Heteroaryl compounds as BTK inhibitors and uses thereof
The present invention relates to imidazo pyridine compounds, and pharmaceutically acceptable compositions thereof, useful as BTK inhibitors.
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, halo, (C(R 5 )(R 5 )) m NR 2 , N(R 4 )C(O)R, N(R 4 )C(O)NR 2 , N(R 4 )CO 2 R, N(R 4 )S(O) 2 R, N(R 4 )S(O)R, N(R 4 )(R 4 ), 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more of C 1 -C 6 alkyl, C 5 -C 6 aryl, 5-6 membered heteroaryl, or halo, or R 1 is 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with aryl; 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 halogen, 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;
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.
2. The compound of claim 1 , wherein Ring A is
3. The compound of claim 1 , wherein 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.
4. The compound of claim 3 , wherein R 1 is
5. The compound of claim 1 , wherein R 1 is absent.
6. The compound of claim 1 , wherein R 2 is H or R 2 is (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 ).
7. The compound of claim 6 , wherein R 2 is —CH 2 OH, —CH 2 NH 2 ,
8. The compound of claim 1 , wherein R 1 and R 2 together form
9. The compound of claim 1 , wherein 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.
10. 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.
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 II-c,
or a tautomer, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , selected from Table 1:
TABLE 1#
7
8
9
10
14
15
16
17
18
19
20
21
22
23
32
34
37
38
42
43
44
49
50
51
52
53
54
55
56
57
58
59
60
61
67
69
70
72
75
77
87
88
91
92
93
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
116
119
120
121
122
124
125
126
127
129
130
131
132
133
135
144
165
168
173
174
175
176
177
178
179
180
181
185
187
188
14. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
15. A method for inhibiting BTK, activity in a patient in need thereof or in a biological sample, comprising:
administering to said patient or contacting said biological sample with a compound of claim 1 , or a physiologically acceptable salt thereof.
16. A method for treating a BTK-mediated disorder in a patient in need thereof, comprising:
administering to said patient a compound of claim 1 ; wherein the disorder is at least one disease selected from the group consisting of 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, autoimmune polyglandular disease, autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic 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, and Graves' disease.
17. A method for treating lupus in a subject in need thereof, comprising:
administering to said subject a compound of claim 1 , or a physiologically acceptable salt thereof.