293.0 [M+H] + .

[0630] Step 4: The title compound was prepared from (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)allyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (67 mg, 0.23 mmol, 1.0 equiv) and 2-chloro-5-fluoropyrimidine in a manner similar to that described for Example 63. LCMS: m / z=389.1 [M+H] + .

[0631] Example 100: Synthesis of (7S,8aS)-7-(3-(3,4-difluorophenyl)propyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0632]

[0633] To a solution of (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)allyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (20 mg, 0.052 mmol, 1.0 equiv) in EtOAc (1.5 mL) was added 10% Pd / C (10 mg). The mixture was stirred at room temperature under H2 atmosphere for 1.5 hours and concentrated in vacuo. The title compound was purified by silica gel chromatography (30% EtOAc in hexanes to 75% EtOAc in hexanes gradient) as a white solid. LCMS: m / z=391.1 [M+H] + .

[0634] Example 101: Synthesis of (7S,8aS)-7-((2-(3,4-difluorophenyl)cyclopropyl)methyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0635]

[0636] To N 2 Et2O3 was further diluted with DCE (0.75 mL) under atmosphere. 2 To an ice / salt cooled solution of Zn solution (15 wt% in PhMe, 417 uL, 0.46 mmol, 5.0 eq) was added dropwise a solution of TFA (35 uL, 0.46 mmol, 5.0 eq) in DCE (0.75 mL). After stirring for 20 min, CH 2 I 2 (37uL, 0.46mmol, 5.0 equivalents) in DCE (0.75mL). After another 20 minutes, a solution of (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)allyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one (36mg, 0.093mmol, 1.0 equivalents) in DCE (1.0mL) was added to the mixture. The mixture was warmed to room temperature and stirred for 72 hours, at which time the reaction was quenched with 1N HCl aqueous solution (1.0mL). After stirring for 20 minutes, the mixture was stirred in DCM and saturated NaHCO 3The phases were separated and the organics were washed with brine, dried (MgSO4), filtered and concentrated. Purification by silica gel chromatography (30% EtOAc in hexanes to 80% EtOAc in hexanes gradient) followed by reverse phase HPLC afforded (7S,8aS)-7-((2-(3,4-difluorophenyl)cyclopropyl)methyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one as a mixture of stereoisomers. LCMS: m / z=403.1 [M+H] + .

[0637] Example 102: Synthesis of 6-((7S,8aS)-7-(3-(3,4-difluorophenyl)butyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile

[0638]

[0639] Step 1: A solution of (7S,8aS)-6-oxo-7-(prop-2-yn-1-yl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (500 mg, 1.80 mmol, 1.0 equiv), diisopropylamine (365 mg, 3.60 mmol, 2.0 equiv), copper(I) bromide (90 mg, 0.63 mmol, 0.35 equiv) and paraformaldehyde (108 mg, 2.0 equiv, relative to monomer) in dioxane (2.5 mL) was heated at 100 ° C for 18 hours in a sealed tube. The mixture was cooled to room temperature and partitioned between EtOAc and 1N HCl aqueous solution. The layers were separated and the organic layer was washed with 1N HCl aqueous solution and brine in sequence. The organics were dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (gradient of 45% EtOAc in hexanes to 85% EtOAc in hexanes) afforded (7S,8aS)-7-(3λ 5 -Butane-2,3-dien-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester, as a yellow solid. LCMS: m / z=293.1[M+1] + .

[0640] Step 2: Allene (85 mg, 0.29 mmol, 1.0 eq.), (3,4-difluorophenyl)boronic acid (92 mg, 0.58 mmol, 2.0 eq.), PtOH 2 (PPh 3 ) 2 [BF 4 ] 2(24 mg, 0.15 mmol, 0.05 eq.), KOH (82 mg, 1.45 mmol, 5.0 eq.) in a solution containing H 2 A mixture of 2-nitropropene (0.125 mL) and dioxane (2.5 mL) was stirred in a sealed vial at 100 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc, and MgSO 4 . The mixture was filtered and concentrated. Purification by silica gel chromatography (gradient from 30% EtOAc in hexane to 75% EtOAc in hexane) gave a mixture of (7S,8aS)-7-((E)-3-(3,4-difluorophenyl)but-2-en-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester and (7S,8aS)-7-(3-(3,4-difluorophenyl)but-3-en-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester. LCMS: m / z=407.2[M+1] + .

[0641] Step 3: To a solution of the olefin isomer from step 2 in EtOAc / MeOH (2:1, 4 mL) was added 10% Pd / C (25 mg). The heterogeneous mixture was stirred under H 2 Stir for 1 hour under atmosphere. The mixture was filtered and concentrated. The concentrate was dissolved in MeOH (0.5 mL) and treated with dioxane (1.0 mL) containing 4N HCl. The mixture was stirred at room temperature for 1 hour and concentrated to give the resulting amine (7S,8aS)-7-(3-(3,4-difluorophenyl)butyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one hydrochloride as a white solid. LCMS: m / z=309.2[M+1] + .

[0642] Step 4: A mixture of (7S,8aS)-7-(3-(3,4-difluorophenyl)butyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one hydrochloride (17 mg, 0.05 mmol, 1.0 eq), 6-fluoronicotinonitrile (18 mg, 0.15 mmol, 3.0 eq), DIEA (25 mg, 0.20 mmol, 4.0 eq) in NMP (1.0 mL) was stirred in a sealed vial at 120° C. for 72 h. The mixture was purified by reverse phase HPLC. Further purification by silica gel chromatography (gradient of 40% EtOAc in hexanes to 85% EtOAc in hexanes) afforded 6-((7S,8aS)-7-(3-(3,4-difluorophenyl)butyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile as a white solid. LCMS: m / z = 411.1 [M+1]+ .

[0643] Example 103: Synthesis of (7S,8aS)-7-(3-(3,4-difluorophenyl)butyl)-2-(5-fluoropyrimidin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0644]

[0645] The title compound was prepared from (7S,8aS)-7-(3-(3,4-difluorophenyl)butyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (15 mg, 0.049 mmol, 1.0 equiv) and 2-chloro-5-fluoropyrimidine in a similar manner as described for Example 102, Step 4. LCMS: m / z=405.1 [M+H] + .

[0646] Example 104: Synthesis of (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)butyl)-2-(5-fluoropyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0647]

[0648] Step 1: 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine (1.00 g, 5.05 mmol, 1.0 equiv), 4,4,4',4',5,5,5",5"-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.60 g, 6.31 mmol, 1.25 equiv), potassium acetate (991 mg, 10.1 mmol, 2.0 equiv) and PdCl 2 A mixture of (dppf)DCM (206 mg, 0.252 mmol, 0.05 equiv) in DMF (8.0 ml) was heated to 100 °C for 20 hours. The mixture was diluted with EtOAc and filtered through celite, and concentrated to give 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine as a black precipitate. LCMS: m / z=164.1 [M+H-86] + .

[0649] Step 2: (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)butyl)hexahydropyrrolo[1,2-a]pyrazine-6(2H)-one was prepared from (7S,8aS)-7-(3l5-but-2,3-dien-1-yl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (130 mg, 0.444 mmol, 1.0 equiv) and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (153 mg mixture of isomers, 0.623 mmol, 1.40 equiv). LCMS: m / z = 314.2 [M+H] + .

[0650] Step 3: The title compound was prepared from (7S,8aS)-7-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)butyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (1.7 mg, 0.0054 mmol, 1.0 equiv) and 2-bromo-5-fluoropyridine in a manner similar to that described for the synthesis of Example 62, Step 3. LCMS: m / z=409.1 [M+H] + .

[0651] Example 105: Synthesis of 6-((7S,8aS)-7-(3-(3,4-difluorophenyl)-3-hydroxypropyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile

[0652]

[0653] Step 1: To a solution of tert-butyl (7S,8aS)-7-allyl-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (1.87 g, 6.68 mmol, 1.0 eq.) in THF (3.5 mL) was added 9-BBN solution (0.5 M in THF, 20.0 mL, 10.0 mmol, 1.5 eq.) under N 2 The mixture was stirred at room temperature for 20 hours, cooled to 0°C, and 1 N NaOH aqueous solution (1.5 mL) was added, followed by dropwise addition of 30% H 2 O 2 Aqueous solution (1.5 mL). Stirring was continued for 1 hour while the mixture was slowly warmed to room temperature. The mixture was diluted with brine and extracted with EtOAc and DCM in sequence. The combined organics were washed with MgSO 4Dry, filter and concentrate. Purify by silica gel chromatography (0% MeOH in EtOAc to 15% MeOH in EtOAc gradient) to give (7S,8aS)-7-(3-hydroxypropyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a clear oil. LCMS: m / z=299.2 [M+H] + .

[0654] Step 2: A mixture of the obtained (7S, 8aS)-7-(3-hydroxypropyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (400 mg, 1.34 mmol, 1.0 equiv) and Dess-Martin periodinane (682 mg, 1.61 mol, 1.2 equiv) in DCM (3.5 mL) was stirred at room temperature for 3.5 hours and concentrated in vacuo. Purification by silica gel chromatography (EtOAc) gave (7S, 8aS)-6-oxo-7-(3-oxopropyl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a clear oil. LCMS: m / z=297.1[M+H] + .

[0655] Step 3: In N 2 To a solution of 4-bromo-1,2-difluorobenzene (111 mg, 0.574 mmol, 2.0 equiv) in THF (2.0 mL) cooled to -78°C was added a solution of n-butyl lithium (1.6 M in hexane, 0.359 mL, 0.574 mmol, 2.0 equiv). The mixture was stirred for 20 minutes, at which time a solution of (7S,8aS)-6-oxo-7-(3-oxopropyl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (85 mg, 0.287 mmol, 1.0 equiv) in THF (2.0 mL) was slowly added. The mixture was stirred at -78°C for 1 hour and the mixture was heated to 40 ℃ for 1 hour by adding saturated NH 4 Cl was quenched and extracted with EtOAc. Purification by silica gel chromatography (30% EtOAc in hexane to 80% EtOAc in hexane gradient) gave (7S,8aS)-7-(3-(3,4-difluorophenyl)-3-hydroxypropyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a mixture of diastereomers. LCMS: m / z=411.2[M+H] + .

[0656] Step 4: To a solution of (7S,8aS)-7-(3-(3,4-difluorophenyl)-3-hydroxypropyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (18 mg, 0.044 mmol, 1.0 equiv) in MeOH (0.5 mL) was added 4N HCl in dioxane (1.5 mL). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The concentrate was dissolved in NMP (1.0 mL). DIEA (28 mg, 0.22 mmol, 5.0 equiv) and 6-fluoronicotinonitrile (19 mg, 0.15 mmol, 3.5 equiv) were added, and the mixture was stirred in a sealed vial at 120 °C for 72 hours. Purification by reverse phase HPLC gave the title compound as a mixture of diastereomers. LCMS: m / z=457.3[M+H] + .

[0657] Example 106: Synthesis of 6-((7S,8aS)-7-(3,3-difluoro-3-(2-methoxypyridin-4-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinonitrile

[0658]

[0659] Step 1: Cool to -15°C in N 2 To a solution of 4-iodo-2-methoxypyridine (174 mg, 0.739 mmol, 1.1 equiv) in THF (2.0 mL) was added i-PrMgCl-LiCl solution (1.3 M THF solution, 0.568 mL, 0.739 mmol, 1.1 equiv). After stirring for 20 minutes, a solution of (7S, 8aS)-6-oxo-7-(3-oxopropyl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (199 mg, 0.671 mmol, 1.0 equiv) in THF (2.0 mL) was added. The mixture was stirred for 1 hour while warming to room temperature and the mixture was heated to room temperature by adding saturated NH 4 The solution was quenched with aqueous Cl and extracted with EtOAc (2×). 4 Dry, filter and concentrate. Purify by silica gel chromatography (0% MeOH in EtOAc to 5% MeOH in EtOAc gradient) to give (7S,8aS)-7-(3-hydroxy-3-(2-methoxypyridin-4-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a clear oil. LCMS: m / z=406.2 [M+H] + .

[0660] Step 2: To a solution of (7S,8aS)-7-(3-hydroxy-3-(2-methoxypyridin-4-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (105 mg, 0.258 mmol, 1.0 equiv) in DCM (3 mL) was added Dess-Martin periodinane (164 mg, 0.387 mmol, 1.5 equiv). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc in hexanes to 100% EtOAc in hexanes gradient) gave (7S,8aS)-7-(3-hydroxy-3-(2-methoxypyridin-4-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester as a white solid. LCMS: m / z = 404.2 [M+H] + .

[0661] Step 3: To a solution of tert-butyl (7S,8aS)-7-(3-hydroxy-3-(2-methoxypyridin-4-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (90 mg, 0.22 mmol, 1.0 eq) in DCM (2.0 ml) was added DAST (90 mg, 0.56 mmol, 2.5 eq). EtOH (5.1 mg, 0.11 mmol, 0.5 eq) was added and the mixture was stirred at room temperature for 26 hours, at which time a solution of DeoxoFluor (2.7 M solution in PhMe, 0.16 mL, 0.44 mmol, 2.0 eq) was added and stirring was continued for 96 hours. DeoxoFluor (2.7 M solution in PhMe, 0.20 mL, 0.55 mmol, 2.5 eq) was added. The mixture was heated to 60 °C with stirring for 24 hours. The mixture was cooled to room temperature and saturated with NaHCO 3 The organic matter was washed with MgSO 4 Dry, filter and concentrate. Purify by silica gel chromatography (0% MeOH in hexane to 5% MeOH in hexane gradient) to give (7S,8aS)-7-(3,3-difluoro-3-(2-methoxypyridin-4-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester. LCMS: m / z=426.1[M+H] + .

[0662] Step 4: The title compound was prepared from (7S,8aS)-7-(3,3-difluoro-3-(2-methoxypyridin-4-yl)propyl)-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (3 mg, 0.007 mmol, 1.0 equiv) and 6-fluoronicotinonitrile in a manner similar to that described for the synthesis of Example 10, Step 5. LCMS: m / z=428.1 [M+H] + .

[0663] Examples 107-110: Examples 107-110 were prepared in a similar manner as described in Examples 1-5.

[0664]

[0665] II. Biological Evaluation

[0666] Example 111: In vitro functional assay for muscarinic acetylcholine receptor activity

[0667] Human M was stably expressed using aequorin (Perkin Elmer). 1 Recipient CHO-K1 cells were grown in F12 medium containing 0.4 mg / mL Geneticin and 0.25 mg / mL, 10% FBS. The cells were grown to confluence and frozen for later assay. On the day of the experiment, the cells were thawed in a 37°C water bath, resuspended in F12 with DMEM / HAM with HEPES (Invitrogen) + 0.1% protease-free BSA (assay buffer), and centrifuged to remove the freezing medium. After centrifugation, the supernatant was removed and 12 mL of assay buffer was added. Coelenterazine h (Promega) was added to the cells at a final concentration of 5 μM and incubated in the dark for 4 hours at room temperature. The compound mastering plate-96 deep well (Corning) was formatted in an 8-point DRC in an assay buffer containing 0.2% DMSO, with a starting concentration of 60 uM (2x). After incubation for 4 hours, the cells were plated at 5×10 5 The cells were seeded at a concentration of 10 cells / well in 96-well white-wall tissue culture treated clear bottom plates (VWR). Compounds were added to the daughter plates and the cells were incubated with compounds for 30 minutes at room temperature in the dark.

[0668] Calcium flux was measured using FlexStation 3 (Molecular Devices). To measure antagonist dose-response, the EC80 of acetylcholine was injected into the daughter plate using the automated compound transfer function of the Flex Station, and the increase in luminescence over time was measured. Antagonist activity was analyzed as a concentration-dependent decrease in the EC80 acetylcholine response. Dose-response curves were generated using Prism (GraphPad Software). The IC of the compound was calculated from the dose-response curve. 50 The results are shown in Table 1.

[0669] Table 1

[0670] Examples# <![CDATA[M1 IC 50 ]]> <![CDATA[M2 IC 50 ]]> <![CDATA[M3 IC 50 ]]> Examples# <![CDATA[M1 IC 50 ]]> <![CDATA[M2 IC 50 ]]> <![CDATA[M3 IC 50 ]]> 1 D D D 40 A D D 2 A C C 41 A C C 3 B D C 42 D C D 4 A B B 43 C C C 5 B C D 44 C C D 6 B C D 45 A A B 7 C C D 46 A C C 8 D D D 47 B D D 9 B C D 48 A C C 10 A B C 49 A C C 11 A B B 50 B D D 12 B C C 52 B B C 13 A B B 53 A C D 14 B C C 54 A B C 15 B D C 55 B C C 16 B B B 56 A B B 17 A C C 57 C C D 18 C C D 58 A B B 19 A B C 59 A B C 20 B C C 60 A A B 21 A C C 61 B C D 22 A B C 62 A C C 25 A C B 63 A D C 26 B D C 64 A B C 27 B D C 65 B C D 28 A B B 66 B D D 30 A C C 67 A B A 31 C D D 68 A B A 32 A B C 71 C C D 33 B C C 72 A C C 34 A C C 78 A C C 35 A D D 87 B C C 37 A C C 88 A C C 38 C D D 89 A C C 39 B D C 93 A D C

[0671] A = IC less than 100 nM 50 ; B=IC 50 Less than 1 μM (1000 nM) but greater than or equal to 100 nM; C = IC 50 Less than 10 μM (10000 nM) but greater than or equal to 1 μM (1000 nM); D = IC 50 Greater than 10 μM (10000 nM); NT = not tested.

[0672] Exemplary compounds, pharmaceutical compositions and methods

[0673] Compound 1: Compound of formula (IA):

[0674]

[0675] Where: E is -CH 2 -、-CH 2 CH 2 -、-O-CH 2 -or-CH 2 -O-; X is a bond, -C≡C-, -C(=O)--CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-; Y is a bond, -O- or -N(R 8 )-;R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 Alkyl; each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 Alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; each R 6 are independently selected from hydrogen, deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 Alkyl; R 8 is hydrogen or C 1-6 Alkyl; R 9 is hydrogen or C 1-6 Alkyl; each R 10 Independently selected from H and C 1-6 Alkyl; R 11 It is C 1-6 Alkyl; each R 12 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 Alkyl; each R 13 independently selected from hydrogen, deuterium, halogen, -OH and C1-6 alkyl; a is 1, 2, 3, 4 or 5; m is 0, 1, 2 or 3; n is 1, 2, 3, 4 or 5; p is 0, 1, 2 or 3; and each q is independently 0, 1, 2, 3 or 4;

[0676] or a pharmaceutically acceptable salt or solvate thereof.

[0677] Compound 2: Compound 1 or a pharmaceutically acceptable salt or solvate thereof, wherein: E is -CH 2 -; X is a bond, -CH 2 O-、-CH 2 CH 2 O-、-O-、-N(R 7 )-、-S(O) 2 -、-CH 2 N(R 7 )-or-CH 2 CH 2 N(R 7 )-; Y is a bond, -O- or -N(R 8 )-;R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; each R 2 Independently selected from H and C 1-6 Alkyl; each R 3 Independently selected from H and C 1-6 Alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ; and R9 It is C 1-6 alkyl.

[0678] Compound 2: Compound 1 having a structure of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

[0679]

[0680] Compound 4: Compound 1 having a structure of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

[0681]

[0682] Compound 5: Compound 1 having a structure of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof:

[0683]

[0684] Compound 6: Compound 1 having the structure of formula (Id) or a pharmaceutically acceptable salt or solvate thereof:

[0685]

[0686] Compound 7: Compound 1 having a structure of formula (Ie) or a pharmaceutically acceptable salt or solvate thereof:

[0687]

[0688] Compound 8: Any one of Compounds 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0689] Compound 9: Any one of Compounds 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A 4-membered, 5-membered or 6-membered cycloalkyl ring substituted with a haloalkoxy group.

[0690] Compound 10: Any one of Compounds 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6Alkoxy, C 1-6 Haloalkyl or C 1-6 A 5- or 6-membered heteroaryl ring substituted with a haloalkoxy group.

[0691] Compound 11: Any one of Compounds 1 to 8 or 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0692] Compound 12: Any one of Compounds 1 to 8 or 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0693] Compound 13: Any one of Compounds 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A 5-membered or 6-membered heterocycloalkyl ring or a 4-membered, 5-membered or 6-membered cycloalkyl ring substituted with a haloalkoxy group.

[0694] Compound 14: Compound 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0695] Compound 15: Any one of Compounds 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0696] Compound 16: Compound 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0697]

[0698] Compound 17: Compound 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0699] Compound 18: Any one of Compounds 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0700] Compound 19: Any one of Compounds 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

[0701] Compound 20: Any one of Compounds 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond and Y is a bond.

[0702] Compound 21: Any one of Compounds 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond and Y is -O-.

[0703] Compound 22: Any one of Compounds 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond and Y is -N(H)-.

[0704] Compound 23: Any one of Compounds 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH 2 N(H)- and Y is a bond.

[0705] Compound 24: Any one of Compounds 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(O) 2 - and Y is a bond.

[0706] Compound 25: Any one of Compounds 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 and each R 3 It's H.

[0707] Compound 26: Any one of Compounds 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1, 2 or 3.

[0708] Compound 27: Compound 26, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3.

[0709] Compound 28: Compound 26, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

[0710] Compound 29: Compound 26, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

[0711] Compound 30: Any one of Compounds 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 yes

[0712] Compound 31: Any one of Compounds 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 yes

[0713] Compound 32: Any one of Compounds 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 yes

[0714] Compound 33: Any one of Compounds 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 yes

[0715] Compound 34: Any one of Compounds 1 to 33, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 and -S(O) 2 R 11 .

[0716] Compound 35: Any one of Compounds 1 to 34, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 6 are independently selected from halogen and -CN.

[0717] Compound 36: Any one of Compounds 1 to 35, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2.

[0718] Compound 37: Compound 36, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0719] Compound 38: Compound 36, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

[0720] Compound 39: Any one of Compounds 1 to 33, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0721] Compound 40: a compound 1 selected from the following formula:

[0722]

[0723]

[0724] or a pharmaceutically acceptable salt or solvate thereof. Compound 41: Compound 1 selected from the following formula:

[0725]

[0726]

[0727] or a pharmaceutically acceptable salt or solvate thereof.

[0728] Compound 42: Compound 1 selected from the following formula:

[0729]

[0730] or a pharmaceutically acceptable salt thereof.

[0731] Pharmaceutical composition 43: A pharmaceutical composition comprising any one of Compounds 1 to 42 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0732] Method 44: A method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of Compounds 1 to 42, or a pharmaceutically acceptable salt or solvate thereof.

[0733] Method 45: A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of Compounds 1 to 42, or a pharmaceutically acceptable salt or solvate thereof.

[0734] Method 46: Method 45, wherein the demyelinating disease is a demyelinating disease of the central nervous system.

[0735] Method 47: Method 46, wherein the disease is multiple sclerosis.

[0736] Method 48: Method 45, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0737] Method 49: A method of treating a neuropathic disease, optionally peripheral neuropathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of Compounds 1 to 41, or a pharmaceutically acceptable salt or solvate thereof.

[0738] Method 50: Method 49, wherein the neuropathic disease is diabetic neuropathy.

[0739] Method 51: Any of methods 44 to 50, further comprising administering one or more immunomodulators.

[0740] Method 52: Method 51, wherein the one or more immunomodulators are selected from: IFN-β1 molecules; corticosteroids; polymers of glutamate, lysine, alanine and tyrosine or glatiramer; antibodies or fragments thereof directed against α-4 integrin or natalizumab; anthracenedione molecules or mitoxantrone; fingolimod or FTY720 or other SIPl function modulators; dimethyl fumarate; antibodies directed against the α subunit of the IL-2 receptor of T cells (CD25) or daclizumab; antibodies directed against CD52 or alemtuzumab; antibodies directed against CD20; and dihydroorotate dehydrogenase inhibitors or teriflunomide.

[0741] Method 53: A method for modulating muscarinic acetylcholine receptors in a subject 1 A method for treating a subject with a leukemic activity, comprising administering to the subject any one of Compounds 1 to 41 or a pharmaceutically acceptable salt or solvate thereof.

[0742] Method 54: Method 53, wherein the compound acts as a selective M1 antagonist.

[0743] Compound 55: Compound 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 yes

[0744] Any feature of any exemplary compound, pharmaceutical composition, or method is applicable to any or all other compounds, pharmaceutical compositions, or methods described herein. In addition, any feature of an exemplary compound, pharmaceutical composition, or method may be combined in any manner, in part or in whole, independently with other compounds, pharmaceutical compositions, or methods described herein, for example, the features of one, two, or three or more exemplary compounds, pharmaceutical compositions, or methods may be combined in whole or in part. In addition, any feature of an exemplary compound, pharmaceutical composition, or method may be optional. Any method described herein may be performed using any compound or composition described herein, and any compound or pharmaceutical composition described herein may be used to perform the method described herein.

Claims

1. Use of a compound of formula (IA) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof: in ： E is -CH 2 -, -CH 2 CH 2 - or -O-CH 2 -; X is a key, or -CH 2 N(R 7 )-; Y is a bond; R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution; Each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; Each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Each R 6 are independently selected from deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 alkyl; Each R 9 Independently C 1-6 alkyl; Each R 10 Independently selected from H and C 1-6 alkyl; R 11 It is C 1-6 alkyl; Each R 12 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; Each R 13 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; a is 1 or 2; m is 0, 1, 2, or 3; n is 1 or 2; p is 0, 1, 2, or 3; as well as Each q is independently 0, 1, 2, 3 or 4; wherein each heterocycloalkyl ring and heteroaryl ring independently contains at least one heteroatom selected from nitrogen, oxygen and sulfur.

2. The use according to claim 1, in: E is -CH 2 -; X is a bond or -CH 2 N(R 7 )-; Y is a bond; R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution; Each R 2 Independently selected from H and C 1-6 alkyl; Each R 3 Independently selected from H and C 1-6 alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) 2 R 11 ;as well as R 9 It is C 1-6 alkyl.

3. Use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof: in: X is a key, or -CH 2 N(R 7 )-; Y is a bond; R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution; Each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; Each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Each R 6 are independently selected from deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 alkyl; Each R 9 Independently C 1-6 alkyl; Each R 10 Independently selected from H and C 1-6 alkyl; R 11 It is C 1-6 alkyl; m is 0, 1, 2, or 3; n is 1 or 2; p is 0, 1, 2, or 3; as well as Each q is independently 0, 1, 2, 3 or 4; wherein each heterocycloalkyl ring and heteroaryl ring independently contains at least one heteroatom selected from nitrogen, oxygen and sulfur.

4. Use of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof: in: X is a key, or -CH 2 N(R 7 )-; Y is a bond; R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution; Each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; Each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Each R 6 are independently selected from deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 alkyl; Each R 9 Independently C 1-6 alkyl; Each R 10 Independently selected from H and C 1-6 alkyl; R 11 It is C 1-6 alkyl; m is 0, 1, 2, or 3; n is 1 or 2; p is 0, 1, 2, or 3; as well as Each q is independently 0, 1, 2, 3 or 4; wherein each heterocycloalkyl ring and heteroaryl ring independently contains at least one heteroatom selected from nitrogen, oxygen and sulfur.

5. Use of a compound of formula (Ic) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof: in: X is a key, or -CH 2 N(R 7 )-; Y is a bond; R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution; Each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; Each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Each R 6 are independently selected from deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 alkyl; Each R 9 Independently C 1-6 alkyl; Each R 10 Independently selected from H and C 1-6 alkyl; R 11 It is C 1-6 alkyl; m is 0, 1, 2, or 3; n is 1 or 2; p is 0, 1, 2, or 3; as well as Each q is independently 0, 1, 2, 3 or 4; wherein each heterocycloalkyl ring and heteroaryl ring independently contains at least one heteroatom selected from nitrogen, oxygen and sulfur.

6. Use of a compound of formula (Id) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof: in: X is a key, or -CH 2 N(R 7 )-; Y is a bond; R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution; Each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; Each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Each R 6 are independently selected from deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 alkyl; Each R 9 Independently C 1-6 alkyl; Each R 10 Independently selected from H and C 1-6 alkyl; R 11 It is C 1-6 alkyl; m is 0, 1, 2, or 3; n is 1 or 2; p is 0, 1, 2, or 3; as well as Each q is independently 0, 1, 2, 3 or 4; wherein each heterocycloalkyl ring and heteroaryl ring independently contains at least one heteroatom selected from nitrogen, oxygen and sulfur.

7. Use of a compound of formula (Ie) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof: in: X is a key, or -CH 2 N(R 7 )-; Y is a bond; R 1 yes wherein ring A is a 5- or 6-membered heteroaryl ring, a 5- or 6-membered heterocycloalkyl ring, or a 4-, 5-, or 6-membered cycloalkyl ring, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy substitution; Each R 2 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; Each R 3 independently selected from hydrogen, deuterium, halogen, -OH and C 1-6 alkyl; R 4 yes Each R 5 are independently selected from halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Each R 6 are independently selected from deuterium, halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)(C 1-6 alkyl), -(C(R 10 ) 2 ) q -O-(C 1-6 Alkyl) and -S(O) 2 R 11 ; R 7 is hydrogen or C 1-6 alkyl; Each R 9 Independently C 1-6 alkyl; Each R 10 Independently selected from H and C 1-6 alkyl; R 11 It is C 1-6 alkyl; m is 0, 1, 2, or 3; n is 1 or 2; p is 0, 1, 2, or 3; as well as Each q is independently 0, 1, 2, 3 or 4; wherein each heterocycloalkyl ring and heteroaryl ring independently contains at least one heteroatom selected from nitrogen, oxygen and sulfur.

8. The use according to any one of claims 1 to 7, wherein R 1 yes 9. The use according to any one of claims 1 to 7, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A 4-membered, 5-membered or 6-membered cycloalkyl ring substituted with a haloalkoxy group.

10. The use according to any one of claims 1 to 7, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A 5- or 6-membered heteroaryl ring substituted with a haloalkoxy group.

11. The use according to any one of claims 1 to 7, wherein R 1 yes 12. The use according to any one of claims 1 to 7, wherein R 1 yes 13. The use according to any one of claims 1 to 7, wherein ring A is optionally substituted with halogen, -CN, -N(R 10 ) 2 , C 1-6 Alkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A 5-membered or 6-membered heterocycloalkyl ring or a 4-membered, 5-membered or 6-membered cycloalkyl ring substituted with a haloalkoxy group.

14. The use according to claim 13, wherein R 1 yes 15. The use according to any one of claims 1 to 7, wherein R 1 yes 16. The use according to claim 15, wherein R 1 yes 17. The use according to claim 15, wherein R 1 yes 18. The use according to any one of claims 1 to 7, wherein m is 0.

19. The use according to any one of claims 1 to 7, wherein q is 0.

20. The use according to any one of claims 1 to 7, wherein X is a bond and Y is a bond.

21. The use according to any one of claims 1 to 7, wherein X is -CH 2 N(H)- and Y is a bond.

22. The use according to any one of claims 1 to 7, wherein each R 2 and each R 3 It's H.

23. The use according to any one of claims 1 to 7, wherein n is 2.

24. The use according to any one of claims 1 to 7, wherein n is 1.

25. The use according to any one of claims 1 to 7, wherein R 4 yes 26. The use according to any one of claims 1 to 7, wherein R 4 yes 27. The use according to any one of claims 1 to 7, wherein R 4 yes 28. The use according to any one of claims 1 to 7, wherein R 4 yes 29. The use according to any one of claims 1 to 7, wherein each R 6 are independently selected from halogen, -CN, -N(R 10 ) 2 and -S(O) 2 R 11 .

30. The use according to any one of claims 1 to 7, wherein each R 6 are independently selected from halogen and -CN.

31. The use according to any one of claims 1 to 7, wherein p is 1 or 2.

32. The use according to claim 31, wherein p is 2.

33. The use according to claim 31, wherein p is 1.

34. The use according to any one of claims 1 to 7, wherein p is 0.

35. The use according to claim 1, wherein the compound of formula (IA) is selected from:

36. Use of a compound selected from the following or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof:

37. Use of a compound selected from the following or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a neurodegenerative disease, a demyelinating disease, or a neuropathic disease in a subject in need thereof:

38. The use according to any one of claims 1-7, 35, 36 and 37, wherein the medicament further comprises one or more immunomodulators.

39. The use according to claim 38, wherein the one or more immunomodulators are selected from: IFN-β1 molecules; corticosteroids; polymers of glutamate, lysine, alanine and tyrosine or glatiramer; antibodies or fragments thereof against α-4 integrin or natalizumab; anthracenedione molecules or mitoxantrone; fingolimod or FTY720 or other SIP1 function modulators; dimethyl fumarate; antibodies against the α subunit of the IL-2 receptor of T cells (CD25) or daclizumab; antibodies against CD52 or alemtuzumab; antibodies against CD20; and dihydroorotate dehydrogenase inhibitors or teriflunomide.

40. The use according to any one of claims 1-7, 35, 36 and 37, wherein the demyelinating disease is a demyelinating disease of the central nervous system.

41. The use according to claim 40, wherein the disease is multiple sclerosis.

42. The use according to any one of claims 1-7, 35, 36 and 37, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

43. The use according to any one of claims 1-7, 35, 36 and 37, wherein the neuropathic disease is peripheral neuropathy.

44. The use according to any one of claims 1-7, 35, 36 and 37, wherein the neuropathic disease is diabetic neuropathy.

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