Granted Patent B2

US 12,441,730 · App. 17/783,967 · Granted Oct 14, 2025

Inventors: Michelle Machacek (Belmont, MA); Michael D. Altman (Needham, MA); Shuhei Kawamura (Cambridge, MA); Michael H. Reutershan (Brighton, MA); David L. Sloman (Newton, MA); Phieng Siliphaivanh (Newton Highlands, MA); Sebastian E. Schneider (Boston, MA); Charles S. Yeung (Dedham, MA); David J. Witter (Ontario, CA); Craig R. Gibeau (Northborough, MA)

Assignee: Merck Sharp & Dohme LLC

C07D471/10C07D519/00

Abstract

Claims (107)

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein

Y is H or OH;

Y 1 is H or OH;

R 1 is H, halogen, or C 1-6 alkyl optionally substituted with halogen;

R 2 is H or D;

each t is independently 0, 1, or 2;

A is

(a) phenyl, optionally substituted with one or two moieties independently selected from OC 1-6 alkyl, halogen, C(O)R 5 , O-cyclopropyl, or an unsaturated heterocycle having 1-3 nitrogen atoms and 0-1 oxygen atoms wherein the unsaturated heterocycle is optionally substituted with C 1-6 alkyl, wherein R 5 is a saturated heterocycle having 1 nitrogen atom and 1 oxygen atom;

(b) an unsaturated 6-membered heterocycle with 1-2 N atoms, wherein the heterocycle is substituted with NHR 3 , wherein the heterocycle is additionally optionally substituted with 1 or 2 halogens, wherein R 3 is saturated heterocycle with 1 nitrogen atom, wherein the R 3 nitrogen is substituted with C(O)C 1-6 alkyl and wherein the R 3 heterocycle is optionally substituted with 1 or 2 halogens;

(c) an unsaturated 6-membered heterocycle with 1 N atom optionally substituted with one, two or three moieties independently selected from halogen, ═O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 fluoroalkyl, 5-membered unsaturated heterocycle having 3 or 4 N atoms, OH, OC 1-6 alkyl, OC 1-6 alkoxy, NC 1-6 alkyl, or NHR 4 , wherein R 4 is saturated heterocycle having 1N atom optionally substituted with one or two C(O)C 1-6 alkyl and wherein the C(O)C 1-6 alkyl is optionally substituted with one or two fluoro atoms;

(d)

i. an unsaturated 5-membered heterocycle with 1 or 2 Nitrogen atoms and 0-1 Oxygen atom optionally substituted with a 5-membered unsaturated heterocycle with 1 nitrogen atom and 1 oxygen atom wherein each heterocycle is independently optionally substituted with C 1-6 alkyl,

ii. an unsaturated 5-membered heterocycle with 2 N atoms optionally substituted with CHF 2 , cyclopropyl, or a phenyl optionally mono-substituted, independently disubstituted, or independently trisubstituted with halogen, C 1-6 alkyl, OC 1-6 alkyl, or C 1-6 fluoroalkyl,

(e) an unsaturated 8-11-membered bicyclic heterocycle with 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, unsubstituted, mono-substituted, independently disubstituted, or independently trisubstituted with

i) CR 6 R 7 R 8 , wherein

R 6 is H, C 1-6 alkyl, or halogen,

R 7 is H, C 1-6 alkyl, halogen or OH, and

R 8 is H, CN, C 1-6 alkyl optionally substituted with CN, halogen, OH, OC 1-6 alkyl, or C 1-6 haloalkyl;

ii) C(O)NR 9 R 10 , wherein

R 9 is H, C 1-6 alkyl, halogen, or C 1-6 haloalkyl, and

R 10 is H, C 1-6 alkyl, C 1-6 alkyl (C 1-6 alkyl) 1-2 , halogen, or C 1-6 haloalkyl,

iii) CN;

iv) C 3 to C 6 saturated or unsaturated carbocycle optionally mono-substituted, independently disubstituted, or independently trisubstituted with C 1-6 alkyl, 1-3 halogens, or CN;

v) halogen;

vi) C 0-6 alkylO(CH 2 ) 0-2 R 11 , wherein:

R 11 is H, C 1-6 alkyl, (C 1-6 alkyl)(OC 1-6 alkyl), OC 1-6 alkyl, C 1-6 alkyl(C 1-6 alkyl) 1-2 , C 1-6 alkyl(C 1-6 alkyl) 1-2 OH, C 3-6 heterocycle or C 3-6 cycloalkyl wherein the C 3-6 heterocycle or C 3-6 cycloalkyl are optionally mono-substituted, independently disubstituted, or independently trisubstituted with C 1-6 alkyl, halogen, CN, or ═O;

vii) ═O;

viii) C 3-6 heterocycle or C 3-6 cycloalkyl wherein the C 3-6 heterocycle or C 3-6 cycloalkyl are optionally mono-substituted, independently disubstituted, or independently trisubstituted with C 1-6 alkyl, C 1-6 cycloalkyl, halogen, CN, or ═O;

ix) N(C 1-6 alkyl)(C 1-6 alkyl)(OC 1-6 alkyl) or N(C 1-6 alkyl)(C 1-6 alkyl), wherein the alkyl moiety is optionally substituted with 5-membered unsaturated ring with 2 nitrogen atoms, 0-1 oxygen atom, wherein the ring is optionally substituted with C 1-6 alkyl, halogen, or C 1-6 haloalkyl;

xi) C 3-6 heterocycle optionally mono-substituted, independently disubstituted, or independently trisubstituted with 5-membered unsaturated ring with 2 nitrogen,

xii) an unsaturated 8-11 membered bicyclic heterocycle with 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, unsubstituted, mono-substituted, independently disubstituted, or independently trisubstituted with C 1-6 alkyl, or halogen,

xiii) unsaturated 5- or 6-membered heterocycle with 1-2 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms optionally mono-substituted or independently disubstituted with C 1-6 alkyl or OC 1-6 alkyl, wherein the alkyl is optionally substituted with 1-3 halogens xiv) C 1-6 alkyl optionally substituted with CN or halogen; or

(f) unsaturated 13-membered tricyclic heterocycle with 1 oxygen, wherein the tricyclic heterocycle is optionally substituted with OH,

provided that the compound of formula I is not:

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

Y is H or OH;

Y 1 is H or OH;

(a) phenyl, optionally substituted with one or two moieties independently selected from OC 1-6 alkyl, halogen, C(O)R 5 , O-cyclopropyl, or an unsaturated heterocycle having 1-3 nitrogen atoms and 0-1 oxygen atoms wherein the unsaturated heterocycle is optionally substituted with C 1-6 alkyl, wherein R 5 is a saturated heterocycle having 1 nitrogen atom and 1 oxygen atom;

(b) an unsaturated 6-membered heterocycle with 1-2 N atoms, wherein the heterocycle is substituted with NHR 3 , wherein the heterocycle is additionally optionally substituted with 1 or 2 halogens, wherein R 3 is saturated heterocycle with 1 nitrogen atom, wherein the R 3 nitrogen is substituted with C(O)C 1-6 alkyl and wherein the R 3 heterocycle is optionally substituted with 1 or 2 halogens;

(c) an unsaturated 6-membered heterocycle with 1 N atom optionally substituted with one, two or three moieties independently selected from halogen, ═O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 fluoroalkyl, 5-membered unsaturated heterocycle having 3 or 4 N atoms, OH, OC 1-6 alkyl, OC 1-6 alkoxy, NC 1-6 alkyl, or NHR 4 , wherein R 4 is saturated heterocycle having 1N atom optionally substituted with one or two C(O)C 1-6 alkyl and wherein the C(O)C 1-6 alkyl is optionally substituted with one or two fluoro atoms;

(d)

i. an unsaturated 5-membered heterocycle with 1 or 2 Nitrogen atoms and 0-1 Oxygen atom optionally substituted with a 5-membered unsaturated heterocycle with 1 nitrogen atom and 1 oxygen atom wherein each heterocycle is independently optionally substituted with C 1-6 alkyl,

ii. an unsaturated 5-membered heterocycle with 2 N atoms optionally substituted with CHF 2 , cyclopropyl, or an phenyl optionally mono-substituted, independently disubstituted, or independently trisubstituted with halogen, C 1-6 alkyl, OC 1-6 alkyl, or C 1-6 fluoroalkyl,

(e) an unsaturated 8-11-membered bicyclic heterocycle with 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, unsubstituted, mono-substituted, independently disubstituted, or independently trisubstituted with

i) CR 6 R 7 R 8 , wherein

R 6 is H, CH 3 , or F,

R 7 is H, CH 3 , F or OH, and

R 8 is H, CN, CH 3 , F, OH, OCH 3 , CF 3 , or CH 2 CN;

ii) C(O)NR 9 R 10 , wherein

R 9 is H, CH 3 , F, or CF 3 , and

R 10 is H, CH 3 , CH 3 (CH 3 ) 2 , F, or CF 3 ,

iii) CN;

iv) C 3 to C 6 saturated or unsaturated carbocycle optionally mono-substituted, independently disubstituted, or independently trisubstituted with C 1-6 alkyl, 1-3 halogens, or CN;

v) halogen;

vi) C 0-6 alkylO(CH 2 ) 0-2 R 11 , wherein:

R 11 is H, CH 3 , CH 2 OCH 3 , OCH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH,

x) N(C 1-6 alkyl)(C 1-6 alkyl)(OC 1-6 alkyl) or N(C 1-6 alkyl)(C 1-6 alkyl), wherein the alkyl moiety is optionally substituted with 5-membered unsaturated ring with 2 nitrogen atoms, 0-1 oxygen atom, wherein the ring is optionally substituted with C 1-6 alkyl, halogen, or C 1-6 haloalkyl;

xiii) unsaturated 5- or 6-membered heterocycle with 1-2 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms optionally mono-substituted or independently disubstituted with C 1-6 alkyl or OC 1-6 alkyl, wherein the alkyl is optionally substituted with 1-3 halogens xiv) C 1-6 alkyl optionally substituted with CN or halogen; or

(f) unsaturated 13-membered tricyclic heterocycle with 1 oxygen, wherein the tricyclic heterocycle is optionally substituted with OH.

3. The compound claim 1 , or a pharmaceutically acceptable salt thereof, wherein

Y is H or OH;

Y 1 is H or OH;

A is

(a) phenyl, optionally substituted with one or two moieties independently selected from OCH 2 CH 3 , Cl, O-cyclopropyl, C(O)R 5 , or an unsaturated 5-membered heterocycle having 1-3 nitrogen atoms and 0-1 oxygen atoms wherein the unsaturated heterocycle is optionally substituted with cyclopropyl or C 1-6 alkyl,

wherein R 5 is

(b) an unsaturated 6-membered heterocycle with 1 or 2 N atoms substituted with NHR 3 , wherein the heterocycle is additionally optionally substituted with 1 or 2 halogens, wherein R 3 is a saturated heterocycle with 1 nitrogen atom wherein the R 3 nitrogen is substituted with C(O)CH 3 , and wherein the R 3 heterocycle is additionally optionally independently substituted with 1 or 2 halogens;

(c) unsaturated 6-membered heterocycle with 1 N atom optionally substituted with one, two or three moieties independently selected from Cl, Br, F, ═O, CH 3 , CF 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , OCH 2 CH 2 OH, NHCH 3 , cyclopropyl, OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 3 , OH, or 5-membered unsaturated heterocycle having 3 or 4 nitrogen atoms;

(d)

i. unsaturated 5-membered heterocycle with 1 nitrogen atom and 1 oxygen atom substituted with 5-membered unsaturated heterocycle with 1 nitrogen atom and 1 oxygen atom wherein each heterocycle is optionally independently substituted with CH 3 ,

ii. unsaturated 5-membered heterocycle with 2 nitrogen atoms optionally substituted with CHF 2 , cyclopropyl or an phenyl wherein the phenyl is optionally mono-substituted, independently disubstituted, or independently trisubstituted with F, CH 3 , OCH 3 , cyclopropyl, or CHF 2 ;

(e) unsaturated 8-11-membered bicyclic heterocycle with 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, unsubstituted, mono-substituted, independently disubstituted, or independently trisubstituted with

Br, F, Cl, I, CH 3 , CN, CH(CH 3 ) 2 , CH 2 OH, C(CH 3 ) 2 OH, C(O)NHCH 3 , C(O)N(CH 3 ) 2 , CF 3 , CHF 2 , C(CH 3 ) 2 OCH 3 , CH(CH 3 )OCH 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH(OH)CF 3 , CH(OH)CH 3 , (CH 2 ) 2 CN, CH 2 CF 3 , CH(CH 3 ) 2 , CH 2 CH 3 , cyclopropyl, cyclopropyl-CH 3 , ═O, OH, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , O(CH 2 ) 2 OCH 3 , OCH 2 C(CH 3 ) 2 OH, N(CH 3 )(CH 2 ) 2 OCH 3 , CH(CH 3 )CN,

or

(f) unsaturated 13-membered tricyclic heterocycle with 1 O, wherein the tricyclic heterocycle is optionally substituted with OH.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein

Y is H or OH;

Y 1 is H or OH;

A is

(a) phenyl, optionally substituted with one or two moieties independently selected from OCH 2 CH 3 , Cl, O-cyclopropyl, C(O)R 5 , or an unsaturated 5-membered heterocycle having 3 nitrogen atoms substituted with cyclopropyl or CH 3 , or an unsaturated 5-membered heterocycle having 2 nitrogen atoms and 1 oxygen atom optionally substituted with cyclopropyl,

wherein R 5 is

(b)

optionally substituted with 1 or 2 moieties independently selected from F or Cl;

(c)

optionally substituted with 1, 2, or 3 moieties independently selected from Cl, F, Br, ═O, CH 3 , CF 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , OCH 2 CH 2 OH, NHCH 3 , cyclopropyl, OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 3 , OH,

(d)

optionally substituted with CHF 2 , cyclopropyl or an phenyl, wherein the phenyl is optionally mono-substituted, independently disubstituted, or independently trisubstituted with F, CH 3 , OCH 3 , cyclopropyl, or CHF 2 ,

(e) an unsaturated 8-11-membered bicyclic heterocycle with 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, selected from

wherein the bicyclic heterocycle is unsubstituted, mono-substituted, independently disubstituted, or independently trisubstituted with

Br, F, Cl, I, CH 3 , CN, CH(CH 3 ) 2 , CH 2 OH, C(CH 3 ) 2 OH, C(O)NHCH 3 , C(O)N(CH 3 ) 2 , CF 3 , CHF 2 , C(CH 3 ) 2 OCH 3 , CH(CH 3 )OCH 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH(OH)CF 3 , CH(OH)CH 3 , (CH 2 ) 2 CN, CH 2 CF 3 , CH(CH 3 ) 2 , CH 2 CH 3 , cyclopropyl, cyclopropyl-CH 3 , ═O, OH, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , O(CH 2 ) 2 OCH 3 , OCH 2 C(CH 3 ) 2 OH, N(CH 3 )(CH 2 ) 2 OCH 3 , CH(CH 3 )CN,

or

(f)

substituted with OH.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein A is selected from

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Y is OH and Y 1 is H.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Y is H and Y 1 is OH.

8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Y is H and Y 1 is H.

9. The compound of claim 1 , of formula Ia

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , of formula Ib

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , of formula Ic,

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , which is one of the following:

or a pharmaceutically acceptable salt thereof.

13. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method for treating cancer comprising administering to a patient in need there of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignments (2)

Continuity (3)

References Cited (270)