Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-10131676-B2
Application number	US-201715721470-A
Country	US
Kind code	B2
Filing date	Sep 29, 2017
Priority date	Feb 5, 2016
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors.

First claim

The invention claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein:
R 1 is H or optionally substituted C 1 -C 6 alkyl;
X 1 and X 2 together form an optionally substituted pyridyl:

Y 1 is O;
Y 2 is —C(R 6 ) 2 —;
R 3 and R 4 are independently H, halo, or optionally substituted C 1 -C 6 alkyl, or R 3 and R 4 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
each R 6 is independently H, halo, or optionally substituted C 1 -C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a C 2 -C 6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
L is absent, —O—, —S—, —S(O)—, —S(O) 2 —, —NR′— or —C(R 8 ) 2 —;
R 7 is H or optionally substituted C 1 -C 6 alkyl;
each R 8 is independently H, halo, or optionally substituted C 1 -C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and
R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
wherein each optionally substituted pyridyl, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl ring is independently optionally substituted by one or more substituents, provided that the designated atom's normal valence is not exceeded, selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —NHNH 2 , ═NNH 2 , imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, —S(O)OH, —S(O) 2 OH, sulfonamido, —SH, thioxo, N-oxide, —Si(R 100 ) 3 wherein each R 100 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —OC(O)R, and —C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; and
further wherein:
each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro;
each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one to five ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C═O) or N-oxide (N—O—) moieties and/or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro; and
each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one to five ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1 , wherein R 1 is methyl.

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

4. The compound of claim 1 , wherein both R 3 and R 4 are fluoro, or either R 3 or R 4 are fluoro and the other is hydrogen, or R 3 and R 4 form a cyclopropyl or R 3 joins with R 6 to form a cyclopropyl.

5. The compound of claim 1 , wherein R 3 joins with R 6 to form a cyclopropyl.

6. The compound of claim 1 , wherein both R 3 and R 4 are hydrogen.

7. The compound of claim 1 , wherein R 3 and R 4 together with the carbon atom to which they are attached, form a cyclopropyl.

8. The compound of claim 1 , wherein L is absent, —O— or —C(R 8 ) 2 —.

9. The compound of claim 8 , wherein L is —C(R 8 ) 2 — and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

10. The compound of claim 1 , wherein R 9 is pyridyl, phenyl or 2,3-dihydro-1H-indenyl, each of which is optionally substituted.

11. The compound of claim 10 , wherein R 9 is optionally substituted phenyl.

12. The compound of claim 10 , wherein R 9 is pyridyl, phenyl or 2,3-dihydro-1H-indenyl, each independently optionally substituted with one or two substituents selected from cyano, halo, optionally substituted C 1 -C 6 alkyl and C 1 -C 6 alkoxy.

13. The compound of claim 12 , wherein R 9 is phenyl independently optionally substituted with one or two halo, cyano or C 1 -C 6 alkyl optionally substituted with halo.

14. The compound of claim 13 , wherein R 9 is phenyl independently optionally substituted with one or two halo or C 1 -C 6 alkyl optionally substituted with halo.

15. The compound of claim 13 , wherein R 9 is phenyl substituted with cyano.

16. The compound of claim 1 , wherein the pyridyl of

is independently optionally substituted with cyano, halo, alkyl, heteroaryl, aryl, heterocyclyl, cycloalkyl, alkoxy, or —S(O) 2 —C 1 -C 6 alkyl.

17. The compound of claim 16 , wherein the pyridyl is independently optionally substituted with cyano, halo, or —S(O) 2 —C 1 -C 6 alkyl.

18. The compound of claim 1 , wherein the pyridyl of

is unsubstituted.

19. The compound of claim 1 , wherein the pyridyl of

is independently optionally substituted with halo, alkyl, heteroaryl, aryl, heterocyclyl, cycloalkyl, or alkoxy.

20. The compound of claim 1 , wherein ring A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

21. The compound of claim 1 , wherein ring A is oxadiazolyl.

22. The compound of claim 1 , wherein L is —C(R 8 ) 2 — and two R 8 together with the carbon atom to which they are attached form a cycloalkyl ring.

23. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

24. A compound having the structure:

Assignees

• Denali Therapeutics Inc

Inventors

• Estrada Anthony A
• Feng Jianwen A
• Fox Brian
• Leslie Colin Philip
• Lyssikatos Joseph P
• Pozzan Alfonso
• Sweeney Zachary K
• De Vicente Fidalgo Javier

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title