IP Library › Granted Patent US 12,729,207

Granted Patent B2

US 12,729,207 · App. 18/032,548 · Granted Sep 8, 2026

Heterocyclic spiro compounds and methods of use

Inventors: Brian Alan Lanman (Woodland Hills, CA); Abhisek Banerjee (Bangalore, IN); Margaret Chu-Moyer (Brookline, MA); Dongcheng Dai (Corvallis, OR); Josephine Eshon (Ithaca, NY); David Huang (Thousand Oaks, CA); Matthew R. Kaller (Ventura, CA); Heejun Lee (Thousand Oaks, CA); Patricia Lopez (Woodland Hills, CA); Vu Van Ma (Oak Park, CA); Francesco Manoni (Newbury Park, CA); Jose M Medina (Thousand Oaks, CA); Alexander J. Pickrell (Westlake Village, CA); John C. Stellwagen (Newbury Park, CA); Zhen Sun (Shanghai, CN); Nuria A. Tamayo (Newbury Park, CA); Wenhan Zhang (Thousand Oaks, CA); Kai Zhu (Westlake Village, CA)

Assignee: AMGEN INC.

C07D487/10 A61K45/06 A61P35/00 C07D519/00

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Quick Facts

Patent No.: US 12,729,207
App. No.: 18/032,548
Granted: Sep 8, 2026
Kind: B2

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Abstract

Provided are compounds of Formula (I) having activity as inhibitors of G12C mutant KRAS protein, pharmaceutical compositions comprising the compounds, and uses and methods of treating certain disorders, such as cancer, including but not limited to lung, pancreatic and colorectal cancers.

Claims (494)

1 . A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R 1 at each occurrence independently is H, 2 H, C 1-4 haloalkyl, C 1-4 alkoxy, —CH 2 OH, —(CH 2 )O(C 1-4 alkyl), —(CH 2 )O(C 1-4 haloalkyl), —(CH 2 )-C 1-4 dialkylamino, aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidine-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl;

R 2 is H, 2 H, halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, —CH 2 CN, —CH 2 OH, C 1-4 alkoxy, or C 1-4 haloalkoxy;

wherein, optionally, one R 1 and R 2 together with the carbon atoms to which they are attached form a

group;

R 3 at each occurrence independently is H, halogen, CN, OH, C 1-4 alkyl, C 1-4 haloalkyl, —CH 2 CN, —CH 2 OH, C 1-4 alkoxy, or C 1-4 haloalkoxy, wherein two substituents R 3 attached to the same carbon atom optionally form together with said carbon atom a C 3-6 cycloalkyl or a carbonyl group;

A at each occurrence independently is CR 3 R 3 or absent;

R 4 is 1,2,3,4-tetrahydro-8-quinolinyl, 6 or 10 membered aryl, or 5 to 10 membered heteroaryl,

wherein the aryl or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from OH, halogen, —CN, NH 2 , C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —SO 2 NH 2 , and —NHSO 2 CH 3 ,

wherein the C 1-4 alkyl is optionally substituted with OH;

X 1 is CR 5 or N;

X 2 is CH, CF, or N;

X 3 is C or N;

X 4 is C or N;

R 5 is H, halogen, CN, —COO(C 1-4 alkyl), C 1-4 alkyl, C 2-4 alkenyl, C 1-4 haloalkyl, —(CH 2 ) m (C 1-4 alkoxy), —(CH 2 ) m (C 1-4 haloalkoxy), C 3-5 cycloalkyl, C 3-5 cyclohaloalkyl, or C 3-5 heterocycloalkyl;

B together with the atoms to which it is attached forms a 4 to 7 membered fully saturated, fully unsaturated, or partially unsaturated carbocyclic or heterocyclic ring system,

wherein the heterocyclic ring system comprises 1 to 5 heteroatoms independently selected from N, O, and S,

wherein the ring system is optionally substituted with 1 to 5 substituents R 6 ;

R 6 at each occurrence independently is halogen, OH, —CN, —NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —C(═O)C 1-6 alkyl, —R 7 -(C 3-5 cycloalkyl), —R 7 -(C 3 5 cyclohaloalkyl), —R 7 -(C 3-6 heterocycloalkyl), —R 7 -(phenyl), or —R 7 -(5 to 6 membered heteroaryl),

wherein the C 1-6 alkyl is optionally substituted with C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 dialkylamino, —CO(C 1-4 alkylamino) or —CO(C 1-4 dialkylamino),

wherein the C 1-6 haloalkyl is optionally substituted with a OH,

wherein the C 3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from (=O) and C 1-6 alkyl,

wherein the phenyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-4 alkoxy,

wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, —(CH 2 ) 1-3 OH, (CH 2 ) 1-3O (C 1-4 alkyl), —(CH 2 ) 1-3O (C 1-4 haloalkyl), C 1-4 alkyl, and C 1-4 haloalkyl,

wherein two substituents R 6 together optionally form a —(CH 2 ) n — group creating a ring together with the ring atom or ring atoms to which the two substituents R 6 are attached,

wherein the —(CH 2 ) n — group optionally has one —CH 2 — group substituted with one heteroatom selected from N, O, and S, and

wherein the —(CH 2 ) n — group is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-6 alkyl;

R 7 is (CH 2 ) m or CO;

n is 1, 2, 3, 4, 5 or 6; and

m is 0 or 1.

2 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

(a) R 1 at each occurrence independently is H, 2 H, C 1-4 haloalkyl, —CH 2 OH, —(CH 2 )O(C 1-4 alkyl), —(CH 2 )O(C 1-4 haloalkyl), or —(CH 2 )-C 1-4 dialkylamino; or

(b) R 2 is H or halogen; or

3 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

one R 1 and R 2 together with the carbon atoms to which they are attached form

4 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

R 3 at each occurrence independently is H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, or —CH 2 OH.

5 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

(a) one A is absent and the other A is CR 3 R 3 ; or

(b) both A are absent.

6 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

7 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

R 4 is 6 or 10 membered aryl or 5 to 10 membered heteroaryl,

wherein the aryl or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from OH, halogen, —CN, NH 2 , C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, —SO 2 NH 2 , and —NHSO 2 CH 3 , wherein the C 1-4 alkyl is optionally substituted with OH.

8 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the 6 or 10 membered aryl is: (a) phenyl; or (b) naphthalenyl; and the 5 to 10 membered heteroaryl is 1,3-thiazolyl, pyrazolyl, pyridyl, benzothiophenyl, indolyl, indazolyl, 1,3-benzothiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzoxadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazo[1,5-a]pyridinyl, or pyrazolo[3,4-b]pyridinyl.

9 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

R 4 is

10 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

X 1 is N, X 2 is N, X 3 is C, and X 4 is C; or

X 1 is CR 5 , X 2 is N, X 3 is C, and X 4 is C; or

X 1 is CR 5 , X 2 is CH, X 3 is C, and X 4 is C; or

X 1 is CR 5 , X 2 is CH, X 3 is N, and X 4 is C; or

X 1 is CR 5 , X 2 is CH, X 3 is C, and X 4 is N.

11 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

R 5 is H, halogen, CN, —COO(C 1-4 alkyl), C 1-4 alkyl, C 2-4 alkenyl, C 1-4 haloalkyl, —(CH 2 ) m (C 1-4 alkoxy), or, C 3-5 cycloalkyl.

12 . The compound according to claim 11 or a

pharmaceutically acceptable salt thereof, wherein

R 5 is F, CI, or methyl.

13 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

B together with the atoms to which it is attached forms a ring system selected from

wherein the ring system is optionally substituted with 1 to 5 substituents R 6 .

14 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

B together with the atoms to which it is attached forms a ring system selected from

15 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein the compound is a compound of:

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 , R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 , R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 3; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 4; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 2; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 ,

R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 , R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 , R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 5; or

wherein

R 1 at each occurrence independently, R 2 , R 3 at each occurrence independently, R 4 , R 5 , and R 6 at each occurrence independently are defined as in claim 1 ; and

p is 0 to 3.

16 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

R 6 at each occurrence independently is C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, —R 7 —(C 3-5 cycloalkyl), —R 7 —(C 3-6 heterocycloalkyl), —R 7 -(phenyl), or —R 7 -(5 to 6 membered heteroaryl),

wherein the C 1-6 alkyl is optionally substituted with C 1-4 alkoxy,

wherein the C 3-6 heterocycloalkyl is optionally substituted with C 1-6 alkyl,

wherein the phenyl is optionally substituted with C 1-4 alkoxy,

wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, —(CH 2 ) 1-3 OH and C 1-4 alkyl, and

wherein two substituents R 6 together optionally form a —(CH 2 ) n — group creating a ring together with the ring atom or ring atoms to which the two substituents R 6 are attached,

and the —(CH 2 ) n — group optionally has one —CH 2 — group substituted with an —O— atom.

17 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein

R 6 at each occurrence independently is methyl, oxetan-3-yl, or 1,4-dimethyl-1H-pyrazol-5-yl,

wherein two substituents R 6 together optionally form a —(CH 2 ) n — group creating a ring together with the ring atom or ring atoms to which the two substituents R 6 are attached.

18 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein:

(a) R 7 is (CH 2 ) m ; or

(b) n is 1; or

(d) any combination of (a), (b), and (c).

19 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is

8-fluoro-2-(5-(fluoromethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(5-methyl-1H-indazol-4-yl)-3-quinolinecarbonitrile;

8-(5-methyl-1H-indazol-4-yl)-3-(4-methyl-1-piperazinyl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-a]pyridine-7-carbonitrile;

8-(5-methyl-1H-indazol-4-yl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-2-(1,3-thiazol-2-yl)imidazo[1,2-a]pyridine-7-carbonitrile;

4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonitrile;

(P)-1-(6-(3,7,7-trimethyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(6-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(6-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-3,7,7-trimethyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-3,7,7-trimethyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(1,6-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3,7,7-trimethyl-4-(6-methyl-1H-indazol-7-yl)-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(3-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3,7,7-trimethyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(1R,9R)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6-(5-(trifluoromethyl)-1H-indazol-4-yl)-3-azatricyclo [7.1.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

1-(6-(4-(6-chloro-5-methyl-1H-indazol-4-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano [4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-(1R,8S)-6-(3-hydroxy-1-naphthalenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [6.2.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

(1R,8S)-6-(3-hydroxy-1-naphthalenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [6.2.1.02,7] undeca-2,4,6-triene-5-carbonitrile or (1S,8R)-6-(3-hydroxy-1-naphthalenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [6.2.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

(M)-(1R,8S)-6-(3-hydroxy-1-naphthalenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [6.2.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-6-(6-hydroxy-8-isoquinolinyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [7.1.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-6-(7-hydroxy-5-quinolinyl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [7.1.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

(P)-(1R,9R)-6-(6-hydroxy-8-quinolinyl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [7.1.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

(P)-(1R,9R)-6-(7-hydroxy-5-quinolinyl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo [7.1.1.02,7] undeca-2,4,6-triene-5-carbonitrile;

1-(6-(7-methoxy-3-methyl-4-(5-methyl-1H-indazol-4-yl)-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

8-(3-hydroxy-1-naphthalenyl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3,4-dihydro-2H-chromene-7-carbonitrile;

(M)-8-(3-hydroxy-1-naphthalenyl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3,4-dihydro-2H-chromene-7-carbonitrile;

1-((5S)-5-methyl-6-(3-methyl-4-(5-methyl-1H-indazol-4-yl)-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-((5S)-6-(7-fluoro-3-methyl-4-(5-methyl-1H-indazol-4-yl)-2-quinolinyl)-5-methyl-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(1R,9R)-6-(2-chloro-5-hydroxyphenyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-6-(2-fluoro-5-hydroxyphenyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-6-(5-hydroxy-2-methylphenyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1R,9R)-6-(5-hydroxy-2-methylphenyl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1R,9R)-6-(2-chloro-5-hydroxyphenyl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

1-(6-(3-chloro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3-chloro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-chloro-4-(5-hydroxy-2-methylphenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3-chloro-4-(5-hydroxy-2-methylphenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-chloro-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(3-chloro-4-(1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-chloro-4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(3-chloro-4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-chloro-4-(6-chloro-5-methyl-1H-indazol-4-yl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(5-methyl-1H-indazol-4-yl)-3-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-2-naphthalenecarbonitrile;

8-(5-methyl-1H-indazol-4-yl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3,4-dihydro-1H-2-benzopyran-7-carbonitrile;

1-(1,6-dimethyl-1H-indazol-7-yl)-6,6-dimethyl-3-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-2-naphthalenecarbonitrile;

3′-hydroxy-6,6-dimethyl-3-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro [1,1′-binaphthalene]-2-carbonitrile;

(P)-8-(5-methyl-1H-indazol-4-yl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3,4-dihydro-1H-2-benzopyran-7-carbonitrile;

8-(1,6-dimethyl-1H-indazol-7-yl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3,4-dihydro-2H-chromene-7-carbonitrile;

1-(6-(7-chloro-8-(1,6-dimethyl-1H-indazol-7-yl)-3,4-dihydro-2H-chromen-6-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

8-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3,4-dihydro-2H-chromene-7-carbonitrile;

2-(8,8-difluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

8-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-6-((5S)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3,4-dihydro-2H-chromene-7-carbonitrile;

(P)-1-(6-(3-chloro-4-(6-chloro-5-methyl-1H-indazol-4-yl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7-chloro-8-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3,4-dihydro-2H-chromen-6-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1S,8R)-5-methyl-6-(1,5,6-trimethyl-1H-indazol-7-yl)-3-azatricyclo[6.2.1.02, 7]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(3-chloro-5-hydroxy-2-methylphenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(1R,9R)-6-(7-fluoro-5-methyl-1H-indazol-4-yl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

4-(5-chloro-1H-indol-4-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(1R,9R)-6-(5-chloro-6-methyl-1H-indazol-4-yl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-10, 10-dimethyl-6-(7-methylimidazo[1,5-a]pyridin-8-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

4-(3-chloro-6-methyl-1H-indol-7-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3-methyl-7-(2-propanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3-methyl-7-(2-propanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-methyl-7-(2-propanyl)-4-(1,5,6-trimethyl-1H-indazol-7-yl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(1R,9R)-6-(2-chloro-3-fluoro-5-hydroxyphenyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-6-(2-chloro-5-hydroxy-3-pyridinyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1R,9R)-6-(7-hydroxy-5-quinoxalinyl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

4-(6-hydroxy-1-naphthalenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(M)-1-(6-(4-(3-chloro-5-hydroxy-2-methylphenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(2-chloro-5-hydroxy-3-methylphenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-((2H3)-2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

2-(2-((2E)-4-(dimethylamino)-2-butenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

2-(2-((2E)-4,4-difluoro-2-butenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(7R)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(trifluoromethyl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile or (7S)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(trifluoromethyl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4′-(5-methyl-1H-indazol-4-yl)-2′-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7′,8′-dihydro-5′H-spiro[cyclopropane-1,6′-quinoline]-3′-carbonitrile;

6,6-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile;

(5R,7S)-5,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile or (5S,7R)-5,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,7-dihydrospiro[cyclopenta [b]pyridine-6, 1′-cyclopropane]-3-carbonitrile;

4-(1,6-dimethyl-1H-indazol-7-yl)-6,6-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile;

(P)-4-(1,6-dimethyl-1H-indazol-7-yl)-6,6-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile;

(7R)-4-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile or (7S)-4-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(7R)-4-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(7S)-4-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(7R)-4-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile or (7S)-4-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(P)-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

1-(6-(3-(difluoromethyl)-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

4′-(5-methyl-1H-indazol-4-yl)-2′-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-2,3,5,5′,6,8′-hexahydrospiro[pyran-4,7′-pyrano[4,3-b]pyridine]-3′-carbonitrile;

(3R)-4′-(5-methyl-1H-indazol-4-yl)-2′-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4,5,5′,8′-tetrahydrospiro[furan-3,7′-pyrano[4,3-b]pyridine]-3′-carbonitrile or (3S)-4′-(5-methyl-1H-indazol-4-yl)-2′-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4,5,5′,8′-tetrahydrospiro[furan-3,7′-pyrano[4,3-b]pyridine]-3′-carbonitrile;

6,6-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-((5R)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile or 6,6-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-((5S)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile;

(P)-6,6-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-((5R)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile;

(P)-4-(1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(6aR,7aR)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5R)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aR,7aR)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5S)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aR,7aS)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5R)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aR,7aS)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5S)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aS,7aR)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5R)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aS,7aR)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5S)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aS,7aS)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5R)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aS,7aS)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-((5S)-5-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a, 7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile;

4-(3-hydroxy-1-naphthalenyl)-6,6-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile;

(P)-4-(3-hydroxy-1-naphthalenyl)-6,6-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta [b]pyridine-3-carbonitrile;

(P)-(6aR,7aS)-4-(4-fluoro-3-hydroxy-1-naphthalenyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a, 7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile;

(M)-(6aR,7aS)-4-(4-fluoro-3-hydroxy-1-naphthalenyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a, 7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile;

(P)-4-(4-fluoro-3-hydroxy-1-naphthalenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(M)-2-((5S)-5-(fluoromethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile and (P)-2-((5R)-5-(fluoromethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(5aR,6aR)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-b]pyridine-3-carbonitrile or (5aR,6aS)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-b]pyridine-3-carbonitrile or (5aS,6aR)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-b]pyridine-3-carbonitrile or (5aS,6aS)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-b]pyridine-3-carbonitrile;

(4bR,5aR)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile or (4bR,5aS)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile or (4bS,5aR)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile or (4bS,5aS)-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b, 5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile;

(6R)-6-cyclopropyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile or (6S)-6-cyclopropyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;

(4bR,5aR)-5,5-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile or (4bR,5aS)-5,5-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b, 5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile or (4bS,5aR)-5,5-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile or (4bS,5aS)-5,5-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-b]pyridine-3-carbonitrile;

(P)-(6aR,7aS)-2-(2-((2E)-4-(dimethylamino)-2-butenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(3-hydroxy-1-naphthalenyl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile (3 rd eluting isomer);

(P)-(6aS,7aR)-2-(2-((2E)-4-(dimethylamino)-2-butenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(3-hydroxy-1-naphthalenyl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile;

7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(1,5,6-trimethyl-1H-indazol-7-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(1,5,6-trimethyl-1H-indazol-7-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(P)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(1,5,6-trimethyl-1H-indazol-7-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(1R,9R)-10, 10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-10, 10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-4-((5R)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile or (1R,9R)-10, 10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-4-((5S)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;

4′-(5-methyl-1H-indazol-4-yl)-2′-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5′,8′-dihydrospiro[cyclobutane-1,7′-pyrano[4,3-b]pyridine]-3′-carbonitrile;

7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,7-dihydrofuro [3,4-b]pyridine-3-carbonitrile;

4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,1′-cyclopropane]-3-carbonitrile;

(1R,9R)-6-(1,6-dimethyl-1H-indazol-7-yl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(M)-(1R,9R)-6-(1,6-dimethyl-1H-indazol-7-yl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1R,9R)-6-(3-hydroxy-1-naphthalenyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1s,9s)-6-(1,6-dimethyl-1H-indazol-7-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

4-(5-hydroxy-2-methylphenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(1s,9s)-6-(5-hydroxy-2-methylphenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(M)-(1R,9R)-10,10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(6aR,7aS)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile or (6aS,7aR)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile;

(M)-(1s,9s)-6-(1,6-dimethyl-1H-indazol-7-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1s,9s)-6-(5-hydroxy-2-methylphenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(P)-4-(5-hydroxy-2-methylphenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(P)-(1R,9R)-6-(3-hydroxy-1-naphthalenyl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(1s,9s)-3-(1,6-dimethyl-1H-indazol-7-yl)-5-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-4-carbonitrile;

(M)-(1s,9s)-3-(1,6-dimethyl-1H-indazol-7-yl)-5-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-4-carbonitrile;

(M)-(6aR,7aS)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a, 7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile;

(M)-(6aS,7aR)-4-(1,6-dimethyl-1H-indazol-7-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,6a, 7,7a-tetrahydro-5H-cyclopropa[h]quinoline-3-carbonitrile;

4-(1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(5-chloro-1H-indazol-4-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(P)-4-(1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(7-fluoro-5-methyl-1H-indazol-4-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(7-fluoro-5-methyl-1H-indazol-4-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

4-(5-chloro-1H-indazol-4-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

7,7-dimethyl-4-(5-methyl-1H-pyrazolo [3,4-b]pyridin-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(2-chloro-5-hydroxy-3-methylphenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

4-(2-amino-3,5-dichloro-6-fluorophenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(P)-4-(2-amino-3,5-dichloro-6-fluorophenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

1-(6-((1R,9R)-5-fluoro-6-(3-hydroxy-1-naphthalenyl)-10, 10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

(1S,8R)-6-(5-methyl-1H-indazol-4-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

(1R,8S)-6-(5-methyl-1H-indazol-4-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1S,8R)-6-(5-methyl-1H-indazol-4-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

(1R,8S)-6-(5-hydroxy-2-methylphenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1S,8R)-6-(5-hydroxy-2-methylphenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1R,8S)-6-(5-hydroxy-2-methylphenyl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

(1S,8R)-6-(1,6-dimethyl-1H-indazol-7-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

(P)-(1S,8R)-6-(1,6-dimethyl-1H-indazol-7-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-triene-5-carbonitrile;

4-(6-chloro-5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

7-cyclopropyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

2-(8,8-difluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-methoxy-4-(5-methyl-1H-indazol-4-yl)-3-quinolinecarbonitrile;

7-methoxy-4-(5-methyl-1H-indazol-4-yl)-2-((5R)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile or 7-methoxy-4-(5-methyl-1H-indazol-4-yl)-2-((5S)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

1-(6-(3,7,7-trimethyl-4-(5-methyl-1H-indazol-4-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(1R,9R)-6-(1H-indazol-7-yl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

1-(6-(4-(3-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-(1R,9R)-6-(1H-indazol-7-yl)-10,10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

(M)-1-(6-(4-(5-hydroxy-2-methylphenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3,7,7-trimethyl-4-(5-methyl-1H-indazol-4-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3,7,7-trimethyl-4-(1,5,6-trimethyl-1H-indazol-7-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3,7,7-trimethyl-4-(1,5,6-trimethyl-1H-indazol-7-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(6-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(6-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(2-chlorophenyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3-quinolinecarbonitrile;

(1R,9R)-10, 10-dimethyl-6-(6-methyl-1H-indazol-7-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

1-(6-((1R,9R)-5-fluoro-6-(5-hydroxy-2-methylphenyl)-10, 10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-(1R,9R)-10,10-dimethyl-6-(6-methyl-1H-indazol-7-yl)-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

4-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(P)-4-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(P)-1-(6-((1R,9R)-5-fluoro-6-(5-hydroxy-2-methylphenyl)-10,10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-fluoro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3-fluoro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-((1R,9R)-5-fluoro-10, 10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1R,9R)-5-fluoro-10,10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((1R,9R)-5-fluoro-6-(3-hydroxy-1-naphthalenyl)-10,10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3-fluoro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

7,7-dimethyl-4-(6-methyl-1H-indazol-7-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(P)-7,7-dimethyl-4-(6-methyl-1H-indazol-7-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

(1R,9R)-6-(2-chloro-4-fluoro-5-hydroxyphenyl)-10, 10-dimethyl-4-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-triene-5-carbonitrile;

1-(6-(4-(5-chloro-6-methyl-1H-indazol-7-yl)-3-fluoro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(5-hydroxy-2-(trifluoromethyl) phenyl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(5-chloro-6-methyl-1H-indazol-7-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

1-(6-((7R)-4-(2,4-difluorophenyl)-7-(1,4-dimethyl-1H-pyrazol-5-yl)-3-methyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((7R)-4-(1,6-dimethyl-1H-indazol-7-yl)-7-(1,4-dimethyl-1H-pyrazol-5-yl)-3-methyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(4-(3-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(6-chloro-1,5-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

2-amino-7-fluoro-4-(3,7,7-trimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridin-4-yl)-1-benzothiophene-3-carbonitrile;

(M)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3-fluoro-7-(3-oxetanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(1,6-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(5-methyl-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

1-(6-(3-methyl-4-(5-methyl-1H-indazol-4-yl)-7-(4-methyl-1,3-thiazol-5-yl)-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(2-chlorophenyl)-7-(1-methyl-1H-imidazol-2-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

1-(6-(4-(2-chloro-5-hydroxyphenyl)-3-methyl-7-(1-methyl-1H-pyrazol-5-yl)-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(2-chlorophenyl)-2-(8,8-difluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(1-methyl-1H-pyrazol-5-yl)-3-quinolinecarbonitrile;

4-(2-chlorophenyl)-7-(2-methyl-1H-imidazol-1-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(2-methyl-1H-imidazol-1-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(5-methyl-1H-imidazol-1-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-chlorophenyl)-7-(5-methyl-1H-imidazol-1-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

1-(6-(4-(6-hydroxy-1-naphthalenyl)-3-methyl-7-(2-propanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(6-hydroxy-1-naphthalenyl)-3-methyl-7-(2-propanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(6-hydroxy-1-naphthalenyl)-3,7-dimethyl-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(6-hydroxy-1-naphthalenyl)-3-methyl-7-(3-oxetanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(6-hydroxy-1-naphthalenyl)-7-((2R)-1-methoxy-2-propanyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one or 1-(6-(4-(6-hydroxy-1-naphthalenyl)-7-((2S)-1-methoxy-2-propanyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(2-fluoro-5-hydroxyphenyl)-3-methyl-7-(4-methyl-1,3-thiazol-5-yl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7-cyclopropyl-4-(6-hydroxy-1-naphthalenyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(6-hydroxy-1-naphthalenyl)-3-methyl-7-((2R)-3,3,3-trifluoro-2-hydroxypropyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one or 1-(6-(4-(6-hydroxy-1-naphthalenyl)-3-methyl-7-((2S)-3,3,3-trifluoro-2-hydroxypropyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-methyl-4-(5-methyl-1H-indazol-4-yl)-7-(2-propanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(2,3-dimethylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-fluoro-6-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

(P)-4-(2-fluoro-6-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2,4-difluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

4-(2-chlorophenyl)-7-(2-(hydroxymethyl)-4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

4-(2-fluorophenyl)-7-(4-(hydroxymethyl)-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

(P)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

(M)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

(M)-4-(2,3-dimethylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

(P)-4-(2,3-dimethylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

(P)-4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2,3-dimethylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

(M)-4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

(P)-4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

4-(2,4-difluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1,5-naphthyridine-3-carbonitrile;

4-(2-fluorophenyl)-7-(4-(methoxymethyl)-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(4-(hydroxymethyl)-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(2,4-difluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

(8R)-4-(2-fluorophenyl)-8-methyl-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile or (8S)-4-(2-fluorophenyl)-8-methyl-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

(8R)-4-(2-fluorophenyl)-8-methyl-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(2,4-difluorophenyl)-7-(4-methoxyphenyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(2-chloro-5-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(3-fluoro-2-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(2,4-difluorophenyl)-2-((5S)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(4-methyl-1,3-thiazol-5-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(2,4-difluorophenyl)-2-((5R)-5-methyl-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(4-methyl-1,3-thiazol-5-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(2-fluoro-5-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

(P)-4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

(M)-4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

(P)-4-(2-chloro-5-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

4-(3-fluoro-2-pyridinyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-((2H3)-2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

7-cyclopropyl-4-(2-fluorophenyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

1-(6-((7R)-4-(2,3-dimethylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(7R)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile or (7S)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(M)-(7R)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(P)-(7S)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(P)-(7R)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6, 7,8-tetrahydro-3-quinolinecarbonitrile;

(M)-(7S)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(7S)-4-(2-fluorophenyl)-7-methyl-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6, 7,8-tetrahydro-3-quinolinecarbonitrile;

(7R)-4-(2-fluorophenyl)-7-methyl-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

(7R)-4-(2,4-difluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile or (7S)-4-(2,4-difluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

4-(2-chloro-4-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2,4-difluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(M)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(P)-4-(2-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(7R)-4-(2-chloro-4-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile;

4-(2-fluoro-6-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(4-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(P)-4-(2-chloro-4-fluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-chloro-6-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-fluoro-5-methoxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(P)-4-(2-chlorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-chloro-5-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2,3-difluorophenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-fluoro-5-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-fluoro-6-methylphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(P)-4-(2-fluoro-6-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(4-(methoxymethyl)-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(3-fluoro-2-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(3-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

4-(2-fluorophenyl)-7-(4-(hydroxymethyl)-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6-dihydro-3-quinolinecarbonitrile;

(7R)-4-(3-fluoro-2-pyridinyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile or (7S)-4-(3-fluoro-2-pyridinyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

(7S)-4-(3-fluoro-2-pyridinyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6, 7,8-tetrahydro-3-quinolinecarbonitrile;

4-(2-chloro-5-(difluoromethyl) phenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

(6R)-4-(5-methyl-1H-indazol-4-yl)-6-(2-propanyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile or (6S)-4-(5-methyl-1H-indazol-4-yl)-6-(2-propanyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;

(P)-1-(6-(3-ethenyl-4-(5-methyl-1H-indazol-4-yl)-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-fluoro-7-methoxy-4-(5-methyl-1H-indazol-4-yl)-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-chloro-4-(5-methyl-1H-indazol-4-yl)-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7-chloro-8-(5-methyl-1H-indazol-4-yl)-3,4-dihydro-2H-chromen-6-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

4-(2-fluoro-3-hydroxyphenyl)-7-(4-methyl-1,3-thiazol-5-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile;

(P)-1-(6-(4-(1,6-dimethyl-1H-indazol-7-yl)-3-methyl-7-(3-methyl-3-oxetanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-7,7-dimethyl-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

1-(6-(4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

8-(5-methyl-1H-indazol-4-yl)-2-phenyl-6-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-a]pyridine-7-carbonitrile;

7-methoxy-4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile;

2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-7-methyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;

(7)-2-(8,8-difluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-methyl-4-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile;

4-(5,6-dimethyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-3-quinolinecarbonitrile; or 4-(5-methyl-1H-indazol-4-yl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile.

20 . The compound according to claim 1 or a

pharmaceutically acceptable salt thereof, wherein:

(a) the compound is 1-(6-(4-(3-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(5-fluoro-6-(3-hydroxy-1-naphthalenyl)-10,10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-chloro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(3-chloro-5-hydroxy-2-methylphenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(5-methyl-6-(1,5,6-trimethyl-1H-indazol-7-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(5-fluoro-10, 10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(3-fluoro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3-fluoro-7-(3-oxetanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one; or

1-(6-(4-(2,4-difluorophenyl)-7-(1,4-dimethyl-1H-pyrazol-5-yl)-3-methyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one; or

(b) the compound is (M)-1-(6-(4-(3-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((1R,9R)-5-fluoro-6-(3-hydroxy-1-naphthalenyl)-10,10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3-chloro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(4-(3-chloro-5-hydroxy-2-methylphenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1S,8R)-5-methyl-6-(1,5,6-trimethyl-1H-indazol-7-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1R,9R)-5-fluoro-10,10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(3-fluoro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3-fluoro-7-(3-oxetanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one; or

1-(6-((7R)-4-(2,4-difluorophenyl)-7-(1,4-dimethyl-1H-pyrazol-5-yl)-3-methyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one; or

(c) the compound is (P)-1-(6-(4-(3-hydroxy-1-naphthalenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1R,9R)-5-fluoro-6-(3-hydroxy-1-naphthalenyl)-10,10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((1S,9S)-5-fluoro-6-(3-hydroxy-1-naphthalenyl)-10,10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1S,9S)-5-fluoro-6-(3-hydroxy-1-naphthalenyl)-10,10-dimethyl-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(3-chloro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(3-chloro-5-hydroxy-2-methylphenyl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((1S,8R)-5-methyl-6-(1,5,6-trimethyl-1H-indazol-7-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1R,8S)-5-methyl-6-(1,5,6-trimethyl-1H-indazol-7-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((1R,8S)-5-methyl-6-(1,5,6-trimethyl-1H-indazol-7-yl)-3-azatricyclo[6.2.1.02,7]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3,7,7-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((1R,9R)-5-fluoro-10,10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-((1S,9S)-5-fluoro-10, 10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-((1S,9S)-5-fluoro-10,10-dimethyl-6-(5-methyl-1H-indazol-4-yl)-3-azatricyclo[7.1.1.0 2,7 ]undeca-2,4,6-trien-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(M)-1-(6-(3-fluoro-4-(3-hydroxy-1-naphthalenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(P)-1-(6-(4-(5-chloro-1,6-dimethyl-1H-indazol-7-yl)-3-fluoro-7-(3-oxetanyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one; or 1-(6-((7S)-4-(2,4-difluorophenyl)-7-(1,4-dimethyl-1H-pyrazol-5-yl)-3-methyl-5,6,7,8-tetrahydro-2-quinolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one.

21 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22 . A method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 .

23 . The method according to claim 22 , wherein one or more cells express KRAS G12C mutant protein.

24 . The method of claim 22 , wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

25 . The method according to claim 22 , wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

26 . The method according to claim 22 , which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 25, 2025

From: LANMAN, BRIAN ALAN; BANERJEE, ABHISEK; CHU-MOYER, MARGARET; DAI, DONGCHENG; ESHON, JOSEPHINE; HUANG, DAVID; KALLER, MATTHEW R.; LEE, HEEJUN; LOPEZ, PATRICIA; MA, VU VAN; MANONI, FRANCESCO; MEDINA, JOSE M.; PICKRELL, ALEXANDER J.; STELLWAGEN, JOHN C.; SUN, ZHEN; TAMAYO, NURIA A.; ZHANG, WENHAN; ZHU, KAI

To: AMGEN INC.

Reel/Frame 070629/0230 →

Priority Claims (1)

WO PCT/CN2020/122197 · Oct 20, 2020 · international

Continuity (1)

Related Publication 20240059703A1 · Feb 22, 2024

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