Pyrrolo pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9233111-B2
Application number	US-201214130536-A
Country	US
Kind code	B2
Filing date	Jul 7, 2012
Priority date	Jul 8, 2011
Publication date	Jan 12, 2016
Grant date	Jan 12, 2016

Abstract

The present invention describes new pyrrolo pyrimidine derivatives and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel pyrrolo pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein,
R1 is hydrogen or C 1 -C 6 alkyl optionally substituted by hydroxy;
R2 is hydrogen or halogen;
R3 is hydrogen or halogen;
R4 is hydrogen,
R5 is phenyl optionally substituted by halogen; SF 5 ; NR6R7; hydroxy; C 1 -C 6 alkoxy; C 1 -C 6 alkenyl; C 1 -C 6 alkyl carbonyl; C 1 -C 6 alkyl optionally substituted by hydroxy, halogen, or C 1 -C 6 alkoxy; or C 3 -C 6 cycloalkyl optionally substituted by halogen, hydroxy, or C 1 -C 6 alkyl optionally substituted by halogen; or
R5 is a 4-14 membered mono- or bicyclic heterocyclyl or heteroaryl ring system comprising 1, 2 or 3 heteroatoms selected from N, S and O that ring being optionally substituted by halogen; hydroxy; C 1 -C 6 alkoxy optionally substituted by hydroxy or halogen; or C 1 -C 6 alkyl optionally substituted by hydroxy or halogen;
or R4 and R5 together with the atoms to which they are bound form a piperidone ring, optionally comprising an annulated phenyl ring, any such ring being optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl each of which substitution member may optionally be substituted by halogen or hydroxy;
R6 and R7 are independently selected from hydrogen or C 1 -C 6 alkyl;
or R6 and R7 together with the nitrogen atom to which they are bound form a 4-8 membered saturated azacycloalkane ring, optionally substituted by halogen, hydroxy or C 1 -C 6 alkyl;
X is O, S(O) n wherein n is 0, 1 or 2, or

wherein q is 2 or 3, and R10 is absent;
or X is CH or N; and R10 is hydrogen, hydroxy, —NR6R7, —CO—R11, —S(O) P —R12 wherein p is 1 or 2,
R 11 is C 1 -C 6 alkyl optionally substituted by hydroxy, cyano, halogen, carboxy or C 1 -C 6 alkoxy carbonyloxy; or NR6R7; and
R12 is C 1 -C 6 alkyl or NR6R7.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen; R5 is phenyl substituted by halogen; C 1 -C 6 alkoxy; C 1 -C 6 alkyl optionally substituted by halogen or hydroxy; or C 3 -C 6 cycloalkyl optionally substituted by halogen, hydroxy, or C 1 -C 6 alkyl optionally substituted by halogen; X is O, S(O) n wherein n is 0, 1 or 2, or

wherein q is 2 or 3, and R10 is absent;
and the remaining variables are as defined in claim 1 .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl optionally substituted by hydroxy; X is O, S(O) n wherein n is 0, 1 or 2, or

wherein q is 2 or 3, and R10 is absent;
and the remaining variables are as defined in claim 1 .

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen; R5 is phenyl substituted by halogen; C 1 -C 6 alkoxy; C 1 -C 6 alkyl optionally substituted by halogen or hydroxy; or C 3 -C 6 cycloalkyl optionally substituted by halogen, hydroxy, or C 1 -C 6 alkyl optionally substituted by halogen; X stands for 0 and R10 is absent; or X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined in claim 1 .

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen; R5 is phenyl substituted by C 1 -C 6 alkoxy; C 1 -C 6 alkyl optionally substituted by halogen or hydroxy; or C 3 -C 6 cycloalkyl optionally substituted by halogen, hydroxy, or C 1 -C 6 alkyl optionally substituted by halogen; X stands for N, R10 is hydrogen or —CO—R11, R11 stands for NR6R7 wherein R6 and R7 are independently hydrogen or methyl; and the remaining variables are as defined in claim 1 .

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen, R5 is azetidine optionally substituted by C 1 -C 6 alkoxy, X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined in claim 1 .

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl optionally substituted by hydroxy, X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined in claim 1 .

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one substituted by C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl optionally substituted by hydroxy in the 6-position of said isoquinolin-ring, X stands for N, and R10 is hydrogen or —CO—R11, and the remaining variables are as defined in claim 1 .

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen, R5 is azetidine optionally substituted by C 1 -C 6 alkoxy, X stands for 0, and the remaining variables are as defined in claim 1 .

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl optionally substituted by hydroxy, X stands for 0, and the remaining variables are as defined claim 1 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from:
4-(4-{5-Fluoro-3-[4-(1-fluoro-cyclopropyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,
4-(4-{3-[(3,3-Dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-5-fluoro-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,
4-(4-{5-Fluoro-2-methyl-3-[(5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,
4-(4-{5-Fluoro-3-[4-isopropyl-methyl-amino)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,
3-Methyl-1H-indole-6-carboxylic acid {3-[6-(1-dimethylcarbamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,
4-(4-{5-Fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,

Assignees

• Heng Richard
• Hoegenauer Elizabeth Kate
• Koch Guido
• Pulz Robert Alexander
• Vulpetti Anna
• Waelchli Rudolf
• Novartis Ag

Inventors

• Heng Richard
• Hoegenauer Elizabeth Kate
• Koch Guido
• Pulz Robert Alexander
• Vulpetti Anna
• Waelchli Rudolf

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title