US 12,268,668 B2
Autotaxin inhibitor compounds
John Howard Hutchinson, San Diego, CA (US); and David Lonergan, San Diego, CA (US)
Assigned to Sabre Therapeutics LLC, South San Francisco, CA (US)
Filed by Sabre Therapeutics LLC, South San Francisco, CA (US)
Filed on Oct. 4, 2023, as Appl. No. 18/481,141.
Application 15/060,398 is a division of application No. 14/926,877, filed on Oct. 29, 2015, granted, now 9,334,261, issued on May 10, 2016.
Application 18/481,141 is a continuation of application No. 17/662,403, filed on May 6, 2022, granted, now 11,779,568.
Application 17/662,403 is a continuation of application No. 16/874,073, filed on May 14, 2020, granted, now 11,344,533, issued on May 31, 2022.
Application 16/874,073 is a continuation of application No. 15/970,337, filed on May 3, 2018, granted, now 10,688,081, issued on Jun. 23, 2020.
Application 15/970,337 is a continuation of application No. 15/261,659, filed on Sep. 9, 2016, granted, now 9,999,615, issued on Jun. 19, 2018.
Application 15/261,659 is a continuation of application No. 15/060,398, filed on Mar. 3, 2016, granted, now 9,468,628, issued on Oct. 18, 2016.
Application 14/926,877 is a continuation of application No. PCT/US2014/066706, filed on Nov. 20, 2014.
Claims priority of provisional application 62/038,121, filed on Aug. 15, 2014.
Claims priority of provisional application 61/907,965, filed on Nov. 22, 2013.
Prior Publication US 2024/0189281 A1, Jun. 13, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/4155 (2006.01); A61K 9/00 (2006.01); A61K 9/06 (2006.01); A61K 9/08 (2006.01); A61K 9/20 (2006.01); A61K 9/48 (2006.01); A61K 31/4439 (2006.01); A61K 45/06 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 405/14 (2006.01); C07D 493/10 (2006.01)
CPC A61K 31/4155 (2013.01) [A61K 9/0014 (2013.01); A61K 9/0019 (2013.01); A61K 9/0053 (2013.01); A61K 9/06 (2013.01); A61K 9/08 (2013.01); A61K 9/20 (2013.01); A61K 9/48 (2013.01); A61K 31/4439 (2013.01); A61K 45/06 (2013.01); C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 405/14 (2013.01); C07D 493/10 (2013.01)] 18 Claims
 
1. A method for the treatment of fibrosis in a mammal comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof:

OG Complex Work Unit Chemistry
wherein,
R1 is —F, —Cl, —Br, —CN, vinyl, C3-C6cyloalkyl, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —O—C1-C4 alkyl, or —S—C1-C4 alkyl;
R2 is H, halogen, —CN, —NO2, —OH, —OR9, —SR9, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —C(═O)R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4hydroxyalkyl, C1-C4 heteroalkyl, C3-C6cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;
R3 is H, halogen, —CN, —OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4alkoxy, or C1-C4fluoroalkoxy;
Ring A is a monocyclic aryl, bicyclic aryl, monocyclic heterocycloalkyl, monocyclic heteroaryl or bi cyclic heteroaryl;
each RA is H halogen —CN—NO2, —OH, —OR9, —SR9, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —C (=O)R9, —OC(═O)R9, —CO2R10, —OCO2, R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O) R9, —NHC(═O)OR9, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;
m is 0, 1, or 2;
L1 is absent, C1-C6alkylene, C1-C6fluoroalkylene, or C3-C6cycloalkylene;
Q is —CO2H, —CO2(C1-C6alkyl), —OH, —CN, —B(OH)2, C(═O)NHSO2R9, —C(═O)N(R10)2, —SO2NHC(═O)R9, —CN, tetrazolyl, —OP(═O)(OH)2, —P(═O)(OH)2 or carboxylic acid bioisostere;
L2 is absent, C1-C4alkylene, or C3-C7cycloalkylene;
L3 is —S—, S(═O), S(═O)2, or —O—;
Ring B is a monocyclic aryl, bicyclic aryl, monocyclic heteroaryl or bicyclic heteroaryl;
each RB is independently H, halogen, —CN, —NO2, —OH, —OR9, —SR9, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —C(═O)R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted phenyl, C1-C4alkylene-(substituted or unsubstituted phenyl), substituted or unsubstituted monocyclic heteroaryl, C1-C4alkylene-(substituted or unsubstituted monocyclic heteroaryl), a substituted or unsubstituted bicyclic heteroaryl, or C1-C4alkylene-(substituted or unsubstituted bicyclic heteroaryl);
or each RB is independently hydrogen, 1-propyl, ethyl, methyl, 2-propyl, —CH2CH2OH, —CH2CH2OC(O)NH2, —CH2CH2NH2, —CH2CH2NHC(O)NH2, —CH2CH2C H2CO2H, —CH2CH2CH2CONH2, —CH2CF3, —CD2CD3, —(CH2)6NH2, —(CH2)4CCH, —CH2C(CH3)2C H2OH, —(CH2)6NHC(O)N-fluorescein, —CH2CH2CH2C(O)NHCH3, —CH2CH2CH2C(O)NH(CH3)2, —CH2CH2C(CH3)2C(O)NH2, —CH2CH2CH2C(O)NH2, —CH2CH2CH2C(O)NHCH3, —CH2CH2CH2C (O)NH(CH3)2, or —CH2CH2C(CH3)2C(O)NH2;
n is 0, 1, or 2;
R9 is C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted bi cyclic heteroaryl;
each R10 is independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl; or
two R10 groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle;
wherein if any of R2, R9, R10, RA, and RB is substituted, then it is substituted with one or two groups independently selected from halogen, —CN, —NH2, —OH, —NH(CH3), —N(CH3)2, —CH3, —CH2CH3, —CF3, —OCH3, and —OCF3.