MerTK-specific pyrazolopyrimidine compounds

Patent metadata

Field	Value
Publication number	US-9603850-B2
Application number	US-201514678678-A
Country	US
Kind code	B2
Filing date	Apr 3, 2015
Priority date	Apr 11, 2014
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

The present invention includes pyrazolopyrimidine compounds of Formula I that selectively inhibit Mer tyrosine kinase (MerTK) activity and/or Tyro3 tyrosine kinase activity, and use of these pyrazolopyrimidine compounds as anti-cancer agents, immunostimulatory and immunomodulatory agents, anti-platelet agents, anti-infective agents, and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.

First claim

The invention claimed is:

1. A compound of Formula I:

wherein:
R 1 is aryl;
R 2 is —R 5 R 6 , where R 5 is a covalent bond or C 1 to C 3 alkyl and R 6 is cycloalkyl or heterocycloalkyl, and wherein R 6 is optionally substituted from one to two times with hydroxyl;
R 3 is H, alkyl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, or alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
R 4 is H, loweralkyl, halo, or loweralkoxy;
R 7 is alkyl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, or alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
R 8 is alkyl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, or alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , having the Formula I′, or I″:

3. A compound of Formula I:

wherein:
R 11 is —R 9 (R 10 ) n , where R 9 is alkyl, alkenyl, -alkylaryl, heterocyclo, aryl, heteroaryl and R 10 is hydrogen, alkyl, haloalkyl, alkoxyalkyl, —O-alkylaryl, hydroxyalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heterocyclooxy, heterocyclolalkyloxy, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, halo, hydroxyl, alkoxy, haloalkoxy, mercapto, alkyl-S(O) m —, haloalkyl-S(O) m —, alkenyl-S(O) m —, alkynyl-S(O) m —, cycloalkyl-S(O) m —, cycloalkylalkyl-S(O) m —, aryl-S(O) m —, arylalkyl-S(O) m —, heterocyclo-S(O) m —, heterocycloalkyl-S(O) m —, amino, carboxy, alkylamino, —(CH 2 ) m —NHalkyl, —(CH 2 ) m —N(alkyl) 2 , —(CH 2 ) m —NH(CH 2 ) m OH, —(CH 2 ) m —NH(CH 2 ) m cycloalkyl, —(CH 2 ) m —NH(CH 2 ) 2-3 heterocyclo, —(CH 2 ) m —NH(CH 2 ) m aryl, —(CH 2 ) m —NH(CH 2 ) 2-3 heteroaryl, —(CH 2 ) m NH(CH 2 ) 2-3 N(alkyl) 2 , alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstitutedamino, acylamino, acyloxy, ester, amide, S(O) 2 OR 19 , —CONHNH 2 , cyano, nitro, aminosulfonyl, COOH, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, —C(CH 2 ) 2 R 19 , and wherein R 10 is optionally substituted one two or three times;

m=0, 1, 2 or 3;
n=0, 1 or 2;
R 12 is —R 15 R 16 , where R 15 is a covalent bond or C 1 to C 3 alkyl and R 16 is cycloalkyl or heterocycloalkyl, wherein R 16 is optionally substituted one, two or three times with;
R 13 is selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heteroaryl, heteroarylalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times;
R 14 is H, loweralkyl, halo, or loweralkoxy;
R 17 is alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkylheterocycloalkyl, heterocyclo, heterocycloalkyl, heteroaryl, heteroarylalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times;
R 18 is alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, aryl, arylalkyl; cycloalkyl, cycloalkylalkyl, alkylheterocycloalkyl, heterocyclo, heterocycloalkyl, heteroaryl, heteroarylalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times;
R 17 and R 18 can form a cycloalkyl group that can be optionally substituted one, two or three times;
R 19 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, heteroaryl, or heteroarylalkyl;
or a pharmaceutically acceptable composition or salt thereof.

4. The compound of claim 3 , having a Formula selected from the group consisting of:

5. The compound of claim 1 , having the structure:

6. The compound of claim 1 , wherein R 1 is phenyl optionally substituted 1, 2 or 3 times with heterocycloalkylalkyl which is a substituent of the formula —R′R″, wherein R′ is substituted or unsubstituted C 1 -C 2 alkyl, and R″ is an optionally substituted piperazine or morpholine group; R 5 is a covalent bond and R 6 is cycloalkyl substituted with a hydroxyl group.

7. The compound of claim 6 , wherein R 1 is phenyl substituted 1 time with heterocycloalkylalkyl, wherein R′ is unsubstituted C 1 alkyl, and R″ is an optionally substituted piperazine group.

8. A pharmaceutically acceptable composition, comprising an effective amount of a compound of claim 5 or its pharmaceutically acceptable salt, in a pharmaceutically acceptable carrier.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Wang Xiaodong
• Frye Stephen

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title