Aminomethyl-Biaryl Derivatives Complement Factor D inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2016145247-A1
Application number	US-201414904693-A
Country	US
Kind code	A1
Filing date	Jul 17, 2014
Priority date	Jul 18, 2013
Publication date	May 26, 2016
Grant date	—

Abstract

The present invention provides a compound of formula (I), a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

What is claimed is:

1 . A compound according to formula (I)

or a salt thereof, wherein
A is —C(O)NH—, —C≡C—, —CH 2 CH 2 —, S(O) 2 N(H)—, or —CHR 10 O—, wherein the carbon or sulfur is attached to the ring comprising X, Y and Z; or
A is —N(R 16 )CH 2 — or —OCH 2 —, wherein the nitrogen or oxygen is attached to the ring comprising X, Y and Z; or
R is hydroxy, amino or C 1 -C 4 alkoxy;
R 1 is hydrogen, phenyl, C 3 -C 6 cycloalkyl, amido, halo C 1 -C 6 alkyl or C 1 -C 6 alkyl optionally substituted by hydroxy, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or cyano;
R 1a is hydrogen or C 1 -C 4 alkyl, or CR 1 R 1a taken in combination form a carbonyl, imine or a 3-6 member cycloalkyl; or
R 1a is absent and CR 1 and R 11 , taken in combination, form a saturated, unsaturated or aromatic 4, 5 or 6 member azacycle;
T is CR 2 or N;
U is CR 14 or N;
V is CR 12 or N;
W is CR 13 or N, wherein 0, 1, or 2 of T, U, V and W are N; or
V is N, W is S, T is absent and U is CR 14 ;
B is CR 3 or N;
X is CR 6 or N;
Y is CR 5 or N;
Z is CR 7 or N, wherein 0 or 1 of B, X, Y and Z are nitrogen; or
X is N, B is CR 3 and one of Y or Z is S or N(H) and other of Y or Z is absent;
R 2 is hydrogen, C 1 -C 4 alkyl or halogen;
R 3 is hydrogen, halogen, hydroxy, cyano, amino, NHR 8 , N(R 8 ) 2 , N(R 8 )C(O)R 9 , —C(O)NHR 8 , —C(O)N(R 8 ) 2 , OR 9 , S(O) 2 R 9 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, heterocycloalkyl having 4 to 7 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O and S, and heteroaryl having 5, 6, 9 or 10 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O and S, wherein each heterocycloalkyl, heteroaryl, phenyl is optionally substituted with 0, 1, 2, or 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyC 1 -C 4 alkyl, halogen, or C 3 -C 6 cycloalkyl, wherein each heterocycloalkyl or heteroaryl is optionally further substituted by 0 or 1 phenyl groups and wherein each alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl group is optionally substituted with 0, 1, or 2 substituents independently selected from the group consisting of hydroxy, C 3 -C 6 cycloalkyl, amino, NHR 8 , N(R 8 ) 2 , OR 9 , 5 or 6 member heteroaryl having 1 or 2 ring heteroatoms independently selected from N, O and S, and heterocycloalkyl having 4 to 7 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O and S, which heteroaryl or heterocycloalkyl is substituted with 0, 1, or 2 independently selected C 1 -C 4 alkyl substituents;
R 4 represents 0, 1, or 2 substituents independently selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 4 -alkyl, C(O)NH 2 , NHC(O)C 1 -C 4 alkyl, CH 2 NHC(O)C 1 -C 4 alkyl, amino, mono- and di-C 1 -C 4 alkylamino and hydroxyC 1 -C 4 alkyl;
R 5 is hydrogen, halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 6 is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 7 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, haloC 1 -C 4 alkyl or haloC 1 -C 4 alkoxy, or
R 7 is phenyl or a 5 or 6 member heteroaryl having 1, 2, or 3 ring heteroatoms selected from N, O or S; each of which is optionally substituted by 0, 1, or 2 substituents selected from C 1 -C 4 alkyl, aminoC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, halogen, C 1 -C 4 alkoxy, hydroxy, amino or mono- or di-C 1 -C 4 alkylamino; or
R 3 and either R 5 or R 7 taken in combination form a —O(CH 2 ) n O— group wherein n is 1 or 2; or
R 3 and R 7 taken in combination with the atoms to which they are attached form a 5 or 6 member aromatic heterocycle having 1 or 2 ring heteroatoms selected from N, O or S and which is optionally substituted with C 1 -C 4 alkyl, C(O)C 1 -C 4 alkyl, C(O)NH2, C(O)NHC 1 -C 4 alkyl, C(O)N(C 1 -C 4 alkyl) 2 , S(O) 2 C 1 -C 4 alkyl, S(O) 2 C 3 -C 6 cycloalkyl, optionally substituted S(O) 2 phenyl, where the phenyl is optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl, or C 1 -C 4 alkoxy or C 1 -C 4 alkoxy;
R 8 is independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, benzyl, C 1 -C 4 alkanoyl, benzoyl, phenyl, 4 to 6 member heterocycloalkyl, heteroaryl, wherein C 1 -C 6 alkyl or haloC 1 -C 6 alkyl is optionally substituted with C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, cyano, 4 to 6 member heterocycloalkyl or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1, or 2 substituents selected from C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, CH 2 CO 2 H, C 3 -C 6 cycloalkyl or C 1 -C 4 alkoxy, and wherein each heterocycloalkyl or heteroaryl is optionally substituted by 0, 1, or 2 substituents independently selected from C 1 -C 4 alkyl, CO 2 C 1 -C 4 alkyl, C(O)NH C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or a fused benzo ring, and wherein each cycloalkyl is optionally substituted with 0, 1, or 2 independently selected halogen or C 1 -C 4 alkyl;
R 9 is independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, benzyl, benzoyl, phenyl, 4 to 6 member heterocycloalkyl, heteroaryl, wherein C 1 -C 6 alkyl or haloC 1 -C 6 alkyl is optionally substituted with C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted with C 1 -C 4 alkyl, cyano, 4 to 6 member heterocycloalkyl or heteroaryl, wherein phenyl or benzyl are optionally substituted with 0, 1, or 2 substituents selected from C 1 -C 4 alkyl, CH 2 CO 2 H, C 3 -C 6 cycloalkyl or C 1 -C 4 alkoxy, and wherein each heterocycloalkyl or heteroaryl are optionally substituted by 0, 1, or 2 substituents independently selected from C 1 -C 4 alkyl, CO 2 C 1 -C 4 alkyl, C(O)NH C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or a fused benzo ring, which benzo is optionally substituted with halogen;
R 10 is hydrogen or C 1 -C 4 alkyl or R 7 and R 10 , taken in combination, form a —(CH 2 ) p — group or a —O—(CH 2 ) q — group, wherein p is 2, 3, or 4 and q is 1 or 2;
R 11 is hydrogen or C 1 -C 4 alkyl;
R 12 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 13 is hydrogen or halogen;
R 14 is hydrogen or halogen;
R 15 is hydrogen, C 1 -C 4 alkyl, or NHC(O)R 16 ; and
R 16 is C 1 -C 4 alkyl or cyclopropyl each of which is optionally substituted by phenyl; or
R 7 and R 16 taken in combination for a divalent C 2 -C 3 alkylene group.

2 . A compound according to formula (Ia)

or a salt thereof, wherein
A is —C(O)NH—, —C≡C—, —CH 2 CH 2 —, S(O) 2 N(H)—, or —CHR 10 O—, wherein the carbon or sulfur is attached to the ring comprising X, Y and Z; or
A is —NHCH 2 — or —OCH 2 —, wherein the nitrogen or oxygen is attached to the ring comprising X, Y and Z; or
R is hydroxy, amino or C 1 -C 4 alkoxy;
R 1 is hydrogen, phenyl, C 3 -C 6 cycloalkyl, amido, halo C 1 -C 4 alkyl or C 1 -C 4 alkyl optionally substituted by hydroxy, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy or cyano;
R 1a is hydrogen or C 1 -C 4 alkyl, or CR 1 R 1a taken in combination form a carbonyl (C═O), imine (C═NH) or a 3-6 member cycloalkyl;
R 1a is absent and CR 1 and R 11 , taken in combination, form a saturated, unsaturated or aromatic 4, 5 or 6 member azacycle;
T is CR 2 or N;

Assignees

• Belanger David B
• Flohr Stefanie
• Gelin Christine Fang
• Jendza Keith
• Ji Nan
• Liu Donglei
• Lorthiois Edwige Lilliane Jeanne
• Karki Rakeshri Ganesh
• Mainolfi Nello
• Powers James J
• Randl Stefan Andreas
• Rogel Olivier
• Vulpetti Anna
• Yoon Taeyoung
• Novartis Ag

Inventors

• Belanger David
• Flohr Stefanie
• Gelin Christine Fang
• Jendza Keith
• Ji Nan
• Karki Rajeshri Ganesh
• Liu Donglei
• Lorthiois Edwoge Liliane Jeanne
• Mainolfi Nello
• Powers James J
• Randi Stefan Andreas
• Rogel Oliver
• Vulpetti Anna
• Yoon Taeyoung

Classifications

• A61P7/06

  Antianaemics · CPC title

• A61P37/08

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P37/06

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