Pyridines, pyrimidines, and pyrazines, as BTK inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9738648-B2
Application number	US-201414904547-A
Country	US
Kind code	B2
Filing date	Jul 30, 2014
Priority date	Jul 31, 2013
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

The present invention relates to pyridine, pyrimidine, and pyrazine compounds, and pharmaceutically acceptable compositions thereof, useful as BTK inhibitors.

First claim

We claim:

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:
X is N;
X 1 is CR 2 ;
X 2 is N or CR 2 ;
each R 2 is independently selected from —R, halogen, -haloalkyl, —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 3-10 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, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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 3-10 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, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
L is a divalent group selected from C 3-10 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, or sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or L is a divalent group selected from C 1-6 aliphatic-C 3-10 aryl, C 1-6 aliphatic-3-8 membered saturated or partially unsaturated carbocyclic ring, C 1-6 aliphatic-3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a C 1-6 aliphatic-5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
Y is O, S, SO 2 , SO, C(O), CO 2 , C(O)N(R), —NRC(O), —NRC(O)N(R), —NRSO 2 , or N(R); or Y is absent; and
R 1 is C 2-6 alkenyl or C 2-6 alkynyl, which is optionally substituted; or R 1 is CN.

2. The compound of claim 1 , wherein each R 2 is independently phenyl or pyrazolyl.

3. The compound of claim 1 , wherein each R 2 is independently —OR or —N(R) 2 .

4. The compound of claim 1 , wherein each R 2 is independently hydrogen,

5. The compound of claim 1 , wherein L is

6. The compound of claim 1 , wherein Y is NR,

7. The compound of claim 1 , wherein Y is absent.

8. The compound of claim 1 , wherein R 1 is —CN, —CH 2 CN,

9. The compound of claim 1 , of formula I-a1,

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , of formula I-a2,

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , selected from

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

13. A process for manufacturing a compound of formula I according to claim 1 , comprising the steps of:
reacting a compound of formula (II-a)

wherein X, X 1 , and X 2 , are as defined in claim 1 ;
with a compound to yield a compound of formula I:

wherein X, X 1 , X 2 , R 1 , L and Y are as defined in claim 1 .

Assignees

• Merck Patent Gmbh

Inventors

• Liu-Bujalski Lesley
• Nguyen Ngan
• Qiu Hui
• Jones Reinaldo
• Mochalkin Igor
• Caldwell richard d

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title