3,5-disubstituted-3H-imidazo[4,5-b]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of c-Met protein kinases

Patent metadata

Field	Value
Publication number	US-11066402-B2
Application number	US-201715705005-A
Country	US
Kind code	B2
Filing date	Sep 14, 2017
Priority date	Mar 30, 2012
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

The present invention provides compounds useful as c-Met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of c-Met kinase mediated disease or disorders with them.

First claim

We claim:

1. A compound of formula (IA-I)

or a tautomer, stereoisomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, or N-oxide thereof; wherein
X is CR 1 or N;
D is monocyclic aryl; wherein D is substituted with a group E which is selected from —CONH—O—(CR x R y ) p —OR x , and —CONH—O—(CR x R y ) p -[cycloalkyl]-(CR x R y ) p —OR x ; and further D can optionally be substituted with one or more of R z ;
L 2 is —(CR a R b )—;
Cy 2 is substituted or unsubstituted heteroaryl;
each occurrence of R 1 and R 2 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b R b , —C(═Y)—NR a R b , —NR a R b —C(═Y)—NR a R b , —S(═O) q —NR a R b —, —NR a R b —S(═O) q —NR a R b , —NR a R b —NR a R b , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl;
each occurrence of Y is independently selected from O, S, and NR a ;
each occurrence of R a and R b may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl, or when two R a and/or R b substituents are directly bound to a common atom, they may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR c or S;
each occurrence of R c is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 cycloalkylalkyl, and substituted or unsubstituted C 3-6 cycloalkenyl;
each occurrence of R x and R y is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOR z , —C(O)R z , —C(S)R z , —C(O)NR z R z , —C(O)ONR z R z , —NR z R z , —NR z CONR z R z , —N(R z )SOR z , —N(R z )SO 2 R z , —(═N—N(R z )R z ), —NR z C(O)OR z , —NR z C(O)R z —, —NR x C(S)R y —NR z C(S)NR z R z , —SONR z R z —, —SO 2 NR z R z —, —OR z , —OR z C(O)NR z R z , —OR z C(O)OR z —, —OC(O)R z , —OC(O)NR z R z , —R z NR z C(O)R z , —R z OR z , —R z C(O)OR z , —R z C(O)NR z R z , —R z C(O)R z , —R z OC(O)R z , —SR z , —SOR z , —SO 2 R z , and —ONO 2 , or any two of R x and R y which are directly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR z or S, or (ii) an oxo (═O), thio (═S) or imino (═NR z ); wherein
each occurrence of R z is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and —ONO 2 , or any two of R z which are directly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR ′ (where R ′ is H or alkyl) or S, or (ii) an oxo (═O), thio (═S) or imino (═NR z );
each occurrence of p independently represents 1, 2, 3, 4, 5, 6, 7 or 8; and
each occurrence of q independently represents 0, 1 or 2,

with the proviso that when Cy 2 is substituted or unsubstituted heteroaryl, each occurrence of R 1 and R 2 is hydrogen, and E is —CONH—O—(CR x R y ) p —OR x , then p is not 2.

2. A compound of claim 1 , wherein
D is

E is selected from —CONH—O—(CR x R y ) p —OR x , and —CONH—O—(CR x R y ) p -[cycloalkyl]-(CR x R y ) p —OR x ; and
X 1 , X 2 and X 3 are independently selected from —CR z or —CR z ═CR z .

3. A compound of claim 1 , wherein Cy 2 is selected from

4. A compound of claim 1 , wherein L 2 is —CH 2 —, —CH(OH)—, —CHF—, —CF 2 —, —CH (CH 3 )— or —C(CH 3 ) 2 —.

5. A compound of formula (IA-I):

or a tautomer, stereoisomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, or N-oxide thereof, wherein
-L 2 -Cy 2 is

(where the squiggly line represents the bond to the bicyclic core in formula (IA-I));
each occurrence of R a and R b are independently selected from hydrogen, halogen, and substituted or unsubstituted (C 1-6 ) alkyl, or both together with the carbon atom to which they are attached form a saturated 3 to 6 member cyclic ring which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR e and S (where R e is R z );
Z is selected from CR c , S, O, NR c , R c C═CR c , —N═CR c —, and —R c C═N—;
Z 1 is selected from N, NR c and CR c ;
Z 2 and Z 3 are independently selected from C or N;
R c is absent or selected from hydrogen, hydroxy and halogen;
X is CR 1 or N;
D is monocyclic aryl; wherein D is substituted with a group E which is selected from —CONH—O—(CR x R y ) p —OR x , and —CONH—O—(CR x R y ) p -[cycloalkyl]-(CR x R y ) p —OR x ; and further D can optionally be substituted with one or more of R z ;
each occurrence of R 1 and R 2 may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —OR a , —S(═O) q —R a , —NR a R b , —C(═Y)—R a , —CR a R b —C(═Y)—R a , —CR a R b —Y—CR a R b R b , —C(═Y)—NR a R b , —NR a R b —C(═Y)—NR a R b , —S(═O) q —NR a R b —, —NR a R b —S(═O) q —NR

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Vakkalanka Swaroop K V S
• Nagarathnam Dhanapalan
• Viswanadha Srikant
• Muthuppalaniappan Meyyappan
• Babu Govindarajulu
• Bhavar Prashant K

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title