Azaquinazoline inhibitors of atypical protein kinase C

Patent metadata

Field	Value
Publication number	US-10414763-B2
Application number	US-201514668022-A
Country	US
Kind code	B2
Filing date	Mar 25, 2015
Priority date	Mar 25, 2014
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

Abstract

The present application provides a compound of formula (I)

and/or a salt thereof, wherein R 1 , G, and X are as defined herein. A compound of formula (I) and/or its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders. Compositions comprising a compound of Formula (I) and/or a salt thereof are also provided.

First claim

The invention claimed is:

1. A compound of formula (I)

or a salt thereof, wherein:
G is a group of formula

X is chosen from the group consisting of halogen, —CN, —C(═O)R 28 , —C(═O)OR 28 , —C(═O)NR 24 R 28 , —C(═O)C(═O)R 28 , —NR 24 R 28 , —NR 24 NR 24 R 28 , —N═NR 28 , —NR 24 OR 28 , —NR 24 C(═O)R 28 , —NR 24 C(═O)C(═O)R 28 , —NR 24 C(═O)OR 28 , —NR 24 C(═O)C(═O)OR 28 , —NR 24 C(═O)NR 24 R 28 , —NR 24 C(═O)NR 24 C(═O)R 28 , —NR 24 C(═O)NR 24 C(═O)OR 28 , —NR 24 C(═O)C(═O)NR 24 R 28 , —NR 24 S(═O) 2 R 28 , —NR 24 S(═O) 2 NR 24 R 28 , —OR 28 , —OC(═O)R 28 , —OC(═O)NR 24 R 28 , —OC(═O)OR 28 , —OS(═O)R 28 , —OS(═O) 2 R 28 , —OS(═O) 2 OR 28 , —OS(═O) 2 NR 24 R 28 , —S(═O) n R 28 , —S(═O) 2 NR 24 R 28 , and —S(═O)NR 24 R 28 ;
or X is chosen from the group consisting of C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-11 aryl, C 7-16 arylalkyl, C 3-11 cycloalkyl, C 4-17 Cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, and 6-21 membered heteroarylalkyl wherein each of the foregoing are optionally substituted by 1-10 R 19 ,
R 1 is chosen from the group consisting of C 3-11 cycloalkyl optionally substituted with 1-10 R 19 , and C 1-6 haloalkyl;
R 2 , R 3 , R 4 , and R 5 , are each independently selected from the group consisting of H, halogen, —CN, —C(═O)R 20 , —C(═O)OR 20 , —C(═O)NR 22 R 23 , —C(═O)C(═O)R 20 , —C(═NR 25 )R 20 , —C(═NR 25 )NR 22 R 23 , —C(═NOH)NR 22 R 23 , —C(═NOR 26 )R 20 , —C(═NNR 22 R 23 )R 20 , —C(═NNR 24 C(═O)R 21 )R 20 , —C(═NNR 24 C(═O)OR 21 )R 20 , —C(═S)NR 22 R 23 , —NC, —NO 2 , —NR 22 R 23 , —NR 24 NR 22 R 23 , —N═NR 24 , —NR 24 OR 26 , —NR 24 C(═O)R 20 , —NR 24 C(═O)C(═O)R 20 , —NR 24 C(═O)OR 21 , —NR 24 C(═O)C(═O)OR 21 , —NR 24 C(═O)NR 22 R 23 , —NR 24 C(═O)NR 24 C(═O)R 20 , —NR 24 C(═O)NR 24 C(═O)OR 20 , —NR 24 C(═NR 25 )NR 22 R 23 , —NR 24 C(═O)C(═O)NR 22 R 23 , —NR 24 C(═S)R 20 , —NR 24 C(═S)OR 20 , —NR 24 C(═S)NR 22 R 23 , —NR 24 S(═O) 2 R 21 , —NR 24 S(═O) 2 NR 22 R 23 , —NR 24 P(═O)R 38 R 38 , —NR 24 P(═O)(NR 22 R 23 )(NR 22 R 23 ), —NR 24 P(═O)(OR 20 )(OR 2 ), —NR 24 P(═O)(SR 20 )(SR 2 ), —OR 20 , —OCN, —OC(═O)R 20 , —OC(═O)NR 22 R 23 , —OC(═O)OR 20 , —OC(═NR 25 )NR 22 R 23 , —OS(═O)R 20 , —OS(═O) 2 R 20 , —OS(═O) 20 R 20 , —OS(═O) 2 NR 22 R 23 , —OP(═O)R 38 R 38 , —OP(═O)(NR 22 R 23 )(NR 22 R 23 ), —OP(═O)(OR 20 )(OR 20 ), —OP(═O)(SR 20 )(SR 20 ), —Si(R 24 ) 3 , —SCN, —S(═O) n R 20 , —S(═O) 2 OR 20 , —SO 3 R 27 , —S(═O) 2 NR 22 R 23 , —S(═O)NR 22 R 23 , —SP(═O)R 38 R 38 , —SP(═O)(NR 22 R 23 )(NR 22 R 23 ), —SP(═O)(OR 20 )(OR 20 ), —SP(═O)(SR 20 )(SR 20 ), —P(═O)R 38 R 38 , —P(═O)(NR 22 R 23 )(NR 22 R 23 ), —P(═O)(OR 20 )(OR 20 ), and —P(═O)(SR 20 )(SR 20 );
or R 2 , R 3 , R 4 , and, R 5 , are each independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-11 aryl, C 7-16 arylalkyl, C 3-11 cycloalkyl, C 4-17 cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, and 6-21 membered heteroarylalkyl wherein each of the foregoing groups may be optionally substituted with 1-10 R 19 ,
or any of R 2 and R 3 or R 4 and R 5 can, together with the atoms to which they are attached, form a C 6-11 aryl, C 3-11 cycloalkyl, 3-15 membered heterocycloalkyl or a 5-15 membered heteroaryl wherein each of the foregoing groups may be optionally substituted by 1-10 R 19 ;
R 19 at each occurrence is independently chosen from the group consisting of C 1-6 alkyl optionally substituted by 1-13 R 39 , C 2-6 alkenyl optionally substituted by 1-11 R 39 , C 2-6 alkynyl optionally substituted by 1-9 R 39 , C 6-11 aryl optionally substituted by 1-11 R 39 , C 7-16 arylalkyl optionally substituted by 1-19 R 39 , C 3-11 cycloalkyl optionally substituted by 1-21 R 39 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 39 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 39 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 39 , 5-15 membered heteroaryl optionally substituted by 1-15 R 39 , 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 39 , halogen, —CN, —C(═O)R 30 , —C(═O)OR 30 , —C(═O)NR 32 R 33 , —C(═O)C(═O)R 30 , —C(═NR 35 )R 30 , —C(═NR 35 )NR 32 R 33 , —C(═NOH)NR 32 R 33 , —C(═NOR 36 )R 30 , —C(═NNR 32 R 33 )R 30 , —C(═NNR 34 C(═O)R 31 )R 30 , —C(═NNR 34 C(═O)OR 31 )R 30 , —C(═S)NR 32 R 33 , —NC, —NO 2 , —NR 32 R 33 , —NR 34 NR 32 R 33 , —N═NR 34 , ═NR 30 , ═NOR 30 , —NR 34 OR 36 , —NR 34 C(═O)R 30 , —NR 34 C(═O)C(═O)R 30 , —NR 34 C(═O)OR 31 , —NR 34 C(═O)C(═O)OR 31 , —NR 34 C(═O)NR 32 R 33 , —NR 34 C(═O)NR 34 C(═O)R 30 , —NR 34 C(═O)NR 34 C(═O)OR 30 , —NR 34 C(═NR 35 )NR 32 R 33 , —NR 34 C(═O)C(═O)NR 32 R 33 , —NR 34 C(═S)R 30 , —NR 34 C(═S)OR 30 , —NR 34 C(═S)NR 32 R 33 , —NR 34 S(═O) 2 R 31 , —NR 34 S(═O) 2 NR 32 R 33 , —NR 34 P(═O)R 38 R 38 , —NR 34 P(═O)(NR 32 R″)(NR 32 R″), —NR 34 P(═O)(OR 30 )(OR 30 ), —NR 34 P(═O)(SR 30 )(SR 30 ), —OR 30 , ═O, —OCN, —OC(═O)R 30 , —OC(═O)NR 32 R 33 , —OC(═O)OR 30 ), —OC(═NR 35 )NR 32 R 33 , —OS(═O)R 30 , —OS(═O) 2 R 30 , —OS(═O) 2 OR 30 , —OS(═O) 2 NR 32 R 33 , —OP(═O)R 38 R 38 , —OP(═O)(NR 32 R 33 )(NR 32 R 33 ), —OP(═O)(OR 30 )(OR 30 ), —OP(═O)(SR 30 )(SR 30 ), —Si(R 34 ) 3 , —SCN, ═S, —S(═O),R 30 , —S(═O) 2 OR 30 , —SO 3 R 37 , —S(═O) 2 NR 32 R 33 , —S(═O)NR 32 R 33 , —SP(═O)R 38 R 38 , —SP(═O)(NR 32 R 33 )(NR 32 R 33 ), —SP(═O)(OR 30 )(OR 30 ), —SP(═O)(SR 30 )(SR 30 ), —P(═O)R 38 R 38 , —P(═O)(NR 32 R 33 )(NR 32 R 33 ), —P(═O)(OR 30 )(OR 30 ), and —P(═O)(SR 30 )(SR 30 );
R 20 , R 21 , R 24 , R 25 , R 26 , R 27 , R 30 , R 31 , R 34 , R 35 , R 36 and R 37 at each occurrence is independently chosen from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-11 aryl, C 7-16 arylalkyl, C 3-11 cycloalkyl, C 4-17 Cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, and 6-21 membered heteroarylalkyl wherein each of the foregoing groups (except for Hydrogen) may be optionally substituted by 1-10 R 19 ;
R 28 at each occurrence is independently chosen from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-6 alkynyl, C 6-11 aryl, C 7-16 arylalkyl, C 3-11 cycloalkyl, C 4-17 cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, and 6-21 membered heteroarylalkyl wherein each of the foregoing groups may be optionally substituted by 1-10 R 19 ;
R 22 , R 23 , R 32 and R 33 at each occurrence is independently chosen from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-11 aryl, C 7-16 arylalkyl, C 3-11 cycloalkyl, C 4-17 cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, and 6-21 membered heteroarylalkyl wherein each of the foregoing groups (except for Hydrogen) may be optionally substituted by 1-10 R 19 ;
or any R 22 and R 23 and/or R 32 and R 33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-10 R 19 or a 5-15 membered heteroaryl optionally substituted by 1-10 R 19 ;

R 38 at each occurrence is independently chosen from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-11 aryl, C 7-16 arylalkyl, C 3-11 cycloalkyl, C 4-17 cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, and 6-21 membered heteroarylalkyl wherein each of the foregoing groups may be optionally substituted by 1-10 R 19 ;
or any two R 38 attached to the same phosphorus atom can, toget

Assignees

• Cancer Research Tech Ltd

Inventors

• Dorsey Bruce D
• Dugan Benjamin J
• Fowler Katherine M
• Hudkins Robert L
• Mesaros Eugen F
• Monck Nathaniel J T
• Morris Emma L
• Olowoye Ikeoluwa
• Ott Gregory R
• Pave Gregoire A
• Roffey Jonathan R A
• Soudy Christelle N
• Zificsak Craig A
• Zulli Allison L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title