Heteroaryl compounds as BTK inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-11098041-B2
Application number	US-201916378383-A
Country	US
Kind code	B2
Filing date	Apr 8, 2019
Priority date	Oct 6, 2014
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

Imidazo pyridine compounds, and pharmaceutically acceptable compositions thereof are useful as BTK inhibitors.

First claim

We claim:

1. A compound of formula I,

or a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a phenyl or pyridine;
R 1 is H, F, (C(R 5 )(R 5 )) m NR 2 , N(R 4 )C(O)R, N(R 4 )C(O)NR 2 , N(R 4 )(R 4 ), 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 is absent;
R 2 is H, (C(R 5 )(R 5 )) m OR 4 , (C(R 5 )(R 5 )) m N(R 4 )COR, (C(R 5 )(R 5 )) m N(R 4 )C(O)C(O)NR 2 , or (C(R 5 )(R 5 )) m N(R 4 )(R 4 ); or R 2 is absent;
or R 1 and R 2 together with the atoms to which they are connected, form a fused 3-7 membered ring which is optionally substituted with C 1 -C 6 alkyl or C(O)R;
wherein R 1 and R 2 are both not H; and wherein R 1 and R 2 are both not absent;
each R 3 is independently F, Cl, Br, I, methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight or branched pentyl, or straight or branched hexyl; each of which is optionally substituted;
each R 4 is independently —R, —SO 2 R, —SOR, —C(O)R, —CO 2 R, or —C(O)N(R) 2 ;
each R 5 is independently —R, halogen, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
each R is independently hydrogen, C 1-6 aliphatic, C 5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted; or
two R groups on the same atom are taken together with the atom to which they are attached to form a C 5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-15 membered fused aryl ring; a 6-15 membered saturated or partially unsaturated fused carbocyclic ring; a 10-15 membered fused heteroaryl ring; or a 6-15 membered saturated or partially unsaturated fused heterocyclic ring; each of which is optionally substituted;
Ring Z is

each R a is independently —R, halogen, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
m is 1, 2, or 3;
n is 0, 1, or 2; and
p is 0, 1, 2, or 3
wherein “optionally substituted” means groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with —F, —Cl, —Br, —I, deuterium, —OH, protected hydroxy, alkoxy, oxo, thiooxo, —NO 2 , —CN, CF 3 , N 3 , —NH 2 , protected amino, —NH-alkyl, —NH-alkenyl, —NH-alkynyl, —NH-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino, -diarylamino, -diheteroarylamino, —O-alkyl, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclic, —C(O)-alkyl, —C(O)-alkenyl, —C(O)-alkynyl, —C(O)-carbocyclyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocyclyl, —CONH 2 , —CONH— alkyl, —CONH-alkenyl, —CONH-alkynyl, —CONH-carbocyclyl, —CONH-aryl, —CONH-heteroaryl, —CONH— heterocyclyl, —OCO 2 -alkyl, —OCO 2 -alkenyl, —OCO 2 -alkynyl, —OCO 2 -carbocyclyl, —OCO 2 -aryl, —OCO 2 -heteroaryl, —OCO 2 -heterocyclyl, —OCONH 2 , —OCONH-alkyl, —OCONH-alkenyl, —OCONH— alkynyl, —OCONH-carbocyclyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocyclyl, —NHC(O)-alkyl, —NHC(O)-alkenyl, —NHC(O)-alkynyl, —NHC(O)-carbocyclyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl, —NHCO 2 -alkyl, —NHCO 2 -alkenyl, —NHCO 2 -alkynyl, —NHCO 2 -carbocyclyl, —NHCO 2 -aryl, —NHCO 2 -heteroaryl, —NHCO 2 -heterocyclyl, —NHC(O)NH 2 , —NHC(O)NH-alkyl, —NHC(O)NH-alkenyl, —NHC(O)NH-alkenyl, —NHC(O)NH-carbocyclyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocyclyl, NHC(S)NH 2 , —NHC(S)NH— alkyl, —NHC(S)NH-alkenyl, —NHC(S)NH-alkynyl, —NHC(S)NH-carbocyclyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclyl, —NHC(NH)NH 2 , —NHC(NH)NH-alkyl, —NHC(NH)NH-alkenyl, —NHC(NH)NH-alkenyl, —NHC(NH)NH-carbocyclyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocyclyl, —NHC(NH)-alkyl, —NHC(NH)-alkenyl, —NHC(NH)-alkenyl, —NHC(NH)-carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)— heterocyclyl, —C(NH)NH-alkyl, —C(NH)NH-alkenyl, —C(NH)NH-alkynyl, —C(NH)NH-carbocyclyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclyl, —S(O)-alkyl, —S(O)-alkenyl, —S(O)-alkynyl, —S(O)-carbocyclyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclyl, —SO 2 NH 2 , —SO 2 NH-alkyl, —SO 2 NH-alkenyl, —SO 2 NH-alkynyl, —SO 2 NH-carbocyclyl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —SO 2 NH-heterocyclyl, —NHSO 2 -alkyl, —NHSO 2 -alkenyl, —NHSO 2 -alkynyl, —NHSO 2 -carbocyclyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHSO 2 -heterocyclyl, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , -mono-, di-, or tri-alkyl silyl, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S— carbocyclyl, —S-aryl, —S-heteroaryl, —S-heterocyclyl, and methylthiomethyl.

2. The compound of claim 1 , wherein Ring A is

3. The compound of claim 1 , wherein R 1 is

4. The compound of claim 1 , wherein R 1 is absent.

5. The compound of claim 1 , wherein R 2 is —CH 2 OH, —CH 2 NH 2 ,

6. The compound of claim 1 , wherein R 1 and R 2 together form

7. The compound of claim 1 , wherein each R 3 is independently is cyclopropyl, phenyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, piperidine-one, pyrimidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydropyridine, tetrahydropyran, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which is optionally substituted.

8.

Assignees

• Merck Patent Gmbh

Inventors

• Gaillard Pascale
• Seenisamy Jeyaprakashnarayanan
• Liu-Bujalski Lesley
• Caldwell richard d
• Potnick Justin
• Qiu Hui
• Neagu Constantin
• Jones Reinaldo
• Won Annie Cho
• Goutopoulos Andreas
• Sherer Brian A
• Johnson Theresa L
• Gardberg Anna

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P17/14

  for baldness or alopecia · CPC title