RU2781639C2 - Spirocyclic compounds and methods for their production and use - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to compounds of the formula (II), as well as pharmaceutical compositions based on them.

EFFECT: new compounds are obtained, which can be used as MAGL activity inhibitors.

7 cl, 1 tbl

Description

CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application No. 62/551,721, filed August 29, 2017, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Monoacylglycerol lipase (MAGL) is an enzyme responsible for the hydrolysis of endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate-based lipid, in the nervous system.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides, for example, compounds and compositions that are MAGL modulators and their use as medical agents, processes for their preparation, and pharmaceutical compositions that contain the disclosed compounds as at least one active ingredient. The present invention also contemplates the use of the disclosed compounds as medicaments and/or in the manufacture of medicaments for inhibiting MAGL activity in warm-blooded animals such as humans.

In one aspect, a compound of formula (III) is provided,

where

X represents -CH ₂ - or -C(O)-;

Y is a bond, C _1-6 alkyl, C _1-6 haloalkyl, or C _3-8 cycloalkyl;

R ¹ is H or C _1-6 alkyl;

R ² is H or C _1-6 alkyl;

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -CH ₂ C(O)N(H)SO ₂ R ⁸ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

each R ⁸ is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

n is 0 or 1; and

m is 1 or 2; with the proviso that if n is 0, then m is 2; and if n is 1, then m is 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is a bond. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -CH ₂ -. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is a C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -CH ₂ -. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is C _3-8 cycloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is cyclopropyl.

In another aspect, a compound of formula (I) is provided,

where

X represents -CH ₂ - or -C(O)-;

R ¹ is H or C _1-6 alkyl;

R ² is H or C _1-6 alkyl;

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

n is 0 or 1; and

m is 1 or 2; with the proviso that if n is 0, then m is 2; and if n is 1, then m is 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (I) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is H. In another embodiment, a compound of formula (I) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ² is H. In another embodiment, a compound of formula (I) or (III) or a solvate, hydrate, tautomer thereof, N-oxide, stereoisomer, or pharmaceutically acceptable salt, wherein R ¹ and R ² are both H. In another embodiment, a compound of formula (I) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt, where X represents -CH ₂ -. In another embodiment, a compound of formula (I) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein X is -C(O)-. In another embodiment, a compound of formula (I) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein n is 0 and m is 2. In another embodiment, a compound of formula ( I) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1 and m is 1.

In another aspect, a compound of formula (II) is provided,

where

Y represents -CH ₂ - or -C(O)-;

Z is C _3-6 cycloalkyl;

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

R ¹¹ is H, C _1-6 alkyl or —C _1-6 alkyl-O-C _1-6 alkyl;

R ¹² is C _1-6 alkyl;

R ¹³ is H or C _1-6 alkyl; and

v is 0 or 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹³ is H. In another embodiment, a compound of formula (II) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt, where v is 0. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt, where v is 1 In another embodiment, there is provided a compound of formula (II), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is -C(O)-. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -CH ₂ -. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -C(O)-. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹² is —CH ₃ .

In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring, optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , with two adjacent R ⁴ forming a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two adjacent R ⁴ , with two adjacent R ⁴ forming an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two adjacent R ⁴ , with two adjacent R ⁴ forming a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ⁵ is selected from C _1-6 alkyl, C _{1- 6} heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl, and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (I), (II) is provided. or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is selected from:

В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 5-членное гетероарильное кольцо, замещенное одним, двумя или тремя R⁴, при этом каждый R⁴ независимо выбран из галогена, -CN, С_1-6алкила, С_1-6галогеналкила, С_3-8циклоалкила, С_2-9гетероциклоалкила, фенила, -OR⁷, -СО₂Н и -СН₂СО₂Н, и при этом С_2-9гетероциклоалкил и фенил необязательно замещены одним или двумя R⁵. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 5-членное гетероарильное кольцо, замещенное одним или двумя R⁴, при этом каждый R⁴ независимо выбран из галогена, С_1-6алкила, С_2-9гетероциклоалкила и фенила, и при этом С_2-9гетероциклоалкил и фенил необязательно замещены одним или двумя R⁵, и каждый R⁵ независимо выбран из галогена, С_1-6алкокси, С_2-9гетероциклоалкила или -СО₂Н. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой незамещенное 5-членное гетероарильное кольцо. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 5-членное гетероарильное кольцо, выбранное из пиразольного, тиазольного, изоксазольного, оксазольного и имидазольного кольца. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 6-членное гетероарильное кольцо, замещенное одним, двумя или тремя R⁴, при этом каждый R⁴ независимо выбран из галогена, -С_1-6алкила, С_1-6галогеналкила и С_2-9гетероциклоалкила, где С_2-9гетероциклоалкил необязательно замещен одним или двумя R⁵. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 6-членное гетероарильное кольцо, замещенное одним или двумя R⁴, при этом каждый R⁴ независимо выбран из галогена, С_1-6алкила, С_1-6галогеналкила и С_2-9гетероциклоалкила, где С_2-9гетероциклоалкил необязательно замещен одним R⁵, и R⁵ представляет собой -СО₂Н. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой незамещенное 6-членное гетероарильное кольцо. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 6-членное гетероарильное кольцо, выбранное из пиридинового, пиримидинового, пиридазинового и пиразинового кольца. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 9-10-членное бициклическое гетероарильное кольцо, необязательно замещенное одним, двумя или тремя R⁴. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 9-членное бициклическое гетероарильное кольцо, замещенное одним, двумя или тремя R⁴. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 9-членное бициклическое гетероарильное кольцо, замещенное одним, двумя или тремя R⁴, при этом каждый R⁴ независимо выбран из галогена, -CN, С_1-6алкила, С_1-6галогеналкила, С_3-8циклоалкила, -OR⁷ и -CO₂R⁶. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 9-членное бициклическое гетероарильное кольцо, замещенное одним или двумя R⁴, при этом каждый R⁴ независимо выбран из галогена, С_1-6алкила и С_1-6галогеналкила. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой незамещенное 9-членное бициклическое гетероарильное кольцо. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ представляет собой 9-членное бициклическое гетероарильное кольцо, выбранное из бензотиофенового, индольного, бензимидазольного, бензотиазольного, бензофуранового, бензоксазольного, пиразолопиридинового, имидазопиридинового и пирролопиридинового кольца. В другом варианте осуществления представлено соединение формулы (I), (II) или (III) или его сольват, гидрат, таутомер, N-оксид, стереоизомер или фармацевтически приемлемая соль, где R³ выбран из:

In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ , each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , - CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ independently selected from halo, C _1-6 alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N- oxide, stereoisomer or pharmaceutically acceptable salt, where R ³ represents an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole , thiazole, isoxazole, oxazole and imidazole rings. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , each R ⁴ is independently selected from halogen, -C _1-6 alkyl, C _1-6 haloalkyl and C _2-9 heterocycloalkyl, where C _2-9 heterocycloalkyl is optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I), (II), or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , each R ⁴ being independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, where C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ , and R ⁵ is - CO ₂ H. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine , pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-10 membered bicyclic heteroaryl ring, optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one , two or three R ⁴ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one , two or three R ⁴ , each R ⁴ is independently selected from halo, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ being independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (I), (II) or (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another aspect, a compound of formula (IV) is provided,

where

X is a bond, -C(O)- or -S(O) ₂ -;

R ¹ is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl and C _1-9 heteroaryl; wherein C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl and C _1-9 heteroaryl are optionally substituted with one, two or three R ² ;

each R ² is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl; and

R ³ is H, C _1-6 alkyl or —C _1-6 alkyl-O-C _1-6 alkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is a bond. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -C(O)-. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -S(O) ₂ -. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-6 alkyl. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-6 haloalkyl. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _3-8 cycloalkyl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _2-9 heterocycloalkyl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is phenyl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-9 heteroaryl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is H. In another embodiment, a compound of formula (IV) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ³ represents C _1-6 alkyl.

In another embodiment, a pharmaceutical composition is provided comprising a compound of formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, and at least at least one pharmaceutically acceptable excipient.

In another embodiment, a method is provided to relieve pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide or pharmaceutically acceptable salt. In another embodiment, a method is provided for the management of neuropathic pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) described herein, or a solvate, hydrate thereof , tautomer, N-oxide, or a pharmaceutically acceptable salt. In another embodiment, a method is provided to relieve pain associated with inflammation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) described herein, or solvate, hydrate, tautomer, N-oxide or pharmaceutically acceptable salt.

In another embodiment, a method of treating a disease or disorder in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV) described herein, or a solvate thereof. , a hydrate, a tautomer, an N-oxide, or a pharmaceutically acceptable salt, wherein the disease is selected from migraine, epilepsy/seizure disorder, neuromyelitis optic nerve (NMO), Tourette's syndrome, chronic motor tic disorder, chronic vocal tic disorder, and abdominal pain associated with irritable bowel syndrome. In another embodiment, a method is provided for treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide or pharmaceutically acceptable salt. In another embodiment, a method is provided for treating epilepsy/seizure disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) described herein, or a solvate thereof. , hydrate, tautomer, N-oxide or pharmaceutically acceptable salt. In another embodiment, a method is provided for treating neuromyelitis optic nerve (NMO) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) described herein, or its solvate, hydrate, tautomer, N-oxide or pharmaceutically acceptable salt. In another embodiment, a method of treating Tourette's syndrome in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) described herein, or a solvate, hydrate thereof , tautomer, N-oxide, or a pharmaceutically acceptable salt. In another embodiment, a method of treating a chronic motor tic disorder in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV) described herein, or a solvate thereof. , hydrate, tautomer, N-oxide or pharmaceutically acceptable salt. In another embodiment, a method of treating a chronic vocal tic disorder in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV) described herein, or a solvate thereof. , hydrate, tautomer, N-oxide or pharmaceutically acceptable salt. In another embodiment, a method is provided for the management of abdominal pain associated with irritable bowel syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) described in herein, or a solvate, hydrate, tautomer, N-oxide or pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates, at least in part, to MAGL modulators or inhibitors. For example, compounds provided herein are capable of inhibiting MAGL.

As used herein and in the appended claims, the singular form includes the plural form of the entity being defined, unless the context clearly indicates otherwise. Thus, for example, reference to "agent" includes a plurality of such agents, and reference to a "cell" includes reference to one or more cells (or a plurality of cells) and their equivalents. When ranges are used herein to describe physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments thereof are intended to be included. The term "approximately", when referring to a number or range of numbers, means that the number or range of numbers to which it refers is an approximation within the variation of readings from experiment to experiment (or within the statistical error of an experiment), and thus thus, the number or number range varies from 1% to 15% of the specified number or number range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "comprising") is not intended to exclude an element that, in some other embodiments, such as an embodiment of any compositions in accordance with the present invention, composition, method or process, or the like, described in this document may "consist of" or "essentially consist of" the features described.

Definitions

When used in this specification and the appended claims, unless otherwise indicated, the following expressions have the meaning given below.

As used herein, C ₁ -C _x includes C ₁ -C ₂ , C ₁ -C ₃ ... C ₁ -C _x . C ₁ -C _x means the number of carbon atoms that form the fragment that it denotes (excluding optional substituents).

"Amino" means the radical -NH ₂ .

"Cyano" means the -CN radical.

"Nitro" means the radical -NO ₂ .

"Oxa" means the radical -O-.

"Oxo" means the radical =O.

"Thioxo" means the radical =S.

"Imino" means the radical =N-H.

"Oximo" means the radical =N-OH.

"Alkyl" or "alkylene" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds, having from one to fifteen carbon atoms (eg, C ₁ -C ₁₅ alkyl). In certain embodiments, the implementation of the alkyl contains from one to thirteen carbon atoms (for example, C ₁ -C ₁₃ alkyl). In certain embodiments, the implementation of the alkyl contains from one to eight carbon atoms (for example, C ₁ -C ₈ alkyl). In other embodiments, the implementation of the alkyl contains from one to six carbon atoms (for example, C ₁ -C ₆ alkyl). In other embodiments, the implementation of the alkyl contains from one to five carbon atoms (for example, C ₁ -C ₅ alkyl). In other embodiments, the implementation of the alkyl contains from one to four carbon atoms (eg, C ₁ -C ₄ alkyl). In other embodiments, the implementation of the alkyl contains from one to three carbon atoms (for example, C ₁ -C ₃ alkyl). In other embodiments, the implementation of the alkyl contains from one to two carbon atoms (for example, C ₁ -C ₂ alkyl). In other embodiments, the implementation of the alkyl contains one carbon atom (for example, C ₁ alkyl). In other embodiments, the implementation of the alkyl contains from five to fifteen carbon atoms (for example, C ₅ -C ₁₅ alkyl). In other embodiments, the implementation of the alkyl contains from five to eight carbon atoms (for example, C ₅ -C ₈ alkyl). In other embodiments, the implementation of the alkyl contains from two to five carbon atoms (for example, C ₂ -C ₅ alkyl). In other embodiments, the implementation of the alkyl contains from three to five carbon atoms (for example, 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 is attached to the rest of the molecule by a single bond. Unless otherwise specifically stated in the description, the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl .

"Alkoxy" means a radical linked via an oxygen atom, of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

"Alkenyl" means a straight or branched hydrocarbon radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having from two to twelve carbon atoms. In certain embodiments, the implementation of alkenyl contains from two to eight carbon atoms. In other embodiments, the implementation of alkenyl contains from two to six carbon atoms. In other embodiments, the implementation of alkenyl contains from two to four carbon atoms. Alkenyl is attached to the rest of the molecule via a single bond, e.g. ethenyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but-1-enyl, pent-1-enyl, penta-1,4 -dienyl, etc. Unless otherwise specifically stated in the description, the alkenyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl .

"Alkynyl" means a straight or branched hydrocarbon radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond having from two to twelve carbon atoms. In certain embodiments, the alkynyl contains two to eight carbon atoms. In other embodiments, the alkynyl contains two to six carbon atoms. In other embodiments, the alkynyl contains two to four carbon atoms. The alkynyl is attached to the rest of the molecule via a single bond, eg ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specifically stated in the description, the alkynyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl .

"Aryl" means a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removal of a hydrogen atom from a carbon atom of the ring. The aromatic monocyclic or polycyclic hydrocarbon ring system contains exclusively hydrogen and six to eighteen carbon atoms, with at least one of the rings in the ring system being completely unsaturated, i.e. it contains a cyclic delocalized π-electron system containing (4n+2) π-electrons, in accordance with Hückel's theory. The ring system from which the aryl groups are derived includes, without limitation, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl , cyano, nitro, aryl, aralkyl, aralkenyl, aralkinil, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each R ^b is independently is a straight bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain.

"Aryloxy" means a radical linked via an oxygen atom, of the formula -O-aryl, where aryl is defined above.

"Aralkyl" means a radical of the formula -R ^c -aryl, where R ^c is an alkylene chain as defined above, eg methylene, ethylene, and the like. The portion of the aralkyl radical which is the alkylene chain is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for the aryl group.

"Aralkyloxy" means a radical bonded via an oxygen atom, of the formula -O-aralkyl, where aralkyl is defined above.

"Aralkenyl" means a radical of the formula -R ^d -aryl, where R ^d is an alkenylene chain as defined above. The aryl portion of the aralkenyl radical is optionally substituted as described above for the aryl group. The portion of the aralkenyl radical which is the alkenylene chain is optionally substituted as defined above for the alkenylene group.

"Aralkynyl" means a radical of the formula -R ^e -aryl, where R ^e is an alkynylene chain as defined above. The aryl portion of the aralkynyl radical is optionally substituted as described above for the aryl group. The portion of the aralkynyl radical which is the alkynylene chain is optionally substituted as defined above for the alkynylene chain.

"Cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems having three to fifteen carbon atoms. In certain embodiments, the implementation of cycloalkyl contains from three to ten carbon atoms. In other embodiments, the implementation of cycloalkyl contains from five to seven carbon atoms. Cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyl is saturated (ie, containing only C-C single bonds) or partially unsaturated (ie, containing one or more double bonds). Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In certain embodiments, the implementation of cycloalkyl contains from three to eight carbon atoms (for example, C ₃ -C ₈ cycloalkyl). In other embodiments, the implementation of cycloalkyl contains from three to seven carbon atoms (for example, C ₃ -C ₇ cycloalkyl). In other embodiments, the implementation of cycloalkyl contains from three to six carbon atoms (for example, C ₃ -C ₆ cycloalkyl). In other embodiments, the implementation of cycloalkyl contains from three to five carbon atoms (for example, C ₃ -C ₅ cycloalkyl). In other embodiments, the implementation of cycloalkyl contains from three to four carbon atoms (for example, C ₃ -C ₄ cycloalkyl). Partially unsaturated cycloalkyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenil, aralkinil, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each R ^b is independently is a straight bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain.

"Halogen" or "halogen" means substituents representing bromine, chlorine, fluorine or iodine.

"Haloalkyl" means an alkyl radical as defined above which is substituted by one or more halogen radicals as defined above.

"Haloalkoxy" means an alkoxy radical as defined above which is substituted by one or more halogen radicals as defined above.

"Fluoroalkyl" means an alkyl radical as defined above which is substituted by one or more fluorine radicals as defined above, e.g. . The alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for the alkyl group.

"Heteroalkyl" means a straight or branched chain alkyl radical free of unsaturation, having from one to fifteen carbon atoms (e.g., C ₁ -C ₁₅ alkyl), consisting of carbon and hydrogen atoms and one or two heteroatoms selected from O, N and S, where the nitrogen or sulfur atoms may be optionally oxidized and the nitrogen atom may be quaternized. The heteroatom(s) may be located(s) at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the moiety to which it is attached. The heteroalkyl is attached to the rest of the molecule by a single bond. Unless otherwise specifically stated in the description, the heteroalkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl .

"Heterocycloalkyl" means a stable 3-18 membered non-aromatic ring radical which contains two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, a heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which includes fused, spiro- or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. In some embodiments, the heterocycloalkyl is attached to the rest of the molecule via any atom of the ring(s). Examples of such heterocycloalkyl radicals include, without limitation, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperazolidinyl, oxazolidinyl, , 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thioxo, cyano, nitro, aryl , aralkyl, aralkenyl, aralkinil, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl, alkyl, alkyl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each R ^b is independently a straight bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain.

"Heteroaryl" means a radical derived from a 5-18 membered aromatic ring radical which contains from one to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i. it contains a cyclic delocalized π-electron system containing (4n+2) π-electrons, in accordance with Hückel's theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is(are) optionally oxidized(s). One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule via any atom of the ring(s). Unless otherwise specifically stated in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thioxo, cyano, nitro, aryl , aralkyl, aralkenyl, aralkinil, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl a, -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 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl, alkyl, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R ^b independently represents a straight bond or a straight or branched alkylene or alkenylene chain, and R ^c represents a straight or branched alkylene or alkenylene chain.

"N-heteroaryl" means a heteroaryl radical as defined above, which contains at least one nitrogen atom, and in which the point of attachment of the heteroaryl radical to the rest of the molecule is the nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

"C-heteroaryl" means a heteroaryl radical as defined above, wherein the point of attachment of the heteroaryl radical to the rest of the molecule is the carbon atom of the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

"Heteroaryloxy" means a radical linked via an oxygen atom, of the formula -O-heteroaryl, where heteroaryl is defined above.

"Heteroarylalkyl" means a radical of the formula -R ^c -heteroaryl, where R ^c represents an alkylene chain as defined above. If heteroaryl is a nitrogen-containing heteroaryl, then the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for the heteroaryl group.

"Heteroarylalkoxy" means a radical linked via an oxygen atom, of the formula -OR ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If heteroaryl is a nitrogen-containing heteroaryl, then the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroaryl alkoxy radical is optionally substituted as defined above for the heteroaryl group.

In some embodiments, the compounds disclosed herein contain one or more centers of asymmetry and thus form enantiomers, diastereomers, and other stereoisomeric forms that are defined in terms of absolute stereochemistry as (R)- or as (S)-. Unless otherwise indicated, all stereoisomeric forms of the compounds disclosed herein are intended to be considered within the context of the present invention. When the compounds described herein contain alkene double bonds, and unless otherwise indicated, the present invention is intended to include both E- and Z-geometric isomers (e.g., cis or trans). that all possible isomers are included, as well as their racemic and optically pure forms, and all tautomeric forms. The term "geometric isomer" means the E or Z geometric isomers (eg cis or trans) of an alkene double bond. The term "positional isomer" means structural isomers with respect to the central ring, such as ortho, meta and para isomers with respect to the benzene ring.

"Tautomer" means a molecule where a proton shift is possible from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein are in the form of tautomers. Under conditions where tautomerization is possible, there will be a chemical equilibrium of the tautomers. The exact ratio of tautomers depends on several factors, including physical condition, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following.

"Optional" or "optionally" implies that the event or circumstance described below may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl radical is substituted or unsubstituted, and that the description includes both substituted aryl radicals and unsubstituted aryl radicals.

A "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any of the compounds described herein is intended to encompass any and all forms of pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutical acid addition salt" means those salts which retain the biological efficacy and free base properties which are not biologically or otherwise undesirable and which are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, and the like. Also included are salts formed using organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and they include, for example, acetic 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, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Amino acid salts such as arginates, gluconates and galacturonates are also contemplated (see, for example, Berge S. M. 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 forms with enough of the desired acid to form the salt.

"A pharmaceutically acceptable base addition salt" means those salts which retain the biological efficacy and free acid properties which are not biologically or otherwise undesirable. Such salts are obtained by adding an inorganic base or an organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, without limitation, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, 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, chlorprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

As used herein, the terms "treatment" or "treatment" or "mitigation" or "alleviation" are used interchangeably herein. Such terms mean an approach to obtain beneficial or desired results, including without limitation therapeutic benefit and/or prophylactic benefit. By "therapeutic benefit" is meant the elimination or amelioration of the underlying disorder being treated. Also, therapeutic benefit is achieved by eliminating or reducing the intensity of one or more physiological symptoms associated with the underlying disorder, so that the patient is improved despite the fact that the patient is still affected by the underlying disorder. In the case of prophylactic benefit, the compositions are administered to a patient at risk for developing a particular disease, or to a patient who exhibits one or more physiological symptoms of a disease, despite the fact that the disease has not been diagnosed.

Connections

Compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described in this document are MAGL modulators. In some embodiments, the compounds are MAGL inhibitors. Compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described in this document, and compositions containing such compounds are useful in the treatment of pain.

In some embodiments, a compound of formula (I) is provided,

where

X represents -CH ₂ - or -C(O)-;

R ¹ is H or C _1-6 alkyl;

R ² is H or C _1-6 alkyl;

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

n is 0 or 1; and

m is 1 or 2; with the proviso that if n is 0, then m is 2; and if n is 1, then m is 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein n is 0 and m is 2. In another embodiment, a compound of formula (I) is provided, or solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where n is 1 and m is 1.

In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is H. In another embodiment, a compound of formula (I) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ¹ represents C _1-6 alkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is —CH ₃ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ² is H. In another embodiment, a compound of formula (I) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ² represents C _1-6 alkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ² is —CH ₃ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is H and R ² is H. In another embodiment, a compound of formula ( I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ¹ is H and R ² is C _1-6 alkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is H and R ² is —CH ₃ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-6 alkyl and R ² is H. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is represented, wherein R ¹ is —CH ₃ and R ² is H. In another embodiment, a compound of formula (I) is represented or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-6 alkyl and R ² is C _1-6 alkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is —CH ₃ and R ² is —CH ₃ .

In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -CH ₂ -. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -C(O)-.

In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is —CH ₂ CO ₂ H. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is —CO ₂ H. In another an embodiment is a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (I) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In some embodiments, a compound of formula (I) is provided having the structure of formula (Ia),

where

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl; and

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is —CH ₂ CO ₂ H. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is —CO ₂ H. In another an embodiment is a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (Ia) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In some embodiments, a compound of formula (I) is provided having the structure of formula (Ib),

where

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl; and

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _3-8 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl; and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is -C ₁ -C ₆ alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is -CO ₂ H. In another an embodiment is a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (Ib) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In some embodiments, a compound of formula (I) is provided having the structure of formula (Ic),

where

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl; and

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl; and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is -CO ₂ H. In another in an embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine, and pyrazine rings. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _3-8 aloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is O-ehaloalkyl. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (Ic) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In some embodiments, a compound of formula (I) is provided having the structure of formula (Id),

where

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl; and

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl; and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutical a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R3 is an oxazole ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is -CO ₂ H. In another an embodiment is a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (Id) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (II) is provided,

where

Y represents -CH ₂ - or -C(O)-;

Z is C _3-6 cycloalkyl;

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C ₂ - ₉ heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

R ¹¹ is H, C _1-6 alkyl or -C _1-6 alkyl-O-C _1-6 alkyl;

R ¹² is C _1-6 alkyl;

R ¹³ is H or C _1-6 alkyl; and

v is 0 or 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹³ is H. In another embodiment, a compound of formula (II) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ¹³ represents C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹³ is —CH ₃ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹³ is —CH ₂ CH ₃ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹² is —CH ₃ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹² is —CH ₃ and R ¹³ is H. In another embodiment, a compound formula (II) or its solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ¹² represents -CH ₃ and R ¹³ represents C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹² is —CH ₃ and R ¹³ is —CH ₃ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹² is —CH ₃ and R ¹³ is —CH ₂ CH ₃ .

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is H. In another embodiment, a compound of formula (II) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ¹¹ represents C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₃ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₂ CH ₃ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is -C _1-6 alkyl-O-C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —C _1-6 alkyl-OCH ₃ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₂ CH ₂ OCH ₃ .

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -CH ₂ -. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -C(O)-.

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided wherein v is 0. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer thereof is provided. , N-oxide, stereoisomer, or pharmaceutically acceptable salt, wherein v is 1. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein v is 1, and Z is cyclopropyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein v is 1 and Z is cyclobutyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein v is 1 and Z is cyclopentyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein v is 1 and Z is cyclohexyl.

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is -CO ₂ H. In another an embodiment is a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R3 is a pyrimidine ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (II) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, there is provided a compound of formula (II) having the structure of formula (IIa),

where

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl; and

R ¹¹ is C _1-6 alkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₃ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₂ CH ₃ .

In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R5. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl; and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutical a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is -CO ₂ H. In another in an embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine, and pyrazine rings. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and ^-CO ₂ R ₆ . In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (IIa) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, there is provided a compound of formula (II) having the structure of formula (IIb),

where

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl; and

R ¹¹ is C _1-6 alkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₃ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₂ CH ₃ .

In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is —CO ₂ H. In another in an embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine, and pyrazine rings. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl, and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (IIb) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, there is provided a compound of formula (II) having the structure of formula (IIc),

where

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, -C _1-6 alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ and -CH ₂ CO ₂ R ⁶ ; wherein C _2-9 heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ ; or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, with the cycloalkyl and heterocycloalkyl ring optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-9 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl; and

R ¹¹ is C _1-6 alkyl or -C _1-6 alkyl-O-C _1-6 alkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is C _1-6 alkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₃ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₂ CH ₃ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is -C _1-6 alkyl-O-C _1-6 alkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —C _1-6 alkyl-OCH ₃ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹¹ is —CH ₂ CH ₂ OCH ₃ .

In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl; and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , where each R ⁴ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is —CO ₂ H. In another an embodiment is a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ , when each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (IIc) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In some embodiments, a compound of formula (III) is provided,

where

X represents -CH ₂ - or -C(O)-;

Y is a bond, C _1-6 alkyl, C _1-6 haloalkyl, or C _3-8 cycloalkyl;

R ¹ is H or C _1-6 alkyl;

R ² is H or C _1-6 alkyl;

R ³ is a 5-6 membered heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring; wherein the 5-6 membered heteroaryl ring and the 9-10 membered bicyclic heteroaryl ring are optionally substituted with one, two or three R ⁴ ;

each R ⁴ is independently selected from C _1-6 alkyl, halogen, -CN, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, _{-C 1-6} alkyl-(C _2-9 heterocycloalkyl), phenyl, -CH ₂ -phenyl, C _1-9 heteroaryl, -OR ⁷ , -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -CH ₂ C(ON(H)SO ₂ R ⁸ ; while C _{2 -9} heterocycloalkyl, -C _1-6 alkyl(C _2-9 heterocycloalkyl), phenyl and C _1-9 heteroaryl are optionally substituted with one or two R ⁵ , or two adjacent R ⁴ form a 6-membered cycloalkyl or 6-membered heterocycloalkyl ring, wherein the cycloalkyl and heterocycloalkyl rings are optionally substituted with one or two R ⁵ ;

each R ⁵ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl ), C _2-9 heterocycloalkyl, -CO ₂ R ⁶ , -CH ₂ CO ₂ R ⁶ and -C _1-6 alkyl(C _2-9 heterocycloalkyl) optionally substituted with C _1-6 alkyl;

each R ⁶ is independently selected from H and C _1-6 alkyl;

each R ⁷ is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl;

each R ⁸ is independently selected from C _1-6 alkyl, C _1-6 haloalkyl and C _3-8 cycloalkyl;

n is 0 or 1; and

m is 1 or 2; with the proviso that if n is 0, then m is 2; and if n is 1, then m is 1;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein n is 0 and m is 2. In another embodiment, a compound of formula (III) is provided, or solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where n is 1 and m is 1.

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is H. In another embodiment, a compound of formula (III) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ¹ represents C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is —CH ₃ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ² is H. In another embodiment, a compound of formula (III) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ² represents C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ² is —CH ₃ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is H and R ² is H. In another embodiment, a compound of formula ( III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ¹ is H and R ² is C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is H and R ² is —CH ₃ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-6 alkyl and R ² is H. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is represented, wherein R ¹ is —CH ₃ and R ² is H. In another embodiment, a compound of formula (III) is represented or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-6 alkyl and R ² is C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is —CH ₃ and R ² is —CH ₃ .

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -CH ₂ -. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -C(O)-.

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is a bond. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -CH ₂ -. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is -CF ₂ -. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is C _3-8 cycloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein Y is cyclopropyl.

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-6 membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5-membered heteroaryl ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ s, with two adjacent R ⁴ form a 6-membered heterocycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered heterocycloalkyl ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is selected from C _1-6 alkyl, C _1-6 heteroalkyl, C _3-8 cycloalkyl, -C _1-6 alkyl(C _3-8 cycloalkyl), C _2-9 heterocycloalkyl and -CH ₂ CO ₂ H. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl a ring substituted by two adjacent R ⁴ , wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted by one R ⁵ , and R ⁵ is C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _1-6 heteroalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _3-8 cycloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is —C _1-6 alkyl(C _3-8 cycloalkyl). In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ , and R ⁵ is C _2-9 heterocycloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered heterocycloalkyl ring substituted with one R ⁵ and R ⁵ is -CH ₂ CO ₂ H. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically a suitable salt wherein R ³ is a 5-membered heteroaryl ring substituted with two or three R ⁴ , whereby two adjacent R ⁴ forms a 6-membered cycloalkyl ring optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form an unsubstituted 6-membered cycloalkyl ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted by two adjacent R ⁴ s, wherein the two adjacent R ⁴ form a 6-membered cycloalkyl ring substituted with one R ⁵ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _2-9 heterocycloalkyl and phenyl, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ , and each R ⁵ is independently selected from halogen, C _{1- 6} alkoxy, C _2-9 heterocycloalkyl, or —CO ₂ H. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 5- membered heteroaryl ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 5-membered heteroaryl ring selected from pyrazole, thiazole, isoxazole, oxazole, and imidazole rings. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazole ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a thiazole ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an isoxazole ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an oxazole ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an imidazole ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 6-membered heteroaryl ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl, -OR ⁷ , -CO ₂ H and -CH ₂ CO ₂ H, wherein C _2-9 heterocycloalkyl and phenyl are optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one, two or three R ⁴ , wherein each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, with C _2-9 heterocycloalkyl optionally substituted with one or two R ⁵ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 6-membered heteroaryl ring substituted with one or two R ⁴ , wherein each R ⁴ is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, and C _2-9 heterocycloalkyl, wherein C _2-9 heterocycloalkyl is optionally substituted with one R ⁵ and R ⁵ is —CO ₂ H. In another an embodiment is a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, wherein R ³ is a 6-membered heteroaryl ring selected from pyridine, pyrimidine, pyridazine and pyrazine rings. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridine ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrimidine ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyridazine ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a pyrazine ring.

In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9- or 10-membered bicyclic heteroaryl ring optionally substituted with one, two, or three ^R4 . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 9-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 9-membered bicyclic heteroaryl ring selected from benzothiophene, indole, benzimidazole, benzothiazole, benzofuran, benzoxazole, pyrazolopyridine, imidazopyridine and pyrrolopyridine rings. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring optionally substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is an unsubstituted 10-membered bicyclic heteroaryl ring. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two or three R ⁴ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one, two, or three R ⁴ , wherein each R ⁴ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OR ⁷ and -CO ₂ R ⁶ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -OC _1-6 alkyl and -CO ₂ R ⁶ . In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one or two R ⁴ , each R ⁴ is independently selected from halo, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a halogen. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is C _1-6 alkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring substituted with one R ⁴ , wherein R ⁴ is is a C _1-6 haloalkyl. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is a 10-membered bicyclic heteroaryl ring selected from quinolone, isoquinolone, quinazoline, quinoxaline, phthalazine and naphthyridine rings. In another embodiment, a compound of formula (III) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is selected from:

In another embodiment, a compound of formula (IV) is provided,

where

X is a bond, -C(O)- or -S(O) ₂ -;

R ¹ is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl and C _1-9 heteroaryl; wherein C _3-8 cycloalkyl, C _2-9 heterocycloalkyl, phenyl and C _1-9 heteroaryl are optionally substituted with one, two or three R ² ;

each R ² is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl; and R ³ is H, C _1-6 alkyl or —C _1-6 alkyl-O-C _1-6 alkyl; or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is H. In another embodiment, a compound of formula (IV) or a solvate, hydrate thereof is provided. , tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt, where R ³ represents C _1-6 alkyl. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is —CH ₃ . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is —CH ₂ CH ₃ . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ³ is -C _1-6 alkyl-O-C _1-6 alkyl.

In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is a bond. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -C(O)-. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein X is -S(O) ₂ -.

In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-6 alkyl. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-6 haloalkyl. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _3-8 cycloalkyl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _3-8 cycloalkyl optionally substituted with one halogen atom. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _3-8 cycloalkyl optionally substituted with one C _1-6 alkyl. In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _2-9 heterocycloalkyl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is phenyl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-9 heteroaryl optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-9 heteroaryl selected from oxazole and pyrazine; wherein the oxazole and pyrazine are optionally substituted with one, two or three R ² . In another embodiment, a compound of formula (IV) or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof is provided, wherein R ¹ is C _1-9 heteroaryl selected from oxazole and pyrazine; while oxazole and pyrazine are unsubstituted.

Additional embodiments provided herein include combinations of one or more of the specific embodiments set forth above.

In some embodiments, a compound disclosed herein is selected from Examples 1-229.

In another embodiment, a compound is provided having the structure:

where R ¹ , R ² , R ³ , X, m and n are defined in the formula (I) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ¹ , R ² , R ³ , X, m and n are defined in the formula (I) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Ia) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Ia) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Ib) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Ib) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Ic) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Ic) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Id) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ is defined in the formula (Id) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ , R ¹¹ , R ¹² , R ¹³ , Y, Z and v are defined in the formula (II) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ , R ¹¹ , R ¹² , R ¹³ , Y, Z and v are defined in the formula (II) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ and R ¹¹ are defined in the formula (IIa) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ and R ¹¹ are defined in the formula (IIa) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ and R ¹¹ are defined in the formula (IIb) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ and R ¹¹ are defined in the formula (IIb) described in this document, and x and y represent at least one amino acid (aa).

In another embodiment, a compound is provided having the structure:

where R ³ and R ¹¹ are defined in the formula (IIc) described in this document, and x and y represent at least one amino acid (aa). In another embodiment, a compound is provided having the structure:

where R ³ and R ¹¹ are defined in the formula (IIc) described in this document, and x and y represent at least one amino acid (aa).

This document describes monoacylglycerol lipase (MAGL) inhibitors characterized by the structure of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), ( III), or (IV). In one embodiment, the MAGL inhibitors are covalent MAGL inhibitors, i. compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) react with serine residue in MAGL to form a modified serine residue containing the remaining group in formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc) , (III), or (IV); in such an embodiment, the leaving group in formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or ( IV) is removed from a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) . In a further embodiment, covalent inhibitors of MAGL react irreversibly with a serine residue in MAGL to form a modified serine residue.

Часть в соединениях формулы (Ia), которая является остающейся группой, представляет собой

Часть в соединениях формулы (Ib), которая является остающейся группой, представляет собой

Часть в соединениях формулы (Ic), которая является остающейся группой, представляет собой

Часть в соединениях формулы (Id), которая является остающейся группой, представляет собой

Часть в соединениях формулы (II), которая является остающейся группой, представляет собой

Часть в соединениях формулы (IIa), которая является остающейся группой, представляет собой

Часть в соединениях формулы (IIb), которая является остающейся группой, представляет собой

Часть в соединениях формулы (IIc), которая является остающейся группой, представляет собой

Часть в соединениях формул (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), или (IV), которая является уходящей группой, представляет собой

The portion in the compounds of formula (I) which is the remaining group is

The portion in the compounds of formula (Ia) which is the remaining group is

The portion in the compounds of formula (Ib) which is the remaining group is

The portion in the compounds of formula (Ic) which is the remaining group is

The portion in the compounds of formula (Id) which is the remaining group is

The portion in the compounds of formula (II) which is the remaining group is

The portion in the compounds of formula (IIa) which is the remaining group is

The portion in the compounds of formula (IIb) which is the remaining group is

The portion in the compounds of formula (IIc) which is the remaining group is

The part in compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) which is a leaving group, is

Getting connections

The compounds used in the reactions described herein are prepared according to organic synthetic procedures using commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Acros Organics (Gehl, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, Illinois), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hopog, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardina, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, Maryland) and WuXi (Shanghai, China).

Suitable reference books and scientific papers that describe in detail the synthesis of reagents useful in the preparation of the compounds described herein, or which provide links to articles that describe the preparation, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons , Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 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 this document, or which provide links to articles that describe preparation, include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "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, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "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, in 8 volumes; "Organic Reactions" (1942-2000) by John Wiley & Sons, in more than 55 volumes and "Chemistry of Functional Groups" by John Wiley & Sons, in 73 volumes.

Specific and similar reagents can also be identified using the American Chemical Society Chemical Abstracts Index of Known Chemicals, available from many public and university libraries, and online databases (American Chemical Society, Washington, DC). Chemicals that are known but not commercially available in catalogs are not necessarily made to order from chemical synthesis plants, with many of the standard chemical plants (eg listed above) providing custom synthesis services. By reference to the preparation and selection of pharmaceutical salts of the compounds described herein, P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Additional Forms of Compounds Disclosed Herein

Isomers

In addition, in some embodiments, the compounds described herein are in the form of geometric isomers. In some embodiments, the implementation of the compounds described in this document contain one or more double bonds. The compounds provided herein include all cis-, trans-, syn-, anti-, "entgegen-" (E-), and "zusammen-" (Z-) isomers, as well as their respective mixtures. In some situations, the compounds are in the form of tautomers. The compounds described in this document include all possible tautomers corresponding to the formulas described in this document. In some situations, the compounds described herein contain one or more chiral centers, and each center is in the R-configuration or in the S-configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms, as well as their respective mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers obtained in a single preparation step, by mixing or by interconversion, are applicable in the applications described herein. In some embodiments, the compounds described herein are obtained as optically pure enantiomers by chiral chromatographic resolution of a racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes (eg, crystalline diastereomeric salts) are preferred. In some embodiments, diastereomers have different physical properties (eg, melting points, boiling points, solubility, reactivity, etc.) and are separated using such differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation/separation techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical method that does not result in racemization.

Labeled compounds

In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those specified herein, except that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that are included in the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. The compounds described herein and their pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives which contain the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful for drug and/or substrate tissue distribution analysis. Isotopes of tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly preferred due to their ease of preparation and detection. In addition, substitution by heavy isotopes such as deuterium, ie. ² H provides some therapeutic advantages, due to higher metabolic stability, for example, an increase in the half-life in vivo or a decrease in the required dose. In some embodiments, the isotopically labeled compounds, a pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.

In some embodiments, the compounds described herein are labeled using other methods, including, without limitation, using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein are in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

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

solvates

In some embodiments, the compounds described herein are in the form of solvates. In some embodiments, methods for treating diseases are provided by administering such solvates. In addition, this document describes methods of treating diseases by administering such solvates in the form of pharmaceutical compositions.

The solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during a crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are, for convenience, prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from a mixture of aqueous/organic solvents using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein are in unsolvated as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated forms are considered equivalent to the unsolvated forms.

Prodrugs

In some embodiments, the compounds described herein are in the form of a prodrug. Also described herein are methods of treating diseases by administering such prodrugs. In addition, this document describes methods of treating diseases, carried out by administering such prodrugs in the form of pharmaceutical compositions.

In some embodiments, prodrugs include compounds wherein an amino acid residue or polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked via an amide or ester bond to a free amino, hydroxy, or carboxylic acid residue group in compounds described in this document. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone . In other embodiments, prodrugs include compounds in which a nucleic acid residue or an oligonucleotide of two or more (eg, two, three, or four) nucleic acid residues is covalently linked to a compound described herein.

Pharmaceutically acceptable prodrugs of the compounds described herein also include, without limitation, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, tertiary amine quaternary derivatives, N-substituted Mannich bases, Schiff bases, amino acid conjugates, esters. phosphoric acid, metal salts and sulfonic acid esters. In some embodiments, compounds having free amino, amido, hydroxy, or carboxyl groups are converted into prodrugs. For example, free carboxyl groups are derivatized as amides or alkyl esters. In some instances, all such prodrug moieties include groups including, but not limited to, ether, amine, and carboxylic acid functional groups.

Hydroxy-containing prodrugs include esters such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphoric acid esters, sulfonic acid esters, sulfuric acid esters , disulfide containing esters, ethers, amides, carbamates, hemisuccinates, dimethylamino acetates, and phosphoryloxymethyloxycarbonyls as listed in Advanced Drug Delivery Reviews 1996, 19, 115.

Prodrugs that are amine derivatives include, without limitation, the following groups and combinations of groups:

as well as sulfonamides and phosphonamides.

In some cases, sites in any part of the aromatic ring are subject to various metabolic reactions, therefore, the introduction of appropriate substituents on aromatic ring structures reduces, minimizes or eliminates this metabolic pathway.

Pharmaceutical compositions

In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) , described in this document, is administered in the form of a chemically pure substance. In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein is combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) excipient, a physiologically acceptable (or acceptable) excipient, or a physiologically acceptable (or acceptable) carrier), selected depending on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

Accordingly, provided herein is a pharmaceutical composition comprising at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc ), (III), or (IV) described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) are(are) acceptable(s) or suitable(s) if the carrier is compatible with the other ingredients of the composition and is not harmful to the recipient (t .e. subject) composition.

In one embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (Ib) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (Ic) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (Id) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (II) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (IIa) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (IIb) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient and a compound of formula (IIc) or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (Ib) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (Ic) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (Id) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (II) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (IIa) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (IIb) or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided essentially consisting of a pharmaceutically acceptable excipient and a compound of formula (IIc) or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) , described herein, is substantially pure, that is, it contains less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as contaminating intermediates or by-products that are formed, for example , at one or more stages of the synthesis process.

Such formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, ophthalmic, or aerosol administration, although the most appropriate form of administration in any particular instance will depend on the extent and severity of the condition, to be treated, and the nature of the particular compound used. For example, the disclosed compositions are formulated as a unit dose and/or formulated for oral or subcutaneous administration.

Exemplary pharmaceutical compositions are administered in the form of a pharmaceutical preparation, e.g., in solid, semi-solid, or liquid form, which contains one or more of the disclosed compounds as the active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. applications. In some embodiments, the active ingredient is formulated, for example, with standard non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active compound of the present invention is included in the pharmaceutical composition in an amount sufficient to provide the desired effect on the disease process or condition.

In some embodiments, to prepare solid compositions such as tablets, the main active ingredient is admixed with a pharmaceutical carrier, such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and with other pharmaceutical diluents, such as water, to form a solid preformulated composition containing a homogeneous mixture based on the disclosed compound or its non-toxic pharmaceutically acceptable salt. When such preformulated compositions are referred to as homogeneous, this means that the active ingredient is evenly distributed throughout the composition so that the composition is easily divided into equally effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the composition of the present invention is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or with any of the following: (1) fillers or diluents such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) moisturizers such as glycerin; (4) disintegrants such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, sodium docusate, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, in some embodiments, the compositions contain buffering agents. In some embodiments, solid compositions of this type are also used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.

In some embodiments, the tablet is obtained by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using a binder (eg, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (eg, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant, or dispersant. In some embodiments, molded tablets are obtained by molding in a suitable device a mixture of the composition of the present invention moistened with an inert liquid diluent. In some embodiments, tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, have a break line or are prepared with coatings and shells, such as enteric coatings and other coatings.

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 tinctures. In addition to the composition of the present invention, in some embodiments, liquid dosage forms contain inert diluents such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, oils (optionally cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, the suspensions, in addition to the composition of the present invention, contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

In some embodiments, formulations for rectal or vaginal administration are in the form of a suppository, which is prepared by mixing the composition of the present invention with one or more suitable non-irritating excipients or carriers, comprising, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature and will therefore melt in the body cavity and release the active agent.

Dosage forms for transdermal administration of the composition of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any necessary preservatives, buffers or propellants.

In some embodiments, ointments, pastes, creams and gels contain, in addition to the composition of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites , silicic acid, talc and zinc oxide, or mixtures thereof.

In some embodiments, the powders and sprays contain, in addition to the composition of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and powdered polyamide, or mixtures of such substances. In some embodiments, the sprays further comprise conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

In some embodiments, the compounds described herein are formulated as eye drops for ophthalmic administration.

The compositions and compounds disclosed herein are alternatively administered as an aerosol. This is provided by obtaining an aqueous aerosol, liposomal preparation or particulate matter containing the compound. In some embodiments, a non-aqueous suspension (eg, with a fluorocarbon propellant) is used. In some embodiments, ultrasonic nebulizers are used because they minimize the effect of shear on the agent, which results in degradation of the compounds contained in the compositions of the present invention. Typically, an aqueous aerosol is prepared by formulating an aqueous solution or suspension of the composition of the present invention together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition of the present invention, but generally include non-ionic surfactants (Tween species, Pluronic species or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid , lecithin and amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are usually obtained from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administration provide the composition of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which are resuspended in sterile injectable solutions or dispersions immediately prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, dissolved components that make the composition isotonic with the blood of the intended patient, or suspending agents, or thickeners.

Examples of suitable aqueous and non-aqueous carriers that are used in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and organic esters. for injection, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

Also contemplated are pharmaceutical formulations for enteral use comprising the disclosed compound, an enteric material, and a corresponding pharmaceutically acceptable carrier or excipient. Enteric materials means polymers that are essentially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal juice at specific pH values. The small intestine is part of the gastrointestinal tract (intestine) from the stomach to the large intestine and includes the duodenum, jejunum, and ileum. The pH in the duodenum is about 5.5, the pH in the jejunum is about 6.5, and the pH in the distal ileum is about 7.5. Accordingly, enteric materials are insoluble, for example, at pH up to 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 methyl cellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, propionate, cellulose acetate phthalate Cellulose maleate, cellulose acetate butyrate, cellulose acetate propionate, methyl methacrylic acid-methyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, methyl vinyl ether-maleic anhydride copolymer (Gantrez ES series), ethyl methyl acrylate-methyl methacrylate-chlorotrimethylammonium copolymer, ethyl acrylate, natural resins, such like zein, shellac and gum, rosin, and some commercially available enteric dispersion systems (eg Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric and Aquateric). The solubility of each of the above materials is either known or easily determined in vitro.

The dose of a composition containing at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein differs depending on the condition of the patient (eg, human), i.e., disease stage, general health, age, and other factors.

The pharmaceutical compositions are administered in a manner suitable for the disease being treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the route of administration. In general, a suitable dosage and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., improved clinical outcome such as more frequent complete or partial remissions, or longer disease-free life and /or overall survival, or reduction in symptom severity). Optimal doses are usually determined using experimental models and/or clinical trials. In some embodiments, the implementation of the optimal dose depends on the body weight, weight or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times a day or more. Ways

This document discloses methods for modulating MAGL activity. Contemplated methods, for example, involve bringing said enzyme into contact with a compound described herein. In some embodiments, the compound used in one or more of the above methods is one of the general group, subgroup, or specific compounds described herein, such as a compound of formula (I), (Ia), (Ib), (Ic) , (Id), (II), (IIa), (IIb), (IIc), (III), or (IV). In some embodiments, provided herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) wherein the compound is a MAGL inhibitor. In some embodiments, provided herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) wherein the compound is a selective MAGL inhibitor. The ability of the compounds described herein to modulate or inhibit MAGL is assessed using procedures known in the art and/or described herein. In another aspect of the present invention, methods are provided for treating a disease associated with MAGL expression or activity in a patient. In some embodiments, provided herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) wherein the compound is selective for inhibition of MAGL over inhibition of other serine hydrolases. In some embodiments, provided herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) wherein the compound is 10, 100, or 1000 times more selective for MAGL inhibition than other serine hydrolases.

In another embodiment, a method for managing pain in a patient is provided, comprising administering a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a solvate, hydrate, tautomer, V-oxide, or pharmaceutically acceptable salt thereof, to a patient in need thereof to relieve said pain. In another embodiment, a method for managing neuropathic pain in a patient is provided, comprising administering a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb) , (IIc), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to a patient in need thereof, to eliminate said neuropathic pain. In another embodiment, a method is provided for the management of inflammatory pain in a patient, comprising administering a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a solvate, hydrate, tautomer, V-oxide, or pharmaceutically acceptable salt thereof, to a patient in need thereof, to relieve said pain due to inflammation .

Also in some embodiments, provided herein are methods for treating and/or preventing a disorder in a patient in need thereof, such as one or more of acute or chronic pain, bone cancer pain, rheumatoid arthritis pain, pruritus, vomiting. or nausea, Down's syndrome, Parkinson's disease, epilepsy, NSAID-induced ulcer, opioid addiction, marijuana addiction, nicotine addiction, traumatic brain injury, ischemia, renal ischemia, cancers (eg, cancerous solid tumors such as breast cancer, lung cancer, head and neck cancer, ovarian cancer, sarcoma, melanoma and/or prostate cancer); cancers such as melanoma, metastatic tumors, kidney or bladder cancers, brain cancers, gastrointestinal cancers (such as colon cancer), leukemia, or homeoblastosis (such as myeloid leukemia, cancer of the lymphatic system, or monocytic leukemia ), liver injury, lung injury, blunt skeletal muscle injury, inflammatory disorders, and/or anxiety disorders. Contemplated methods include administering a pharmaceutically effective amount of a disclosed compound.

In some embodiments, provided herein is a method of treating, ameliorating, and/or preventing injury due to ischemia, eg, hepatic ischemia, or reperfusion, in a patient in need thereof, comprising administering a disclosed compound. This document discusses methods of treating patients with liver disorders due to oxidative stress and/or damage due to inflammation, for example, this document discusses methods of treating liver fibrosis, iron overload and/or the effects of corticosteroid therapy that leads to liver damage, in a patient, needing it.

In some embodiments, provided herein is a method for managing chronic pain, such as pain due to inflammation, visceral pain, back pain, postoperative pain, and pain associated with migraine, osteoarthritis, or rheumatoid arthritis.

In some embodiments, provided herein are methods for improving cognitive function in a patient suffering from Down syndrome or Alzheimer's disease, comprising administering an effective amount of the disclosed compound. Examples of patients suffering from Down syndrome are pediatric patients (eg, patients aged 0-11 years, 0-18 years, 0-6 years, or, for example, 12-18 years), adult patients (eg, 18 years or older) or, for example, older patients (eg, 18-40 years old, 20-50 years old). In some embodiments, such patients also suffer from additional cognitive impairment and/or dementia and/or seizures, which in some embodiments are due to the production of prostaglandins and/or beta-amyloid. For example, such patients also suffer from symptoms associated with early, middle, or late stage cognitive impairment, or have one or more of the following: loss of the ability to speak, deterioration in communication skills, progressive loss of activities of daily living, and such which include psychotic behavior. This document provides, for example, a method of treating a patient with Down syndrome or Alzheimer's disease with cognitive impairment, which involves the introduction of an effective amount of the disclosed compound. Such disclosed methods result in an improvement in cognitive function, eg as measured by an IQ test kit or by a cognitive test kit developed by Arizona professionals (eg measured by a cognitive test kit designed for use on individuals with Down Syndrome). For example, patients treated using the disclosed method are characterized by at least one of increased memory capacity, improved memory, or improved speech. In some embodiments, such disclosed methods result in an improvement in the patient's quality of life, as measured by the Adaptive Behavior Scale following said administration.

In other embodiments, a method is provided for at least partially providing a patient with Down syndrome with a neuroprotective agent (such as the disclosed compounds) that delays the onset of neurodegeneration or substantially prevents neurodegeneration. The introduction to the patient is carried out before the onset of neurodegeneration and/or the manifestation of symptoms of neurodegeneration. This document discusses methods of treating and/or improving cognitive decline, increasing sleep duration and/or improving sleep quality and/or treating PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) in a patient in need thereof, comprising administering the disclosed connections.

In another embodiment, a method is provided for treating a disease or disorder in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the disease or disorder is selected from the group consisting of migraine, epilepsy/seizure disorder, neuromyelitis optic nerve (NMO), Tourette's syndrome, chronic motor tic disorder, chronic vocal tic disorder, and irritable bowel syndrome associated abdominal pain. In another embodiment, a method is provided for treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa) , (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating epilepsy/seizure disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating neuromyelitis optic nerve (NMO) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II ), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating Tourette's syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa ), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating a chronic motor tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating a chronic vocal tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for the management of abdominal pain associated with irritable bowel syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id ), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for the management of pain associated with irritable bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided to relieve pain associated with Crohn's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), ( II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, a method is provided for the treatment of pain associated with cancer, pain associated with peripheral neuropathy, central pain, fibromyalgia, migraine, vaso-occlusive sickle cell pain crises, functional chest pain, rheumatoid arthritis, osteoarthritis, functional dyspepsia or spasticity, pain, disorders sleep or bladder dysfunction associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II) , (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided to relieve cancer pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II) , (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided to relieve pain associated with peripheral neuropathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II ), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for the management of central pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa ), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating fibromyalgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa) , (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa) , (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for the treatment of vaso-occlusive pain crises in sickle cell anemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II ), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating spasticity, pain, sleep disturbance, or bladder dysfunction associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib) , (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided to relieve functional chest pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa ), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating osteoarthritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa) , (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating functional dyspepsia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa ), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, a method is provided for lowering intraocular pressure (IOP) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II) , (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating glaucoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa) , (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, a method is provided for treating atopic dermatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa ), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, a method is provided to relieve itching in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa) , (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments disclosed herein, a method is provided for synergistically potentiating the activity of opioid analgesics in a patient being treated with opioid analgesics, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic ), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments disclosed herein, a method is provided for reducing acute side effects associated with an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), ( Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the disclosed compound used in one or more of the above methods is one of the general group, subgroup, or specific compounds described herein, such as a compound of formula (I), (Ia), (Ib), (Ic ), (Id), (II), (IIa), (IIb), (IIc), (III), or (IV).

The disclosed compounds are administered to patients (animals and humans) in need of such treatment at doses that will provide optimal pharmaceutical efficacy. It will be understood that the required dosage for use in any particular application will vary from patient to patient, not only depending on the particular compound or composition chosen, but also depending on the route of administration, the nature of the condition being treated, the age and condition of the patient. , parallel use of drugs or a special diet that the patient will then adhere to, and other factors, while the appropriate dose will be finally determined by the attending physician. For the treatment of the clinical conditions and diseases noted above, the subject compound disclosed herein is administered orally, subcutaneously, topically, parenterally, as a spray by inhalation or rectally in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and carrier media. Parenteral administration includes subcutaneous injections, intravenous or intramuscular injections or infusion techniques.

Combination therapies are also contemplated herein, for example, the co-administration of a disclosed compound and an additional active agent as part of a specific treatment regimen designed to provide the beneficial effect of the combined action of such therapeutic agents. The beneficial effect of the combination includes, without limitation, pharmacokinetic or pharmacodynamic synergy due to the combination of therapeutic agents. The administration of such therapeutic agents in combination is usually carried out over a period of time (usually over several weeks, months or years, depending on the combination chosen). Combination therapy is intended to cover the administration of a plurality of therapeutic agents sequentially, that is, when each therapeutic agent is administered at a different time, as well as the administration of such therapeutic agents, or at least two therapeutic agents, substantially simultaneously.

As such, simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition (eg, tablets or capsules in a fixed ratio of each therapeutic agent) or multiple single formulations (eg, capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is dependent on any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct tissue mucosal absorption. Therapeutic agents are administered by the same or 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.

Combination therapy also encompasses the administration of the therapeutic agents described above in additional combination with other biologically active ingredients and non-drug therapies. If the combination therapy further provides for a non-drug treatment, the non-drug treatment is carried out at any appropriate time, provided that a beneficial effect is achieved from the combined action of the combination of therapeutic agents and non-drug treatment. For example, in appropriate cases, a beneficial effect is achieved if the non-drug treatment is removed in time from the administration of therapeutic agents, perhaps days or even weeks.

The components of the combination are administered to the patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and are therefore administered at the same time. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered either simultaneously or sequentially.

In some embodiments, for the pain management in question, the disclosed compound is co-administered with another pain management therapeutic agent, such as an opioid, cannabinoid receptor modulator (CB-1 or CB-2), a COX-2 inhibitor, acetaminophen, and/or a non-steroidal anti-inflammatory drug. Additional therapeutic agents, for example for pain relief, which are co-administered include morphine, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol.

Other therapeutic agents considered for co-administration include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib, parecoxib, rimonabant and/or etoricoxib.

The following examples are provided for illustrative purposes only with respect to various embodiments and should not be construed as limiting the present invention in any way.

EXAMPLES

List of abbreviations

As used above and throughout the description of the present invention, it should be understood that the following abbreviations have the following meanings, unless otherwise indicated.

I. Chemical synthesis

Unless otherwise indicated, reagents and solvents were used as received from commercial suppliers. For synthetic transformations sensitive to moisture and/or oxygen, anhydrous solvents and oven-dried glassware were used. The output values have not been optimized. Response times are approximate and have not been optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants (J) are given in hertz. For proton spectra, the solvent peak was used as a control peak.

Example 1 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(5,6,7,8-

tetrahydroimidazo[1,2-a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Step 1. Synthesis of 1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-

diazaspiro[4.5]decane-1,8-dicarboxylate

1,1,1,3,3,3-hexafluoropropan-2-ol (2.00 g, 11.9 mmol, 1.50 eq.), DCM (20 ml) itrifosgene (1.18 g, 3.97 mmol, 0.50 eq.). N,N-diisopropylethylamine (2.55 g, 19.7 mmol, 2.50 eq.) was added dropwise at 0° C. and the solution was stirred for 3 hours at room temperature before adding tert-butyl-1,8- diazaspiro[4.5]decane-1-carboxylate (1.90 g, 7.91 mmol, 1.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (20 ml). The mixture was extracted with DCM (3×20 ml) and the organic layers were combined, washed with water (3×10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 1.58 g of 1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-

diazaspiro[4.5]decane-1,8-dicarboxylate (46% yield). LCMS (ESI, mass/charge): 435 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-

8-carboxylate

1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-

diazaspiro[4.5]decane-1,8-dicarboxylate (1.58 g, 3.64 mmol, 1.00 eq.), 1,4-dioxane (15 ml) and concentrated hydrochloric acid (5 ml). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 1.15 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8- carboxylate (crude). LCMS (ESI, mass/charge): 335 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tert

-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (500 mg, 1.50 mmol, 1, 00 eq.) and ACN (7.5 ml). To the resulting solution was then added 1-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2- a ]pyrazine-2-carboxylic acid (440 mg, 1.65 mmol, 1.10 eq.) , HATU (597 mg, 1.57 mmol, 1.05 eq.) and N,N-diisopropylethylamine (483 mg, 3.74 mmol, 2.50 eq.). The vial was closed with a rubber septum screw cap and the contents stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to half the original volume, then purified by silica gel chromatography to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tert-butoxycarbonyl) -5,b,7,8-tetrahydroimidazo[1,2- a ]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate as a white solid (804 mg, 92%). LCMS (ESI, mass/charge): 584 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,6,7,8-

tetrahydroimidazo[1,2-a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (400 mg, 0.6900 mmol, 1.00 eq.), DCM (2.25 ml) and TFA (0, 75 ml, 9.79 mmol, 14.29 eq.). The solution was stirred at room temperature for 1.5 hours, diluted with DCM (30 ml) and quenched with 1N HCl. NaOH (15 ml). The organics were separated, washed with sodium hydroxide (2×15 ml, 1N NaOH), dried over Na ₂ SO ₄ and filtered through celite. The filtrate was concentrated to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,b,7,8-tetrahydroimidazo[1,2-a]pyrazine-

2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate as a white solid (280 mg, 84%). ¹ H NMR (400 MHz, Chloroform-d) δ 7.38 (s, 1H), 5.81-5.69 (m, 1H), 4.23-4.08 (m, 4H), 4.06 - 3.98 (m, 4H), 3.31 - 3.24 (m, 2H), 3.21 - 2.92 (m, 4H), 2.04 (s, 1H), 2.05 - 1 .82 (m, 4H), 1.49-1.39 (m, 2H). LCMS (ESI, mass/charge): 484 [M+H] ⁺ .

Example 2 1,1,1,3,3,3-Hexaphropropan-2-yl-1-(7-cyclopropyl-5,6,7,8-

tetrahydroimidazo[12- a ]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-cyclopropyl-5,6,7,8-

tetrahydroimidazo[1,2- a ]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

To a solution of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,6,7,8-tetrahydroimidazo

[1,2-a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (Example 1, 75.0 mg, 0.16 mmol, 1.00 eq.) in THF ( 0.60 ml) were added successively AcOH (88.1 mg, 1.55 mmol, 10.00 eq.), (1-ethoxycyclopropoxy)trimethylsilane (94.7 mg, 0.54 mmol, 3.50 eq.) and sodium cyanoborohydride (29.2 mg, 0.47 mmol, 3.00 eq.). The reaction mixture was stirred at reflux for 2 hours and allowed to cool to room temperature. After dilution with 1 N. NaOH (5 ml) the resulting solution was extracted with DCM (2×10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC and lyophilized to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,2- a ] pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (33.6 mg, 41%). ¹ H NMR (400 MHz, Chloroform-d) δ 7.37 (s, 1H), 5.80-5.70 (m, 1H), 4.23-4.10 (m, 2H), 4.09 -4.03 (m, 2H), 4.01 - 3.95 (m, 2H), 3.84 (s, 2H), 3.23 - 3.11 (m, 2H), 3.09 - 2 .93 (m, 4H), 2.05-1.80 (m, 5H), 1.50-1.39 (m, 2H), 0.62-0.47 (m, 4H). LCMS (ESI, mass/charge): 524 [M+H] ⁺ .

Example 3 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(2-cyclopropylimidazo[1,2-b]

pyridazine-3-carbonyl)-168-diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of methyl 2-cyclopropylimidazo[1,2-b]pyridazine-3-carboxylate

To a 20 ml microwave vial was added methyl 2-bromo-3-cyclopropyl-3-oxo-propanoate (1.29 g, 5.26 mmol, 1.00 eq.), pyridazine-3-amine (500, 0 mg, 5.26 mmol, 1.00 eq) and methanol (10 ml). The vial was sealed with a cap with a rubber membrane and heated in a microwave oven to 120°C for 20 min. After cooling, the volatiles were removed on a rotary evaporator and purified by silica gel chromatography to give methyl 2-cyclopropylimidazo[1,2-b]pyridazine-3-carboxylate (187 mg, 16%). LCMS (ESI, mass/charge): 218 [M+H] ⁺ .

Stage 2. Synthesis of 2-cyclopropylimidazo[1,2-b]pyridazine-3-carboxylic acid

To an 8 ml scintillation vial was added methyl 2-cyclopropylimidazo[1,2-b]pyridazine-3-carboxylate (187.0 mg, 0.86 mmol, 1.00 eq.), THF (3.5 ml) and methanol (2.0 ml) followed by the addition of LiOH (2.0 ml, 10 mmol, 11.63 eq.). The reaction mixture was stirred at room temperature for 18 hours, then acidified to pH 4-5 using 2N hydrochloric acid. HCl. The mixture was diluted with DCM (20 ml), extracted with DCM (3×20 ml), dried over Na ₂ SO ₄ , filtered through Celite and concentrated to give 2-cyclopropylimidazo[1,2-b]pyridazine-3-carboxylic acids (55 mg, 31%). LCMS (ESI, mass/charge): 203 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(2-cyclopropylimidazo

[1,2-b]pyridazine-3-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (78 mg, 0.23 mmol, 1.00 eq.) and DMF (1 ml) followed by the addition of HATU (111 mg, 0.29 mmol, 1.25 eq.), 2-cyclopropylimidazo[1,2-b]pyridazine-3-carboxylic acid (55 mg, 0 .27 mmol, 1.16 eq.) and N,N-diisopropylethylamine (75 mg, 0.58 mmol, 2.50 eq.). The reaction mixture was stirred at room temperature for 5 hours before diluting with DMF (2 ml). The crude mixture was purified by reverse phase HPLC and lyophilized to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(2-cyclopropylimidazo[1,2-b]pyridazin-

3-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (70 mg, 57%). ¹ H NMR (400 MHz, Chporoform-d) δ 8.35-8.29 (m, 1H), 7.91-7.82 (m, 1H), 7.09-7.00 (m, 1H) , 5.83 - 5.70 (m, 1H), 4.34 - 4.16 (m, 2H), 3.60 - 3.44 (m, 2H), 3.33 - 3.18 (m, 2H), 3.16 - 2.94 (m, 2H), 2.21 - 2.02 (m, 3H), 1.94 - 1.82 (m, 2H), 1.70 - 1.50 ( m, 2H), 1.25 - 0.97 (m, 4H). LCMS (ESI mass/charge): 520 [M+H] ⁺ .

Example 4

1,8-diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of tert-butyl-4-(5-formylthiazol-2-yl)piperazine-1-carboxylate

2-bromo-5-formylthiazole (150 mg, 0.78 mmol, 1.00 eq.), ACN (40 ml), K ₂ CO ₃ (269 mg, 1.95 mmol, 2.50 eq. ) and tert-butyl piperazine-1-carboxylate (174 mg, 0.94 mmol, 1.20 eq.). The reaction mixture was stirred at 80° C. for 16 hours. The resulting solution was cooled to room temperature and the ACN was removed in vacuo. The crude mixture was dissolved in EtOAc (20 ml) and diluted with brine (10 ml sat. aq. NaCl solution). The solution was extracted with EtOAc (3×20 ml), dried over Na ₂ SO ₄ , filtered through celite and concentrated to give tert-butyl 4-(5-formylthiazol-2-yl)piperazine-1-carboxylate (83 mg, 36%, crude) ¹ H NMR (400 MHz, Chloroform-d) δ 9.71 (s, 1H), 7.86 (s, 1H), 3.82-3.42 (m, 8H), 1, 48 (s, 9H).

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-((2-(piperazin-1-yl)thiazol-5-

yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

Добавляли уксусную кислоту (19,2 мкл,1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (75.0 mg, 0.22 mmol), tert-Butyl 4-(5-formylthiazol-2-yl)xcherazine-1-carboxylate (83.4 mg, 0.28 mmol, 1.27 eq.), DCM (1 ml) and molecular sieves

Acetic acid (19.2 µl,

0.34 mmol, 1.55 eq.) and the solution was stirred at room temperature for 1.5 hours before adding NaBH(OAc) ₃ (59.4 mg, 0.28 mmol, 1.27 eq.). The reaction mixture was stirred for 16 hours before being diluted with additional DCM (20 ml) and sat. aq. NaHCO ₃ solution (10 ml). The organics were extracted (2×10 ml DCM), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give a pale yellow solid. This material was dissolved in DCM (1 ml) to which TFA (0.20 ml, 2.61 mmol, 11.64 eq.) was added and the reaction mixture was stirred at room temperature for 4 h. HPLC to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-((2-(piperazin-1-yl)thiazol-5-yl)methyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate (9.1 mg, 8%). ¹ H NMR (400 MHz, Chloroform-d) δ 6.94 (s, 1H), 5.82-5.68 (m, 1H), 4.26-4.10 (m, 2H), 3.63 (s, 2H), 3.48 - 3.36 (m, 4H), 3.07 - 2.87 (m, 5H), 2.80 - 2.70 (m, 2H), 2.09 - 1 .88 (m, 2H), 1.86-1.58 (m, 6H), 1.52-1.35 (m, 2H). LCMS (ESI, mass/charge): 516 [M+H] ⁺ .

Example 5 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(4-(pyrrolidin-1-

yl)pyrimidine-5-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of methyl 2-chloro-4-(pyrrolidin-1-yl) pyrimidine-5-carboxylate

Methyl 2,4-dichloropyrimidine-5-carboxylate (2.00 g, 9.66 mmol, 1.00 eq.), ACN (30 ml), N,N-diisopropylethylamine (2.50 g, 19.32 mmol, 3.37 eq.) and pyrrolidine (0.69 g, 9.66 mmol, 1.00 eq.). The solution was stirred for 4.5 hours at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl 2-chloro-4-(pyrrolidin-1-yl)pyrimidine-5-carboxylate (1.60 g, 69%). LCMS (ESI mass/charge): 242 [M+H] ⁺ .

Stage 2. Synthesis of 2-chloro-4-(pyrrolidin-1-yl)pyrimidine-5-carboxylic acid

Methyl 2-chloro-4-(pyrrolidin-1-yl)pyrimidine-5-carboxylate (1.00 g, 4.14 mmol, 1.00 eq.), THF (20.0 ml) and MeOH (4.0 ml) followed by the addition of LiOH (5 N, 4.0 ml, 20.00 mmol, 4.83 eq.). The reaction mixture was stirred at room temperature for 15 minutes. and acidified to pH 4-5 using 2N. HCl. The resulting solution was extracted with DCM (3×30 ml). The combined organics were dried over Na ₂ SO ₄ , filtered through celite and concentrated under reduced pressure to give 2-chloro-4-(pyrrolidin-1-yl)pyrimidine-5-carboxylic acid (630 mg, crude). LCMS (ESI, mass/charge): 228 [M+H] ⁺ .

Step 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(2-chloro-4-(pyrrolidine-

1-yl)pyrimidin-5-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (295 mg, 0.88 mmol, 1.00 equiv.), 2-chloro-4-(pyrrolidin-1-yl)pyrimidine-5-carboxylic acid (221 mg, 0.97 mmol, 1.10 equiv.), HATU (352 mg, 0.93 mmol, 1 05 eq.) and ACN (3.5 ml). The solution was stirred for a short time to cool to 0°C. N,N-dizopropylethylamine (285.2 mg, 2.21 mmol, 2.50 eq.) was added and the reaction mixture was stirred at 0-5° C. for 1 hour and then 26.5 hours at room temperature. The resulting solution was diluted with DCM (20 ml) and water (10 ml), extracted with DCM (3×20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(2-chloro-4-(pyrrolidin-1-

yl)pyrimidine-5-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (348 mg, 73%). LCMS (ESI mass/charge): 544 [M+H]+.

Step 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(4-(pyrrolidin-1-yl)pyrimidin-

5-carbonyl)-1,8-diaz aspiro [4.5] decan-8-carboxylate

In a 4 ml scintillation scintillation

[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-1-(2-chloro-4-pyrrolidin-1-yl-pyrimidin-5-

carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (75.0 mg, 0.14 mmol, 1.00 eq.), palladium hydroxide (36.0 mg, 0.05 mmol, 0.35 eq.), ammonium formate (70 mg, 1.11 mmol, 7.93 eq.), methanol (0.50 ml) and ethyl acetate (1.00 ml). The vial was capped with a rubber septum cap to which a needle was attached with a lumen to the atmosphere, then the vial was placed in a heating block at a temperature of 65°C for 2 hours. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was concentrated, purified by preparative reverse-phase HPLC and lyophilized to give the title compound (27.8 mg, 40% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.55 - 8.52 (m, 1H), 6.55 - 6.48 (m, 1H), 5.81 - 5.69 (m, 1H) , 4.26 - 4.13 (m, 2H), 3.71 - 3.56 (m, 4H), 3.42 - 3.28 (m, 2H), 3.18 - 2.90 (m, 4H), 2.11-2.92 (m, 6H), 1.89-1.78 (m, 2H), 1.57-1.45 (m, 2H). LCMS (ESI, mass/charge): 510 [M+H] ⁺ .

Example 6 1,1,1,3,3,3-Hexafluoropropan-2-yl-2-((1-isopropyl-3-phenyl-1H-pyrazole-

4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-carboxylate

Stage 1. Synthesis of (E)-1-isopropyl-2-(1-phenylethylidene)hydrazine

Into a 250 ml round bottom flask was placed 1-phenylethan-1-one (5.94 g, 49.5 mmol, 1.00 eq.), propan-2-ylhydrazine hydrochloride (10.9 g, 99.0 mmol, 2 00 eq.) and ethanol (80 ml). The resulting solution was stirred overnight at 70°C and concentrated under reduced pressure to obtain 16.0 g of (E)-1-isopropyl-2-(1-phenylethylidene)hydrazine (crude). LCMS (ESI, mass/charge): 177 [M+H] ⁺ .

Stage 2. Synthesis of 1-isopropyl-3-phenyl-1H-pyrazole-4-carbaldehyde

(E)-1-(1-phenylethylidene)-2-(propan-2-yl)hydrazine (1.00 g, 5.68 mmol, 1.00 eq.) and N,N -dimethylformamide (20 ml). Phosphoryl trichloride (6.91 g, 45.4 mmol, 8.00 eq) was added at 0°C. The reaction mixture was stirred overnight at 60° C. and quenched with water (150 ml). The resulting solution was extracted with ethyl acetate (2×200 ml) and the organic layers were combined, washed with brine (2×150 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 370 mg of 1-isopropyl-3-phenyl-1H-pyrazole-4-carbaldehyde (30% yield). LCMS (ESI mass/charge): 215 [M+H] ⁺ .

Step 3. Synthesis of tert-butyl 2-((1-isopropyl-3-phenyl-1H-pyrazol-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-carboxylate

In a 50 ml round bottom flask were placed 1-isopropyl-3-phenyl-1H-pyrazole-4-carbaldehyde (300 mg, 1.40 mmol, 1.00 eq.), 1,2-dichloroethane (10 ml) and t- butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (336 mg, 1.40 mmol, 1.00 eq.). The mixture was stirred for 1 hour at room temperature before adding sodium triacetoxyborohydride (890 mg, 4.20 mmol, 3.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (30 ml). The resulting solution was extracted with dichloromethane (2×50 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 760 mg of tert-butyl 2-((1-isopropyl-3-phenyl-1H-pyrazol-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-carboxylate (yield 93%). LCMS (ESI, mass/charge): 439 [M+H] ⁺ .

Stage 4. Synthesis of 2-((1-isopropyl-3-phenyl-1H-pyrazol-4-yl)methyl)-2,8-diazaspiro[4.5]decane

In a 100 ml round bottom flask was placed tert-butyl 2-((1-isopropyl-3-phenyl-1H-pyrazol-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-carboxylate (760 mg , 1.74 mmol, 1.00 eq.), dichloromethane (15 ml) and trifluoroacetic acid (3 ml). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 900 mg of 2-((1-isopropyl-3-phenyl-1H-pyrazol-4-yl)methyl)-2,8-diazaspiro[4.5]decane (crude). LCMS (ESI, mass/charge): 339 [M+H] ⁺ .

Stage 5. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-2-((1-isopropyl-3-phenyl-1H-pyrazol-4-yl)methyl)-2,8-diazaspiro [4.5]decane-8-carboxylate

Triphosgene (181 mg, 0.610 mmol, 0.70 eq.), dichloromethane (15 ml) and 1,1,1,3,3,3-hexafluoropropan-2-ol (292 mg, 1 .74 mmol, 2.00 eq.). N,N-diisopropylethylamine (337 mg, 2.61 mmol, 3.00 eq) was added at 0°C. The mixture was stirred for 2 hours at room temperature before adding 2-((1-isopropyl-3-phenyl-1H-pyrazol-4-yl)methyl)-2,8-diazaspiro[4.5]decane (294 mg, 0.870 mmol , 1.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (30 ml). The resulting solution was extracted with dichloromethane (2×50 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by reverse phase HPLC to give 71.4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-2-((1-isopropyl-3-phenyl-1H- pyrazol-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-carboxylate (15% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 7.80 (d, J=7.2 Hz, 2H), 7.39-7.44 (m, 3H), 7.28-7.32 (m , 1H), 5.70 - 5.79 (m, 1H), 4.47 - 4.56 (m, 1H), 3.38 - 3.55 (m, 6H), 2.62 (br, 2H ), 2.41 (s, 2H), 1.66 (t, J=7.0 Hz, 2H), 1.54-1.61 (m, 10H). LCMS (ESI, mass/charge): 533 [M+H] ⁺ .

Example 7 1,1,1,3,3,3-Hexaphgorpr opan-2-yl-2-((3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5- yl)methyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Step 1. Synthesis of ethyl(E)-2-(methoxyimino)-4-oxohexanoate

In a 100 ml round bottom flask were placed ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol, 1.00 eq.) in ethanol (30 ml) and O-methylhydroxylamine hydrochloride (1.59 g, 19. 0 mmol, 1.10 eq.) under nitrogen atmosphere. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 3.40 g of ethyl (E)-2-(methoxyimino)-4-oxohexanoate (97% crude yield). LCMS (ESI, mass/charge): 202 [M+H] ⁺ .

Stage 2. Synthesis of ethyl 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate

Ethyl (E)-2-(methoxyimino)-4-oxohexanoate (3.40 g, 16.9 mmol, 1.00 eq.) in ethanol (40 ml) and ocean-4-ylhydrazine were placed in a 100 ml round bottom flask. hydrochloride (3.10 g, 20.3 mmol, 1.20 eq) under nitrogen. The resulting solution was refluxed to reflux temperature overnight and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 4.00 g of ethyl 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate (94% yield). LCMS (ESI, mass/charge): 253 [M+H] ⁺ .

Stage 3. Synthesis of (3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl) methanol

Ethyl 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-carboxylate (4.00 g, 15.8 mmol, 1.00 eq.) was placed in a 100 ml round bottom flask. ) in tetrahydrofuran (40 ml) and lithium borohydride (1.70 g, 77.3 mmol, 5.00 eq.) under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and quenched with water (30 ml). The resulting solution was extracted with ethyl acetate (3×30 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 3.00 g (3-ethyl-1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)methanol (90% yield). LCMS (ESI mass/charge): 211 [M+H] ⁺ .

Stage 4. Synthesis of 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carbaldehyde

In a 100 ml round bottom flask was placed (3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)methanol (3.00 g, 14.3 mmol, 1.00 eq. .) in dichloromethane (30 ml) and pyridinium chlorochromate (6.20 g, 28.8 mmol, 2.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (30 ml). The resulting solution was extracted with dichloromethane (3×30 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 3.00 g of 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carbaldehyde (100% yield). LCMS (ESI, mass/charge): 209 [M+H] ⁺ .

Stage 5. Synthesis of tert-butyl-2-((3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)methyl)-2,8-diazaspiro[4.5]decane -8-carboxylate

To a 100 ml round bottom flask was charged 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-carbaldehyde (208 mg, 1.00 mmol, 1.00 eq.) in DCE ( 10 ml), 1-butyl-2,8-diazaspiro[4.5]decane-8-carboxylate (360 mg, 1.50 mmol, 1.50 eq.) and triethylamine (202 mg, 2.00 mmol, 2.00 equiv.). The resulting solution was stirred for 30 minutes. at room temperature before adding sodium triacetoxyborohydride (636 mg, 3.00 mmol, 3.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with dichloromethane (3×10 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 400 mg of tert-butyl-2-((3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)methyl)-2.8 -diazaspiro[4.5]decane-8-carboxylate (93% yield). LCMS (ESI, mass/charge): 433 [M+H] ⁺ .

Stage 6. Synthesis of 2-((3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)methyl)-2,8-diazaspiro[4.5]decane

tert-Butyl-2-((3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)methyl)-2,8-diazaspiro[ 4.5]decane-8-carboxylate (400 mg, 0.920 mmol, 1.00 eq.) in dichloromethane (10 ml) and trifluoroacetic acid (2.5 ml). The resulting solution was stirred for 5 hours at room temperature and concentrated under reduced pressure to give 300 mg of 2-((3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl) methyl)-2,8-diazaspiro[4.5]decane (crude). LCMS (ESI, mass/charge): 333 [M+H] ⁺ .

Step 7. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-2-((3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5- yl)methyl)-2,8-diazaspiro[4.5]decan-8-carboxylate

In a 50 ml round bottom flask were placed triphosgene (94.0 mg, 0.320 mmol, 0.35 eq.) in dichloromethane (5 ml) and 1,1,1,3,3,3-hexafluoropropan-2-ol (228 mg , 1.36 mmol, 1.50 eq.) under nitrogen atmosphere. N-ethyl-N-isopropylpropan-2-amine (350 mg, 2.71 mmol, 3.00 eq.) was added dropwise at 0°C, after which the mixture was stirred for 2 hours at 0°C before adding drops of a solution of 2-[[3-ethyl-1-(oxan-4-yl)-1H-pyrazol-5-yl]methyl]-2,8-diazaspiro[4.5]decane (300 mg, 0.900 mmol, 1.00 equiv.) in dichloromethane (5 ml). The reaction mixture was stirred for 3 hours at 0° C. and quenched with water (20 ml). The mixture was extracted with dichloromethane (3×20 ml) and the organic layers were combined, washed with brine (2×20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (360 mg) was purified by reverse phase HPLC to give 123.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-2-((3-ethyl-1-(tetrahydro-2H -pyran-4-yl)-1H-pyrazol-5-yl)methyl)-2,8-diazaspiro[4.5]decan-8-carboxylate (26% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 5.89 (s, 1H), 5.70 - 5.79 (m, 1H), 4.34 - 4.45 m, 1H), 4.08 - 4.13 (m, 2H), 3.37-3.60 (m, 8H), 2.55-2.66 (m, 4H), 2.26-2.39 (m, 4H), 1, 75 - 1.79 (m, 2H), 1.52 - 1.69 (m, 6H), 1.19 - 1.24 (m, 3H). LCMS (ESI, mass/charge): 527 [M+H] ⁺ .

Example 8 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-((1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazole-4 -yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

Stage 1. Synthesis of (E)-1-(1-(3-bromophenyl)ethylidene)-2-isopropylhydrazine

In a 100 ml round bottom flask were placed 1-(3-bromophenyl)ethan-1-one (2.00 g, 10.1 mmol, 1.00 eq.), propan-2-ylhydrazine (0.747 g, 10.1 mmol , 1.00 eq.) and ethanol (20 ml) under nitrogen. The resulting solution was stirred overnight at 80°C and concentrated under reduced pressure to obtain 3.00 g of (E)-1-(1-(3-bromophenyl)ethylidene)-2-shopropylhydrazine (crude). LCMS (ESI, mass/charge): 255 [M+H] ⁺ .

Stage 2. Synthesis of 3-(3-bromophenyl)-1-isopropyl-1H-pyrazole-4-carbaldehyde

N,N-dimethylformamide (100 ml) was placed in a 250 ml round bottom flask under nitrogen. Phosphoryl trichloride (18.0 g, 118 mmol, 10.0 eq.) was added dropwise at 0°C. The resulting solution was stirred for 1 hour at room temperature before adding (E)-1-(1-(3-bromophenyl)ethylidene)-2-isopropylhydrazine (3.00 g, 11.8 mmol, 1.00 eq.) . The reaction mixture was stirred overnight at 50° C. and quenched with water (30 ml). The pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The mixture was extracted with ethyl acetate (3×50 ml) and the organic layers were combined, washed with brine (1×50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 2.13 g of 3-(3-bromophenyl)-1-isopropyl-1H-pyrazole-4-carbaldehyde (62% yield). LCMS (ESI, mass/charge): 293 [M+H] ⁺ .

Step 3. Synthesis of tert-butyl 1-((3-(3-bromophenyl)-1-isopropyl-1H-pyrazol-4-yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

In a 100 ml round bottom flask was placed tert-butyl-1,8-diazaspiro[4.5]decane-8-carboxylate (500 mg, 2.08 mmol, 1.00 eq.), 1,2-dichloroethane (10 ml), triethylamine (630 mg, 6.23 mmol, 3.00 eq.) and 3-(3-bromophenyl)-1-isopropyl-1H-pyrazole-4-carbaldehyde (609 mg, 2.08 mmol, 1.00 eq. ). The mixture was stirred for 1 hour at room temperature before sodium triacetoxyborohydride (1.32 g, 6.24 mmol, 3.00 eq.) was added. The reaction mixture was stirred overnight at room temperature and quenched with water (20 ml). The resulting solution was extracted with dichloromethane (3 x 30 ml) and the organic layers were combined, washed with brine (1 x 30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 520 mg of tert-butyl-1-((3-(3-bromophenyl)-1-isopropyl-1H-pyrazol-4-yl)methyl)-1,8-diazaspiro[4.5]decane -8-carboxylate as light yellow oil (48% yield). LCMS (ESI, mass/charge): 517 [M+H] ⁺ .

Step 4. Synthesis of tert-butyl-1-((1-isopropyl-3-(3-(1pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)-1,8-diazaspiro[4.5] decane-8-carboxylate

tert-Butyl-1-((3-(3-bromophenyl)-1-isopropyl-1H-pyrazol-4-yl)methyl)-1,8-diazaspiro[4.5]decan-8- carboxylate (1.08 g, 2.09 mmol, 1.00 eq.), pyrrolidine (223 mg, 3.14 mmol, 1.50 eq.), tris(dibenzylideneacetone)dipalladium (96.2 mg, 0.105 mmol, 0.05 eq), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (195 mg, 0.314 mmol, 0.15 eq), sodium tert-butoxide (301 mg, 3.14 mmol, 1.50 eq.) and toluene (20 ml) under nitrogen. The reaction mixture was stirred overnight at 80° C. and quenched with water (20 ml). The resulting solution was extracted with dichloromethane (3×30 ml) and the organic layers were combined, washed with brine (1×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 578 mg of tert-butyl-1-((1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)-1 ,8-diazaspiro[4.5]decane-8-carboxylate (55% yield). LCMS (ESI, mass/charge): 508 [M+H] ⁺ .

Stage 5. Synthesis of 1-((1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)-1,8-diazaspiro[4.5]decane

tert-Butyl-1-((1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)-1,8-diazaspiro [4.5]decane-8-carboxylate (578 mg, 1.14 mmol, 1.00 eq.), 1,4-dioxane (15 ml) and concentrated aqueous hydrochloric acid (3 ml). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 461 mg of 1-((1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)methyl )-1,8-diazaspiro[4.5]decane (crude). LCMS (ESI, mass/charge): 408 [M+H] ⁺ .

Stage 6. Synthesis of 1,1D,3,3,3-hexafluoropropan-2-yl-1-((1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl )methyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Triphosgene (77.0 mg, 0.259 mmol, 0.70 eq.) and dichloromethane (10 ml) were placed in a 40 ml round bottom flask. 1,1,1,3,3,3-Hexafluoropropan-2-ol (124 mg, 0.740 mmol, 2.00 eq.) and N,N-diisopropylethylamine (239 mg, 1.85 mmol, 5.15 eq.) .) at 0°C. The mixture was stirred for 2 hours at room temperature before adding 1-((1-isopropyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)-1,8- diazaspiro[4.5]decane (150 mg, 0.370 mmol, 1.00 eq.). The reaction mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure. The crude product (530 mg) was purified by reverse phase HPLC to give 26.0 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-((1-isopropyl-3-(3-( pyrrolidin-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (12% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 7.65 (s, 1H), 7.21 (t, J=8.0 Hz 1H), 6.85 (d, J=7.5 Hz 1H) , 6.78 (s, 1H), 6.58 - 6.60 (m, 1H), 6.07 - 6.16 (m, 1H), 4.47 - 4.85 (m, 1H), 4 .08-4.12(m, 2H), 3.61(s, 2H), 3.29-3.33(m, 4H), 2.98-3.06(m, 2H), 2.71 - 2.76 (m, 2H), 2.01 - 2.06 (m, 4H), 1.66 - 1.87 (m, 6H), 1.52 (d, J=6.6 Hz, 6H ), 1.40-1.44 (m, 2H). LCMS (ESI mass/charge): 602 [M+H] ⁺ .

Example 9 1,1,1,3,3,3-Hexafluoropropan-2-yl-2-(pyridazin-3-ylmethyl)-2,8-diazaspiro[4.5]decan-8-carboxylate

Stage 1. Synthesis of pyridazine-3-carbaldehyde

Pyridazin-3-ylmethanol (220 mg, 2.00 mmol, 1.00 eq.), DCE (10 ml) and manganese dioxide (870 mg, 10.0 mmol, 5.00 eq. ). The resulting solution was stirred for 4 hours at 70° C. and the solids were filtered off. The filtrate was concentrated under reduced pressure to give 250 mg of pyridazine-3-carbaldehyde (crude). LCMS (ESI, mass/charge): 109 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-2-(pyridazin-3-ylmethyl)-2,8-diazaspiro[4.5]decan-8-carboxylate

In a 50 ml round bottom flask was placed 1,1,1,3,3,3-hexafluoropropan-2-yl-2,8-diazaspiro[4.5]decan-8-carboxylate (150 mg, 0.450 mmol, 1.00 eq. ), DCM (10 ml), triethylamine (189 mg, 1.87 mmol, 3.00 eq.) and pyridazine-3-carbaldehyde (48.0 mg, 0.440 mmol, 1.00 eq.). The mixture was stirred for 1 hour at room temperature before sodium triacetoxyborohydride (285 mg, 1.34 mmol, 3.00 eq.) was added. The reaction mixture was stirred overnight at room temperature and quenched with water (40 ml). The resulting solution was extracted with dichloromethane (3×80 ml) and the organic layers were combined, washed with water (3×20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 144.7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-2-(pyridazin-3-ylmethyl)-2,8-diazaspiro[4.5] decane-8-carboxylate (76% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 9.09 - 9.11 (m, 1H), 7.62 - 7.65 (m, 1H), 7.44 - 7.48 (m, 1H) , 5.72 - 5.78 (m, 1H), 3.98 (s, 2H), 3.41 - 3.55 (m, 4H), 2.69 - 2.73 (m, 2H), 2 .49 (s, 2H), 1.68-1.72 (m, 2H), 1.58-1.64 (m, 4H). LCMS (ESI, mass/charge): 427 [M+H] ⁺ .

Example 10 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(7-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a] pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-l-(5,6,7,8-tetrahydroimidazo[1,2- a ]pyrazine-2-carbonyl)- 1,8-diazaspiro[4.5]decan-8-carboxylate (example 1, 75 mg, 0.16 mmol), DCE (1 ml), dihydrofuran-3(2H)-one (60 mg, 0.70 mmol, 4 .50 eq.) and TEA (47 mg, 0.47 mmol, 3.00 eq.). The reaction mixture was stirred for 1.5 hours at room temperature before adding sodium triacetoxyborohydride (99 mg, 0.47 mmol, 3.00 eq.). The resulting solution was stirred for 4 hours at room temperature and diluted with DCM (10 ml) and 1N. NaOH (5 ml). The mixture was extracted with 1 N. NaOH (3×5 ml) and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC and lyophilized to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydroimidazo [1,2- a ]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (71 mg, 86%). ¹ H NMR (400 MHz, Chloroform-d) δ 7.39 (s, 1H), 5.81-5.69 (m, 1H), 4.24-4.09 (m, 2H), 4.09 - 3.88 (m, 5H), 3.87 - 3.63 (m, 5H), 3.31 - 3.09 (m, 3H), 3.08 - 2.90 (m, 3H), 2 .90 - 2.78 (m, 1H), 2.21 - 2.08 (m, 1H), 2.07 - 1.79 (m, 5H), 1.52 - 1.35 (m, 2H) . LCMS (ESI, mass/charge): 554 [M+H] ⁺ .

Example 11 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-((4,6-dichloro-1H-indol-2-yl)methyl)-1,8-diazaspiro[4.5] decane-8-carboxylate

Stage 1. Obtaining ethyl 4,6-dichloro-1H-indole-2-carboxylate

3,5-dichlorophenyl-hydrazine hydrochloride (2 g, 9.4 mmol, 1.00 eq.), p-toluenesulfonic acid monohydrate (20 mg, 0.11 mmol, 0.01 eq.) and benzene ( 30 ml). Ethyl pyruvate (1.1 g, 9.4 mmol, 1.00 eq.) was added and the mixture, in a Dean-Stark trap-equipped flask, heated to reflux for 2 hours and cooled to room temperature. The resulting solution was concentrated under reduced pressure and set aside. A separate flask containing n-toluenesulfonic acid monohydrate (3.1 g, 16.3 mmol, 1.73 eq.) in benzene (30 mL) was fitted with a Dean-Stark trap and refluxed to reflux for 2 h. Both mixtures were combined and transferred to a sealed tube, purged with N ₂ and heated to 140° C. overnight. The mixture was cooled, diluted with DCM (3 ml) and washed with us. NaHCO ₃ solution (5 ml) and saline solution (5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give ethyl 4,6-dichloro-1H-indole-2-carboxylate (700 mg, 28% yield). LCMS (ESI mass/charge): 229.0 [M+H] ⁺ .

Stage 2. Obtaining 4,6-dichloro-1H-indole-2-carboxylic acid

Ethyl 4,6-dichloro-1H-indole-2-carboxylate (700 mg, 2.7 mmol, 1 eq.) and ethanol (20 ml) were placed in a flask. Lithium hydroxide (162 mg, 6.76 mmol, 2.5 eq.) was dissolved in water (3 ml) and transferred to the reaction mixture at 0°C. The mixture was stirred at reflux for 3 hours before acidifying to pH 4 with 1N hydrochloric acid. HCl. The mixture was poured into EtOAc (5 ml), washed with brine (2×5 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 4,6-dichloro-1H-indole-2-carboxylic acid (451 mg, yield 72%). LCMS (ESI, mass/charge): 229.9 [M+H] ⁺ .

Stage 3. Obtaining tert-butyl-1-(4,6-dichloro-1H-indole-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

tert-Butyl-1,8-diazaspiro[4.5]decane-8-carboxylate (165 mg, 0.69 mmol, 1 eq.), 4,6-dichloro-1H-indole-2-carboxylic acid (219 mg, 0.95 mmol, 1.39 eq.) and DMF (5 ml). The mixture was stirred until all reagents had dissolved before adding HATU (339 mg, 0.89 mmol, 1.29 eq.) and TEA (383 μl, 2.75 mmol, 3.99 eq.). The reaction mixture was stirred overnight at room temperature, poured into EtOAc (5 ml), washed with us. NaHCO ₃ solution (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified on silica to give tert-butyl-1-(4,6-dichloro-1H-indole- 2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (247 mg, 79% yield). LCMS (ESI, mass/charge): 452.1 [M+H] ⁺ .

Stage 4. Preparation of (4,6-dichloro-1H-indol-2-yl)(1,8-diazaspiro[4.5]decan-1-yl)methanone

tert-Butyl-1-(4,6-dichloro-1H-indole-2-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (156 mg, 0.34 mmol, 1, 00 eq.) and dissolved DCM (3 ml). The mixture was cooled to 0° C. and TFA (0.9 ml, 11.7 mmol, 21.5 eq.) was added dropwise. The resulting solution was stirred for 3 hours at room temperature. The mixture was diluted with DCM (5 ml) and washed with us. NaHCO ₃ solution (3×5 ml). The aqueous layer had a pH~10 and was extracted with DCM (3×10 ml), and the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain (4,6-dichloro-1H-indole-2- yl)(1,8-diazaspiro[4.5]decan-1-yl)methanone (222, 87% yield). LCMS (ESI, mass/charge): 353.1 [M+H] ⁺ .

Step 5. Preparation of 1-((4,6-dichloro-1H-indol-2-yl)methyl)-1,8-dnazaspnro[4.5]decane

(4,6-Dichloro-1H-indol-2-yl)(1,8-diazaspiro[4.5]decan-1-yl)methanone (222 mg, 0.63 mmol, 1 eq.) was placed in a flask and placed under vacuum conditions. A magnetic stirrer and a rubber septum lid were added and the flask was purged with N ₂ . Added dry THF using a syringe (~5 ml) and the mixture was cooled to 0°C. A solution of LiAlH ₄ (0.79 ml, 1.8 mmol, 3 eq.) was transferred with a syringe and added dropwise. The mixture was stirred at room temperature for 2 hours. According to LCMS analysis, the desired product was absent, so the solution was heated to 60°C for 1 hour, after which the temperature was raised to 70°C overnight, namely for 16 hours. The mixture was cooled to 0°C before adding water (47 μl), 15% by weight aqueous NaOH solution (47 μl) and additional water (141 μl). The mixture was stirred at room temperature for 10 minutes, filtered through a pad of celite and washed thoroughly with THF. The solution was dried over Na ₂ SO ₄ , decanted and concentrated under reduced pressure to give 1-((4,6-dichloro-1H-indol-2-yl)methyl)-1,8-diazaspiro[4.5]decane (199 mg, yield 93%). LCMS (ESI, mass/charge): 339.9 [M+H] ⁺ .

Step 6. Preparation of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-((4,6-dichloro-1H-

indol-2-yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

Triphosgene (350 mg, 1.18 mmol, 2 eq.) and DCM (5 ml) were added to the vial. After the solids had dissolved, the solution was cooled to 0° C. and purged with N ₂ . Hexafluoroisopropanol (470 μl, 3.8 mmol, 6.5 eq.) and N,N-diisopropylethylamine (1028 μl, 5.9 mmol, 10 eq.) were added. The mixture was stirred for 2 hours at room temperature and set aside. In a separate vial was placed 1-[(4,6-dichloro-1H-indol-2-yl)methyl-1,8-diazaspiro[4.5]decane (199 mg, 0.59 mmol, 1 eq.), DCM (2 ml) and N,N-diisopropylethylamine (0.2 ml, 1.15 mmol, 10 eq.). The vial was purged with N ₂ after which the contents were transferred into the HFIP chloroformate solution using a syringe. The resulting solution was allowed to stir overnight at room temperature. The mixture was diluted with DCM (5 ml), washed with sat. NaHCO ₃ solution (3×5 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure, and purified on a silica gel via flash column chromatography to give 1,1,1,3,3,3-hexafluoropropane-2- yl-1-((4,6-dichloro-1H-indol-2-yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (35 mg, 11% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.42 (s, 1H), 5, 85-5.71(m, 1H), 4.33-4.16(m, 2H), 3.79(s, 2H), 3.12-2.89(m, 2H), 2.82- 2.64 (m, 2H), 1.98-1.63 (m, 6H), 1.59-1.44 (m, 2H). LCMS (ESI, mass/charge): 533.1 [M+H] ⁺ .

Example 12 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(pyrimidin-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of pyrimidine 2 carbonyl chloride

Pyrimidine-2-carboxylic acid (63.2 mg, 0.509 mmol, 1.00 eq.), DCM (5 ml) and thionyl chloride (121 mg, 1.02 mmol, 2.00 eq.) were placed in the flask. The resulting solution was stirred for 1 hour at 40°C. The resulting mixture was concentrated under reduced pressure to give 72.0 mg of pyrimidine-2-carbonyl chloride (99% yield).

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(pyrimidine-2-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (113 mg, 0.341 mmol, 1.00 eq.), pyrimidine- 2-carbonyl chloride (72.0 mg, 0.515 mmol, 1.50 eq.), DCM (5 ml) and TEA (103 mg, 1.02 mmol, 3.00 eq.). The resulting solution was stirred overnight at room temperature and quenched with water (20 ml). The mixture was extracted with DCM (3×30 ml) and the organic layers were combined, washed with brine (3×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (101 mg) was purified by reverse phase HPLC to give 75.2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(pyrimidine-2-carbonyl)-1,8- diazaspiro[4.5]decane-8-carboxylate (51% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.81 (d, J=5.2 Hz, 2H), 7.34 (t, J=7.2 Hz, 1H), 5.72-5, 80 (m, 1H), 4.18 - 4.27 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.15 - 3.24 (m, 2H), 2 .96 - 3.08 (m, 2H), 2.01 - 2.11 (m, 2H), 1.86 - 1.90 (m, 2H), 1.48 - 1.62 (m, 2H) . LCMS (ESI, mass/charge): 441 [M+H] ₊ .

Example 13 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-nicotinoyl-1,8-

diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of 1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate

Triphosgene (4.75 g, 16.0 mmol, 0.80 eq.) and DCM (50 ml) were placed in a flask. 1,1,1,3,3,3-Hexafluoropropan-2-ol (6.72 g, 40.0 mmol, 2.00 eq) and N,N-diisopropylethylamine (7.74 g, 59. 9 mmol, 3.00 eq.) at 0°C. The mixture was stirred for 2 hours at room temperature before adding tert-butyl-1,8-diazaspiro[4.5]decane-1-carboxylate (4.80 g, 20.0 mmol, 1.00 eq.). The resulting solution was stirred overnight at room temperature and quenched with water (50 ml). The mixture was extracted with DCM (3×100 ml) and the organic layers were combined, washed with brine (3×100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 3.96 g of 1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5] decane-1,8-dicarboxylate (yield 46%). LCMS (ESI, mass/charge): 435 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate

1-(tert-Butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate (1 .50 g, 3.45 mmol, 1.00 eq.), dioxane (15 ml) and hydrochloric acid (3 ml). The resulting solution was stirred for 3 hours at room temperature and concentrated under reduced pressure to give 1.15 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan- 8-carboxylate (99% yield). LCMS (ESI, mass/charge): 335 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-nicotinoyl-1,8-diazaspiro[4.5]decane-8-carboxylate

Pyridine-3-carboxylic acid (62.6 mg, 0.503 mmol, 1.50 eq.), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (126 mg, 0.670 mmol, 2.00 eq.) was added to the flask. ), 1-hydroxybenzotriazole (89.0 mg, 0.670 mmol, 2.00 eq) and DCM (5 ml). The resulting solution was stirred for 1 hour at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (115 mg, 0.335 mmol , 1.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (20 ml). The mixture was extracted with DCM (3×30 ml) and the organic layers were combined, washed with brine (3×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (106 mg) was purified by reverse phase HPLC to give 71.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-nicotinoyl-1,8-diazaspiro[4.5]decan- 8-carboxylate (47% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.63-8.69 (m, 2H), 7.75 (d, J=7.6 Hz, 1H), 7.32-7.36 (m , 1H), 5.72 - 5.82 (m, 1H), 4.19 - 4.27 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.13 - 3.19 (m, 2H), 2.95 - 3.08 (m, 2H), 2.01 - 2.14 (m, 2H), 1.83 - 1.90 (m, 2H), 1, 45 - 1.55 (m, 2H). LCMS (ESI, mass/charge): 440 [M+H] ⁺ .

Example 14 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(5-methyl-1H-indole-2-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

Stage 1. Synthesis of 5-methyl-1H-indole-2-carbonyl chloride

The vial was filled with 5-methyl-1H-indole-2-carboxylic acid (175 mg, 1.00 mmol, 1.00 eq.), DCM (10 ml) and oxalyl chloride (381 mg, 3.00 mmol, 3.00 equiv.). N,N-dimethylformamide (0.05 ml) was added at 0°C. The resulting solution was stirred for 4 hours at room temperature and concentrated under reduced pressure to give 194 mg of 5-methyl-1H-indole-2-carbonyl chloride (crude).

Step 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5-methyl-1H-indole-2-carbonyl)-1,8-diazaspiro[4.5]decan-8- carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (334 mg, 1.00 mmol, 1.00 eq.), DCM (10 ml) and N,N-diisopropylethylamine (258 mg, 2.00 mmol, 2.00 eq.). 5-methyl-1H-indole-2-carbonyl chloride (194 mg, 1.00 mmol, 1.00 eq) was added at 0°C. The resulting solution was stirred overnight at room temperature before quenching with water (10 ml). The mixture was extracted with DCM (3×10 ml) and the organic layers were combined, washed with water (3×10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 22.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5-methyl-1H-indole-2-carbonyl)-1, 8-diazaspiro[4.5]decane-8-carboxylate (5% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 8.85 - 9.40 (s, 1H), 7.40 - 7.50 (s, 1H), 7.30 - 7.39 (m, 1H) , 7.05 - 7.20 (m, 1H), 5.60 - 6.00 (m, 1H), 4.10 - 4.40 (m, 3H), 3.60 - 4.10 (m, 2H), 2.82 - 3.40 (m, 4H), 2.40 - 2.50 (s, 3H), 1.90 - 2.30 (m, 4H), 1.40 - 1.55 ( m, 2H). LCMS (ESI, mass/charge): 492 [M+H] ⁺ .

Example 15 2-((8-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl )-1H-indole-5-carboxylic acid

Stage 1. Synthesis of methyl 4-amino-3-iodobenzoate

Methyl 4-aminobenzoate (9.00 g, 59.5 mmol, 1.00 eq.), THF (100 ml) and 1-iodo-5-pyrrolidinedione (16.2 g, 72.0 mmol, 1.20 equiv.). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The residue was diluted with water (50 ml) and extracted with DCM (3×50 ml), the organic layers were combined, washed with water (3×50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 7.60 g of methyl 4-amino-3-iodobenzoate (46% yield) as a yellow solid. LCMS (ESI, mass/charge): 278 [M+H] ⁺ .

Step 2. Synthesis of methyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate

Methyl 4-amino-3-iodobenzoate (7.50 g, 27.1 mmol, 1.00 eq.), DCM (50 ml), triethylamine (7.20 g, 71.3 mmol, 2, 63 eq.) and trifluoroacetic anhydride (8.90 g, 42.4 mmol, 1.57 eq.) as described in Example 1, step 1. The residue was chromatographed on a silica gel column to give 8.00 g of methyl-3- iodine-4-(2,2,2-trifhoracetamido)benzoate (yield 79%) as a yellow solid.

Stage 3. Synthesis of methyl 2-(hydroxymethyl)-1H-indole-5-carboxylate

Methyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate (3.73 g, 10.0 mmol, 1.00 eq.), N,N-dimethylformamide (50 ml), prop -2-yn-1-ol (0.840 g, 15.0 mmol, 1.50 eq.), triethylamine (5.05 g, 50.0 mmol, 5.00 eq.), copper iodide (0.190 g, 1 .00 mmol, 0.10 eq.) and bis(triphenylphosphine)palladium(II) chloride (0.350 g, 0.500 mmol, 0.05 eq.) under a nitrogen atmosphere. The resulting solution was stirred overnight at 60° C. and diluted with water (500 ml). The mixture was extracted with EtOAc (3×500 ml) and the organic layers were combined, washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 1.80 g of methyl 2-(hydroxymetal)-1H-indole-5-carboxylate (85% yield) as a brown oil. LCMS (ESI, mass/charge): 206 [M+H] ⁺ .

Stage 4. Synthesis of 2-(hydroxymethyl)-1H-indole-5-carboxylic acid

Methyl-2-(hydroxymethyl)-1H-indole-5-carboxylate (800 mg, 3.90 mmol, 1.00 equiv.), MeOH (5 ml), water (5 ml) and sodium hydroxide (234 mg, 5.85 mmol, 1.50 eq.). The resulting solution was stirred overnight at 60° C. and concentrated under reduced pressure. The residue was diluted with water (25 ml) and the pH was adjusted to 4 ~ 5 with 1N. hydrochloric acid solution. The solid was filtered off, washed with water (3×10 ml) and dried to give 620 mg of 2-(hydroxymethyl)-1H-indole-5-carboxylic acid (83% yield) as a light brown solid. LCMS (ESI, mass/charge): 192 [M+H] ⁺ .

Stage 5. Synthesis of 2-formyl-1H-indole-5-carboxylic acid

2-(Hydroxymethyl)-1H-indole-5-carboxylic acid (0.300 g, 1.57 mmol, 1.00 eq.), ether (10 ml) and manganese dioxide (1.37 g, 15 7 mmol, 10.0 eq.). The resulting solution was stirred overnight at room temperature as described in example 10, step 1. The solid was filtered off and washed with ACN (3×10 ml). The filtrate was combined and concentrated under reduced pressure to give 0.189 g of 2-formyl-1H-indole-5-carboxylic acid (64% yield) as a yellow oil. LCMS (ESI, mass/charge): 190 [M+H] ⁺ .

Stage 6. Synthesis of 1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate

1,1,1,3,3,3-hexafluoropropan-2-ol (2.00 g, 11.9 mmol, 1.50 eq.), DCM (20 ml) and triphosgene (1.18 g , 3.97 mmol, 0.50 eq.). N,N-diisopropylethylamine (2.55 g, 19.7 mmol, 2.50 eq.) was added dropwise at 0°C. The solution was stirred for 3 hours at room temperature. Then tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate (1.90 g, 7.91 mmol, 1.00 eq.) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 ml) as described in Example 6, step 4. The residue was chromatographed on a silica gel column to give 1.58 g of 1-tert-butyl-8-(1.1 ,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate (46% yield) as a yellow oil. LCMS (ESI, mass/charge): 435 [M+H] ⁺ .

Stage 7. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate

1-tert-Butyl-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate (1.58 g, 3.64 mmol, 1.00 eq.), 1,4-dioxane (15 ml) and concentrated hydrochloric acid (5 ml) as described in example 9, step 5. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 1.15 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (crude) as off-white solid. LCMS (ESI, mass/charge): 335 [M+H] ⁺ .

Step 8. Synthesis of 2-((8-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-1,8-diazaspiro[4.5]decan-1-yl) methyl)-1H-indole-5-carboxylic acid

2-formyl-1H-indole-5-carboxylic acid (132 mg, 0.700 mmol, 1.00 equiv.), DCE (10 ml), 1,1,1,3,3,3-hexafluoropropane-2 -yl-1,8-diazaspiro[4.5]decane-8-carboxylate (234 mg, 0.700 mmol, 1.00 eq.) and sodium triacetoxyborohydride (445 mg, 2.10 mmol, 3.00 eq.). The resulting solution was stirred overnight at room temperature and quenched with water (10 ml) as described in Example 6, step 3. The crude product was purified by reverse phase HPLC to give 125.2 mg of 2-((8-(((1 ,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-1H-indole-5-carboxylic acid (yield 57 %) as a white solid. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.22 (s, 1H), 8.76 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz , 1H), 6.42 (s, 1H), 6.05-6.20 (m, 1H), 4.12-4.28 (m, 2H), 3.80-3.90 (s, 2H ), 3.00-3.20 (m, 2H), 2.80-2.90 (m, 2H), 1.90-2.00 (m, 2H), 1.70-1.89 (m , 4H), 1.55-1.65 (m, 2H). LCMS (ESI, mass/charge): 508 [M+H] ⁺ .

Example 16 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(5,7-dichloro-1H-indole-2-carbonyl)-1,8-Diazaspiro[4.5]decan-8 -carboxylate

Stage 1. Synthesis of 1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro [4.5] decan-1,8-dicarboxylate

The flask contained 1,1,1,3,3,3-hexafluoropropan-2-ol (2.00 g, 11.9 mmol, 1.50 eq.), DCM (20 ml) and triphosgene (1.18 g , 3.97 mmol, 0.50 eq.). N,N-diisopropylethylamine (2.55 g, 19.7 mmol, 2.50 eq.) was added dropwise at 0°C. The solution was stirred for 3 hours at room temperature. Then tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate (1.90 g, 7.91 mmol, 1.00 eq.) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 ml) as described in Example 6, step 4. The residue was chromatographed on a silica gel column to give 1.58 g of 1-(tert-butyl)-8-(1 ,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate (46% yield) as a yellow oil. LCMS (ESI, mass/charge): 435 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate

1-(tert-Butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate (1 .58 g, 3.64 mmol, 1.00 eq.), 1,4-dioxane (15 ml) and concentrated hydrochloric acid (5 ml) as described in example 9, step 5. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 1.15 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (crude) as a dirty -white solid. LCMS (ESI, mass/charge): 335 [M+H] ⁺ .

Stage 3. Synthesis of ethyl-(E)-2-(2-(2,4-dichlorophenyl)hydrazinylidene)propanoate

(2,4-dichlorophenyl)hydrazine (10.0 g, 56.8 mmol, 1.00 eq.), EtOH (50 ml), ethyl 2-oxopropanoate (6.59 g, 56.8 mmol , 1.00 eq.) and triethylamine (5.74 g, 56.8 mmol, 1.50 eq.). The resulting solution was heated under reflux overnight and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 3.15 g of ethyl (E)-2-(2-(2,4-dichlorophenyl)hydrazinylidene)propanoate (31% yield) as a light yellow solid. LCMS (ESI, mass/charge): 275 [M+H] ⁺ .

Stage 4. Synthesis of ethyl 5,7-dichloro-1H-padol-2-carboxylate

Ethyl (E)-2-(2-(2,4-dichlorophenyl)hydrazinylidene)propanoate (3.00 g, 10.9 mmol, 1.00 eq.), AcOH (50 ml ) and zinc chloride (27.2 g, 200 mmol, 18.3 eq.). The resulting solution was refluxed for 4 hours. The solution was then cooled to room temperature and poured into water (200 ml). The solid was collected by filtration, washed with water (3×10 ml) and dried to give 2.30 g of ethyl 5,7-dichloro-1H-indole-2-carboxylate (82% yield) as a brown solid. LCMS (ESI mass/charge): 258 [M+H] ⁺ .

Stage 5. Synthesis of 5,7-dichloro-1H-indole-2-carboxylic acid

Ethyl 5,7-dichloro-1H-indole-2-carboxylate (516 mg, 2.00 mmol, 1.00 eq.), MeOH (1 ml), water (5 ml) and hydroxide sodium (120 mg, 3.00 mmol, 1.50 eq.). The resulting solution was stirred overnight at 60°C. The solution was concentrated until its volume was reduced by half. The pH was then adjusted to 4-5 with an aqueous solution of hydrochloric acid (1 mol/l), which resulted in the precipitation of a solid. The solid was collected by filtration, washed with water (3x10 ml) and dried to give 294 mg of 5,7-dichloro-1H-indole-2-carboxylic acid (64% yield) as a light brown solid. LCMS (ESI mass/charge): 228 [M-H] ^- .

Stage 6. Synthesis of 5,7-dichloro-1H-indole-2-carbonyl chloride

5,7-dichloro-1H-indole-2-carboxylic acid (230 mg, 1.00 mmol, 1.00 eq.), DCM (10 ml) and oxalyl chloride (381 mg, 3.00 mmol, 3 .00 equiv.). N,N-dimethylformamide (0.05 ml) was added at 0°C as described in Example 16, step 3. The resulting solution was stirred for 4 hours at room temperature and concentrated under reduced pressure to give 248 mg of 5,7-dichloro -1H-indole-2-carbonyl chloride (crude) as a yellow solid.

Step 7. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,7-dichloro-1H-indole-2-carbonyl)-1,8-diazaspiro[4.5]decan- 8-carboxylate

DCM (10 ml), 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (334 mg, 1.00 mmol, 1 .00 eq.) and N,N-diisopropylethylamine (258 mg, 2.00 mmol, 2.00 eq.). The resulting solution was stirred overnight at room temperature and quenched with water (10 ml). 5,7-Dichloro-1H-indole-2-carbonyl chloride (248 mg, 1.00 mmol, 1.00 eq.) was added at 0° C. as described in Example 16, Step 4. The crude product was purified by reverse phase HPLC to give 60.9 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,7-dichloro-1H-indole-2-carbonyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate (yield 11%) as a light yellow solid. ¹ H NMR (300 MHz, Chloroform-d) δ 9.48 (br, 1H), 7.54 (s, 1H), 7.28 (s, 1H), 6.78 (s, 1H), 5.64- 5.89 (m, 1H), 4.12-4.37 (m, 2H), 3.85-4.12 (m, 2H), 2.90-3.18 (m, 4H), 1, 96-2.30 (m, 4H), 1.42-1.58 (m, 2H). LCMS (ESI, mass/charge): 546 [M+H] ⁺ .

Example 17 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(5-methylbenzo[b]thiophene-2-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

Stage 1. Synthesis of 1-(tert-butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate

1,1,1,3,3,3-hexafluoropropan-2-ol (2.00 g, 11.9 mmol, 1.50 eq.), DCM (20 ml), triphosgene (1.18 g , 3.97 mmol, 0.50 eq.). N,N-diisopropylethylamine (2.55 g, 19.7 mmol, 2.50 eq.) was added dropwise at 0°C. The solution was stirred for 3 hours at room temperature. Then tert-butyl-1,8-diazaspho[4.5]decane-1-carboxylate (1.90 g, 7.91 mmol, 1.00 eq.) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 ml) as described in Example 6, step 4. The residue was chromatographed on a silica gel column to give 1.58 g of 1-(tert-butyl)-8-(1 ,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate (46% yield) as a yellow oil. LCMS (ESI, mass/charge): 435 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate

1-(tert-Butyl)-8-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1,8-diazaspiro[4.5]decan-1,8-dicarboxylate (1 .58 g, 3.64 mmol, 1.00 eq.), 1,4-dioxane (15 ml) and concentrated hydrochloric acid (5 ml) as described in example 9, step 5. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 1.15 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (crude) as a dirty -white solid. LCMS (ESI, mass/charge): 335 [M+H] ⁺ .

Stage 3. Synthesis of 5-methylbenzo[b]thiophene-2-carboxylic acid

In a round bottom flask were placed 5-methyl-1-benzothiophene (296 mg, 2.00 mmol, 1.00 eq.) and a simple ether (20 ml). n-Butyl lithium (2.0 ml, 5.00 mmol, 2.50 eq., 2.5 M in hexane) was added dropwise at -78°C. The mixture was stirred for 0.5 hours at -78°C and filled with dried carbon dioxide (prepared with sodium bicarbonate and concentrated sulfuric acid). The resulting solution was stirred for 15 minutes. at -78°C and stirred overnight at room temperature. Ice water (20 ml) was added at 0° C. and the pH was adjusted to 3-4 with hydrochloric acid solution (1 mol/l). The mixture was extracted with ether (3 x 20 ml) and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 91.0 mg of 5-methylbenzo[b]thiophene-2-carboxylic acid (yield 24%) as a light yellow solid. LCMS (ESI mass/charge): 191 [M-H] ^- .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5-methylbenzo[b]thiophene-2-carbonyl)-1,8-diazaspiro[4.5]decan-8- carboxylate

5-methylbenzo[b]thiophene-2-carboxylic acid (91.0 mg, 0.470 mmol, 1.00 eq.), DCM (10 ml), N,N-diisopropylethylamine (122 mg, 0.940 mmol, 2 00 eq.), 1-hydroxybenzotriazole (64.0 mg, 0.470 mmol, 1.00 eq.), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (91.0 mg, 0.470 mmol, 1.00 eq.) and 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (159 mg, 0.480 mmol, 1.00 eq.). The resulting solution was stirred overnight at room temperature and quenched with water (10 ml) as described in Example 15, step 3. The crude product was purified by reverse phase HPLC to give 71.8 mg of 1,1,1,3,3, 3-Hexafluoropropan-2-yl-1-(5-methylbenzo[b]thiophene-2-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (30% yield) as a white solid. ¹ H NMR (300 MHz, Chloroform-d) δ 7.67-7.82 (m, 1H), 7.50-7.67 (m, 2H), 7.2-7.23 (m, 1H), 5.77 -5.89 (m, 1H), 4.08-4.23 (m, 2H), 3.82-3.97 (m, 2H), 2.94-3.30 (m, 4H), 2 .46 (s, 3H), 2.03-2.20 (m, 2H), 1.90-2.03 (m, 2H), 1.42-1.55 (m, 2H). LCMS (ESI mass/charge): 509 [M+H] ⁺ .

Example 18 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-cyclopropyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin- 2-carboxamido)-4-methylpiperidine-1-carboxylate

Step 1. Synthesis of methyl 5,6,7,8-tetrahydroimndazo[1,2-а]pyrazine-2-carboxylate

MeOH (25 ml) was placed into the flask. Thionyl chloride (5 ml) was added dropwise at room temperature. 7-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (2.50 g, 9.35 mmol, 1.00 eq) was added as described in Example 14 Step 3 to give 2.16 g of methyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (crude) as a brown solid. LCMS (ESI, mass/charge): 182 [M+H] ⁺ .

Step 2. Synthesis of methyl 7-cyclopropnl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate

Methyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (2.16 g, 11.9 mmol, 1.00 eq.), (1-Thoxycyclopropoxy)trimethylsilane was placed in the flask. (7.27 g, 41.7 mmol, 3.50 sq.), THF (25 ml), AcOH (7.16 g, 119 mmol, 10.0 eq.) and sodium cyanoborohydride (2.26 g, 36 .0 mmol, 3.00 equiv.). The resulting solution was stirred for 2 hours at 80° C. and quenched with water (25 ml) as described in example 2, step 1. The residue was chromatographed to give 2.00 g of methyl-7-cyclopropyl-5,6,7,8 -tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (97% yield over two steps) as a yellow oil. LCMS (ESI, mass/charge): 222 [M+H] ⁺ .

Stage 3. Synthesis of 7-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2 carboxylic acid

Methyl 7-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (1.90 g, 8.59 mmol, 1.00 eq.), lithium hydroxide was placed in the flask. (1.03 g, 43.0 mmol, 5.00 eq.), THF (16 ml) and water (4 ml). The resulting solution was stirred overnight at 50°C. The pH of the solution was adjusted to 5.0 with hydrochloric acid (1 mol/l) as described in Example 3, step 2. The resulting mixture was concentrated under reduced pressure to give 2.10 g of 7-cyclopropyl-5,6,7, 8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (crude) as a yellow oil. LCMS (ESI mass/charge): 208 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate

Triphosgene (12.2 g, 41.1 mmol, 1.50 eq.), DCM (50 ml), 1,1,1,3,3,3-hexafluoropropan-2-ol (20.6 g , 122 mmol, 4.50 eq.). N,N-diisopropylethylamine (17.6 g, 136 mmol, 5.00 eq.) was added dropwise at 0°C. The resulting solution was stirred for 2 hours at 0°C. tert-Butyl-N-(4-metalpiperidin-4-yl)carbamate (5.84 g, 27.2 mmol, 1.00 eq.) was added. The resulting solution was stirred for 2 hours at 0° C. and quenched with water (100 ml) as described in example 6, step 4. The residue was chromatographed on a silica gel column to give 4.90 g of 1,1,1,3,3 ,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (44% yield) as a yellow oil. LCMS (ESI, mass/charge): 409 [M+H] ⁺ .

Stage 5. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (5.83 g, 14.3 mmol, 1.00 eq.), DCM (50 ml) and TFA (10 ml) as described in example 1, step 1. The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to obtain 4.40 g 1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate (quantitative) as a yellow oil. LCMS (ESI, mass/charge): 309 [M+H] ⁺ .

Stage 6. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((4-methoxybenzyl)amino)-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate (4.40 g, 14.3 mmol, 1.00 eq.), 4-methoxybenzaldehyde (2.04 g, 15.0 mmol, 1.05 eq.), EtOH (20 mL). The resulting solution was stirred for 2 hours at 80°C and cooled to room temperature. Sodium borohydride (1.63 g, 43.1 mmol, 3.00 eq.) was added at room temperature. The resulting solution was stirred overnight at room temperature and quenched with water (20 ml). The resulting solution was extracted with DCM (3 x 20 ml) and the organic layers were combined, washed with brine (2 x 20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 3.00 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((4-methoxybenzyl)amino)-4-methylpiperidine-1-carboxylate ( 49% yield as a white solid. LCMS (ESI, mass/charge): 429 [M+H] ⁺ .

Stage 7. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((4-methoxybenzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-((4-methoxybenzyl)amino)-4-methylpiperidine-1-carboxylate (3.00 g, 7.00 mmol, 1.00 eq.), DCE (20 ml), triethylamine (2.12 g, 21.0 mmol, 3.00 eq.) and paraformaldehyde (2.10 g, 70.0 mmol, 10.0 eq.). The resulting solution was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (4.66 g, 22.0 mmol, 3.00 eq.) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 ml) as described in Example 12, step 1. The residue was chromatographed on a silica gel column to give 2.70 g of 1,1,1,3,3,3- hexafluoropropan-2-yl-4-((4-methoxybenzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (87% yield) as a white solid. LCMS (ESI, mass/charge): 443 [M+H] ⁺ .

Stage 8. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-((4-methoxybenzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (3.30 g, 7 46 mmol, 1.00 eq.), EtOAc (30 ml) and palladium on carbon (1.0 g), and also introduced hydrogen. The resulting solution was stirred overnight at room temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 2.40 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate (quantitative yield ) as a yellow oil. LCMS (ESI, mass/charge): 323 [M+H] ⁺ .

Stage 9. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-cyclopropyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine -2-carboxamido)-4-methyl piperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate (141 mg, 0.438 mmol, 1.00 eq.), ACN (5 ml), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (175 mg, 0.460 mmol, 1.05 eq.), N,N-diisopropylethylamine ( 142 mg, 1.10 mmol, 2.50 eq.) and 7-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (100 mg, 0.483 mmol, 1, 10 eq.). The resulting solution was stirred overnight at room temperature and quenched with water (5 ml) as described in Example 1, step 2. The crude product (200 mg) was purified by reverse phase HPLC to give 11.5 mg of 1,1,1, 3,3,3-hexafluoropropan-2-yl-4-(7-cyclopropyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-4-methylpiperidine- 1-carboxylate (5% yield) as a light yellow solid. ¹ H NMR (300 MHz, Chloroform-d) δ 7.32 (s, 1H), 5.70-5.79 (m, 1H), 3.99-4.03 (m, 2H), 3.94 (s, 2H), 3.72-3.78 (m, 2H), 3.32-3.44 (m, 2H), 3.08-3.12 (m, 5H), 2.58-2 .63 (m, 2H), 1.90-1.96 (m, 1H), 1.65-1.73 (m, 2H), 1.42 (s, 3H), 0.52-0.62 (m, 4H). LCMS (ESI, mass/charge): 512 [M+H] ⁺ .

Example 19 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(4-cyano-1,3-dimethyl-1H-pyrazole-5-carbonyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate

Stage 1. Synthesis of 1-(4-bromo-1,3-dimethyl-1H-pyrazole-5-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylic acid

1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (500 mg, 1.50 mmol, 1.00 eq.), ACN (7.5 ml), 4-bromo-1,3-dimethyl-1H-pyrazole-5-carboxylic acid (440 mg, 1.65 mmol, 1.10 eq.), HATU (597 mg, 1.57 mmol, 1.05 eq.) and N,N-diisopropylethylamine (483 mg, 3.74 mmol, 2.50 eq.). The vial was capped with a rubber septum and the contents were stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to half the original volume and purified by silica gel chromatography to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tert-butoxycarbonyl) -5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (804 mg, 92%). LCMS (ESI, mass/charge): 584 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(4-cyano-1,3-dimethyl-1H-pyrazole-5-carbonyl)-1,8-diazaspiro[ 4.5]decane-8-carboxylate

1-(4-Bromo-1,3-dimethyl-1H-pyrazole-5-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylic acid (170 mg, 0.32 mmol , 1.0 eq.) and DMF (1.25 ml). Copper cyanide (142 mg, 1.59 mmol, 5.00 eq) was added in one portion and the vial was capped and microwaved at 220°C for 1 h. The crude product was purified by silica gel chromatography followed by reversed phase HPLC and lyophilization to give 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(4-cyano-1,3-dimethyl-1H-pyrazole-5-carbonyl)-1,8- diazaspiro[4.5]decane-8-carboxylate (75 mg, 49%). ¹ H NMR (400 MHz, Chloroform-d) δ 5.81-5.70 (m, 1H), 4.32-4.14 (m, 2H), 3.85 (s, 3H), 3.66 -3.53 (m, 2H), 3.13-2.91 (m, 4H), 2.36 (s, 3H), 2.20-2.02 (m, 2H), 1.98-1 .87 (m, 2H), 1.57-1.49 (m, 2H). LCMS (ESI, mass/charge): 482 [M+H] ⁺ .

Example 20 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-cyclopropyl-N-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo [4,3-а]pyrazine-3-carboxamido)-4-methylpiperidine-1-carboxylate

Step 1. Synthesis of benzyl 4-((tert-butoxycarbonyl)amino)-4-methylpiperidine 1-carboxylate

Benzyl chloroformate (3.12 g, 18.3 mmol, 1.30 eq.), tert-butyl N-(4-methylpiperidin-4-yl) carbamate (3.00 g, 14.0 mmol, 1 00 eq.), triethylamine (4.25 g, 42.0 mmol, 3.00 eq.) and DCM (30 ml). The resulting solution was stirred overnight at room temperature and quenched with water (30 ml) as described in Example 1, step 1. The residue was chromatographed on a silica gel column to give 2.72 g of benzyl-4-((tert-butoxycarbonyl)amino) -4-methylpiperidine-1-carboxylate (56% yield) as a white oil. LCMS (ESI, mass/charge): 349 [M+H] ⁺ .

Step 2. Synthesis of benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

Benzyl 4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (2.72 g, 7.81 mmol, 1.00 eq.) and DMF (20 ml) were placed in the flask. Sodium hydride (60% in oil, 1.56 g, 39.1 mmol, 3.00 eq) was added at 0°C. The resulting solution was stirred for 0.5 hour at room temperature and then methyl iodide (1.66 g, 11.7 mmol, 1.50 eq.) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 ml). The mixture was extracted with EtOAc (3 x 50 ml) and the organic layers were combined, washed with water (3 x 20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 2.00 g of benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (71% yield) as a white oil. LCMS (ESI, mass/charge): 363 [M+H] ⁺ .

Stage 3. Synthesis of tert-butyl-methyl (4-methylpiperidin-4-yl) carbamate

Benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (1.00 g, 2.76 mmol, 1.00 eq.), palladium on charcoal (100 mg ) and THF (10 ml) under hydrogen atmosphere as described in Example 19, Step 8 to give 0.630 g of tert-butyl-methyl(4-methylpiperidin-4-yl)carbamate (crude) as a white oil. LCMS (ESI, mass/charge): 229 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-ol (1.39 g, 8.27 mmol, 3.00 eq.), triphosgene (0.574 g, 1.93 mmol, 0, 70 eq.) and DCM (20 ml). Then N,N-diisopropylethylamine (1.07 g, 8.28 mmol, 3.00 eq.) was added dropwise at 0°C. The resulting solution was stirred for 2 hours at room temperature. Then tert-butyl-methyl(4-methylpiperidin-4-yl)carbamate (0.630 g, 2.76 mmol, 1.00 eq.) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 ml) as described in Example 6, step 4. The residue was chromatographed on a silica gel column to give 0.400 g of 1,1,1,3,3,3-hexafluoropropane 2-yl-4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (34% yield) as a white oil. LCMS (ESI, mass/charge): 423 [M+H] ⁺ .

Stage 5. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (400 mg, 0.950 mmol, 1 00 eq.), concentrated hydrochloric acid (1 ml) and 1,4-dioxane (3 ml). The resulting solution was stirred for 2 hours at room temperature and then concentrated under reduced pressure as described in Example 8, Step 5 to give 305 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4- methyl 4-(methylamino)piperidine-1-carboxylate (quantitative) as a white solid. LCMS (ESI, mass/charge): 323 [M+H] ⁺ .

Stage 6. Synthesis of ethyl 7-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-а]pyrazine-3-carboxylate

Ethyl 5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (300 mg, 1.53 mmol, 1.00 eq) was placed in the flask, ( 1-ethoxycyclopropoxy)trimethylsilane (799 mg, 4.58 mmol, 3.00 eq.), sodium cyanoborohydride (289 mg, 4.60 mmol, 3.00 eq.), acetic acid (918 mg, 15.3 mmol, 10.0 eq.), EtOH (5 ml) and THF (5 ml). The resulting solution was stirred for 2 hours at 60° C. and quenched with water (10 ml) as described in example 2, step 1. The residue was chromatographed on a silica gel column to give 217 mg of ethyl-7-cyclopropyl-5,6,7, 8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (60% yield) as a yellow solid. LCMS (ESI, mass/charge): 237 [M+H] ⁺ .

Stage 7. Synthesis of 7-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-а]pyrazine-3-carboxylic acid

Ethyl 7-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (217 mg, 0.920 mmol, 1.00 eq. .), lithium hydroxide (66.2 mg, 2.76 mmol, 3.00 eq.), EtOH (5 ml) and water (1 ml), as described in example 3, step 2, to obtain 191 mg of 7- cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylic acid (crude) as a yellow solid. LCMS (ESI, mass/charge): 209 [M+H] ⁺ .

Stage 8. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-cyclopropyl-N-methyl-5,6,7,8-tetrahydro-[1,2,4] triazolo[4,3-a]pyrazine-3-carboxamido)-4-methylpiperidine-1-carboxylate

7-Cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylic acid (191 mg, 0.920 mmol, 1.00 eq.) was added to the flask. ), 1,1,1,3,3,3-hexafluorophopan-2-yl-4-methyl-4-(metalamino)piperidine-1-carboxylate (295 mg, 0.920 mmol, 1.00 eq.), o- (7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (523 mg, 1.38 mmol, 1.50 eq.), N,N-diisopropylethylamine (356 mg, 2.75 mmol, 3.00 eq.) and DMF (5 ml). The resulting solution was stirred overnight at room temperature and quenched with water (10 ml) as described in Example 1, Step 2. The crude product was purified by reverse phase HPLC to give 176.1 mg of 1,1,1,3,3, 3-hexafluoropropan-2-yl-4-(7-cyclopropyl-N-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]piperazine-3-carboxamido) -4-metalpiperidine-1-carboxylate (37% yield) as a white solid. ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 6.05-6.21 (m, 1H), 4.12-4.23 (t, J=5.8 Hz, 2H), 4.00 ( s, 2H), 3.70-3.83 (m, 2H), 3.31-3.51 (m, 2H), 3.03-3.21 (m, 5H), 2.54-2, 71 (m, 2H), 1.95-2.04 (m, 1H), 1.70-1.86 (m, 2H), 1.46 (s, 3H), 0.58-0.69 ( m, 2H), 0.49-0.58 (m, 2H). LCMS (ESI mass/charge): 513 [M+H] ⁺ .

Example 21 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(7-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid

7-(tert-Butyl)-2-ethyl-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (600 mg, 2.03 mmol, 1.00 eq. .), lithium hydroxide (244 mg, 10.2 mmol, 5.00 eq.), THF (8.0 ml) and water (2.0 ml). The reaction mixture was stirred overnight at 50°C. The pH of the solution was adjusted to 5 with hydrochloric acid (1.0 M). The resulting solution was extracted with DCM (5×20 ml) and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 450 mg of 7-(tert-butoxycarbonyl)-5,6,7,8 -tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (83% yield). LCMS (ESI, mass/charge): 268 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine -2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

7-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (140 mg, 0.524 mmol, 1.00 eq.), HATU (299 mg, 0.786 mmol, 1.50 eq.), DIPEA (203 mg, 1.57 mmol, 3.00 eq.) and DMF (10 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (263 mg, 0.786 mmol, 1.50 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 260 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (85% yield). LCMS (ESI, mass/charge): 584 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carbonyl)-1, 8-diazaspiro[4.5]decane-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine- 2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (260 mg, 0.446 mmol, 1.00 eq) and DCM (5 mL). Was added dropwise triperoxonane acid (1.0 ml) at 0°C. The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 215 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,6,7,8-tetrahydroimidazo [1,2-а]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (quantitative yield). LCMS (ESI, mass/charge): 484 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2 -a]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1-(5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carbonyl)-1,8 -diazaspiro[4.5]decan-8-carboxylate (175 mg, 0.362 mmol, 1.00 eq.), 1-chloro-2-methylpropan-2-ol (156 mg, 1.45 mmol, 4.00 eq.) , potassium carbonate (150 mg, 1.09 mmol, 3.00 eq.), sodium iodide (163 mg, 1.09 mmol, 3.00 eq.) and DMF (10 ml). The reaction mixture was stirred overnight at 100° C. and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC to give 26.2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(7-(2-hydroxy-2-methylpropyl)-5 ,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (13% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 7.43 (s, 1H), 5.82-5.73 (m, 1H), 4.23-4.16 (m, 2H), 4.11 -4.03 (m, 4H), 3.90 (s, 2H), 3.24-2.96 (m, 6H), 2.57 (s, 2H), 2.42 (s, 1H), 2.04-1.98 (m, 2H), 1.94-1.85 (m, 2H), 1.50-1.44 (m, 2H), 1.25 (s, 6H). LCMS (ESI, mass/charge): 556 [M+H] ⁺ .

Example 22 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-isopropyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin- 2-carboxamido)-4-methylpiperidine-1-carboxylate

Step 1. Synthesis of benzyl 4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate

tert-Butyl-N-(4-methylpiperidin-4-yl)carbamate (3.00 g, 14.0 mmol, 1.00 eq.), benzyl chloroformate (2.88 g, 16.8 mmol, 1 .20 eq.) and DCM (30 ml). Triethylamine (4.25 g, 43.0 mmol, 3.00 eq.) was added dropwise at room temperature and the reaction mixture was stirred overnight at room temperature before quenching with water (30 ml). The resulting solution was extracted with DCM (3×50 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 3.24 g of benzyl 4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (66% yield). LCMS (ESI, mass/charge): 349 [M+H] ⁺ .

Step 2. Synthesis of benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

Benzyl 4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (3.24 g, 4.00 mmol, 1.00 eq.) and DMF (35 ml) were placed in the flask. Sodium hydride (1.12 g, 27.9 mmol, 3.00 eq., 60% in mineral oil) was added at 0° C. and the mixture was stirred for 30 minutes. at 0°C before adding iodomethane (1.98 g, 14.0 mmol, 1.50 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (40 ml). The resulting solution was extracted with EtOAc (3×50 ml) and the organic layers were combined, washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 2.00 g of benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (59% yield). LCMS (ESI, mass/charge): 363 [M+H] ⁺ .

Stage 3. Synthesis of tert-butyl-methyl (4-methylpiperidin-4-yl) carbamate

Benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (4.00 g, 11.0 mmol, 1.00 eq.), palladium (10% on activated carbon, 1.80 g) and EtOAc (40 ml). The contents of the flask were placed in a hydrogen atmosphere (3 atm.) and left overnight at room temperature. The solids were filtered off and the resulting mixture was concentrated under reduced pressure to give 2.16 g of tert-butyl methyl(4-methylpiperidin-4-yl)carbamate (86% yield). LCMS (ESI, mass/charge): 229 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

Triphosgene (1.41 g, 4.74 mmol, 0.50 eq.), 1,1,1,3,3,3-hexafluoropropan-2-ol (3.18 g, 18.9 mmol, 2.00 eq.) and DCM (25 ml). DIPEA (4.89 g, 37.9 mmol, 4.00 eq.) was added dropwise at 0° C. and the mixture was stirred for 2 hours at room temperature before adding tert-butyl-methyl(4-methylpiperidine-4- yl) carbamate (2.16 g, 9.47 mmol, 1.00 eq.). The reaction mixture was stirred for 2 hours at room temperature and quenched with water (30 ml). The resulting solution was extracted with DCM (3×50 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 2.8 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1- carboxylate (70% yield). LCMS (ESI, mass/charge): 423 [M+H] ⁺ .

Stage 5. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (1.14 g, 0.900 mmol , 1.00 eq.), concentrated aqueous HCl solution (2.0 ml) and 1,4-dioxane (10 ml). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 868 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1 -carboxylate (quantitative yield). LCMS (ESI, mass/charge): 323 [M+H] ⁺ .

Stage 6. Synthesis of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid

7-(tert-Butyl)-2-ethyl-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (600 mg, 2.03 mmol, 1.00 eq. .), LiOH (244 mg, 10.2 mmol, 5.00 eq.), THF (8 ml) and water (2 ml). The reaction mixture was stirred overnight at 50°C. The pH value of the solution was adjusted to 5 with HCl (1.0 M). The resulting solution was extracted with DCM (5×20 ml) and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ filtered and concentrated under reduced pressure to obtain 480 mg of 7-(tert-butoxycarbonyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (88% yield). LCMS (ESI, mass/charge): 268 [M+H] ⁺ .

Step 7. Synthesis of tert-butyl-2-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-methylpiperidin-4-yl)(methyl )carbamoyl)-5,6-dihydroimidazo[1,2-а]pyrazine-7(8Н)-carboxylate

7-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (480 mg, 1.80 mmol, 1.00 eq.), HATU (1.02 g, 2.70 mmol, 1.50 eq.), DIPEA (696 mg, 5.39 mmol, 3.00 eq.) and DCM (10 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl[-4-(methylamino)piperidine-1-carboxylate (868 mg, 2.70 mmol, 1.50 equiv.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (5×20 ml) and the organic layers were combined, washed with brine (3×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 750 mg of tert-butyl-2-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-methylpiperidine -4-yl)(methyl)carbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (88% yield). LCMS (ESI, mass/charge): 572 [M+H] ⁺ .

Stage 8. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine -2-carboxamido)piperidine-1-carboxylate

tert-Butyl-2-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-methylpiperidin-4-yl)(methyl )carbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (750 mg, 0.525 mmol, 1.00 eq) and DCM (10 mL). TFA (2 ml) was added dropwise at 0°C and the reaction mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure. The crude product was dissolved with DCM (20 ml) and the pH of the solution was adjusted to 8.0 with saturated NaHCO ₃ . The resulting solution was extracted with DCM (3 x 20 ml) and the organic layers were combined, washed with brine (2 x 10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 400 mg 1,1,1 ,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(N-methyl-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxamido)piperidine-1- carboxylate (65% yield). LCMS (ESI, mass/charge): 472 [M+H] ⁺ .

Step 9. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-isopropyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine -2-carboxamido)-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(N-methyl-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazin- 2-carboxamido)piperidine-1-carboxylate (80.0 mg, 0.170 mmol, 1.00 eq.), Propan-2-one (49.2 mg, 0.849 mmol, 5.00 eq.), DCE (2 ml ) and HOAc (163 mg, 2.71 mmol, 1.60 eq.). The mixture was stirred for 90 minutes. at 60°C and cooled to room temperature before adding sodium triacetoxyborohydride (90.0 mg, 0.425 mmol, 2.50 eq.). The reaction mixture was stirred overnight at 60° C. and quenched with water (5 ml). The resulting solution was extracted with DCM (3×10 ml) and the organic layers were combined, washed with brine (2×5 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column and the crude product (50 mg) was purified by preparative HPLC to give 6.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-isopropyl-N- methyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate (yield 7%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.34 (s, 1H), 5.81-5.72 (m, 1H), 4.02 (t, J=5.4 Hz, 2H), 3.81 (s, 2H), 3.78-3.73 (m, 2H), 3.44-3.34 (m, 2H), 3.18 (s, 3H), 3.00-2, 92 (m, 3H), 2.66-2.62 (m, 2H), 1.77-1.70 (m, 2H), 1.44 (s, 3H), 1.16 (d, J= 6.6 Hz, 6H). LCMS (ESI, mass/charge): 514 [M+H] ⁺ .

Example 23 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-cyclobutyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin- 2-carboxamido)-4-methylpiperidine-1-carboxylate

tert-butyl-(4-methylpiperidin-4yl)carbamate

Stage 1. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate

The title compound was prepared using the methods described in Example 22 steps 1-5 using tert-butyl-(4-methylpyleridin-4-yl)carbamate in step 1 to give 868 mg of 1,1,1,3, 3,3-hexafluoropropan-2-yl-4-methnl-4-(methylamino)piperidine-1-carboxylate (quantitative yield). LCMS (ESI, mass/charge): 323 [M+H] ⁺ .

Stage 2. Synthesis of benzyl-7-cyclobutyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate

Benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (300 mg, 1.17 mmol, 1.00 eq.), cyclobutanone (817 mg, 11 7 mmol, 10.0 eq.), zinc chloride (238 mg, 1.75 mmol, 1.50 eq.), sodium cyanoborohydride (221 mg, 3.52 mmol, 3.00 eq.) and MeOH (10 ml ). The reaction mixture was stirred overnight at 65° C. and quenched with water (10 ml). The resulting solution was extracted with DCM (3 x 20 ml) and the organics were combined, washed with brine (2 x 10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 250 mg of benzyl benzyl-7-cyclobutyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (69% yield). LCMS (ESI, mass/charge): 312 [M+H] ⁺ .

Stage 3. Synthesis of 7-cyclobutyl-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxylic acid

Benzyl-7-cyclobutyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (230 mg, 0.740 mmol, 1.00 eq.), 10% palladium on activated charcoal ( 120 mg). The contents of the flask were placed in a hydrogen atmosphere (3 atm.). The resulting solution was stirred for 4 hours at room temperature. The solids were filtered off and the resulting mixture was concentrated under reduced pressure to give 155 mg of 7-cyclobutyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (95% yield). LCMS (ESI, mass/charge): 222 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-cyclobutyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine -2-carboxamido)-4-methylpiperidine-1-carboxylate

7-cyclobutyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (155 mg, 0.701 mmol, 1.10 eq.), HATU (266 mg, 0.701 mmol , 1.10 eq.), DIPEA (271 mg, 2.10 mmol, 3.30 eq.) and DMF (5 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate (205 mg, 0.637 mmol, 1.00 eq.) . The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3 x 20 ml) and the organic layers were combined, washed with brine (2 x 10 ml), dried over anhydrous Na ₂ SO ₄ filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC to give 93.8 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-cyclobutyl-N-methyl-5,6,7 ,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate (28% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.34 (s, 1H), 5.77-5.73 (m, 1H), 4.03 (s, 2H), 3.76-3.74 (m, 2H), 3.60 (s, 2H), 3.41-3.33 (m, 2H), 3.16 (s, 3H), 3.01-2.91 (m, 1H), 2.77 (s, 2H), 2.64-2.61 (m, 2H), 2.14 (s, 2H), 1.97-1.92 (m, 2H), 1.81-1, 72 (m, 4H), 1.47 (s, 3H). LCMS (ESI, mass/charge): 526 [M+H] ⁺ .

Example 24 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-(2-hydroxy-2-methylpropyl)-N-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate

Stage 1. Synthesis of benzyl-7-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate

Benzyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (300 mg, 1.17 mmol, 1.00 eq.), 2,2-dimethyloxirane (420 mg , 5.82 mmol, 5.00 eq.), lithium bromide: (254 mg, 2.92 mmol, 2.50 eq.) and MeOH (10 ml). The reaction mixture was stirred overnight at 60° C. and quenched with water (10 ml). The resulting solution was extracted with DCM (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 150 mg of benzyl 7-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (39% yield) . LCMS (ESI mass/charge): 330 [M+H] ⁺ .

Stage 2. Synthesis of 7-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid

7-(2-Psdroxy-2-methylgfopyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (130 mg, 0.395 mmol, 1.00 eq) was placed in the flask, 10% palladium on activated carbon (65 mg) and EtOAc (5 ml). The contents of the flask were placed in a hydrogen atmosphere (3 atm.). The reaction mixture was stirred overnight at room temperature and the solids were filtered off. The resulting mixture was concentrated under reduced pressure to give 90.0 mg of 7-(2-hydroxy-2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (yield 95% ). LCMS (ESI, mass/charge): 240 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-(2-hydroxy-2-methylpropyl)-N-methyl-5,6,7,8-tetrahydroimidazo [1,2-а]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate

7-(2-Hydroxy-2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (90.0 mg, 0.376 mmol, 1.00 eq.) .), HATU (143 mg, 0.376 mmol, 1.00 eq.), DIPEA (146 mg, 1.13 mmol, 3.00 eq.) and DMF (5 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate (prepared as described in example 23, step 1; 146 mg , 0.453 mmol, 1.20 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC to give 41.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-[N-methyl-7-(2- hydroxy-2-methylpropyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-amido]piperidine-1-carboxylate (20% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.37 (s, 1H), 5.78-5.73 (m, 1H), 4.05 (s, 2H), 3.92 (s, 2H ), 3.76-3.73 (m, 2H), 3.43-3.35 (m, 2H), 3.18 (s, 3H), 3.11 (s, 2H), 2.64- 2.60 (m, 2H), 2.57 (s, 2H), 2.43 (s, 1H), 1.74 (s, 2H), 1.44 (s, 3H), 1.25 (s , 6H). LCMS (ESI, mass/charge): 544 [M+H] ⁺ .

Example 25 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-(cyclopropyl-1-d)-N-methyl-5,6,7,8-tetrahydroimidazo[1, 2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate

Stage 1. Synthesis of benzyl-7-(cyclopropyl-1-d)-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxylate

Benzyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (196 mg, 0.763 mmol, 1.00 eq.), (1-ethoxycyclopropoxy)trimethylsilane (398 mg, 2.28 mmol, 3.00 eq.), acetic acid- _d4 (465 mg, 7.62 mmol, 10.0 eq.), sodium cyanobordeuteride (151 mg, 2.29 mmol, 3.00 eq.) and THF (10 ml). The reaction mixture was stirred overnight at 65° C. and quenched with water (10 ml). The resulting solution was extracted with DCM (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 120 mg of benzyl 7-(cyclopropyl-1-(1)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (53% yield). LCMS (ESI, mass/charge): 299 [M+H] ⁺ .

Stage 2. Synthesis of 7-(cyclopropyl-1-d)-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxylic acid

Benzyl 7-(cyclopropyl-1-d)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (120 mg, 0.403 mmol, 1.00 eq.), palladium on charcoal (150 mg) and EtOAc (10 ml). The contents of the flask were placed in a hydrogen atmosphere (3 atm.). The resulting solution was stirred for 5 hours at room temperature. The solids were filtered off and the resulting mixture was concentrated under reduced pressure to give 60.0 mg of 7-(cyclopropyl-1-d)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (yield 72%). LCMS (ESI, mass/charge): 209 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-(cyclopropyl-1-d)-N-methyl-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate

7-(cyclopropyl-1-d)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (90.0 mg, 0.432 mmol, 1.00 eq.) , HATU (164 mg, 0.432 mmol, 1.00 eq.), DIPEA (167 mg, 1.29 mmol, 3.00 eq.) and DMF (10 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate (prepared as described in example 23, step 1; 153 mg , 0.475 mmol, 1.10 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC to give 51.0 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-(cyclopropyl-1-d)-N-methyl -5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate (23% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.34 (s, 1H), 5.80-5.74 (m, 1H), 4.02-3.99 (m, 2H), 3.88 (s, 2H), 3.79-3.72 (m, 2H), 3.44-3.34 (m, 2H), 3.17 (s, 3H), 3.11-3.08 (m , 2H), 2.65-2.61 (m, 2H), 1.78-1.71 (m, 2H), 1.44 (s, 3H), 0.61-0.58 (m, 2H ), 0.55-0.51 (m, 2H). LCMS (ESI, mass/charge): 513 [M+H] ⁺ .

Example 26 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-acetyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin- 2-carboxamido)-4-methylpiperidine-1-carboxylate

Stage 1. Synthesis of benzyl-7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxylate

Benzyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (1.50 g, 5.83 mmol, 1.00 eq.), TEA (2.95 g , 29.2 mmol, 5.00 eq.) and DCM (20 ml). Acetic anhydride (893 mg, 8.75 mmol, 1.50 eq.) was added dropwise at 0° C. and the resulting solution was stirred for 2 hours at 0° C. before being quenched with water (20 ml). The resulting solution was extracted with DCM (3×30 ml) and the organic layers were combined, washed with brine (2×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 1.50 g of benzyl 7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (85% yield). LCMS (ESI mass/charge): 300 [M+H] ⁺ .

Stage 2. Synthesis of 7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxylic acid

Benzyl-7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (600 mg, 1.93 mmol, 1.00 eq.), 10% palladium per activated charcoal (300 mg) and EtOAc (10 ml). The contents of the flask were placed in a hydrogen atmosphere (3 atm.). The reaction mixture was stirred for 4 hours at room temperature before solids were filtered off. The resulting mixture was concentrated under reduced pressure to give 200 mg of 7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (47% yield). LCMS (ESI mass/charge): 210 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-acetyl-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine -2-carboxamido)-4-methylpiperidine-1-carboxylate

7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (100 mg, 0.478 mmol, 1.10 eq.), HATU (182 mg, 0.478 mmol , 1.10 eq.), DIPEA (168 mg, 1.30 mmol, 3.00 eq.) and DMF (5 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(methylamino)piperidine-1-carboxylate (140 mg, 0.435 mmol, 1.00 eq.) . The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (250 mg) was purified by preparative HPLC to give 34.2 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-acetyl-N-methyl-5,6, 7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate (15% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.40 (s, 1H), 5.78-5.75 (m, 1H), 4.86-4.77 (m, 2H), 4.10 -3.90 (m, 4H), 3.77-3.74 (m, 2H), 3.38-3.36 (m, 2H), 3.16 (s, 3H), 2.64-2 .60 (m, 2H), 2.24-2.22 (m, 3H), 1.72 (s, 2H), 1.44 (s, 3H). LCMS (ESI, mass/charge): 514 [M+H] ⁺ .

Example 27 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-methyl-4-(7-(methylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a] pyrazine-2-carboxamido)piperidine-1-carboxylate

Stage 1. Synthesis of benzyl-7-(methylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxylate

Benzyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (200 mg, 0.778 mmol, 1.00 eq.), TEA (236 mg, 2.33 mmol, 3.00 eq.) and DCM (10 ml). Methansulfonyl chloride (134 mg, 1.17 mmol, 1.50 eq.) was added dropwise at 0° C. and the reaction mixture was stirred for 2 hours at 0° C. and quenched with water (10 ml). The resulting solution was extracted with DCM (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 200 mg of benzyl 7-(methylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (77% yield). LCMS (ESI, mass/charge): 336 [M+H] ⁺ .

Stage 2. Synthesis of 7-(methylsulfonyl)-5,6,7,8-tetrahydroniidazo[1,2-a]pnraz nn-2-carboxylic acid

Benzyl 7-(methylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (200 mg, 0.597 mmol, 1.00 eq.), palladium charcoal (200 mg) and EtOAc (10 ml). The contents of the flask were placed in a hydrogen atmosphere (3 atm.). The reaction mixture was stirred overnight at room temperature and the solids were filtered off and removed. The resulting mixture was concentrated under reduced pressure to give 100 mg of 7-(methylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (68% yield). LCMS (ESI, mass/charge): 246 [M+H] ⁺ .

Stage 3. Synthesis of 1,11,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(7-(methylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyrazine-2-carboxamido)piperidine-1-carboxylate

7-(methylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (100 mg, 0.408 mmol, 1.00 sq), HATU (155 mg, 0.408 mmol, 1.00 eq.), DIPEA (158 mg, 1.22 mmol, 3.00 eq.) and DMF (5 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafhorpropan-2-yl-4-amino-4-methylpiperidine-1-carboxylag (138 mg, 0.449 mmol, 1.10 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC to give 135.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(7-(methylsulfonyl)-5,6 ,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)piperidine-1-carboxylate (62% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.48 (s, 1H), 6.89 (br, 1H), 5.80-5.74 (m, 1H), 4.56 (s, 2H ), 4.20-4.17(m, 2H), 3.91-3.85(m, 2H), 3.79-3.77(m, 2H), 3.38-3.29(m , 2H), 2.97 (s, 3H), 2.38-2.34 (m, 2H), 1.73-1.66 (m, 2H), 1.53 (s, 3H). LCMS (ESI mass/charge): 536 [M+H] ⁺ .

Example 28 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-methyl-4-(7-(oxazol-2-yl)-5,6,7,8-tetrahydroimidazo[1, 2-a]pyrazine-2-carboxamido)piperidine-1-carboxylate

Stage 1. Synthesis of tert-butyl-2-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-methylpiperidin-4-yl)carbamoyl) -5,6-dihydroimidazo[1,2-а]pyrazine-7(8H)-carboxylate

7-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (500 mg, 1.87 mmol, 1.00 eq) was placed in the flask, obtained as described in example 22, step 6), HATU (712 mg, 1.87 mmol, 1.00 eq.), DIPEA (725 mg, 5.62 mmol, 3.00 eq.) and DMF (10 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate (577 mg, 1.87 mmol, 1.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with DCM (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 910 mg of tert-butyl-2-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-methylpiperidine- 4-yl)carbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-carboxylate (87% yield). LCMS (ESI, mass/charge): 558 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxamido )piperidine-1-carboxylate

The flask was filled with tert-butyl-2-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-methylpiperidin-4-yl)carbamoyl)- 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (910 mg, 1.63 mmol, 1.00 eq) and DCM (10 mL). Trifluoroacetic acid (2 ml) was added dropwise at room temperature and the reaction mixture was stirred for 2 hours at room temperature. The resulting solution was concentrated under reduced pressure and the crude product was dissolved with DCM (20 ml). The pH value of the solution was adjusted to 8.0 with saturated sodium bicarbonate solution. The resulting solution was extracted with DCM (3 x 20 ml) and the organic layers were combined, washed with brine (2 x 10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 610 mg 1,1,1 ,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxamido)piperidine-1-carboxylate (yield 82 %). LCMS (ESI, mass/charge): 458 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-cyano-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxamido )-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido) was placed in the flask piperidine-1-carboxylate (610 mg, 1.33 mmol, 1.00 eq.), cyanogen bromide (424 mg, 4.00 mmol, 3.00 eq.) and DCM (10 ml). The reaction mixture was stirred overnight at 35° C. and quenched with water (10 ml). The resulting solution was extracted with DCM (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 500 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-cyano-5,6,7,8-tetrahydroimidazo[1,2-a ]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate (78% yield). LCMS (ESI, mass/charge): 483 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(7-(oxazol-2-yl)-5,6,7,8-tetrahydroimidazo[1 ,2-а]pyrazine-2-carboxamido)piperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-cyano-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido )-4-methylpiperidine-1-carboxylate (160 mg, 0.332 mmol, 1.00 eq.), 4-methylbenzene-1-sulfonic acid (171 mg, 0.996 mmol, 3.00 eq.) and DCE (5 ml) . The mixture was stirred for 2 hours at room temperature before adding 2,2-dimethoxyethane-1-ol (352 mg, 3.32 mmol, 10.0 eq.). The reaction mixture was stirred for 30 minutes. at room temperature and washed with saturated NaHCO ₃ solution (10 ml) and water (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The solid was dissolved with DCE (5 ml) and the resulting solution was stirred for 1 hour at 120° C. (microwave) and quenched with water (10 ml). The mixture was extracted with DCM (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC to give 28.0 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(7-(oxazol-2-yl) -5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)piperidine-1-carboxylate (16% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.46 (s, 1H), 7.32 (s, 1H), 6.90-6.89 (m, 2H), 5.80-5.74 (m, 1H), 4.77 (s, 2H), 4.20-4.17 (m, 2H), 4.03-4.00 (m, 2H), 3.92-3.85 (m , 2H), 3.40-3.30 (m, 2H), 2.39-2.36 (m, 2H), 1.73-1.62 (m, 2H), 1.53 (s, 3H ). LCMS (ESI, mass/charge): 525 [M+H] ⁺ .

Example 29 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-methyl-4-(7-(pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1, 2-a]pyrazine-2-carboxamido)piperidine-1-carboxylate

Stage 1. Synthesis of benzyl-7-(pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-а]pyrazine-2-carboxylate

Benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (200 mg, 0.778 mmol, 1.00 eq.), 2-bromopyrazine (149 mg, 0.934 mmol, 1.20 eq), tris(dibenzylideneacetone) dipalladium (35.6 mg, 0.0389 mmol, 0.05 eq), dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine (72.7 mg , 0.156 mmol, 0.20 eq.), cesium carbonate (761 mg, 2.34 mmol, 3.00 eq.) and toluene (10 ml) under nitrogen atmosphere. The reaction mixture was stirred overnight at 90° C. and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 180 mg of benzyl 7-(pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (69% yield). LCMS (ESI, mass/charge): 336 [M+H] ⁺ .

Stage 2. Synthesis of 7-(pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid

Benzyl-7-(pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (180 mg, 0.537 mmol, 1.00 eq.), 10% palladium on activated carbon (180 ml) and EtOAc (10 ml). The contents of the flask were placed in a hydrogen atmosphere (3 atm.). The reaction mixture was stirred overnight at room temperature and the solids were filtered off and removed. The resulting solution was concentrated under reduced pressure to give 105 mg of 7-(pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (80% yield). LCMS (ESI, mass/charge): 246 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(7-(pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1 ,2-а]pyrazine-2-carboxamido)piperidine-1-carboxylate

7-(Pyrazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (105 mg, 0.428 mmol, 1.00 eq.), HATU (163 mg, 0.428 mmol, 1.00 eq.), DIPEA (166 mg, 1.28 mmol, 3.00 eq.) and DMF (5 ml). The mixture was stirred for 30 minutes. at room temperature before adding 1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate (158 mg, 0.514 mmol, 1.20 eq.). The reaction mixture was stirred for 3 hours at 60° C. and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×20 ml) and the organic layers were combined, washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC to give 25.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(7-(pyrazin-2-yl) -5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)piperidine-1-carboxylate (11% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 6, 91 (br, 1H), 5.80-5.75 (m, 1H), 481 (s, 2H), 4.20 (s, 4H), 3.93-3.86 (m, 2H), 3 .41-3.31 (m, 2H), 2.40-2.37 (m, 2H), 1.73-1.64 (m, 2H), 1.54 (s, 3H). LCMS (ESI mass/charge): 536 [M+H] ⁺ .

Example 30 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(1-(3-methylpyridin-2-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro [4.5] decane-8-carboxylate

Stage 1. Synthesis of 1-(3-methylpyridin-2-yl)cyclopropan-1-carbonitrile

The flask was charged with cyclopropanecarbonitrile (1.00 g, 14.9 mmol, 1.50 eq.) and THF (10 mL) under nitrogen. Potassium bis(trimethylsilyl)amide (1M in THF, 12.0 ml, 12.0 mmol, 1.20 eq.) was added at 0°C and the reaction mixture was stirred at 0°C for 1 hour before adding 2-fluoro -3-methylpyridine (1.11 g, 9.99 mmol, 1.00 eq.). The resulting solution was stirred overnight at room temperature and quenched with water (10 ml). The mixture was extracted with EtOAc (3×50 ml) and the organic layers were combined, washed with water (3×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 0.510 g of 1-(3-methylpyridin-2-yl)cyclopropan-1-carbonitrile (32% yield). LCMS (ESI, mass/charge): 159 [M+H] ⁺ .

Stage 2. Synthesis of 1-(3-methylpyridin-2-yl)cyclopropane-1-carboxylic acid

1-(3-methylpyridin-2-yl)cyclopropan-1-carbonitrile (0.510 g, 3.22 mmol, 1.00 eq.), EtOH (10 ml), water (5 ml) and KOH (5 .42 g, 96.6 mmol, 30.0 eq.). The reaction mixture was stirred for 2 days at 140° C. and concentrated under reduced pressure. The resulting mixture was diluted with ACN (30 ml) and the solids were filtered off and removed. The resulting mixture was concentrated under reduced pressure to obtain 0.400 g of 1-(3-methylpyridin-2-yl)cyclopropane-1-carboxylic acid (crude). LCMS (ESI, mass/charge): 178 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(3-methylpyridin-2-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate

1-(3-methylpyridin-2-yl)cyclopropan-1-carboxylic acid (200 mg, 1.13 mmol, 1.00 eq.), HATU (644 mg, 1.69 mmol, 1.50 eq. .), DIPEA (437 mg, 3.38 mmol, 3.00 eq.), 1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8- carboxylate (415 mg, 1.24 mmol, 1.10 eq) and DMF (10 ml). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×50 ml) and the organic layers were combined, washed with water (3×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 125.8 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(3-methylpyridin-2-yl)cyclopropan-1-carbonyl) -1,8-diazaspiro[4.5]decane-8-carboxylate (16% yield). ¹ H NMR: (300 MHz, Chloroform-d) δ 8.36 (t, J=4.8 Hz, 1H), 7.53-7.38 (m, 1H), 7.18-7.00 ( m, 1H), 5.83-5.65 (m, 1H), 4.26-4.05 (m, 2H), 3.18-2.81 (m, 6H), 2.36 (s, 3H), 1.90-1.76 (m, 2H), 1.76-1.60 (m, 2H), 1.53-1.20 (m, 6H). LCMS (ESI, mass/charge): 494 [M+H] ⁺ .

Example 31 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(1-(5-chloropyrimidin-2-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5] decane-8-carboxylate

Stage 1. Synthesis of (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide

Zinc dust (0.813 g, 12.7 mmol, 2.00 eq.) and DMA (10 ml) were placed in a vial equipped with a magnetic stirrer and purged with nitrogen. 1,2-dibromoethane (0.236 g, 1.27 mmol, 0.20 eq.) was added slowly, followed by chlorotrimethylsilane (0.137 g, 1.27 mmol, 0.20 eq.). The reaction mixture was stirred for 15 minutes. at room temperature before adding dropwise methyl-1-bromocyclopropane-1-carboxylate (1.69 g, 9.44 mmol, 1.50 eq.). The resulting solution was stirred for 1 hour at room temperature to obtain a 0.80 M solution of (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide to be used crude.

Stage 2. Synthesis of methyl 1-(5-chloropyrimidin-2-yl)cyclopropan-1-carboxylate

2-bromo-5-chloropyrimidine (900 mg, 4.65 mmol, 1.00 eq.), (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (8.70 ml, 0.80 M in DMA, 6.96 mmol, 1.50 eq.), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (335 mg, 0.460 mmol, 0.10 eq.), copper(I) iodide (89.1 mg, 0.470 mmol, 0.10 eq.) and DMA (5 ml) under nitrogen. The resulting solution was stirred for 3 hours at 80° C. and quenched with water (20 ml). The mixture was extracted with EtOAc (3×30 ml) and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 760 mg of methyl 1-(5-chloropyrimidin-2-yl)cyclopropan-1-carboxylate (77% yield). LCMS (ESI, mass/charge): 213 [M+H] ⁺ .

Stage 3. Synthesis of 1-(5-chloropyrimidin-2-yl)cyclopropane-1-carboxylic acid

Methyl 1-(5-chloropyrimidin-2-yl)cyclopropan-1-carboxylate (212 mg, 1.00 mmol, 1.00 eq.), LiOH (72.0 mg, 3.00 mmol, 3 00 eq.), MeOH (3 ml) and water (0.5 ml). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 198 mg of 1-(5-chloropyrimidin-2-yl)cyclopropane-1-carboxylic acid (crude). LCMS (ESI, mass/charge): 199 [M+H] ⁺ .

Stage 4. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(5-chloropyrimidin-2-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate

1-(5-chlorogagrimidin-2-yl)cyclopropan-1-carboxylic acid (59.4 mg, 0.300 mmol, 1.00 eq.), 1,1,1,3,3,3-hexafluoropropane- 2-yl-1,8-diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.300 mmol, 1.00 eq.), HATU (171 mg, 0.450 mmol, 1.50 eq.), DIPEA (116 mg , 0.900 mmol, 3.00 eq.) and DMF (5 ml). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The resulting solution was extracted with EtOAc (3×30 ml) and the organic layers were combined, washed with water (3×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 75.7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(5-chloropyrimidin-2-yl)cyclopropan-1-carbonyl) -1,8-diazaspiro[4.5]decane-8-carboxylate (49% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 5.89-5.69 (m, 1H), 4.31-4.11 (m, 2H), 3.46 -3.25 (m, 2H), 3.25-2.90 (m, 4H), 2.09-1.86 (m, 2H), 1.86-1.71 (m, 2H), 1 .70-1.40 (m, 6H). LCMS (ESI, mass/charge): 515 [M+H] ⁺ .

Example 32 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(2,2-difluoro-2-(pyrimidin-2-yl)acetyl)-1,8-diazaspiro[4.5] decane-8-carboxylate

Stage 1. Synthesis of ethyl 2,2-difluoro-2-(pyrimidin-2-yl)acetate

Ethyl 2-bromo-2,2-difluoroacetate (2.56 g, 12.6 mmol, 2.00 eq.), copper (1.62 g, 25.3 mmol, 4.00 eq.) and DMSO (10 ml). The resulting solution was stirred for 1 hour at room temperature before adding 2-bromopyrimidine (1.00 g, 6.29 mmol, 1.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (10 ml). The mixture was extracted with EtOAc (3×30 ml) and the organic layers were combined, washed with water (3×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 0.550 g of ethyl 2,2-difluoro-2-(pyrimidin-2-yl)acetate (43% yield). LCMS (ESI, mass/charge): 203 [M+H] ⁺ .

Stage 2. Synthesis of 2,2-difluoro-2-(pyrimidin-2-yl)acetic acid

Ethyl 2,2-difluoro-2-(pyrimidin-2-yl)acetate (202 mg, 1.00 mmol, 1.00 eq.), lithium hydroxide (72.0 mg, 3.01 mmol, 3.00 eq.), EtOH (3 ml) and water (0.5 ml). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 174 mg of 2,2-difluoro-2-(pyrimidin-2-yl)acetic acid (crude). LCMS (ESI, mass/charge): 175 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(2,2-difluoro-2-(pyrimidin-2-yl)acetyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate

2,2-Difluoro-2-(pyrimidin-2-yl)acetic acid (45.0 mg, 0.260 mmol, 1.00 eq.), 1,1,1,3,3,3-hexafluoropropane- 2-yl-1,8-diazaspiro[4.5]decane-8-carboxylate (86.4 mg, 0.260 mmol, 1.00 eq.), HATU (147 mg, 0.390 mmol, 1.50 eq.), DIPEA ( 100 mg, 0.770 mmol, 3.00 eq) and DMF (5 ml). The resulting solution was stirred overnight at room temperature and quenched with water (10 ml). The mixture was extracted with EtOAc (3×30 ml) and the organic layers were combined, washed with water (3×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 61.4 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(2,2-difluoro-2-(pyrimidin-2-yl)acetyl) -1,8-diazaspiro[4.5]decane-8-carboxylate (48% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 8.89 (d, J=4.9 Hz, 2H), 7.48 (t, J=4.9 Hz, 1H), 5.83-5, 65 (m, 1H), 4.31-4.08 (m, 2H), 3.73 (t, J=6.4 Hz, 2H), 3.15-2.90 (m, 4H), 2 .15-1.82 (m, 4H), 1.58-1.35 (m, 2H). LCMS (ESI, mass/charge): 491 [M+H] ⁺ .

Example 33 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(1-(5-cyclopropylpyrimidin-2-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5] decane-8-carboxylate

Stage 1. Synthesis of 2-chloro-5-cyclopropylpyrimidine

5-bromo-2-chloropyrimidine (1.93 g, 9.98 mmol, 1.00 eq.), cyclopropylboronic acid (947 mg, 11.0 mmol, 1.10 eq.), potassium phosphate (6 .36 g, 30.0 mmol, 3.00 eq.) and THF (30 ml). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (1.46g, 1.99mmol, 0.200eq) was added under nitrogen atmosphere and the resulting solution was stirred overnight at 60°C and quenched with water (30mL). The mixture was extracted with EtOAc (3×50 ml) and the organic layers were combined, washed with brine (2×40 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 500 mg of 2-chloro-5-cyclopropylpyrimidine (32% yield). LCMS (ESI, mass/charge): 155 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(5-cyclopropylpyrimidin-2-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate

The title compound was prepared as described in Example 31 steps 1-4 using methyl 1-bromocyclopropane-1-carboxylate in step 1 and 2-chloro-5-cyclopropylpyrimidine in step 2 to give 6 1.6 mg 1 ,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(5-cyclopropylpyrimidin-2-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5]decan-8- carboxylate (yield 32%). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.40 (s, 2H), 6.24-6.09 (m, 1H), 4.23-4.10 (m, 2H), 3, 41-3.35 (m, 2H), 3.35-2.96 (m, 4H), 2.12-2.00 (m, 2H), 1.99-1.86 (m, 1H), 1.84-1.72(m, 2H), 1.60-1.47(m, 4H), 1.46-1.38(m, 2H), 1.13-1.04(m, 2H ), 0.82-0.76 (m, 2H). LCMS (ESI, mass/charge): 521 [M+H] ⁺ .

Example 34 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-(1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropan-1-carbonyl)- 1,8-diazaspiro[4.5]decane-8-carboxylate

Stage 1. Synthesis of 1-(ethoxycarbonyl)cyclopropane-1-carboxylic acid

Diethyl-cyclopropane-1,1-dicarboxylate (10.0 g, 53.7 mmol, 1.00 eq.), KOH (3.00 g, 53.7 mmol, 1.00 eq.) and EtOH were placed in the flask. (100 ml). The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in water (100 ml) and extracted with diethyl ether (2×50 ml). The pH of the aqueous layer was adjusted to 4 with aqueous HCl (1 M) and extracted with EtOAc (3×100 ml). The organic layers were combined, washed with water (50 ml) and brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6.60 g of 1-(ethoxycarbonyl)cyclopropane-1-carboxylic acid ( crude). LCMS (ESI, mass/charge): 159 [M+H] ⁺ .

Stage 2. Synthesis of ethyl 1-(2-acetylhydrazine-1-carbonyl)cyclopropane-1-carboxylate

The flask was filled with 1-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (6.60 g, 40.0 mmol, 1.00 eq.), HATU (22.8 g, 60.0 mmol, 1.50 eq.) , DIPEA (15.5 g, 120 mmol, 3.00 eq.), acetohydrazide (2.96 g, 40.0 mmol, 1.00 eq.) and DCM (100 ml). The resulting mixture was stirred overnight at room temperature and quenched with water (60 ml). The mixture was extracted with DCM (2×50 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by recrystallization to give 4.77 g of ethyl 1-(2-acetylhydrazine-1-carbonyl)cyclopropane-1-carboxylate (crude). LCMS (ESI, mass/charge): 215 [M+H] ⁺ .

Stage 3. Synthesis of ethyl 1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropane-1-carboxylate

Ethyl 1-(2-acetyltrazine-1-carbonyl)cyclopropane-1-carboxylate (3.00 g, 14.0 mmol, 1.00 eq.), Burgess reagent (10.0 g, 42.0 mmol, 3.00 eq.) and toluene (100 ml). The resulting mixture was stirred overnight at 100° C. and concentrated under reduced pressure. The residue was quenched with water (50 ml), extracted with EtOAc (3×100 ml) and the organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 2.80 g ethyl 1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropan-1-carboxylate (crude). LCMS (ESI, mass/charge): 197 [M+H] ⁺ .

Stage 4. Synthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropane-1-carboxylic acid

Ethyl 1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropan-1-carboxylate (1.20 g, 6.12 mmol, 1.00 eq.), LiOH (0.441 g, 18.4 mmol, 3.00 eq.), THF (10 ml) and water (2 ml). The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 5 with aqueous HCl (1M) and concentrated under reduced pressure to give 1.40 g of 1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropan-1-carboxylic acid (uncleaned). LCMS (ESI, mass/charge): 169 [M+H] ⁺ .

Stage 5. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropan-1-carbonyl) -1,8-diazaspiro[4.5]decane-8-carboxylate

1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropan-1-carboxylic acid (76.0 mg, 0.450 mmol, 1.00 eq.), 1,1,1, 3,3,3-Hexafluoropropan-2-yl-1,8-diazaspro[4.5]decane-8-carboxylate (150 mg, 0.450 mmol, 1.00 eq), HATU (256 mg, 0.675 mmol, 1.50 eq.), DIPEA (174 mg, 1.35 mmol, 3.00 eq.) and DMF (5 ml). The resulting solution was stirred overnight at room temperature and quenched with water (10 ml). The mixture was extracted with EtOAc (3×30 ml) and the organic layers were combined, washed with brine (2×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 27.5 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(5-methyl-1,3,4-oxadiazol-2- yl)cyclopropane-1-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (13% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 5.80-5.70 (m, 1H), 4.26-4.10 (m, 2H), 3.50-3.40 (m, 2H) , 3.08-2.90 (m, 4H), 2.53 (s, 3H), 2.05-1.91 (m, 2H), 1.90-1.80 (m, 2H), 1 .68-1.50 (m, 4H), 1.48-1.30 (m, 2H). LCMS (ESI, mass/charge): 485 [M+H] ⁺ .

Example 35 1,1,1,3,3,3-Hexafluoropropan-2-yl-1-((2-(2-(cyclopropanesulfonamido)-2-oxoztyl)-6-(trifluoromethyl)pyridin-3-yl) methyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Step 1. Synthesis of tert-butyl 1-((2-bromo-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate

2-bromo-6-(trifluoromethyl)pyridine-3-carbaldehyde (1.00 g, 3.94 mmol, 1.00 eq.), tert-butyl-1,8-diazaspiro[4.5]decan-8 -carboxylate (1.23 g, 5.12 mmol, 1.30 eq.) and DCE (20 ml). The mixture was stirred at room temperature for 30 minutes. before adding sodium triacetoxyborohydride (2.52 g, 11.9 mmol, 3.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (100 ml). The resulting solution was extracted with DCM (3×100 ml) and the organic layers were combined, washed with brine (2×100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 1.00 g of tert-butal-1-((2-bromo-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[4.5]decan-8- carboxylate (53% yield). LCMS (ESI, mass/charge): 478 [M+H] ⁺ .

Stage 2. Synthesis of tert-butyl-1-((2-(2-ethoxy-2-oxoethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[4.5]decan-8- carboxylate

tert-Butyl 1-((2-bromo-6-(trifluoromethyl)pyridin-3-yl)metal)-1,8-diazaspiro[4.5]decan-8-carboxylate (1000 mg, 2.09 mmol , 1.00 eq.), mesitylene (8 ml), 1-ethyl-3-potassium propanedioate (1430 mg, 8.40 mmol, 4.00 eq.), aplylpapladium chloride dimer (77.0 mg, 0.00 eq.). 0840 mmol, 0.04 eq.), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (392 mg, 0.630 mmol, 0.30 eq.) and DMAP (64.0 mg, 0.520 mmol, 0.25 equiv.) in a nitrogen atmosphere. The reaction mixture was stirred for 6 hours at 140° C. and quenched with water (50 ml). The resulting solution was extracted with EtOAc (2×80 ml) and the organic layers were combined, washed with brine (2×50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 240 mg of tert-butyl-1-((2-(2-ethoxy-2-oxoethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[ 4.5]decane-8-carboxylate (24% yield). LCMS (ESI, mass/charge): 486 [M+H] ⁺ .

Stage 3. Synthesis of 2-(3-((8-(tert-butoxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)acetic acid

Garete-butyl-1-((2-(2-ethoxy-2-oxoethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (230 mg, 0.470 mmol, 1.00 eq.), LiOH (57.0 mg, 2.38 mmol, 5.00 eq.), THF (5 ml) and water (5 ml). The resulting solution was stirred for 3 hours at room temperature. The pH value of the solution was adjusted to 5 with an aqueous solution of HCl (1 M). The resulting solution was extracted with DCM (2×50 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 200 mg of 2-(3- ((8-(tert-butoxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)acetic acid (92% yield). LCMS (ESI, mass/charge): 458 [M+H] ⁺ .

Step 4. Synthesis of tert-butyl-1-((2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[4.5]decan- 8-carboxylate

2-(3-((8-(tert-Butoxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)acetic acid (200 mg, 0.440 mmol, 1.00 eq.), cyclopropanesulfonamide (106 mg, 0.870 mmol, 2.00 eq.), EDCI (252 mg, 1.31 mmol, 3.00 eq.), DMAP (107 mg, 0.880 mmol, 2.00 eq.) and DCM (10 ml). The reaction mixture was stirred overnight at room temperature and quenched with water (30 ml). The resulting solution was extracted with DCM (2×50 ml) and the organic layers were combined, washed with brine (2×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 50 mg of tert-butyl-1-((2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8- diazaspiro[4.5]decane-8-carboxylate (20% yield). LCMS (ESI, mass/charge): 561 [M+H] ⁺ .

Stage 5. Synthesis of 2-(3-((1,8-diazaspiro[4.5]decan-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-N-(cyclopropylsulfonyl)acetamide

tert-Butyl-1-((2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[4.5]decan-8 -carboxylate (50.0 mg, 0.0900 mmol, 1.00 eq.), concentrated HCl (2 ml) and 1,4-dioxane (10 ml). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 41.0 mg of 2-(3-((1,8-diazaspiro[4.5]decan-1-yl)methyl)-6-(trifluoromethyl )pyridin-2-yl)-N-(cyclopropylsulfonyl)acetamide (quantitative yield). LCMS (ESI, mass/charge): 461 [M+H] ⁺ .

Step 6. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-((2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-6-(trifluoromethyl)pyridin-3-yl )methyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Triphosgene (13.0 mg, 0.040 mmol, 0.50 eq.), 1,1,1,3,3,3-hexafluoropropan-2-ol (30.0 mg, 0.180 mmol, 2.00 equiv.) and DCM (10 ml). DIPEA (34.0 mg, 0.260 mmol, 3.00 eq.) was added dropwise at 0°C and the resulting solution was stirred for 1 hour at room temperature before adding 2-(3-((1,8-diazaspiro[ 4.5]decan-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)-N-(cyclopropylsulfonyl)acetamide (41.0 mg, 0.090 mmol, 1.00 eq.). The reaction mixture was stirred overnight at room temperature and quenched with water (20 ml). The resulting solution was extracted with DCM (3×20 ml) and the organic layers were combined, washed with brine (2×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC to give 4.7 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-((2-(2-(cyclopropanesulfonamido)-2-oxoethyl )-6-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (8% yield). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.72 (s, 1H), 8.10-8.05 (m, 1H), 7.78-7.76 (m, 1H), 6, 13-6.12 (m, 1H), 4.24-4.68 (m, 3H), 3.82-3.76 (m, 1H), 3.45-3.40 (m, 1H), 3.28-3.02(m, 2H), 2.99-2.87(m, 1H), 2.31-2.05(m, 4H), 1.77-1.31(m, 6H ), 1.16-1.04 (m, 2H), 1.02-1.95 (m, 2H). LCMS (ESI mass/charge): 655 [M+H] ⁺ .

Example 36 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3 -a]pyrazine-3-carboxamido)-4-methylpiperidine-1-carboxylate

Stage 1. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate

The flask was filled with tert-butyl-N-(4-methylpiperidin-4-yl)carbamate (8.00 g, 37.3 mmol, 1.00 eq.), 1,1,1,3,3,3-hexafluoropropane -2-ol (75.4 g, 449 mmol, 12.0 eq.), N,N-carbonyldiimidazole (9.08 g, 56.0 mmol, 1.50 eq.) and ACN (100 ml). The resulting solution was stirred for 48 hours at 80° C. and quenched with water (50 ml). The mixture was extracted with DCM (3×150 ml) and the organic layers were combined, washed with water (3×50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 11.4 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (yield 75%). LCMS (ESI, mass/charge: 409 [M+H] ⁺ .

Stage 2. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-carboxylate (4.12 g, 10.1 mmol, 1.00 eq.), concentrated HCl (4 ml) and 1,4-dioxane (15 ml). The resulting solution was stirred for 2 hours at room temperature and concentrated under pressure to give 3.11 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate ( quantitative output). LCMS (ESI, mass/charge): 309 [M+H] ⁺ .

Stage 3. Synthesis of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-[1.2,4]triazolo[4,3-а]pyrazine-3-carboxylic acid

7-(tert-Butal)-3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-3,7(8H)-dicarboxylate (3.00 g, 10.1 mmol, 1.00 eq.), LiOH (1.21 g, 30.3 mmol, 3.00 eq.), EtOH (20 ml) and water (2 ml). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 2.70 g of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazine-3-carboxylic acid (crude). LCMS (ESI, mass/charge): 269 [M+H] ⁺ .

Stage 4. Synthesis of tert-butyl-3-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-methylpiperidin-4-yl)carbamoyl) -5,6-dihydro-[1,2,4]triazolo[4,3-а]pyrazine-7(8H)-carboxylate

7-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylic acid (2.70 g, 10 1 mmol, 1.00 eq.), 1,1,1,3,3,3-hexafluoropropan-2-yl-4-amino-4-methylpiperidine-1-carboxylate (3.11 g, 10.1 mmol, 1.00 eq.), HATU (5.76 g, 15.2 mmol, 1.50 eq.), DIPEA (5.21 g, 40.4 mmol, 4.00 eq.) and DMF (50 ml) . The resulting solution was stirred overnight at room temperature and quenched with water (20 ml). The mixture was extracted with EtOAc (3×50 ml) and the organic layers were combined, washed with brine (2×50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 4.33 g of tert-butyl-3-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4- methylpiperidin-4-yl)carbamoyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-carboxylate (77% yield). LCMS (ESI, mass/charge): 559 [M+H] ⁺ .

Stage 5. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4, 3-a]pyrazine-3-carboxamido)piperidine-1-carboxylate

tert-Butyl-3-((1-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4-metalpiperidin-4-yl)carbamoyl)- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.00 g, 1.79 mmol, 1.00 eq.), TFA (3 ml) and DCM (15 ml). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 0.553 g of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(5,6,7 ,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxamido)piperidine-1-carboxylate (crude). LCMS (ESI, mass/charge): 459 [M+H] ⁺ .

Stage 6. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4, 3-a]pyrazine-3-carboxamido)-4-methylpiperidine-1-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-4-methyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3 -a]pyrazin-3-carboxamido)piperidine-1-carboxylate (100 mg, 0.218 mmol, 1.00 eq.), propan-2-one (126 mg, 2.18 mmol, 10.00 eq.), chlorozinc (44.5 mg, 0.327 mmol, 1.50 eq.), MeOH (15 ml) and sodium cyanoborohydride (41.2 mg, 0.654 mmol, 3.00 eq.). The resulting solution was stirred overnight at 65° C., quenched with water (10 ml), extracted with DCM (3×20 ml). The organic layers were combined, washed with brine (2×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 75.6 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-isopropyl-5,6,7,8-tetrahydro-[1, 2,4]triazolo[4,3-a]pyrazine-3-carboxamido)-4-methylpiperidine-1-carboxylate (69% yield). ¹ H NMR (300 MHz, MeOH-d ₄ ) δ 6.22-6.01 (m, 1H), 4.35 (t, J=5.5 Hz, 2H), 3.93 (s, 2H) , 3.91-3.72 (m, 2H), 3.51-3.32 (m, 2H), 3.09-2.90 (m, 3H), 2.47-2.30 (m, 2H), 1.77-1.55 (m, 2H), 1.49 (s, 3H), 1.15 (t, J=6.5 Hz, 6H). LCMS (ESI, mass/charge): 501 [M+H] ⁺ .

Example 37 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-(7-isobutyryl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido) -4-methylpiperidine-1-carboxylate

Stage 1. Synthesis of 1,1,1,3,3,3-hexafgorpropan-2-yl-4-(7-isobutyryl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido )-4-methylpiperidine-1-carboxylate

[2,2,2-Trifluoro-1-(trifluoromethyl)ethyl]-4-methyl-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonylamino)piperidine was placed in the vial. -1-carboxylate (75 mg, 0.16 mmol, example 28), ACN (0.75 ml) and HATU (71.7 mg, 0.19 mmol) before adding 2-methylpropanoic acid (22.8 µl, 0 .25 mmol) and DIPEA (0.10 ml, 0.58 mmol), respectively. The reaction mixture was stirred at room temperature for 24 hours and purified by column chromatography to give 79 mg of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(7-isobutyryl-5,6, 7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-4-methylpiperidine-1-carboxylate (91% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.46 (s, 1H), 6.87 (s, 1H), 5.74 (hept., J=6.2 Hz, 1H), 4.78 (s, 2H), 3.79-4.20 (m, 6H), 3.25-3.40 (m, 2H), 2.84 (hept., J=6.9 Hz, 1H), 2 .34 (d, J=13.8 Hz, 2H), 1.57-1.77 (m, 2H), 1.51 (s, 3H), 1.17 (d, J=6.6 Hz, 6H). LCMS (ESI, mass/charge): 528 [M+H] ⁺ .

Example 38 1,1,1,3,3,3-Hexaphropropan-2-yl-1-(1-(2-cyclopropyl pyrimidin-5-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate

Stage 1. Synthesis of methyl-1-(2-cyclopropylpyrimidin-5-yl)cyclopropan-1-carboxylate

Zinc dust (50 g) and HCl (100 ml, 0.1 M) were placed in a flask. The suspension was stirred for 2-3 minutes and the solids were filtered and washed with water (100 ml), EtOH (100 ml) and diethyl ether (100 ml). The zinc dust was dried under high vacuum at 110° C. for 18 hours. Activated zinc (380 mg, 5.90 mmol) was added to a flame-dried magnetic flask, followed by THF (10.5 ml). Bromine (0.040 mL, 0.78 mmol) was added in one portion using a syringe. To the resulting solution was added 1-bromocyclopropanecarboxylate (2.1 ml, 19.5 mmol) by dropwise addition. The mixture was heated to 55-62° C. (internal) for 3.5 hours. The resulting solution was cooled to RT and solids were allowed to settle. Pd ₂ (dba) ₃ (45.9 mg, 0.050 mmol), QPhos (35.6 mg, 0.050 mmol) and 5-bromo-2-cyclopropyl-pyrimidine (68.0 μl, 2, 51 mmol). THF (11.5 ml) was added under nitrogen atmosphere, followed by dropwise addition of bromo-(1-methoxycarbonylcyclopropyl)zinc (18.5 ml, 3.7 mmol) over 5 minutes. The resulting solution was allowed to stir at room temperature for 1.5 hours. The reaction was quenched with saturated water. NH ₄ Cl solution (5 ml) and then diluted with water. NH ₄ Cl solution (30 ml) and EtOAc (60 ml). The organics were extracted (2×60 ml EtOAc), dried over Na ₂ SO ₄ , decanted and concentrated. The crude material was purified by column chromatography to give 511 mg of methyl 1-(2-cyclopropylpyrimidin-5-yl)cyclopropan-1-carboxylate (94% yield). ¹ H NMR [400 MHz, Chloroform-d] δ 8.51 (d, J=1.8 Hz, 2H), 3.64 (d, J=1.8 Hz, 3H), 2.20-2, 35 (m, 1H), 1.68 (t, J=2.5 Hz, 3H), 0.82-1.39 (m, 6H). LCMS (ESI mass/charge): 219 [M+H] ⁺ .

Stage 2. Synthesis of 1-(2-cyclopropylpyrimidin-5-yl)cyclopropane-1-carboxylic acid

A vial containing methyl 1-(2-cyclopropylpyrimidin-5-yl)cyclopropan-1-carboxylate (511 mg, 2.34 mmol) was charged with THF (7.0 ml) and 5 M LiOH aqueous solution (2.4 ml, 12 mmol). The reaction mixture was stirred at room temperature for 2 hours, after which the reaction mixture was diluted with water (3.0 ml) and EtOAc (3.0 ml). The pH of the organic layer was adjusted to 2 with aqueous HCl (1M). The aqueous layer was extracted with DCM (3×20 ml) and the organics were dried over Na ₂ SO ₄ , decanted and concentrated to give 345 mg of 1-(2-cyclopropyl-pyrimidin-5-yl)-piclopropan-1-carboxylic acid (crude). LCMS (ESI mass/charge): 205 [M+H] ⁺ .

Stage 3. Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-1-(1-(2-cyclopropylpyrimidin-5-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5 ]decane-8-carboxylate

1,1,1,3,3,3-hexafluoropropan-2-yl-1,8-diazaspiro[4.5]decan-8-carboxylate (75 mg, 0.22 mmol), 1-(2-cyclopropylpyrimidine -5-yl)cyclopropanecarboxylic acid (50.4 mg, 0.25 mmol), HATU (102.3 mg, 0.27 mmol), DIPEA (0.10 ml, 0.57 mmol) and DMF (1.0 ml). The reaction mixture was stirred at room temperature for 1.5 hours. The resulting solution was diluted with DMF (2.0 ml) and purified by preparative HPLC to give 71 mg of 1,1,1,3,3,3-hexafluoropropane-2 -yl-1-(1-(2-cyclopropylpyrimidin-5-yl)cyclopropan-1-carbonyl)-1,8-diazaspiro[4.5]decan-8-carboxylate (62% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 2H), 5.82-5.67 (m, 1H), 4.25-4.07 (m, 2H), 3.38 -3.24 (m, 2H), 3.12-2.84 (m, 4H), 2.29-2.17 (m, 1H), 1.98-1.70 (m, 4H), 1 .52-1.42 (m, 2H), 1.33 (t, J=10.7 Hz, 2H), 1.23-1.00 (m, 6H). LCMS (ESI mass/charge): 521 [M+H] ⁺ .

Examples 39-229. Examples 39-229 were prepared using procedures similar to those described in examples 1-38.

II. Biological evaluation

Compounds were tested to evaluate their activity against MAGL using the following in vitro and in vivo assays.

Protein characterization based on in vitro competitive activity.

Proteomes (fractions derived from human prefrontal cortex cells or cell membranes) (50 μl, total protein concentration 1.0 mg/ml) were pre-incubated using various concentrations of inhibitors at 37°C. After 30 min. FP-Rh or HT-01 (1.0 μl, 50 μM in DMSO) was added and the mixture was incubated for another 30 min. at room temperature. Reactions were quenched with SDS loading buffer (15 μl - 4X) and analyzed on SDS-PAGE. After gel visualization, serine hydrolase activity was determined by measuring the fluorescence intensity of bands on the gel corresponding to MAGL using Image J 1.49k software. The IC ₅₀ data from this analysis are shown in Table 1.

Preparation of mouse brain proteomes taken after treatment of mice with an inhibitor

Inhibitors were administered wild-type C57B1/6J by gavage in polyethylene glycol vehicle. Each animal was sacrificed 4 hours after administration and brain proteomes were obtained and analyzed according to previously established methods (see Niphakis, M.J., et al. (2011) ACS Chem. Neurosci. and Long, J.Z., et al. Nat Chem Biol 5:37-44).

The compounds showed activity in the assays described herein, as indicated in Table 1.

Claims (20)

1. Compound having the structure of formula (II)

where Y is -C(O)-; Z is C _3-6 cycloalkyl; R ³ is an unsubstituted 9-10 membered bicyclic heteroaryl ring containing one to six heteroatoms selected from nitrogen, oxygen and sulfur; R ¹¹ is H, C _1-6 alkyl or —C _1-6 alkyl-O-C _1-6 alkyl; R ¹² is C _1-6 alkyl; R ¹³ is H or C _1-6 alkyl; and v is 0; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is H. 3. Connection according to any one of paragraphs. 1, 2, where R ¹¹ represents C _1-6 alkyl. 4. The connection according to any one of paragraphs. 1-3, where R ¹² represents -CH ₃ . 5. Connection according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, where R ³ is selected from:

6. Compound according to claim 1, selected from:

or a pharmaceutically acceptable salt thereof. 7. Pharmaceutical composition for inhibiting MAGL activity, containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.