N1-pyrazolospiroketone acetyl-coa carboxylase inhibitors.
Nl-pyrazolospiroketone acetyl-coa carboxylase inhibitors (57) Abstract The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt of the compound, wherein Rl, R2, R3 and R4 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the in-hibition of an acetyl- CoA carboxylase en-zyme(s) in an animal. (56) Documents Cited ; WO 2009 144 554 Α1 WO 2008 088 689 Α1 WO 2007 011 809 Α1 WO 2009 144 55 Α1 WO 2008 06S508 Α1 WO 2008 125945 Α2 ΕΡ2123 652 A1 ΕΡ 1911 753 Α1 FORM 25 (12) PATENT (19) ΑΡ (11) Patent No: ΑΡ 3283 (73) Applicant(s) PFIZER INC., 235 East 42nd Street, New York, New York 10017, United (21) Application No : AP/P/2012/006269 States of America (22) Filing Date: 29.10.2010 (45) Publication: 28/05/2015 (30) Priority Data (72) Inventors (33) Country (31) Number (32) Date BAGLEY Scott William, United States of America US 61/259,823 10.11.2009 GRIFFITH David Andrew, United States of America KUNG Daniel Wei-Shung, United States of America (84) Designated States: (74) Representative BW GH GM ΚΕ LR LS MW GALLOWAY & COMPANY, Zimbabwe ΜΖ ΝΑ SD SL SZ ΤΖ UG ΖΜ ZW (51) International Classification : C07D 471/10(2006.01) Α61Κ 31/438(2006.01) Α61Ρ 3/10 (2006.01) Α61Ρ 1/16 (2006.01) (54) Title The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt of the compound, wherein R 1 , R 2 , R 3 and R 4 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase enzyme(s) in an animal. A compound of Formula (I)
wherein
R1 is (C1-C6)alkyl, (C3-C7)cycloalkyl, tetrahydrofuranyl or oxetanyl; wherein said (C1-C6)alkyl is optionally substituted with 1 to 2 substituents independently selected from (C1-C3)alkoxy, hydroxy, fluoro, phenyl, tetrahydrofuranyl or oxetanyl;
R2 is hydrogen, halo, (C1-C3)alkyl, or cyano;
R3 are each independently hydrogen or (C1-C3)alkyl;
R4 is a (C6-C10)aryl, 5 to 12 membered heteroaryl or 8 to 12 membered fused heterocyclicaryl; wherein said (C6-C10)aryl, 5 to 12 membered heteroaryl or 8 to 12 membered fused heterocyclicaryl are each optionally substituted with one to three substituents independently selected from (C1-C3)alkyl, (C1-C3)alkoxy, halo, amino, (C1-C3)alkylamino, di(C1-C3)alkylamino, hydroxy, cyano, amido, phenyl, 5 to 6 membered heteroaryl or 5 to 6 membered heterocyclyl; or a pharmaceutically acceptable salt thereof. The compound of claim 1 wherein R1 is (C1-C6)alkyl, (C3-C7)cycloalkyl, or tetrahydrofuranyl; and R2 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof. The compound of claim 2 wherein R1 is ethyl, isopropyl or t-butyl; each R3 is hydrogen; and R4 is phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, indolyl, benzopyrazinyl, benzoimidazolyl, benzoimidazolonyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, indazolyl, indolinonyl, naphthyridinyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, oxo-dihydroquinolinonyl, isoquinolinyl, isoquinolinonyl, dihydroisoquinonyl or oxo-dihydroisoquinonyl, each optionally substituted with one to three substituents independently selected from fluoro, chloro, methyl, methoxy, amino, methylamino, dimethylamino, amido, cyano, phenyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl or morpholinyl; or a pharmaceutically acceptable salt thereof. The compound of claim 3 wherein R1 is isopropyl or t-butyl; R2 is hydrogen; or a pharmaceutically acceptable salt thereof. The compound of claim 4 wherein R4 is indazolyl, benzoimidazolyl, 1-oxo-1,2-dihydroisoquinolinyl, 1 The compound of claim 1 that is 1-Isopropyl-1'-(1 The compound of claim 1 that is a compound of formula
The compound of claim 1 that is 1-isopropyl-1'-(2-methyl-1 The compound of claim 1 that is a compound of formula
The compound of claim 1 that is a compound of formula
or a pharmaceutically acceptable salt thereof. The compound of claim 1that is a compound of formula
or a pharmaceutically acceptable salt thereof. The compound of claim 1 that is a compound of formula
or a pharmaceutically acceptable salt thereof. The compound of claim 1 that is a compound of formula
or a pharmaceutically acceptable salt thereof. The compound of claim 1 that is a compound of formula
or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1 through 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent, or carrier. The composition of claim 15 further comprising at least one additional anti-diabetic agent. The composition of claim 16 wherein said anti-diabetic agent is selected from the group consisting of metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, trodusquemine, reservatrol, hyrtiosal extract, sitagliptin, vildagliptin, alogliptin and saxagliptin. The compound of any one of claims 1 to 14, or the composition of any one of claims 15 to 17, for use in treating or delaying the progression or onset of Type 2 diabetes. The compound of any one of claims 1 to 14, or the composition of any one of claims 15 to 17, for use in treating nonalcoholic fatty liver disease (NAFLD) or hepatic insulin resistance.Patents Granted (Contd.)