IP Library › Granted Patent US 12,723,047

Granted Patent B2

US 12,723,047 · App. 18/033,439 · Granted Sep 1, 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); Matthew R. Kaller (Ventura, 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); Nuria A. Tamayo (Newbury Park, CA); Kai Zhu (Westlake Village, CA)

Assignee: Amgen Inc.

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

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,723,047
App. No.: 18/033,439
Granted: Sep 1, 2026
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

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

Claims (195)

1 . A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R 1 at each occurrence independently is H, C 1-4 alkoxy, —(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, 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, —CH 2 OH, C 1-4 alkyl, C 1-4 haloalkyl, —CH 2 CN, or C 1-4 alkoxy, 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 Z 1 —CH(Z 2 —R 5 )—CH 2 —R 6 ;

Z 1 is O, NH, N(C 1-4 alkyl), or CH 2 ;

Z 2 is absent or CH 2 ;

R 5 is C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl,

wherein the phenyl is optionally substituted with 1 to 3 substituents selected from halogen, —CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy,

wherein the heteroaryl is optionally substituted with 1-3 substituents selected from —CN, C 1-4 alkyl, C 1-4 haloalkyl C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 6 is —CO(NR 7 R 7 ), phenyl, 5,5-dimethyl-3,5-dihydro-4H-imidazol-4-one-2-yl, or 5 to 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-3 substituents selected from —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 7 at each occurrence independently is H or C 1-4 alkyl;

X 1 is CR 8 or N;

X 2 is CH, or N;

X 3 is C or N;

X 4 is C or N;

R 8 is H, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-5 cycloalkyl, or C 3-5 cyclohaloalkyl;

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 selected from N, O, and S,

wherein the ring system is optionally substituted with 1 to 5 substituents R 9 ;

R 9 at each occurrence independently is halogen, OH, —CN, —NH 2 , C(═O)C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-5 cycloalkyl, C 3-5 cyclohaloalkyl, phenyl, or 5 to 6 membered heteroaryl,

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

wherein the phenyl is optionally substituted with 1 to 3 independently selected halogens,

wherein the heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, C 1-4 alkyl, and C 1-4 haloalkyl,

wherein two substituents R 9 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 9 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

n is 1, 2, 3, or 4.

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

R 3 is not —CN; or

Z 2 is absent and R 5 is 2-cyanophenyl; or

R 5 is not pyrazol-3-yl, 2-methyl; or

B is not

the compound is not

(3R)-3-(3-cyanophenyl)-N-methyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)propanamide;

(3S)-3-((2-((7S)-7-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

1-(6-(4-(((2S)-4-methyl-1-(1H-pyrazol-3-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(3S)-3-((2-(8-cyano-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)-3-(2-cyanophenyl)-N-methyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)propanamide;

(3R)-3-(2-cyanophenyl)-N-methyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)propanamide;

(3S)—N, 5-dimethyl-3-((8-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)hexanamide;

(3S)—N,5-dimethyl-3-((7-(2-propanyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexanamide; or

(3S)—N,5-dimethyl-3-((7-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7H-purin-6-yl)amino)hexanamide.

3 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has an IC50 of less than 10 μM in the 2 h coupled exchange assay or the 20 h coupled exchange assay.

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

each R 1 is H.

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

R 2 is H or C 1-4 haloalkyl; or

R 2 is H or CF 3 ; or

R 2 is H.

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

R 3 is H or halogen; or

R 3 is H or F; or

R 3 is H.

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

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

both A are absent.

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

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

Z 1 is NH.

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

Z 2 is CH 2 ; or

Z 2 is absent.

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

R 5 is C 1-4 alkyl or phenyl, wherein the phenyl is optionally substituted with —CN; or

R 5 is —CH(CH 3 ) 2 , phenyl, or 3-cyanophenyl; or

R 5 is —CH(CH 3 ) 2 .

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

(i) R 6 is —CO(NR 7 R 7 ), 5,5-dimethyl-3,5-dihydro-4H-imidazol-4-one-2-yl, or 5 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-3 C 1-4 alkyl substituents; and

R 7 at each occurrence independently is H or C 1-4 alkyl;

(ii) R 6 is —CO(NHR 7 ) or 5 membered heteroaryl, wherein the heteroaryl is optionally substituted with one C 1-4 alkyl substituent; and

R 7 is C 1-4 alkyl; or

(iii) R 6 is —CO(NHCH 3 ), 5,5-dimethyl-3,5-dihydro-4H-imidazol-4-one-2-yl, or 5 membered heteroaryl, wherein the heteroaryl is pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2-oxazole, 1,3-oxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3-thiazole, or 1,3,4-thiadiazol, and the heteroaryl is optionally substituted with one C 1-4 alkyl substituent; or

(iv) R 6 is —CO(NHCH 3 ), or 5 membered heteroaryl, wherein the heteroaryl is, imidazole, 1,2-oxazole, 1,3,4-oxadiazole, 1,3,4-thiadiazol, or 1,2,3-triazole, and the heteroaryl is optionally substituted with one methyl group.

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

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

X 1 is N.

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

X 2 is N.

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

X 3 is C.

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

X 4 is C.

18 . 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 N, X 2 is CH, X 3 is C, and X 4 is C; or

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

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

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

(i) 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 9 ; or

(ii) 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 9 ; or

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

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

(i) when the ring system is optionally substituted with 1 to 2 substituents R 9 ;

R 9 at each occurrence independently is halogen, —CN, C(═O)C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, C 3-5 cycloalkyl, or 5 to 6 membered heteroaryl; or

(ii) when the ring system is optionally substituted with 1 to 2 substituents R 9 ;

R 9 at each occurrence independently is C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, C 3-5 cycloalkyl, or 5 membered heteroaryl; or

(iii) when the ring system is optionally substituted with 1 to 2 substituents R 9 ;

R 9 at each occurrence independently is Cl, —CN, acetyl, methyl, isopropyl, trifluoromethyl, methoxy, cyclopropyl, or 1,3-thiazolyl; or

(iv) when the ring system is optionally substituted with 1 to 2 substituents R 9 ;

R 9 at each occurrence independently is methyl, isopropyl, trifluoromethyl, methoxy, cyclopropyl, or 1,3-thiazolyl.

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

(i) (S)-3-((2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-N,5-dimethylhexanamide;

(3S)-3-((2-(8,8-difluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-methyl-5,6,7,8-tetrahydro-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)—N,5-dimethyl-3-((7-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)hexanamide;

(3S)—N,5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)hexanamide;

(3S)—N,5-dimethyl-3-((3-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-1-isoquinolinyl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)furo[3,2-d]pyrimidin-4-yl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-(((8R)-8-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)hexanamide;

(3S)-3-((6-acetyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)-N,5-dimethylhexanamide;

(3S)—N, 5-dimethyl-3-((2-methyl-5-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)hexanamide;

(3S)—N,5-dimethyl-3-((5-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino)hexanamide;

5,5-dimethyl-2-((2S)-4-methyl-2-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)pentyl)-3,5-dihydro-4H-imidazol-4-one;

(3S)—N, 5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-(((8S)-8-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((7-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((9-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-9H-purin-6-yl)amino)hexanamide;

(3S)-3-((2-(8,8-difluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

1-(6-(4-(((2S)-4-methyl-1-(4H-1,2,4-triazol-3-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(3S)—N, 5-dimethyl-3-((7-(2-propanyl)-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)hexanamide;

(3S)-3-(3-cyanophenyl)-N-methyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)propanamide;

1-(6-(4-(((2S)-4-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(((2S)-1-(1H-imidazol-2-yl)-4-methyl-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(3S)-3-((2-((7R)-7-(hydroxymethyl)-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)—N, 5-dimethyl-3-((7-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)hexanamide;

(3S)-3-((7-cyano-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)-3-((2-(8-fluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)-3-((2-(8-fluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-methyl-5,6,7,8-tetrahydro-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)-3-((7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)-3-((7-chloro-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)—N, 5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-4-yl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(trifluoromethyl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((6-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((7-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanamide;

(3S)—N, 5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(trifluoromethyl)-4-quinazolinyl)amino)hexanamide;

(3S)—N,5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(1,3-thiazol-2-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanamide;

(3S)—N,5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanamide;

(3S)-3-((7-cyclopropyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-N,5-dimethylhexanamide;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(3S)-3-((7-cyclopropyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)-N,5-dimethylhexanamide;

(3S)—N, 5-dimethyl-3-((6-methyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)hexanamide;

(3S)-3-((7-methoxy-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-N,5-dimethylhexanamide;

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

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(1H-1,2,4-triazol-1-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(1H-pyrazol-1-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(1H-1,2,3-triazol-1-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(1,2-oxazol-3-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(3-methyl-1,2-oxazol-5-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(3S)-3-((7,7-dimethyl-2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydro-4-quinazolinyl)amino)-N-methyl-4-phenylbutanamide;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(5-methyl-1,2-oxazol-3-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(4-(((2S)-1-(1H-imidazol-2-yl)-4-methyl-2-pentanyl)amino)-7,7-dimethyl-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

1-(6-(7,7-dimethyl-4-(((2S)-4-methyl-1-(1H-1,2,3-triazol-4-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(3S)—N,5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)hexanamide;

1-(6-(4-(((2S)-4-methyl-1-(1,3-oxazol-2-yl)-2-pentanyl)amino)-5,6,7,8-tetrahydro-2-quinazolinyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-propen-1-one;

(3S)—N, 5-dimethyl-3-((7-methyl-2-(2-(2-(trifluoromethyl)-2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-quinazolinyl)amino)hexanamide;

(3S)—N,5-dimethyl-3-((2-(2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-(1,3-thiazol-2-yl)-4-quinazolinyl)amino)hexanamide; or

(S)-2-((2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-N,4-dimethylpentanamide; or

(ii) (3S)-3-((2-(8,8-difluoro-2-(2-propenoyl)-2,6-diazaspiro[3.4]octan-6-yl)-7-methyl-5,6,7,8-tetrahydro-4-quinazolinyl)amino)-N,5-dimethylhexanamide;