Tricyclic PI3K inhibitor compounds and methods of use

Patent metadata

Field	Value
Publication number	US-10065970-B2
Application number	US-201615258175-A
Country	US
Kind code	B2
Filing date	Sep 7, 2016
Priority date	Sep 8, 2015
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

Described herein are tricyclic compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure:

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.

First claim

We claim:

1. A compound of Formula Ii, Ij, Il or Im:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is Br, Cl, I, C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, —NR 3 R 4 , or —OR 5 ;
R 2 is H, F, Cl, C 1 -C 6 alkyl or —O(C 1 -C 6 alkyl);
R 3 is H or C 1 -C 6 alkyl;
R 4 is H, C 1 -C 6 alkyl, C 2 -C 20 heterocyclyl or C 1 -C 20 heteroaryl;
or R 3 and R 4 form a 4-membered, 5-membered or 6-membered heterocyclyl ring;
R 5 is C 1 -C 6 alkyl, C 2 -C 20 heterocyclyl or C 1 -C 20 heteroaryl; and
A is selected from C 6 -C 20 aryl, —(C 6 -C 20 aryl)-(C 6 -C 20 aryl), —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), —(C 6 -C 20 aryl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), C 2 -C 20 heterocyclyl, and C 1 -C 20 heteroaryl;
where alkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , C(CH 3 ) 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH(CH 3 ) 2 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, cyclopentyl, tetrahydrofuranyl, morpholinyl, piperidyl, piperazinyl, and tetrahydropyranyl.

2. The compound of claim 1 , wherein the compound is of Formula Ii or Ij:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of Formula Il or Im:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein the compound is of Formula Io or Ip:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
Y is O or NR 3 ; and
R 7 is H, cyclopropyl, cyclobutyl or C 1 -C 6 alkyl optionally substituted with F, Cl, —OCH 3 , or —OH;
or R 3 and R 7 form a 4-membered, 5-membered or 6-membered heterocyclyl ring.

5. The compound of claim 4 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Y is NH.

6. The compound of claim 4 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Y is NR 3 , and R 3 and R 7 form a pyrrolidinyl ring.

7. The compound of claim 4 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Y is O.

8. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is Br or substituted pyrazolyl.

9. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

where the wavy line indicates the site of attachment.

10. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A is substituted benzo[d]oxazolyl or substituted benzothiazolyl.

11. The compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

where the wavy line indicates the site of attachment.

12. The compound of claim 1 selected from the group consisting of;
5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine;
4-bromo-1-(2-methyloxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene;
1-(1-(2-methylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carb oxamide;
(S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide;
(S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(S)-2-((1-phenyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(S)-2-((1-(pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(S)-2-((1-(pyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(S)-2-((1-(5-cyanopyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(S)-2-((1-(6-methoxypyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(S)-2-((1-(pyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide;
(S)-2-cyclopropyl-2-((1 (2,2-difluorobenzo[d][1,3]dioxol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-((1-(benzo[d][1.3]dioxol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropyl acetamide;
(S)-2-cyclopropyl-2-((1-3-oxoisoindolin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-cyclopropyl-2-((1-(quinazolin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-cyclopropyl-2(1-(guinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-((1-(3-cyanophenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropyl acetamide;
(S)-2-cyclopropyl-2(1-(quinazolin-6-yl)-8,9-dihydro-7H-6 oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-((1-(2-aminoquinazolin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide;
(S)-2-cyclopropyl-2-((1-(2-methoxy-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-cyclopropyl-2-((1-(4-methylpyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-cyclopropyl-2-((1-(2-(hydroxymethyl)-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide;
(S)-2-cyclopropyl-2-((1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-cyclopropyl-2-((1-(4-(hydroxymethyl)piperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-cyclopropyl-2-((1-(piperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide;
(S)-2-cyclopropyl-2-((1-(2-methoxypyrimidin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]az

Assignees

• Genentech Inc

Inventors

• Braun Marie-Gabrielle
• Garland Keira
• Hanan Emily
• Purkey Hans
• Staben Steven T
• Heald Robert Andrew
• Knight Jamie
• Macleod Calum
• Lu Aijun
• Wu Guosheng
• Yeap Siew Kuen

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/00

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

• A61P43/00

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