Granted Patent B2

US 12,251,387 · App. 18/175,515 · Granted Mar 18, 2025

Inventors: John Patrick Maxwell (Hingham, MA); Paul S. Charifson (Framingham, MA); Qing Tang (Boston, MA); Steven M. Ronkin (Watertown, MA); Katrina Lee Jackson (Cambridge, MA); Albert Charles Pierce (Cambridge, MA); David J. Lauffer (Stow, MA); Pan Li (Lexington, MA); Simon Giroux (Cambridge, MA); Jinwang Xu (Boston, MA); Kevin Michael Cottrell (Cambridge, MA); Mark A. Morris (Somerville, MA); Nathan D. Waal (Cambridge, MA); John J. Court (Littleton, MA); Wenxin Gu (Concord, MA); Hongbo Deng (Southborough, MA)

Assignee: Vertex Pharmaceuticals Incorporated

A61K31/5377A61K31/506A61K31/5386C07D241/40C07D241/42C07D241/44C07D271/12C07D401/12C07D401/14C07D403/12C07D403/14C07D405/12C07D405/14C07D413/04C07D413/12C07D413/14C07D417/12C07D471/04C07D473/40C07D475/00C07D487/04C07D491/048C07D491/052C07D491/056C07D491/08C07D498/08C07D513/04

Abstract

Claims (86)

1. A method for inhibiting cancer cell growth in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

Ring A is:

each R 3 is independently hydrogen, fluoro, chloro, cyano, C 1-4 alkyl, C(O)H, C(O)NH 2 , C(O)NHC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, or OC 1-2 alkyl, wherein each C 1-4 alkyl, C(O)NHC 1-2 alkyl, C(O)OC 1-2 alkyl, and OC 1-2 alkyl is optionally and independently substituted with one, two, or three fluoro substituents, one or two hydroxy substituents, or one or two independently selected OC 1-2 alkyl substituents;

Ring B is:

wherein Ring B is optionally substituted with one, two, three, or four fluoro substituents, one or two independently selected C 1-4 alkyl substituents, or one or two hydroxy substituents; and

wherein each C 1-4 alkyl substituent is optionally substituted with one, two, or three fluoro substituents, one or two hydroxy substituents, or one or two independently selected OC 1-2 alkyl substituents;

X is —NH—, —O—, or —OC 1-4 alkylene-;

Ring C is cyclobutyl or cyclohexyl;

R 1 is hydrogen, C 1-4 alkyl-NHR 4 , C(O)NHR 4 , C(O)OR 4 , NHR 4 , NHC(O)R 4 , NHC(O)NHR 4 , NHC(O)OR 4 , NHS(O) 2 R 4 , or OR 4 ;

R 2 is hydrogen, C 1-4 alkyl-NHR 4 , C(O)NHR 4 , C(O)OR 4 , NHR 4 , NHC(O)R 4 , NHC(O)NHR 4 , NHC(O)OR 4 , NHS(O) 2 R 4 , or OR 4 ; or

R 1 and R 2 , together with the intervening carbon atom(s) to which they are attached, form a dioxane or dioxolane ring;

(1) each R 4 is independently hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, or phenyl;

wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, and phenyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of (a), (b), (c), (d), (e), and (f):

(a) one, two, three, or four fluoro, chloro, bromo, or C 1-4 alkyl;

(b) one, two, or three cyano;

(c) one or two OR 5 ;

(d) NO 2 , CH 2 OR 5 , C 1-4 alkyl-C(O)R 5 , C 1-4 alkyl-C(O) NR 5 R 5 , C 1-4 alkyl-C(O)OR 5 , C 1-4 alkyl-NR 5 R 5 , C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-O—C 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)R 5 , C(O)NR 5 R 5 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OR 5 , C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, NR 5 R 5 , NHC(O)RS, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, or C 3-6 cycloalkyl;

(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and

(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;

wherein each C 1-4 alkyl, CH 2 OR 5 , C 1-4 alkyl-C(O) R 5 , C 1-4 alkyl-C(O) NR 5 R 5 , C 1-4 alkyl-C(O)OR 5 , C 1-4 alkyl-NR 5 R 5 , C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-OC 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)R 5 , C(O)NRSR 5 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OR 5 , C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, NR 5 R 5 , NHC(O)R 5 , OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, C 3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro substituents, one or two independently selected C 1-4 alkyl substituents, one C(O)C 1-4 alkyl substituent, one C(O)OC 1-4 alkyl substituent, one C(O)OC 1-4 alkyl-C 3-5 cycloalkyl substituent, one C(O)OC 3-5 cycloalkyl substituent, one or two hydroxy substituents, one or two independently selected OC 1-4 alkyl substituents, or one or two independently selected SC 1-4 alkyl substituents; or

(2) each R 4 is independently selected from the group consisting of:

(i) a heterocyclyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroisoxazolyl, pyrimidinonyl, pyrimidin-2,4-(1H,3H)-dionyl, dihydropyrrolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyranopyrimidinyl, tetrahydropteridinyl, and tetrahydropyridopyrimidinyl; and

(ii) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and quinolinyl;

wherein each heterocyclyl and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of (a), (b), (c), (d), (e), and (f)

(a) one, two, three, or four fluoro, chloro, bromo, or C 1-4 alkyl;

(b) one, two, or three cyano;

(c) one or two OR 5 ;

(d) NO 2 , CH 2 OR 5 , C 1-4 alkyl-C(O)R 5 , C 1-4 alkyl-C(O) NR 5 R 5 , C 1-4 alkyl-C(O)OR 5 , C 1-4 alkyl-NR 5 R 5 , C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-O—C 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)R 5 , C(O)NR 5 R 5 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OR 5 , C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, NR 5 R 5 , NHC(O)R 5 , OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, or C 3-6 cycloalkyl;

(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and

(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;

wherein each C 1-4 alkyl, CH 2 OR 5 , C 1-4 alkyl-C(O)R 5 , C 1-4 alkyl-C(O)NR 5 R 5 , C 1-4 alkyl-C(O)OR 5 , C 1-4 alkyl-NR 5 R 5 , C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-OC 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)R 5 , C(O)NR 5 R 5 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OR 5 , C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, NR 5 R 5 , NHC(O)R 5 , OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, C 3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro substituents, one or two independently selected C 1-4 alkyl substituents, one C(O)C 1-4 alkyl substituent, one C(O)OC 1-4 alkyl substituent, one C(O)OC 1-4 alkyl-C 3-5 cycloalkyl substituent, one C(O)OC 3-5 cycloalkyl substituent, one or two hydroxy substituents, one or two independently selected OC 1-4 alkyl substituents, or one or two independently selected SC 1-4 alkyl substituents; and

each R 5 is independently hydrogen, C 1-4 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, or pyrimidinyl, wherein each C 1-4 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, and pyrimidinyl is optionally and independently substituted with one, two, or three fluoro substituents, one chloro substituent, one cyano substituent, one or two independently selected C 1-2 alkyl substituents, one CH 2 OH substituent, one or two hydroxy substituents, one or two independently selected OC 1-2 alkyl substituents, one pyrrolidinyl substituent, one spirooxetanyl substituent, or one triazolyl substituent; or

two R 5 , together with the intervening nitrogen atom to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl;

with the proviso that R 1 and R 2 are not simultaneously hydrogen.

2. The method of claim 1 , wherein each R 3 is independently hydrogen.

3. The method of claim 1 , wherein Ring B is:

4. The method of claim 1 , wherein X is —NH—.

5. The method of claim 1 , wherein X is —O— or —OC 1-4 alkylene-.

6. The method of claim 1 , wherein X is —O—.

7. The method of claim 1 , wherein Ring C is cyclobutyl.

8. The method of claim 7 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein Ring C is cyclohexyl.

10. The method of claim 9 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein R 1 is C 1-4 alkyl-NHR 4 , NHR 4 , or OR 4 .

12. The method of claim 1 , wherein R 1 is NHR 4 .

13. The method of claim 1 , wherein R 1 is OR 4 .

14. The method of claim 1 , wherein R 2 is C 1-4 alkyl-NHR 4 , NHR 4 , or OR 4 .

15. The method of claim 1 , wherein R 2 is NHR 4 .

16. The method of claim 1 , wherein R 2 is OR 4 .

17. The method of claim 1 , wherein the compound is of Formula (III-D-1):

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is of Formula (III-D-2):

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound is of Formula (IV):

or a pharmaceutically acceptable salt thereof,

wherein:

each R 3 is independently hydrogen, fluoro, chloro, cyano, C 1-4 alkyl, C(O)H, C(O)NH 2 , or OC 1-2 alkyl, wherein each C 1-4 alkyl and OC 1-2 alkyl is optionally and independently substituted with one, two, or three fluoro substituents or one hydroxy substituent;

R 4 is

X 1 is CH, CF, CCI, CC 1-2 alkyl, or N, wherein the C 1-2 alkyl is optionally substituted with one, two, or three fluoro substituents;

X 2 is CR 4c or N;

R 4a is hydrogen or selected from the group consisting of (a), (b), and (c):

(a) fluoro, chloro, bromo, cyano, NO 2 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-O—C 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O) N(C 1-4 alkyl) 2 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, or C 3-5 cycloalkyl;

(b) a heterocyclyl selected from the group consisting of azetidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and

(c) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;

wherein each C 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-OC 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)N (C 1-4 alkyl) 2 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, and C 3-5 cycloalkyl substituent is optionally and independently substituted with one, two, or three fluoro substituents or one or two non-geminal hydroxy substituents; and

wherein each heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro substituents, one or two independently selected C 1-4 alkyl substituents, one C(O)C 1-4 alkyl substituent, one C(O)OC 1-4 alkyl substituent, one C(O)OC 1-4 alkyl-C 3-5 cycloalkyl substituent, one C(O)OC 3-5 cycloalkyl substituent, or one or two hydroxy substituents;

R 4b is hydrogen or selected from the group consisting of (a), (b), and (c):

(a) fluoro, chloro, bromo, cyano, NO 2 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-O—C 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, or C 3-5 cycloalkyl;

(b) a heterocyclyl selected from the group consisting of azetidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and

(c) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;

wherein each C 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-OC 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)N (C 1-4 alkyl) 2 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, and C 3-5 cycloalkyl substituent is optionally and independently substituted with one, two, or three fluoro substituents or one or two non-geminal hydroxy substituents; and

wherein each heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro substituents, one or two independently selected C 1-4 alkyl substituents, one C(O)C 1-4 alkyl substituent, one C(O)OC 1-4 alkyl substituent, one C(O)OC 1-4 alkyl-C 3-5 cycloalkyl substituent, one C(O)OC 3-5 cycloalkyl substituent, or one or two hydroxy substituents; and

R 4c is hydrogen or selected from the group consisting of (a), (b), and (c):

(a) fluoro, chloro, bromo, cyano, NO 2 , C 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-O—C 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, or C 3-5 cycloalkyl;

(b) a heterocyclyl selected from the group consisting of azetidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and

(c) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;

wherein each C 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl-C 3-5 cycloalkyl, C 1-4 alkyl-OC 3-5 cycloalkyl, C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)N (C 1-4 alkyl) 2 , C(O)NH—C 1-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C(O)OC 3-5 cycloalkyl, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, OC 3-5 cycloalkyl, and C 3-5 cycloalkyl substituent is optionally and independently substituted with one, two, or three fluoro substituents or one or two non-geminal hydroxy substituents; and

wherein each heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro substituents, one or two independently selected C 1-4 alkyl substituents, one C(O)C 1-4 alkyl substituent, one C(O)OC 1-4 alkyl substituent, one C(O)OC 1-4 alkyl-C 3-5 cycloalkyl substituent, one C(O)OC 3-5 cycloalkyl substituent, or one or two hydroxy substituents; or

R 4a and R 4c , together with the intervening carbon atoms to which they are attached, form a dihydrofuranyl, dihydropyranyl, or tetrahydropyridinyl;

with the proviso that X 1 and X 2 are not simultaneously N.

20. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignments (2)

Continuity (7)

References Cited (274)