US 12,064,421 B2
Substituted 1H-pyrazolo[4,3-c]pyridines and derivatives as EGFR inhibitors
Harald Engelhardt, Ebreichsdorf (AT); Mark Petronczki, Vienna (AT); Juergen Ramharter, Vienna (AT); Ulrich Reiser, Vienna (AT); Heinz Stadtmueller, Weigelsdorf (DE); Dirk Scharn, Berlin (DE); and Tobias Wunberg, Hinterbruehl (AT)
Assigned to Boehringer Ingelheim International GmbH, Ingelheim am Rhein (DE)
Filed by Boehringer Ingelheim International GmbH, Ingelheim am Rhein (DE)
Filed on Oct. 29, 2021, as Appl. No. 17/514,145.
Claims priority of application No. 20205297 (EP), filed on Nov. 2, 2020.
Prior Publication US 2022/0133734 A1, May 5, 2022
Int. Cl. C07D 211/04 (2006.01); A61K 31/437 (2006.01); A61K 31/4545 (2006.01); A61K 31/4995 (2006.01); A61K 31/553 (2006.01); A61P 35/00 (2006.01); C07D 519/00 (2006.01); A61K 31/496 (2006.01); A61K 31/5377 (2006.01); A61K 31/5386 (2006.01); A61K 31/541 (2006.01)
CPC A61K 31/437 (2013.01) [A61K 31/4545 (2013.01); A61K 31/4995 (2013.01); A61K 31/553 (2013.01); A61P 35/00 (2018.01); C07D 211/04 (2013.01); C07D 519/00 (2013.01); A61K 31/496 (2013.01); A61K 31/5377 (2013.01); A61K 31/5386 (2013.01); A61K 31/541 (2013.01)] 23 Claims
 
1. A compound of the formula (I)

OG Complex Work Unit Chemistry
wherein
R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, halogen, —OH, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, C3-6cycloalkyl,
C3-6cycloalkoxy, 3-6 membered heterocyclyloxy and 3-6 membered heterocyclyl;
R2 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, halogen, —OH, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, C3-6cycloalkyl,
C3-6cycloalkoxy, 3-6 membered heterocyclyloxy and 3-6 membered heterocyclyl; or
R1 and R2 together with the carbon atoms they are attached form a 5-6 membered heterocyle or a 5-6 membered heteroaromatic ring;
R3 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, halogen, —CN, —OH, —NH2, —NH(C1-6alkyl),
—N(C1-6alkyl)2, C3-6cycloalkyl, C3-6cycloalkoxy, 3-6 membered heterocyclyloxy and 3-6 membered heterocyclyl;
R4 is selected from the group consisting of Ra1 and Rb1;
Ra1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rb1 and/or Rc1;
each Rb1 is independently selected from the group consisting of —ORc1, —N(Rc1)Rc1,
halogen, —CN, —C(═O)Rc1, —C(═O)ORc1, —C(═O)N(Rc1)Rc1, —C(═O)N(H)ORc1, —C(═O)N(C1-4alkyl)ORc1, —S(═O)2Rc1, —S(═O)2N(Rc1)Rc1, —N(H)C(═O)Rc1, —N(C1-4alkyl)C(═O)Rc1, —N(H)C(═O)ORc1, —N(C1-4alkyl)C(═O)ORc1, —N(H)S(═O)2Rc1,
—N(C1-4alkyl)S(═O)2Rc1 and the bivalent substituent ═O;
each Rc1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl,
C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rd1 and/or Re1;
each Rd1 is independently selected from the group consisting of —OR1, —N(Re1)Re1,
halogen, —CN, —C(═O)Re1, —C(═O)ORe1, —C(═O)N(Re1)Re1, —C(═O)N(H)ORe1, —C(═O)N(C1-4alkyl)ORe1, —S(═O)2Re1, —S(═O)2N(Re1)Re1, —N(H)C(═O)Re1, —N(C1-4alkyl)C(═O)Re1, —N(H)C(═O)ORe1, —N(C1-4alkyl)C(═O)ORe1, —N(H)S(═O)2Rc1,
—N(C1-4alkyl)S(═O)2Rc1 and the bivalent substituent ═O;
each Re1 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, —OH, C1-6alkoxy, C1-4alkoxy-C1-4alkyl, hydroxy-C1-4alkyl, halogen, —CN, —NH2, —C(═O)C1-4alkyl, —NH(C1-4alkyl), —N(C1-4alkyl)2 and the bivalent substituent ═O;
X1 is selected from the group consisting of carbon (C) and nitrogen (N);
X2 is selected from the group consisting of carbon (C) and nitrogen (N);
at least one of X1 and X2 is carbon (C);
X3 is selected from the group consisting of nitrogen (N), C(R5), N(R6), C(R5)(R5), oxygen (O), sulphur (S), S(═O), S(═O)2, and C(═O);
X4 is selected from the group consisting of nitrogen (N), C(R7), N(R8), C(R7)(R7), oxygen (O), sulphur (S), S(═O), S(═O)2, and C(═O);
X5 is selected from the group consisting of nitrogen (N), C(R9), N(R10), C(R9)(R9), oxygen (O), sulphur (S), S(═O), S(═O)2, and C(═O);
each bond between ring members in ring A is independently selected from a single bond, a double bond or a (hetero)aromatic bond;
each R5 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkoxy-C1-4alkyl, C1-6haloalkoxy-C1-6alkyl, halogen, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, C3-6cycloalkyl and 3-6 membered heterocyclyl;
each R6 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, C3-6cycloalkyl and 3-6 membered heterocyclyl;
each R7 is independently selected from the group consisting of Ra2 and Rb2;
Ra2 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rb2 and/or Rc2;
each Rb2 is independently selected from the group consisting of —ORc2, —N(Rc2)Rc2,
halogen, —CN, —C(═O)Rc2, —C(═O)ORc2, —C(═O)N(R2)Rc2, —C(═O)N(H)ORe2, —C(═O)N(C1-4alkyl)ORc2, —S(═O)2Rc2, —S(═O)2N(Rc2)Rc2, —N(H)C(═O)Rc2, —N(C1-4alkyl)C(═O)Rc2, —N(H)C(═O)ORc2, —N(C1-4alkyl)C(═O)ORc2, —N(H)S(═O)2Rc2,
—N(C1-4alkyl)S(═O)2Rc2 and the bivalent substituent ═O;
each Rc2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl,
C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different Rd2 and/or Re2;
each Rd2 is independently selected from the group consisting of —ORe2, —N(Re2)Re2,
halogen, —CN, —C(═O)Re2, —C(═O)ORe2, —C(═O)N(Re2)Re2, —C(═O)N(H)ORe2, —C(═O)N(C1-4alkyl)ORe2, —S(═O)2Re2, —S(═O)2N(Re2)Re2, —N(H)C(═O)Re2, —N(C1-4alkyl)C(═O)Re2, —N(H)C(═O)ORe2, —N(C1-4alkyl)C(═O)ORe2, —N(H)S(═O)2Re2,
—N(C1-4alkyl)S(═O)2Rc2 and the bivalent substituent ═O;
each Re2 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10cycloalkenyl, 3-11 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 3-11 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, —OH, C1-6alkoxy, C1-4alkoxy-C1-4alkyl, hydroxy-C1-4alkyl, halogen, —CN, —NH2, —C(═O)C1-4alkyl, —NH(C1-4alkyl), —N(C1-4alkyl)2 and the bivalent substituent ═O;
each R8 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, C3-6cycloalkyl and 3-6 membered heterocyclyl;
each R9 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, halogen, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, C3-6cycloalkyl and 3-6 membered heterocyclyl;
each R10 is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, C3-6cycloalkyl and 3-6 membered heterocyclyl;
or a salt thereof.