Indolizine derivatives as phoshoinositide 3-kinases inhibitors

Patent metadata

Field	Value
Publication number	US-9527869-B2
Application number	US-201514741965-A
Country	US
Kind code	B2
Filing date	Jun 17, 2015
Priority date	Jun 17, 2014
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

Compounds of formula (I), defined herein, inhibit phosphoinositide 3-kinases (PI3K) and are useful for the treatment of disorders associated with PI3K enzymes.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
X 1 , X 2 , X 3 and X 4 are all CH groups;
each R, when present, is —OR 5 , —SR 5 , —S(O) q —R 7 , halogen, —NR 10 R 11 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 5 -C 7 ) cycloalkenyl, (C 2 -C 6 ) alkynyl, (C 2 -C 6 ) hydroxyalkynyl, aryl, heteroaryl, or (C 3 -C 6 ) heterocycloalkyl, each of which may be optionally and independently substituted with one or more groups selected from the group consisting of halogen, —OH,(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 5 -C 7 ) cycloalkenyl, (C 2 -C 6 ) alkynyl, and (C 2 -C 6 ) hydroxyalkynyl;
R 1 is —H, —OR 6 , —SR 6 , —S(O) q —R 8 , halogen, —NR 12 R 13 , —CN, —C(O)NR 12 R 13 , —C(O)OR 16 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 5 -C 7 ) cycloalkenyl, (C 2 -C 6 ) alkynyl, (C 2 -C 6 ) hydroxyalkynyl, aryl, heteroaryl, or (C 3 -C 6 ) heterocycloalkyl, each of which may be optionally and independently substituted with one or more groups selected from the group consisting of halogen, —NR 22 R 23 , —(CH 2 ) n NR 22 R 23 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxyl, (C1-C6) aminoalkoxyl (C 3 -C 6 ) heterocycloalkyloxyl, (C 3 -C 6 ) heterocycloalkyl (C 1 -C 6 ) alkoxyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, and (C 2 -C 6 ) hydroxyalkynyl;
R 2 is —H, —OR 9 , —SR 9 , —S(O) q —R—, halogen, —NR 14 R 15 , —CN, —C(O)NR 14 R 15 , —C(O)OR 18 , —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) haloalkyl, —(C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, (C 3 -C 7 ) cycloalkyl, (C 5 -C 7 ) cycloalkenyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl,(C 2 -C 6 ) hydroxyalkynyl, aryl, heteroaryl, or (C 3 -C 6 ) heterocycloalkyl each of which may be optionally and independently substituted with one or more groups selected from the group consisting of halogen; —NR 24 R 25 , —(CH 2 ) n NR 24 R 25 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl,(C 1 -C 6 ) hydroxyalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, and (C 2 -C 6 ) hydroxyalkynyl;
R 3 and R 4 , are the same or different and are each independently —H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;
Cy is 3H-purin-3-yl, 9H-purin-9-yl, 9H-purin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 6-oxo-5H,6H,7H-pyrrolo[2,3-d]pyrimidin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, or 1,3,5-triazin-2-yl, each of which may be optionally and independently substituted by one or more substituents selected from the group consisting of halogen, —OH, —NR 19 R 20 , —CH 2 NR 19 R 20 ; —CN, —CH(O), —CH═NOH, —C(O)NR 19 R 20 , —C(O)OR 21 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 2 -C 6 ) hydroxyalkynyl, aryl, heteroaryl, and (C 3 -C 6 ) heterocycloalkyl wherein each substituent may be optionally and independently substituted with one or more groups selected from the group consisting of —OH, halogen, —CN, —S(O) 2 NR I R III , —NR III S(O) 2 R II , —NR I R III , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl, and (C 3 -C 6 ) heterocycloalkyl;
wherein R I R II and R III are the same or different and are each independently —H, (C 1 -C 6 ) alkyl or alkanoyl;
R 5 , R 6 , R 9 , R 16 , R 18 , and R 21 are the same or different and are each independently —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, alkanoyl, or aryl alkanoyl;
R 7 , R 8 and R 17 are the same or different and are each independently NR 12 R 13 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, aryl, heteroaryl or(C 3 -C 6 ) heterocycloalkyl, each of which may be optionally and independently substituted with one or more groups selected from the group consisting of halogen, —NR 22 R 23 , —CH 2 NR 22 R 23 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 2 -C 6 ) alkenyl,(C 2 -C 6 ) alkynyl, and (C 2 -C 6 ) hydroxyalkynyl;
R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 19 , R 20 , R 22 , R 23 , R 24 and R 25 are the same or different and are each independently —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, or alkanoyl or, taken together with the nitrogen atom to which they are bonded, anyone of R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 19 and R 20 , R 22 and R 23 , abd R 24 and R 25 may form an optionally substituted 5 to 6 membered heterocycle wherein at least one ring carbon atom in said heterocycle may be replaced by at least one member selected from the group consisting of O, S, N, NH and an oxo substituent;
Z, when present, is —O—, —NH—, —C(O)—, —NHC(O)—, —C(O)NH—, —S—, —S(O)—, or —S(O) 2 —;
m is zero or 1;
n is 1 or 2;
p is zero or an integer ranging from 1 to 3; and
q is an integer ranging from 1 to 2,
or a pharmaceutically acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt according to claim 1 , which is a mixture of diastereoisomers.

3. A compound or pharmaceutically acceptable salt according to claim 1 , wherein:
R 3 is H or (C 1 -C 6 ) alkyl; and
R 4 is H.

4. A compound or pharmaceutically acceptable salt according to claim 1 , wherein:
R 3 is (C 1 -C 6 ) alkyl;
R 4 is H.

5. A compound or pharmaceutically acceptable salt according to claim 1 , wherein:
R 3 is methyl;
R 4 is H; and
Cy is 1H-pyrazolo[3,4-d]pyrimidin-1-yl, which may be optionally substituted by one or more substituents selected from the group consisting of —NR 19 R 20 and aryl wherein said substituents may be optionally substituted by one or more groups selected from the group consisting of —OH and halogen.

6. A compound or pharmaceutically acceptable salt according to claim 5 , wherein:
R 1 is 4-morpholinomethyl, 2-methyl-2,9-diazaspiro[5.5]undecan-9-yl}methyl, 9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}methyl, 7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}methyl, or 5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl]methyl;
R 3 is methyl;
R 4 is H; and
CY is 1H-pyrazolo[3,4-d]pyrimidin-1-yl (I-4), which is substituted in position 4 by —NH 2 and in position 3 by 3-fluoro-5-hydroxyphenyl.

7. A compound or pharmaceutically acceptable salt according to claim 1 , wherein:
R is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen;
R 1 is hydrogen, C 2 -C 6 alkynyl, C 2 -C 6 aminoalkynyl, C 2 -C 6 hydroxyalkynyl, aryl, heteroaryl, C 3 -C 6 heterocycloalkyl, —(CH 2 ) n N 22 N 23 , wherein each aryl and heteroaryl may be optionally substituted by one or two groups independently selected from the group consisting of halogen, cyano, (C 1 -C 6 ) alkyl, —C(O)NR 12 R 13 , (C 3 -C 6 ) heterocycloalkyl, —NR 22 R 23 , —(CH 2 )nR 22 R 23 , (C 3 -C 6 ) heterocycloalkoxyl, and (C 3 -C 6 ) heterocycloalkyl (C 1 -C 6 ) alkoxyl;
R 2 is hydrogen, cyano, (C 1 -C 6 ) haloalkyl, aryl, or heteroaryl;
R 3 is H or (C 1 -C 6 ) alkyl;
R 4 is H;
Cy is 9H-purine-6-amine-9-yl, 3H-purine-6-amine-3-yl, 9H-purin-6-yl, 4-amino-5-cyanopyrimidin-6-yl, 4-amino-5-formylpyrimidin-6-yl, 4-amino-5-bromopyrimidin-6-yl, 4-amino-5-trifluoromethylpyrimidin-6-yl, 4-amino-5-methylpyrimidin-6-yl, 4-amino-5-(N-methtylcarbamoyl)pyrimidin-6-yl, 4-amino-5-carbamoylpyrimidin-6-yl, 4-amino-5-carboxypyrimidin-6-yl, 2-amino-3-pyrazinyl, 4-amino-5-hydroxymethylpyrimidin-6-yl, 4-amino-5-(4-morpholinomethyl)pyrimidin-6-yl, 4-amino-5-(hydroxyiminomethyl)pyrimidin-6-yl, 4-amino-5-(3-hydroxypropyn-1-yl)pyrimidin-6-yl, 4-amino-3-(3-fluoro-5-methoxy

Assignees

• Chiesi Farm Spa

Inventors

• Biagetti Matteo
• Accetta Alessandro
• Capelli Anna Maria
• Guala Matilde
• Retini Michele

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title