IP Library › Granted Patent US 10,323,018

Granted Patent B2

US 10,323,018 · App. 15/544,192 · Granted Jun 18, 2019

Quinazoline and quinoline compounds and uses thereof

Inventors: Brian Scott Freeze (Boston, MA); Kenneth M. Gigstad (Westford, MA); David A. Janowick (Quincy, MA); Hong Myung Lee (Cambridge, MA); Zhan Shi (Concord, MA); Francois Soucy (Stoneham, MA); Stepan Vyskocil (Arlington, MA)

Assignee: Millennium Pharmaceuticals, Inc.

C07D401/14 A61K31/47 A61K31/4709 A61K31/501 A61K31/517 A61K31/541 C07D215/233 C07D401/04 C07D401/12 C07D403/12 C07D403/14 C07D405/14 C07D409/14 C07D417/12 C07D471/04 C07D495/04

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Quick Facts

Patent No.: US 10,323,018
App. No.: 15/544,192
Granted: Jun 18, 2019
Kind: B2

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Abstract

This invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein T, J, R, R 4 , R q , o, R A , W and R B and subsets thereof are as described in the specification. The compounds are inhibitors of NAMPT and are thus useful for treating cancer, inflammatory conditions, and/or T-cell mediated autoimmune disease.

Claims (171)

1. A chemical entity chosen from compounds of formula I:

and pharmaceutically acceptable salts thereof, wherein:

R A is

or YR C R D R E ;

R B is XR 1 R 2 R 3 ;

W is N, CH or CR q ;

Y is selected from C, O, S, and N, provided that (1) when Y is N, then one of R C , R D , and R E is absent and the remaining two of R C , R D , and R E are both not hydrogen and (2) when Y is O or S, then two of R C , R D , and R E are absent and the remaining one of R C , R D , and R E is not hydrogen;

R C , R D , and R E are each independently selected from hydrogen; linear or branched C 1-6 aliphatic, wherein 1 or 2 methylene units of the C 1-6 aliphatic are optionally and independently replaced by O, S, S(O), S(O) 2 , or N(R 25 ); (CH 2 ) q -6-10-membered aryl; (CH 2 ) r -3-10-membered cycloaliphatic; (CH 2 ) x -4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and (CH 2 ) b -5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-6 aliphatic, aryl, cycloaliphatic, heterocycle, and heteroaryl are optionally substituted with one or more R e ;

X is selected from halogen, C, O, S, and N, provided that (1) when X is N, then one of R 1 , R 2 , and R 3 is absent; (2) when X is halogen, then R 1 , R 2 , and R 3 are absent, and (3) when X is O or S, then two of R 1 , R 2 , and R 3 are absent and the remaining one of R 1 , R 2 , and R 3 is not hydrogen;

R 1 , R 2 , and R 3 are each independently selected from hydrogen; linear or branched C 1-6 aliphatic, wherein 1 or 2 methylene units of the C 1-6 aliphatic are optionally and independently replaced by O, S, S(O), S(O) 2 , or N(R 19 ); (CH 2 ) s -6-10-membered aryl; (CH 2 ) t -3-10-membered cycloaliphatic; (CH 2 ) u -4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and (CH 2 ) p -5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-6 aliphatic, aryl, cycloaliphatic, heterocycle, and heteroaryl are optionally substituted with one or more R k ;

or wherein any two of R 1 , R 2 , and R 3 taken together with the atom X to which they are bound, when X is C or N, form a ring selected from 4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur and 3-10-membered cycloaliphatic, wherein the ring is optionally substituted with one or more R b ;

or wherein R 1 , R 2 , and R 3 taken together with the atom X to which they are bound, when X is C, form a ring selected from 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 6-10-membered aryl, wherein the ring is optionally substituted with one or more R b ;

or wherein R 1 , R 2 , and R 3 taken together with the atom X to which they are bound, when X is N, form a 5-10-membered heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more R b ;

is a ring selected from 3-7-membered saturated, partially unsaturated, and aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 8-10-membered saturated, partially unsaturated, and aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R a is independently selected from linear or branched C 1-6 aliphatic and Z 1 —R 8 ;

or wherein two R a taken together with the atom or atoms to which they are bound, form a ring selected from 4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 3-6-membered cycloaliphatic, wherein the ring is optionally substituted with one or more R P ;

each occurrence of R P is independently selected from CN, CH 3 , CF 3 , CH 2 F, CF 2 H, NH 2 , NH(linear or branched C 1-3 aliphatic), N(linear or branched C 1-3 aliphatic) 2 , OH, halogen, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic) and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

each occurrence of Z 1 is independently selected from a direct bond, C 1-3 alkylene chain, O, N(R 16 ), S, S(O), S(O) 2 , C(O), CO 2 , C(O)NR 16 , N(R 16 )C(O), N(R 16 )CO 2 , S(O) 2 NR 16 , N(R 16 )S(O) 2 , OC(O)N(R 16 ), N(R 16 )C(O)NR 16 , N(R 16 )S(O) 2 N(R 16 ), and OC(O), wherein the alkylene chain is optionally substituted with one or more R h ;

each occurrence of R h is independently selected from CN, CH 3 , CF 3 , CH 2 F, CF 2 H, OH, halogen, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic) and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

each occurrence of R b is independently selected from linear or branched C 1-6 aliphatic and Z 2 —R 6 ;

or wherein two R b taken together with the atom or atoms to which they are bound, form a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more R c ;

each occurrence of R c is independently selected from linear or branched C 1-6 aliphatic, CF 3 , CF 2 H, CH 2 F, halogen, OR 12 , (CH 2 ) v —C(O)R 9 , and (CH 2 ) w —NR 10 C(O)R 11 ;

each occurrence of Z 2 is independently selected from direct bond, C 1-3 alkylene chain, O, N(R 17 ), S, S(O), S(O) 2 , C(O), CO 2 , C(O)NR 17 , N(R 17 )C(O), N(R 17 )CO 2 , S(O) 2 NR 17 , N(R 17 )S(O) 2 , OC(O)N(R 17 ), N(R 17 )C(O)NR 17 , N(R 17 )S(O) 2 N(R 17 ), and OC(O), wherein the alkylene chain is optionally substituted with one or more R i ;

each occurrence of R i is independently selected from CN, CH 3 , CF 3 , CH 2 F, CF 2 H, halogen, OH, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic) and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

each occurrence of R k is independently selected from linear or branched C 1-6 aliphatic and Z 3 —R 23 ;

each occurrence of Z 3 is independently selected from direct bond, C 1-3 alkylene chain, O, N(R 24 ), S, S(O), S(O) 2 , C(O), CO 2 , C(O)NR 24 , N(R 24 )C(O), N(R 24 )CO 2 , S(O) 2 NR 24 , N(R 24 )S(O) 2 , OC(O)N(R 24 ), N(R 24 )C(O)NR 24 , N(R 24 )S(O) 2 N(R 24 ), and OC(O), wherein the alkylene chain is optionally substituted with one or more R n ;

each occurrence of R n is independently selected from CN, CH 3 , CF 3 , CF 2 H, CH 2 F, halogen, OH, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic), and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

each occurrence of R e is independently selected from linear or branched C 1-6 aliphatic and Z 4 —R 22 ;

each occurrence of Z 4 is independently selected from direct bond, C 1-3 alkylene chain, O, N(R 20 ), S, S(O), S(O) 2 , C(O), CO 2 , C(O)NR 20 , N(R 20 )C(O), N(R 20 )CO 2 , S(O) 2 NR 20 , N(R 20 )S(O) 2 , OC(O)N(R 20 ), N(R 20 )C(O)NR 20 , N(R 20 )S(O) 2 N(R 20 ), and OC(O), wherein the alkylene chain is optionally substituted with one or more R t ;

each occurrence of R t is independently selected from CN, CH 3 , CF 3 , CF 2 H, CH 2 F, halogen, OH, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic), and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

J is selected from a direct bond; linear or branched C 1-6 aliphatic, wherein 1 or 2 methylene units of J are optionally and independently replaced by O, S, or N(R 13 ) and further wherein the C 1-6 aliphatic is optionally substituted with one or more R j ;

each occurrence of R j is independently selected from fluorine, CH 3 , CF 3 , CH 2 F, CF 2 H, OH, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic), NH 2 , NH(linear or branched C 1-3 aliphatic), N(linear or branched C 1-3 aliphatic) 2 , and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

or wherein two R j taken together with the atom or atoms to which they are bound form a ring selected from 3-6-membered heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur and 3-6-membered cycloaliphatic ring, wherein the ring is optionally substituted with one or more R m ;

each occurrence of R is independently selected from hydrogen and linear or branched C 1-3 aliphatic, wherein the C 1-3 aliphatic is optionally substituted with one or more F;

or wherein one of R j and one of R taken together with the atoms to which they are bound form a ring selected from 3-6-membered heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur and 3-6-membered cycloaliphatic, wherein the ring is optionally substituted with one or more R m ;

R 4 is selected from hydrogen and linear or branched C 1-6 aliphatic;

or wherein one of R and R 4 taken together with the atoms to which they are bound, form a 4-10-membered heterocycle ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more R m ;

or wherein one of R j and R 4 taken together with the atoms to which they are bound, form a 4-10-membered heterocycle ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more R m ;

each occurrence of R m is independently selected from halogen, CF 3 , CF 2 H, CH 2 F, and linear or branched C 1-6 aliphatic,

or wherein two R m taken together with the atom or atoms to which they are bound, form a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more R h ;

each occurrence of R h is independently selected from halogen, CF 3 , CF 2 H, CH 2 F, linear or branched C 1-6 aliphatic, C(O)N(R 18 ) 2 , OH, and O(linear or branched C 1-6 aliphatic);

each occurrence of R 5 is independently selected from hydrogen, CF 3 , CF 2 H, CH 2 F, and linear or branched C 1-6 aliphatic;

each occurrence of R 6 is independently selected from CN, halogen, OR 7 , N(R 19 ) 2 , linear or branched C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10-membered cycloaliphatic, wherein the aryl, heteroaryl, heterocycle, and cycloaliphatic are optionally substituted with one or more R c ;

each occurrence of R 7 is independently selected from hydrogen, CF 3 , CF 2 H, CH 2 F, linear or branched C 1-6 aliphatic, and 6-10-membered aryl;

each occurrence of R 8 is independently selected from CN, halogen, OR 5 , N(R 21 ) 2 , linear or branched C 1-6 aliphatic, 6-10-membered aryl, 3-10-membered cycloaliphatic, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the aryl, cycloaliphatic, heteroaryl, and heterocycle are optionally substituted with one or more R g ;

each occurrence of R g is independently selected from CN, CH 3 , CF 3 , CF 2 H, CH 2 F, halogen, OH, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic) and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

each occurrence of R 9 is independently selected from OH, O(linear or branched C 1-6 aliphatic), N(R 15 ) 2 , and linear or branched C 1-6 aliphatic;

each occurrence of R 10 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 11 is independently selected from OH, OC 1-6 aliphatic, N(R 14 ) 2 , and C 1-6 aliphatic;

each occurrence of R 12 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 13 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 14 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 15 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 16 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 17 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 18 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 19 is independently selected from hydrogen and linear or branched C 1-3 aliphatic;

each occurrence of R 20 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 21 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 22 is independently selected from CN, halogen, OR 28 , N(R 29 ) 2 , and linear or branched C 1-6 aliphatic; 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10-membered cycloaliphatic;

each occurrence of R 23 is independently selected from CN, halogen, OR 30 , SR 30 , N(R 26 ) 2 , and linear or branched C 1-6 aliphatic;

each occurrence of R 24 is independently selected from hydrogen and linear or branched C 1-6 aliphatic;

each occurrence of R 25 is independently selected from hydrogen and linear or branched C 1-3 aliphatic;

each occurrence of R 26 is independently selected from hydrogen and linear or branched C 1-3 aliphatic;

each occurrence of R 27 is independently selected from hydrogen and linear or branched C 1-3 aliphatic;

each occurrence of R 28 is independently selected from hydrogen, CF 3 , CF 2 H, CH 2 F, linear or branched C 1-6 aliphatic, and 6-10-membered aryl;

each occurrence of R 29 is independently selected from hydrogen and linear or branched C 1-3 aliphatic;

each occurrence of R 30 is independently selected from hydrogen, CF 3 , CF 2 H, CH 2 F, linear or branched C 1-6 aliphatic, and 6-10-membered aryl;

T is (CH 2 ) s -6-10-membered aryl or (CH 2 ) z -5-10-membered monocyclic or bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the aryl or heteroaryl are optionally substituted with one or more R d ,

each occurrence of R d is independently selected from CN, halogen, N(R 27 ) 2 , and linear or branched C 1-6 aliphatic;

or wherein taken together two R d together with the atom or atoms to which they are bound, form a 4-10-membered heterocycle ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R q is independently selected from CN, CH 3 , CF 3 , CF 2 H, CH 2 F, halogen, OH, OCH 3 , OCF 3 , OCH 2 F, OCF 2 H, O(linear or branched C 2-3 aliphatic), and linear or branched C 2-3 aliphatic, wherein the C 2-3 aliphatic is optionally substituted with one or more F;

b is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, or 5;

o is 0, 1, 2, or 3;

p is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

s is 0, 1, 2, or 3;

t is 0, 1, 2, or 3;

q is 0, 1, 2, or 3;

u is 0, 1, 2, or 3;

x is 0, 1, 2, or 3;

v is 0, 1, 2, or 3;

w is 0, 1, 2, or 3; and

z is 0, 1, 2, or 3,

further provided that when R B is a tertiary amine or methyl and J is a direct bond, then T is not phenyl or 3-pyridine, wherein the phenyl and 3-pyridine are optionally substituted with one of more R d .

2. The chemical entity of claim 1 chosen from compounds of formula II, compounds of formula III:

and pharmaceutically acceptable salts thereof, wherein

R 1A , R 2A , and R 3A are each independently selected from hydrogen; linear or branched C 1-6 aliphatic, wherein 1 or 2 methylene units of the C 1-6 aliphatic are optionally and independently replaced by O, S, S(O), S(O) 2 , or N(R 19 ); (CH 2 ) s -6-10-membered aryl; (CH 2 ) t -3-10-membered cycloaliphatic; (CH 2 ) u -4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and (CH 2 ) p -5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-6 aliphatic, aryl, cycloaliphatic, heterocycle, and heteroaryl are optionally substituted with one or more R k ,

provided that for formula III, R 1A is not hydrogen and

provided that for formula II, when R 1A , R 2A , and R 3A are each hydrogen and J is a direct bond, the T is not phenyl or 3-pyridine, wherein the phenyl and 3-pyridine are optionally substituted with one or more R d ;

or wherein any two of R 1A , R 2A , and R 3A taken together with the carbon atom to which they are bound, form a ring selected from 4-10-membered heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur and 3-10-membered cycloaliphatic, wherein the ring is optionally substituted with one or more R b ;

or wherein R 1A , R 2A , and R 3A taken together with the carbon atom to which they are bound form a ring selected from 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-10-membered aryl, wherein the ring is optionally substituted with one or more R b ;

each occurrence of R b is independently selected from linear or branched C 1-6 aliphatic and Z 2 —R 6 ;

or wherein two R b taken together with the atom or atoms to which they are bound, form a ring selected from 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more R c ;

each occurrence of R c is independently selected from linear or branched C 1-6 aliphatic, CF 3 , CF 2 H, CH 2 F, halogen, OR 12 , (CH 2 ) v —C(O)R 9 , and (CH 2 ) w —NR 10 C(O)R 11 ;

each occurrence of R k is independently selected from linear or branched C 1-6 aliphatic and Z 3 —R 23 ;

each occurrence of Z 3 is independently selected from direct bond, C 1-3 alkylene chain, O, N(R 24 ), S, S(O), S(O) 2 , C(O), CO 2 , C(O)NR 24 , N(R 24 )C(O), N(R 24 )CO 2 , S(O) 2 NR 24 , N(R 24 )S(O) 2 , OC(O)N(R 24 ), N(R 24 ) C(O)NR 24 , N(R 24 ) S(O) 2 N(R 24 ), and OC(O), wherein the alkylene chain is optionally substituted with one or more R n ;