Amido spirocyclic amide and sulfonamide derivatives

Patent metadata

Field	Value
Publication number	US-9822129-B2
Application number	US-201314382210-A
Country	US
Kind code	B2
Filing date	Mar 1, 2013
Priority date	Mar 2, 2012
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Provided are amido spirocyclic amide and sulfonamide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.

First claim

The invention claimed is:

1. A compound of Formula I:

wherein:
R is (a) an 8-, 9-, or 10-membered bicyclic heteroaryl comprising one heteroatom selected from N, S, and O, and one, two, or three additional N atoms, wherein said bicyclic heteroaryl is unsubstituted or is substituted with one or more substituents selected from the group consisting of deuterium, amino, alkylamino, dialkylamino, alkyl, halo, cyano, haloalkyl, hydroxy, hydroxyalkyl, and alkoxy, and wherein one or more N atoms of said bicyclic heteroaryl is optionally an N-oxide; or
(b) a five- or six-membered nitrogen-linked heterocycloalkyl ring fused to a phenyl or monocyclic five- or six-membered heteroaryl, wherein said phenyl or heteroaryl is unsubstituted or is substituted with one or more substituents selected from the group consisting of deuterium, amino, alkylamino, dialkylamino, alkyl, halo, cyano, haloalkyl, hydroxy, hydroxyalkyl, and alkoxy; and

R 1 is H, —(C 1-4 alkylene) 0-1 C(O)R a , —(C 1-4 alkylene) 0-1 CO 2 R a , —(C 1-4 alkylene) 0-1 S(O)R a , —(C 1-4 alkylene) 0-1 SO 2 R a , —C(O)NH(R a ), —C(O)N(R a ) 2 , or —C(O)C(O)NH(R a );
wherein each R a is independently
(1) alkyl, unsubstituted or substituted with one or more R m substituents,
wherein each R m is independently selected from the group consisting of hydroxy, —NR b R c , alkoxy, cyano, halo, —C(O)alkyl, —CO 2 alkyl, —CONR b R c , —S(O)alkyl, —SO 2 alkyl, —SO 2 NR b R c , aryl, heteroaryl, cycloalkyl, heterocycloalkyl, phenoxy, and —O-alkyl-OH;
wherein R b is H or alkyl;
R c is H, alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl, —CO 2 alkyl, —SO 2 alkyl, —C(O)NH 2 , or C(O)H; and
each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group within R m is unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, haloalkyl, hydroxy, —NR b R c , alkoxy, haloalkoxy, cyano, halo, oxo, —C(O)alkyl, —CO 2 alkyl, —C(O)-heterocycloalkyl, —CONR b R c , —S(O)alkyl, —SO 2 alkyl, —SO 2 -haloalkyl, —SO 2 NR b R c , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
 wherein each alkyl or alkoxy is unsubstituted or substituted with —NR b R c , heterocycloalkyl, heteroaryl, or —C(O)alkyl; and
 each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with alkyl, halo, or —C(O)alkyl;

(2) phenyl, cycloalkyl, heteroaryl, or heterocycloalkyl, each unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, hydroxy, —NR b R c , alkoxy, haloalkoxy, cyano, halo, oxo, —C(O)alkyl, —CO 2 alkyl, —C(O)-heterocycloalkyl, —CONR b R c , —S(O)alkyl, —SO 2 alkyl, —SO 2 -haloalkyl, —SO 2 NR b R c , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein each alkyl or alkoxy is unsubstituted or substituted with —NR b R c , heterocycloalkyl, heteroaryl, or —C(O)alkyl; and
each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with alkyl, halo, or —C(O)alkyl; or

(3) —NR x R y ,
where R x is H or alkyl; and
R y is H, alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl, —CO 2 alkyl, or —SO 2 alkyl;

R 2 and R 3 are each independently H or deuterium; and
n is 1 or 2;
or a stereoisomer thereof, or a pharmaceutically acceptable salt of such a compound or stereoisomer.

2. The compound of claim 1 , wherein R is an 8- or 9-membered heteroaryl, unsubstituted or substituted as described for claim 1 .

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

each unsubstituted or substituted as described for claim 1 .

4. The compound of claim 1 , wherein, R is a five- or six-membered nitrogen-linked heterocycloalkyl ring fused to an unsubstituted or substituted phenyl or monocyclic heteroaryl, as defined in claim 1 .

5. The compound of claim 1 , wherein R is

6. The compound of claim 1 , wherein R 1 is H, —C(O)R a , —CO 2 R a , —S(O)R a , or —SO 2 R a .

7. The compound of claim 1 , wherein R a is methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, isopentyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazoyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl, each unsubstituted or substituted.

8. The compound of claim 1 , wherein R a is phenyl, cycloalkyl, heteroaryl, or heterocycloalkyl, each unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, oxo, methyl, —CONH 2 , acetyl, —SO 2 methyl, —C(O)-isopropyl, pyridazinyl, triazolyl, dimethylaminomethyl, cyano, methyl-triazolyl-methoxy, trifluoromethoxy, pyrrolidinylmethyl, acetylamino, tetrazolylmethyl, methyl-tetrazolyl-methyl, methyl-imidazolyl-methyl, —NHSO 2 methyl, 1,1-dioxothiomorpholinyl, 4-methyl-piperazinylmethyl, —NHCONH 2 , —SO 2 CF 3 , morpholinylmethyl, imidazolyl, —SO 2 NH 2 , methylpiperidinyl, methyl-piperazinyl, —C(O)(4-methyl-piperazinyl), morpholinyl, trifluoromethyl, cyclopropyl, ethyl, isoxazolyl, tetrazolyl, isopropyl, phenyl, fluoro-phenyl, tert-butyl, benzyl, N-methylpyrrolidinyl, N-acetyl-pyrrolidinyl, isobutyl, propyl, methylpyrazolyl, trifluoroethyl, pyrimidinyl, oxo, acetyl, cyano, —CO 2 -tert-butyl, and amino.

9. The compound of claim 1 , wherein R a is alkyl, unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, tert-butoxy, —C(O)NMe 2 , —NHCHO, methoxy, phenoxy, cyano, acetyl, hydroxy, —OCH 2 C(CH 3 )═OH, —NH(acetyl), and —N(Me)(acetyl).

10. The compound of claim 1 , wherein R 1 is —SO 2 R a , where R a is methyl, ethyl, phenyl, benzyl, or 2,2-dimethylpropyl.

11. The compound of claim 1 , wherein R 1 is —C(O)NHR a , wherein R a is methyl, ethyl, propyl, isopropyl, tertobutyl, cyclohexyl, —CH 2 -cyclohexyl, oxetanyl, or methyloxetanyl, or R a is a phenyl or benzyl group, each optionally substituted with one or more substituents selected from the group consisting of cyano, methyl, fluoro, methoxy, and chloro.

12. The compound of claim 1 , wherein both R 2 and R 3 are H.

13. The compound of claim 1 , which is a compound of Formula I-a:

wherein R, R 1 , R 2 , and R 3 are as defined for Formula I;
or a stereoisomer thereof, or a pharmaceutically acceptable salt of such a compound or stereoisomer.

14. A compound selected from the group consisting of:

tert-butyl 2-[(1,3- dihydropyrrolo[3,4- c]pyridine-2- carbonylamino)methyl]-8- azaspiro[2.5]octane-8- carboxylate;

Assignees

• Genentech Inc
• Forma Tm Llc
• Yuen Po-Wai
• Genentech Inc

Inventors

• Bair Kenneth W
• Baumeister Timm R
• DRAGOVICH Peter
• Liu Xiongcai
• Patel Snahel
• Yuen Po-Wai
• Zak Mark
• Zhao Guiling
• Zhang Yamin
• Zheng Xiaozhang

Classifications

• A61P35/04

  specific for metastasis · CPC title

• 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

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title