Granted Patent B2

US 12,441,705 · App. 17/416,415 · Granted Oct 14, 2025

Inventors: Nuria A Tamayo (Newbury Park, CA); Abhisek Banerjee (Karnataka, IN); Jian Jeffrey Chen (San Diego, CA); Kexue Li (Newbury, CA); Liping H. Pettus (Thousand Oaks, CA); Matthew Paul Bourbeau (Woodland Hills, CA); Lei Jia (San Diego, CA)

Assignee: AMGEN INC.

C07D401/14C07D405/14C07D413/14

Abstract

Claims (108)

1. A compound of formula I:

or any pharmaceutically-acceptable salt thereof, wherein:

X 1 is N or —CR 6 ;

X 2 is N or CR 7 ;

X 3 is N or CR 8 ;

X 4 is N or CR 9 ;

wherein 1, 2, or 3 of X 1 , X 2 , X 3 and X 4 are N;

when all of X 2 , X 3 and X 4 are not N; then L is —(C═O)—NR 3 —;

when any of X 2 , X 3 and X 4 is N; then L is —(C═O)—NR 3 — or —NR 3 —(C═O)—;

R 1 is —CN, or a group —Z—R 12 wherein Z is —C 0-4 alk-, —NR 11 —, —NR 11 SO 2 —, —SO 2 NR 11 —, —NR 11 —S(═O)(═NH), —S(═O)(═NH)—, —S—, —S(═O)—, —SO 2 —, C 0-4 alk-O—, —(C═O)—, —(C═O)NR 11 —, —C═N(OH)—, or —NR 11 (C═O); or

the group —Z—R 12 is —N═S(═O)—(R 12 ) 2 , wherein the two R 12 pair can alternatively combine with the sulfur atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S;

R 2 is

(a) a group —Y—R 13 , wherein Y is absent; and R 13 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl,

wherein each said ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, CF 3 , —OH, —OCHF 2 , CN, and oxo; or

(b) a group —Y—R 13 , wherein Y is NH, —O—, —O—(CH 2 )—, —O—(CH 2 )—(CH 2 )—, or —O—(CH 2 )—(CH 2 )—(CH 2 )—, and wherein R 13 is

or R 13 is C 1-6 alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, methyl, CF 3 , —OH, or CN; or

(c) a saturated 5- or 6-membered monocyclic ring wherein each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atom, and wherein each said ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OH, —OC 1-4 haloalk, CN, R 14 , and oxo;

R 3 is H, C 1-4 alk, or C 1-4 haloalk;

R 4 is H, halo, R 4a or R 4b ;

R 5 is H, halo, C 1-8 alk, or C 1-4 haloalk;

R 6 is H, halo, C 1-8 alk, C 1-4 haloalk, —O—C 1-8 alk, or —O—R 6a ; wherein R 6a is a saturated or partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S;

R 7 is H, halo, R 7a or R 7b ;

R 8 is H, halo, C 1-8 alk, C 1-4 haloalk, —OH, —O—R 8a , or —O—R 8b ;

R 9 is H, halo, R 9a or R 9b ;

R x is selected from the group consisting of

Each of R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j is H, halo, R 10k , or R 10l ,

or alternatively, each of R 10a and R 10b pair, R 10c and R 10d pair, R 10e and R 10f pair, R 10g and R 10h pair, or R 10i and R 10j pair, independently, can combine with the carbon atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to the R ring; wherein said 3-, 4-, 5-, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —NR a R a , or oxo;

R 11 is H or C 1-8 alk;

R 12 is H, R 12a , or R 12b ;

R 4a , R 7a , R 8a , R 9a , R 10k , and R 12a is independently, at each instance, selected from the group consisting of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , —NR a C 2-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(R a )C(═O)R b , —C 1-6 alkOC(═O)R b , —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a , R 14 , and oxo;

R 4b , R 7b , R 8b , R 9b , R 10l , and R 12b is independently, at each instance, selected from the group consisting of C 1-6 alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl, Br, —OR a , —OC 1-4 haloalk, or CN;

R 14 is independently, at each instance, selected from the group consisting of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , —NR a C 2-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(R a )C(═O)R b , —C 1-6 alkOC(═O)R b , —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a , and oxo;

R a is independently, at each instance, H or R b ; and

R b is independently, at each instance, C 1-6 alk, phenyl, or benzyl, wherein the C 1-6 alk is being substituted by 0, 1, 2 or 3 substituents selected from halo, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; and the phenyl or benzyl is being substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-4 alk, C 1-3 haloalk, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk.

2. The compound according to claim 1 wherein L is —NR 3 —(C═O); and X 1 is N, X 2 is CR 7 , X 3 is N; and X 4 is CR 9 ; having the formula (Ia):

3. The compound according to claim 1 wherein L is —(C═O)—NR 3 —; and X 1 is CR 6 , X 2 is CR 7 , X 3 is CR 8 ; and X 4 is CR 9 ; having the formula (Ib):

4. The compound according to claim 1 wherein L is —(C═O)—NR 3 —; and X 1 is N, X 2 is CR 7 , X 3 is CR 8 ; and X 4 is CR 9 ; having the formula (Ic):

5. The compound according to claim 1 wherein L is —(C═O)—NR 3 —; and X 1 is N, X 2 is CR 7 , X 3 is N; and X 4 is CR 9 ; having the formula (Id):

6. The compound according to claim 1 wherein R 3 is H or methyl.

7. The compound according to claim 1 wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j is H, halo, C 1-6 alk, or C 1-4 haloalk; and each of R 10a and R 10b pair combine with the carbon atom attached to each of them form a saturated 3-, 4-, or 5-membered monocyclic ring spiro to the R x ring; wherein said ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S.

8. The compound according to claim 1 wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j is H, methyl, or ethyl; and each of R 10a and R 10b pair combine with the carbon atom attached to each of them form a cyclopropyl, cyclobutyl, or cyclopentyl ring spiro to the R x ring.

9. The compound according to claim 1 wherein R x is selected from:

10. The compound according to claim 1 wherein R x is

11. The compound according to claim 1 wherein Z is absent, —NH—, —NHSO 2 —, —SO 2 NH—, —S(═O)(═NH)—, —S—, —S(═O)—, —SO 2 —, —(C═O)—, or —(C═O)NH—.

12. The compound according to claim 1 wherein R 12 is selected from (a) H; (b) C 1-6 alk substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, —OH, —OCH 3 , or cyclopropyl; or (c) a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —C 1-6 alkOH, —OH, —OCH 3 , —NH 2 , or oxo.

13. The compound according to claim 1 wherein R 12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiazinanyl.

14. The compound according to claim 1 wherein R 1 is —CN, or a group —Z—R 12 , wherein Z is absent, —NH—, —NHSO 2 —, —SO 2 NH—, —S(═O)(═NH)—, —S—, —S(═O)—, —SO 2 —, —(C═O)—, or —(C═O)NH—; and R 12 is

(a) H;

(b) oxetanyl, cyclopropyl; or

(c) C 1-6 alk substituted by 0, 1, 2 or 3 OH group(s).

15. The compound according to claim 1 wherein the group —Z—R 12 is —N═S(═O)—(R 12 ) 2 , wherein the two R 12 pair can alternatively combine with the sulfur atom attached to each of them to form a saturated or partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; which is selected from:

16. The compound according to claim 1 wherein R 1 is a group —Z—R 12 , wherein Z is —NHSO 2 — or —SO 2 NH—; and R 12 is oxetanyl, cyclopropyl, or R 12 is C 1-6 alk substituted by 0, 1, 2 or 3 OH group(s).

17. The compound according to claim 1 wherein R 1 is a group —Z—R 12 , wherein Z is —NHSO 2 — and R 12 is —CH 2 —CH 2 —OH.

18. The compound according to claim 1 wherein R 2 is morpholinyl or piperidinyl substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, CF 3 , —OH, —OCHF 2 , CN, or oxo.

19. The compound according to claim 1 wherein R 2 is morpholinyl substituted by 1, 2 or 3 methyl group(s).

20. The compound according to claim 1 wherein R 2 is piperidinyl substituted by 1, 2 or 3 fluoro group(s).

21. The compound according to claim 1 wherein R 2 is

22. The compound according to claim 1 wherein R 4 is methyl.

23. The compound according to claim 1 wherein R 5 is H.

24. The compound according to claim 1 wherein R 6 is H or F.

25. The compound according to claim 1 wherein R 7 is H or F.

26. The compound according to claim 1 wherein R 8 is H.

27. The compound according to claim 1 wherein R 9 is H.

28. The compound of claim 1 , selected from the group consisting of:

Ex. #

Chemical Structure

Name

1

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-6-((2- hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)nicotinamide

1-1

(R)-6-((2-Hydroxyethyl)sulfonamido)-N-(6- methyl-2-(2-methylmorpholino)pyrimidin-4- yl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide

2-1

(R)-N-(6-methyl-2-(2- methylmorpholino)pyrimidin-4-yl)-6-((3- methyloxetan-3-yl)amino)-2-(6- azaspiro[2.5]octan-6-yl)nicotinamide

2-4

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-6-((3- (hydroxymethyl)oxetan-3-yl)amino)-2-(6- azaspiro[2.5]octan-6-yl)nicotinamide

2-6

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-5-((1-hydroxy-2- methylpropan-2-yl)amino)-3-(6- azaspiro[2.5]octan-6-yl)picolinamide

3

6-(Cyclopropylsulfonyl)-N-(2-(4,4- difluoropiperidin-1-yl)-6-methylpyrimidin-4- yl)-4-(6-azaspiro[2.5]octan-6- yl)nicotinamide

4-1

4-(6-Azaspiro[2.5]octan-6-yl)-6-(S- cyclopropylsulfonimidoyl)-N-(2-(4,4- difluoro-1-piperidinyl)-6-methyl-4- pyrimidinyl)-3-pyridinecarboxamide

4-2

4-(6-Azaspiro[2.5]octan-6-yl)-6-(R- cyclopropylsulfonimidoyl)-N-(2-(4,4- difluoro-1-piperidinyl)-6-methyl-4- pyrimidinyl)-3-pyridinecarboxamide

5-1

3-(6-Azaspiro[2.5]octan-6-yl)-5-(R- cyclopropylsulfonimidoyl)-N-(2-(4,4- difluoro-1-piperidinyl)-6-methyl-4- pyrimidinyl)-2-pyridinecarboxamide

5-2

3-(6-Azaspiro[2.5]octan-6-yl)-5-(S- cyclopropylsulfonimidoyl)-N-(2-(4,4- difluoro-1-piperidinyl)-6-methyl-4- pyrimidinyl)-2-pyridinecarboxamide

6

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-5-((2- hydroxyethyl)sulfonamido)-3-(6- azaspiro[2.5]octan-6-yl)picolinamide

7

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-6-((2- hydroxyethyl)sulfonamido)-4-(6- azaspiro[2.5]octan-6-yl)nicotinamide

7-1

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-((2- hydroxyethyl)sulfonamido)-4-(6- azaspiro[2.5]octan-6-yl)pyrimidine-5- carboxamide

8

5-(Cyclopropylsulfonyl)-N-(2-(4,4- difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-3-(6- azaspiro[2.5]octan-6-yl)picolinamide

9

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-2-((2- hydroxyethyl)amino)-5-(6- azaspiro[2.5]octan-6-yl)isonicotinamide

10

N-(2-(4,4-Difluoropiperidin-1-yl)-6- methylpyrimidin-4-yl)-5-((2- hydroxyethyl)sulfonamido)-3-(6- azaspiro[2.5]octan-6-yl)pyrazine-2- carboxamide and,

11

2-(4,4-Difluoropiperidin-1-yl)-N-(4-((2- hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6- yl)phenyl)isonicotinamide;

or any pharmaceutically-acceptable salt thereof.

29. A pharmaceutical composition comprising the compound according to claim 1 or the pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.

30. A method of treating a condition that may be treated with KIF18a inhibitors, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound in accordance to claim 1 , or the pharmaceutically acceptable salt thereof.

31. The method of claim 30 wherein said condition is cancer selected from the group consisting of (a) a solid or hematologically derived tumor selected from cancer of the cancer of the bladder, endometrial, lung squamous cell, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall-bladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, (b) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer or Kaposi's sarcoma.

32. A method of reducing the size of a solid tumor in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound in accordance to claim 1 , or the pharmaceutically acceptable salt thereof.

33. A method of treating a cell proliferation disorder in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound in accordance to claim 1 , or the pharmaceutically acceptable salt thereof.

34. A method of inhibiting KIF18A in a cell, comprising contacting the cell with a compound, or pharmaceutically acceptable salts thereof, in accordance to claim 1 , or the pharmaceutically acceptable salt thereof.

Assignments (1)

Continuity (2)

References Cited (218)