Granted Patent B2

US 12,415,803 · App. 17/271,009 · Granted Sep 16, 2025

Inventors: Richard D. Caldwell (Billerica, MA); Lesley Liu-Bujalski (Billerica, MA); Justin Potnick (Billerica, MA); Constantin Neagu (Billerica, MA); Shashank Kulkarni (Billerica, MA); Reinaldo Jones (Billerica, MA); Hui Qiu (Billerica, MA)

Assignee: Merck Patent GmbH

C07D471/04

Abstract

Claims (137)

1. A compound of formula I,

or a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

X is C(R) 2 or O;

Y is —O—, —S—, —SO 2 —, —SO—, —C(O)—, —CO 2 —, or —NHC(O);

R 1 is C 6-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocylic 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;

Ring Z is C 6-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic 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;

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 ; or two R a groups, together with the atoms to which each is attached, forms a C 6-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic 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;

each R is independently hydrogen, C 1-6 aliphatic, C 6-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic 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 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic 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;

n is 0, 1, or 2; and

p is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein X is CH 2 .

3. The compound of claim 1 , wherein X is O.

4. The compound of claim 1 , wherein R 1 is an optionally substituted 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 1 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound of claim 4 , wherein R 1 is azocinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, piperidine-one, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyridine, tetrahydropyran, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, or azetidinyl; each of which is optionally substituted.

6. The compound of claim 5 , wherein R 1 is selected from:

7. The compound of claim 1 , wherein Ring Z is a 3-8 membered saturated or partially unsaturated carbocyclic ring 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.

8. The compound of claim 7 , wherein Ring Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, or isothiazolyl; each of which is optionally substituted.

9. The compound of claim 8 , wherein Ring Z is

10. The compound of claim 9 , wherein Ring Z is

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

or a tautomer, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , of formula III,

or a tautomer, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , of formula IV,

or a tautomer, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is one of the following compounds:

3-tert-butyl-N-[(5R)-2-{2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide (82);

5-tert-butyl-N-[(5R)-2-{2-[3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (78);

5-tert-butyl-N-[(5R)-2-{2-[5-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-1H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (79);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(R)-2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (153);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (37);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (121);

3-tert-butyl-N-{2-[2-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-1,2,4-oxadiazole-5-carboxamide (85);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (20);

3-tert-butyl-N-[(1R)-6-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide (75);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (12);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (24);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (52);

5-tert-butyl-N-[(5S)-2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-1H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (89);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid ((S)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (155);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(S)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (10);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(S)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (49);

5-tert-butyl-N-[(5R)-2-{2-[5-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-1H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (79);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (30);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (38);

5-tert-butyl-N-[(5R)-2-{2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2-oxazole-3-carboxamide (92);

3-tert-Butoxy-azetidine-1-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (51);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (42);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (46);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(S)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (16);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(S)-8-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (45);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (40);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid ((S)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (163);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (33);

3-tert-butyl-N-{2-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-1,2,4-oxadiazole-5-carboxamide (83);

3-tert-butyl-N-[(1R)-6-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide (74);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(S)-6-[2-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (119);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (123);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (149);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (8);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (160);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (54);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (61);

5-tert-butyl-N-(2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide (86);

5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (41);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid ((S)-6-{2-[3-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (115);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (23);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (39);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (21);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (32);

5-tert-butyl-N-(2-{2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide (84);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (11);

3-tert-Butoxy-azetidine-1-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (43);

5-(1-Methyl-cyclopropyl)-isoxazole-3-carboxylic acid {(R)-2-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (56);

3-tert-butyl-N-{2-[2-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-1,2,4-oxadiazole-5-carboxamide (97);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (124);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (131);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (143);

3-tert-butyl-N-[(5R)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide (1);

5-tert-butyl-N-[2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (3);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (27);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (127);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (142);

5-tert-butyl-N-[(5R)-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2-oxazole-3-carboxamide (72);

5-tert-butyl-N-(2-{2-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2-oxazole-3-carboxamide (91);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (63);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (109);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {6-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (107);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {(S)-6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (165);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (14);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(S)-6-[2-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (119);

5-tert-butyl-N-[(5R)-2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide (87);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(R)-2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (59);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (106);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (151);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {(S)-6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (167);

N-[(5S)-2-[2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (2);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {6-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (108);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (110);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid ((S)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (157);

3-tert-butyl-N-[2-[2-(trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide (6);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (29);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (150);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(5-ethyl-1-methyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (133);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid ((R)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (137);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid (2-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide (120);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (118);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (148);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-amide (69);

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid {2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (58);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-6-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (100);

3-tert-butyl-N-[(1R)-6-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide (96);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (135);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (67);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {(R)-6-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (114);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {6-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (105);

5-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-3-carboxylic acid ((R)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (162);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (35);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (134);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid (6-{2-[3,5-dimethyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (140);

5-tert-Butyl-[1,3,4]oxadiazole-2-carboxylic acid {(S)-8-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl}-amide (19);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (144);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid ((S)-6-{2-[3-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (115);

3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (136);

3-tert-Butoxy-azetidine-1-carboxylic acid {6-[2-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-amide (145);

3-(1-Methyl-cyclopropyl)-[1,2,4]oxadiazole-5-carboxylic acid {2-[2-(1-isopropyl-5-methyl-1H-pyrazol-3-yl)-3H-imidazo [4,5-b]pyridin-7-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl}-amide (117);

3-tert-Butoxy-azetidine-1-carboxylic acid (6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (147) or

5-tert-Butyl-[1,2,4]oxadiazole-3-carboxylic acid ((R)-6-{2-[5-methyl-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-3H-imidazo [4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (156)

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

17. A method for inhibiting BTK, or a mutant thereof, activity in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound of claim 1 , or a physiologically acceptable salt thereof.

18. A method for treating a BTK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of claim 1 .

19. The method of claim 18 , wherein the disorder is selected from inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease, autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenia states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenia purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosis fungoides, acute inflammatory responses, acute respiratory distress syndrome, ischemiaf, reperfusion injury, and Graves' disease.

20. A method for treating lupus in a subject, comprising the step of administering to said subject a compound of claim 1 , or a physiologically acceptable salt thereof.

Assignments (1)

Continuity (2)

References Cited (26)