OA16631A

OA16631A - Pyrazolospiroketone derivatives for use as ACETYL-COA Carboxylase inhibitors

Info

Publication number: OA16631A
Application number: OA1201300432
Authority: OA
Inventors: David Andrew Griffith; Robert Lee Dow; James Alfred SOUTHERS; David James EDMONDS
Original assignee: Pfizer Inc.
Priority date: 2011-04-22
Filing date: 2012-04-09
Publication date: 2015-12-01

Abstract

The invention provides a compound of formula (I) <img file="OA16631A_A0001.tif"/> or a pharmaceutically acceptable salt thereof; wherein G is R1 , R2 and R3 are as descrobed herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetylCoA carboxylase enzyme(s) in an animal.

Description

PYRAZOLOSPIROKETONE DERIVATIVES FOR USE AS ACETYL-COA CARBOXYLASE INHIBITORS

FIELD OF THE INVENTION

This invention relates to substituted pyrazolospiroketone compounds that act as inhibitors of an acetyl-CoA carboxylase(s) and their use in treating diseases, conditions or disorders modulated by the inhibition of acetyl-CoA carboxylase enzyme(s).

BACKGROUND OFTHE INVENTION

Acetyl-CoA carboxylases (ACC) are a famlly of enzymes found in most species and are associated with fatty acid synthesis and metabolism through catalyzing the production of malonylCoA from acetyl-CoA. In mammals, two isoforms of the ACC enzyme hâve been identified. ACC1, which is expressed at high levels in lipogenic tissues, such as fat and the liver, controls the first committed step in the biosynthesis of long-chain fatty acids. If acetyl-CoA is not carboxylated to form malonyl-CoA, it is metabolized through the Krebs cycle. ACC2, a minor component of hepatic ACC but the prédominant isoform in heart and skeletal muscle, catalyzes the production of malonylCoA at the cytosollc surface of mitochondria, and régulâtes how much fatty acid is utilized in βoxidation by inhibiting carnitine palmitoyl transferase. Thus, by increasing fatty acid utilization and by preventing increases In de novo fatty acid synthesis, chronic administration of an ACC inhibitor (ACC-I) may also deplete liver and adipose tissue triglycéride (TG) stores in obese subjects consuming a high or low-fat diet, leading to sélective loss of body fat.

Studies conducted by Abu-Etheiga, et al., suggest that ACC2 plays an essential rôle in controlling fatty acid oxidation and, as such it would provide a target in therapy against obesity and obesity-related diseases, such as type-2 diabètes. See, Abu-Etheiga, L., et al., “Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabètes induced by high-fat/highcarbohydrate diets PNAS. 100(18) 10207-10212 (2003). See also, Choi, C.S., étal., Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity” PNAS, 104(42) 16480-16485 (2007).

It is becoming increasingly clear that hepatic lipid accumulation causes hepatic insulin résistance and contributes to the pathogenesïs of type 2 diabètes. Salvage, et al., demonstrated that ACC1 and ACC2 are both involved in regulating fat oxidation in hépatocytes while ACC1, the dominant isoform in rat liver, is the sole regulator of fatty acid synthesis. Furthermore, in their model, combined réduction of both isoforms is required to significantly lower hepatic malonyl-CoA levels, increase fat oxidation in the fed state, reduce lipid accumulation, and improve insulin action in vivo. Thus, showing that hepatic ACC1 and ACC2 inhibitors may be useful in the treatment of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin résistance. See, Savage, D.B., et al.,

Reversai of diet-induced hepatic steatosis and hepatic insulin résistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2” J Clin Invest doi: 10.1172/JCI27300. See also, Oh, W., et al., Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice PNAS. 102(5) 1384-1389 (2005).

Consequently, there is a need for médicaments containing ACC1 and/or ACC2 inhibitors to treat obesity and obesity-related diseases (such as, NAFLD and type-2 diabètes) by inhibiting fatty acid synthesis and by increasing fatty acid oxidation.

SUMMARY OF THE INVENTION

A first embodiment of the présent invention relates to compounds having the structure of Formula A compound of Formula (I)

Formula (I) or a pharmaceutically acceptable sait thereof; wherein G is

R’ is a (CrCeJalkyl or (C₃-C₇) cylcoalkyl; R² is indolyl, indazolyl, pyrrolopyridinyl, pyrazolopyridinyl, quinolinyl or benzoimidazolyl; wherein each R^a group is optionally substituted with one to two substituents independently selected from a cyano, -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, (C(C3)alkyl, (CrCsJalkoxy and halo; R³ is hydrogen or (CrC3)alkyl; L is a direct bond or -X(C_rC₃)alkylene; X is a direct bond, O or S; R⁴ and R⁵ are each independently hydrogen, (Ci-C₃)alkyl, (C₃-C₇)cycloalkyl or four to seven membered heterocyclyl wherein said (CrC₃)alkyl, (C₃C₇)cycloalkyl or four to seven membered heterocyclyl is optionally substituted with one to three fluoro or (CpC^alkoxy.

A second embodiment of the présent invention is the compound of the first embodiment or a pharmaceutically acceptable sait thereof wherein R² is indolyl, indazolyl, pyrrolopyridinyl, pyrazolopyridinyl, quinolinyl or benzoimidazolyl substituted with a cyano, -L-C(O)NR⁴R or -LNR⁴R⁵.

A third embodiment of the présent invention is the compound of the second embodiment or a pharmaceutically acceptable sait thereof wherein R² is indolyl, indazolyl, pyrrolopyridinyl, pyrazolopyridinyl, quinolinyl or benzoimîdazolyl substituted with a -L-C(O)NR'^,R^S or -1-ΝΗ⁴Π^Ε; and L is a direct bond.

A fourth embodiment of the présent invention is the compound of the first embodiment wherein R¹ is isopropyl, t-butyl or bicycle[1.1.1]pentanyl; or a pharmaceutically acceptable sait thereof. A fifth embodiment of the présent invention is the compound of any of the preceding embodiments wherein R³ is hydrogen; or a pharmaceutically acceptable sait thereof.

Another embodiment of the présent invention is the a compound of the first embodiment

Another embodiment of the présent invention is the compound of the first embodiment wherein G is

Another embodiment of the présent invention is the compound wherein R² is

wherein each R² is substituted with a cyano, -L-C(O)NR⁴R⁵, -L-NR⁴R⁵; or a pharmaceutically acceptable sait thereof.

Yet another embodiment of the présent invention is the compound or the preceding embodiment wherein R² is substituted with a cyano, -C(O)NH_2l -C(O)NHCH₃, -C(O)NHCH₂CH₃, C(O)CH₂CF_3i -OCH₂C(O)NH₂; -NH_2i -NHCH₃ or “NHC(CH₃)₃; or a pharmaceutically acceptable sait thereof.

Another embodiment of the présent invention is the compound wherein G is

pyrrolopyridlnyl, pyrazolopyridînyl, quinolinyl or benzoimidazolyl; wherein each R² group is optionally substituted with one to two substituents independently selected from a cyano, -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, (Ci-C3)alkyl, (CrC^alkoxy and halo; R³ is hydrogen or (Ci-C3)alkyl; L is a direct bond or -X(Ci-C₃)alkylene; X is a direct bond, O or S; and R⁴ and R⁵ are each independently hydrogen, (Ci~C₃)alkyl, (C₃-Cz)cycloalkyl or four to seven membered heterocyclyl wherein said (CrCsJalkyl, (C₃-C₇)cycloalkyl or four to seven membered heterocyclyl is optionally substituted with one to three fluoro or (CrC₃)alkoxy; or a pharmaceutically acceptable sait thereof.

Another embodiment of the présent invention is the compound wherein G is

pyrrolopyridlnyl, pyrazolopyridînyl, quinolinyl or benzoimidazolyl; wherein each R² group is optionally substituted with one to two substituents independently selected from a cyano, -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, (Ci-C₃)alkyl, (CrC₃)alkoxy and halo; R³ is hydrogen; L is a direct bond

or -X(Ci-C₃)alkylene; X is a direct bond, O or S; and R⁴ and R⁵ are each independently hydrogen, (Ci-C₃)alkyl, (C₃-C7)cycloalkyl or four to seven membered heterocyclyl wherein said (Ci-C₃)alkyl, (C₃'C₇)cycloalkyl or four to seven membered heterocyclyl is optionally substituted with one to three fluoro or (Ci-C₃)alkoxy; or a pharmaceutically acceptable sait thereof.

Another embodiment of the présent invention is the compound wherein G is

wherein each R² is substituted with one substitutent that is -L-C(O)NR⁴R^S,

-L-NR⁴R⁵, or (CrC3)alkoxy; R³ is hydrogen; L is a direct bond or -XtCrC^alkylene; X is a direct bond, O or S; and R⁴ and R⁵ are each independently hydrogen or (Ci-C3)alkyl; or a pharmaceutically acceptable sait thereof.

Another embodiment of the présent invention is the compound wherein G is

NR⁴R^S, or (CrCgJalkoxy; L is a direct bond; and R⁴ and R⁵ are hydrogen; or a pharmaceutically acceptable sait thereof.

Another embodiment of the présent invention is the compound wherein G is

wherein each R² is substituted with one substituent that is -L-NR⁴R⁵ or (Ci-C₃)alkoxy; L is a direct bond; and R⁴ and R⁵ are hydrogen; or a pharmaceutically acceptable sait thereof.

substituted with one to two substituents independently selected from a cyano, -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, (CrC3)alkyl, (CrCaJalkoxy and halo; R³ is hydrogen or (CrC3)alkyl; L is a direct bond; and R⁴ and R⁵ are each independently hydrogen or (Ci-C₃)alkyl.

one substituent selected from (CrC₃)alkoxy; and R³ is hydrogen.

Another embodiment of the présent invention ïs the compound of the first embodiment wherein G is

/ /

wherein R¹ is a (Ci-C₆)alkyl; R² is optionally substituted with one to two substituents independently selected from a cyano, -1_-Ο(Ο)ΝΗ⁴Η⁵, -L-NR⁴R⁵, (Ci-C3)alkyl, (CrC^alkoxy and halo; R³ is hydrogen or (Ci-C3)alkyl; L îs a direct bond; and R⁴ and R⁵ are each independently hydrogen or (C_t-C₃)alkyl.

one substituent selected from -L-NR⁴R⁵; R³ is hydrogen; L is a direct bond; and R⁴ and R⁵ are each

substituted with hydrogen.

substituted with one to two substituents independently selected from a cyano, -L-C(O)NR⁴R⁵,

-L-NR⁴R⁵, (Ci-C3)alkyl, (Ci-C3)alkoxy and halo; R³ is hydrogen or (CpC^alkyl; L is a direct bond; and R⁴ and R⁵ are each independently hydrogen or (Ci-C3)alkyl.

one substituent selected from -L-C(O)NR⁴R⁵; R³ is hydrogen; L is a direct bond; and R⁴ and R⁵ are each hydrogen.

Another embodiment of the présent invention is the compound of structure

or a pharmaceutically acceptable sait thereof.

Another embodiment of the présent invention is the compound of structure

Another embodiment of the présent invention is a compound selected from the group consisting of 6-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-ri-l-spiro[indazole-5,4'-pipendÎn]-1 yl)carbonyl]-1 H-indole-3-carboxamide; 5-[( 1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-

5,4'-piperidiη]-1 '-yljcarbonyl]~ 1 H-indazole-3-carboxamide; 6-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydrol'H-spirotindazole-S^'-piperÎdÎnJ-l'-yQcarbonyll-IH-pyrrolota.Z-blpyridine-a-carboxamide; 6-[(1 isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro(indazole-5,4'-piperïdin]-1 '-y|)carbonyl]-1 H-indazole-3carboxamide; 5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro[Îndazole-5,4'-piperidin]-1 '5 yl)carbonyl]-1 H-pyrrolo[2,3-b]pyridine-3-carboxamtde; 5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l Ήspiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-1 H-indole-2-carboxamide; 5-[{1 -isopropyl-7-oxo1,4,6,7-tetrahydro-l ’H-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonylj-1 H-indole-3-carboxamide; 1 '-[(2amino-1H-benzimidazol-5-yl)carbonyl]-1-isopropyl-1,4-dihydrospiro[indazole-5,4'-piperidin]-7(6H)one; 5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spirofindazole-S^'-piperidin]-! '-yl)carbonyl]-N10 methyl-1H-indazole-3-carboxannide; N-ethyl-5-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-l Ήspiro[indazoie-5,4'-pi peridin]-1 ’-y|)carbonyl]-1 H-indazole-3-carboxamide; 5-[(1 -isopropyl-7-oxo1,4,6,7-tetrahydro-l 'H-spiro(indazole-5,4'-piperidin]-1 ‘-y|)carbonyl]-N-(2_l2,2-trifluoroethyl)-1 Hindazole-3-carboxamide; 6-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spirofÎndazole-SA'-piperidin]1 '-y|)carbonylj-1 H-indole-2-carboxamide; 5-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-l Ή15 spiro[indazole-5,4'-piperidin]-1'-yl)carbonyl]-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide; 5-((1 isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spirofindazole-S^'-piperidinl-l '-yl)carbonyl]-1 H-pyrrolo[2,3b]pyridine-2-carboxamide; 1-isopropyl-1 '-{[2-(methylamino)-1 H-benzimidazol-5-yl]carbonyl)-1,4dihydrospiro[indazole-5,4‘-piperidin]-7(6H)-one; 5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l Ήspiro[indazole-5,4'-piperidin]-T-yl)carbonyl]-1 H-benzimidazole-2-carboxamide; 5-[(1 -tert-butyl-720 oxo-1,4,6,7-tetrahydro-l 'H-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-1 H-indazole-3-carboxamide; 5-((1 -tert-butyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro[indazole-5,4'-piperidin]-1 '-y|)carbonyl]-1 Hpyrrolo[2,3-b]pyridine-3-carboxamide; 6-[(2-terÎ-butyl-7-oxo-2,4,6,7-tetrahydro-rH-spiro(indazoleS^'-piperidinJ-l'-yiJcarbonylj-IH-indole-S-carboxamide; 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro1 'H-spiro[indazole-5,4'-piperïdin]-1 '-yl)carbonyl]-1 H-indazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo25 2,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 '-y|)carbonyl]-1 H-pyrrolo[2,3-b]pyridine-3carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spirolindazole-S^'-piperidinJ-l yl)carbonyl]-1 H-indazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidinM'-yl)carbonyl]-1H-indole-2-carboxamide; 5-((2-tert-butyl-7-oxo-2,4,6,7tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 ’-yl)carbonyl]-1 H-indole-3-carboxamide; 6-[(2-tert30 butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spirotindazole-â^'-pipendin]-! ‘-yl) carbonyl]-1 H-indole-2carboxamide; r-[(2-amino-1H-benzimidazol-5-yl)carbonyl]-2-tert-butyl-2,4-dihydrospiro[indazole5,4'-piperidin]-7(6H)-one; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-TH-spiro[indazole-5₁4‘-piperidin]1 '-y|)carbonyl]-N-ethyl-1 H-indazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4’-piperidin]-r-yl)carbonyl]-N-methyl-1H-indazole-3-carboxamide; 5-[(2-tert-butyl-735 oxo-2,4,6,7-tetrahydro-1'H-spiro[indazole-5,4^l-piperidin]-1'-yl)carbonyl]-N-(2,2,2-trifluoroethyl)-1H16631 indazole-3-carboxamide; 2-tert-butyl-1 ‘-{[2-(methylamino)-1 H-benzimidazol-5-yl]carbonyl}-2,4dihydrospiro[indazole-5,4'-piperidin]-7(6H)-one; e-^-tert-butyl^-oxo^Aej-tetrahydro-THspiro[indazole-5,4'-piperidin]-1'-yl)carbonyl]-1 H-pyrrolo[3,2-b]pyridine-3-carboxamide; 6-((2’-tertbutyl-7^,-oxo-6',7'-dihydro-1 H,2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-1-yl)carbonyl]-1 H5 indazole-3-carboxamide; e-KZ'-tert-butyl^’-oxo-e'J'-dihydro-lH,2’H-spiro[piperidine-4,5'pyrano[3,2-c]pyrazol]-1-yl)carbonyl]-1 H-indole-2-carboxamide; 6-[(2'-tert-butyl-7'-oxo-6'l7'-dihydro1 Hl2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-1 -yl)carbonyl]-1 H-indole-3-carboxamide; 5-[(2'tert-butyl-7^,-oxo-6^,,7'-dihydro-1 H,2^,H-spiro[piperidine-4,5^l-pyrano[3,2-c]pyrazol]-1-yl)carbonyl]-1 Hindazole-3-carboxamide; 5-t(2'-terÎ-butyl-7'-oxo-6',7‘-dihydro-1H,2'H-spiro[piperidine-4,5'10 pyrano[3,2-c]pyrazol]-1 -yl)carbonyl]-1 H-indole-2-carboxamide; 5-[(2'-tert-butyl-7'-oxo-6'17‘-dihydro1 H,2'H-spiro[piperidine-4_l5^,-pyrano[3,2-c]pyrazol]-1 -yl)carbonyl]-1 H-indole-3-carboxamide; 5-[(2‘tθrt-butyl·7'-oxo-6',7^,-dihydro-1H,2Ή-spiro[piperidine-4,5^,-pyrano[3,2-c]pyrazol]-1-yl)carbonyl]-1Hpyrrolo[2,3-b]pyridine-3-carboxamide; 1-[(2-amino-lH-benzimidazol-5-yl)carbonyl]-2'-tert-butyl-2'Hspiro[piperidine-4₍5‘-pyrano[3,2-c]pyrazol]-7'(6'H)-one; 2'-tert-butyl-1 4[2-(methylamino)-1 H15 benzimidazol-5-yl]carbonyl}-2'H-spiro[piperidine-4,5^,-pyrano(3,2-c]pyrazol]-7'(6'H)-one; 6-[(2'-tertbutyl-7*-oxo-6', 7'-di hydro-1 H,2'H-spiro[pi peridine-4,5'-pyrano[3,2-c]pyrazol]-1-yl) carbonyl]-1 Hpyrrolo[3,2-b]pyridine-3-carboxamide; and 5-[(2'-tert-butyl-7'-oxo-6',7'-dihydro-1 Η,2Ήspiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-1-yl)carbonyl]-1 H-benzimidazole-2-carboxamide.

or a pharmaceutically acceptable sait thereof.

Yet another embodiment of the présent invention rs a compound selected from the group consisting of 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 'yl)carbonyl]-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1'Hspiro[indazole-5,4'-piperidin]-1'-yl)carbonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; Γ-[(2aminoquinolin-6-yl)carbonyl]-2-tert-butyl-2,4-dihydrospiro[indazole-5,4'-piperidin]-7(6H)-one; 5-((125 isopropyl-7-oxo-1,4,6,7-tetrahydro-TI-l-spiro[indazole-5,4'-pÎperÎdin]-1 '-yl)carbonyl]-N-methyl-1 Hindole-3-carboxamide; 6-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro[indazole-5,4'-piperidin]-1 'yl)carbonyl]-N-methyl-1 H-indole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-T-yl)carbonyl]-N-cyclopropyl-1H-indazole-3-carboxamide; 5-[(2-tertbutyl-7-oxo-2,4,6,7-tetrahydro-1'H-spiro[indazole-5,4'-piperidÎn]-1'-yl)carbonyl]-N-isopropyl-1 H30 indazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1'H-spiro[indazole-5,4'-piperidin]1 '-yl)carbonyl]-N-propyl-1 H-indazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2_l4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-T-yl)carbonyl]-N-(2-methoxyethyl)-1H-indazole-3-carboxamide; 5-((2tert-butyl-7-oxo-2,4,6,7-tetrahydro-1'H-spiro[indazole-5,4'-piperidin]-1'-yl)carbonyl]-N-cyclobutyl-1 Hindazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-rH-spiro[indazole-5₁4'-piperidin]35 1 '-yl)carbonyl]-N-oxetan-3-yl-1 H-indazole-3-carboxamide; 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro16631

Ή-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-Ncyclopropyl-1 H-indazole-3-carboxamide; 6-[(2tert-butyi-7-oxo-2,4,6,7-tetrahydro-1'H-spiro[indazole-5,4’-pipendin]-r-yl)carbonyl]-N-methyl-1 Hindazole-3-carboxamide; 6-[(2-tert-butyl-7-oxo-2,4₁6,7-tetrahydro-rH-spiro[indazole-5,4'-piperidin]1 ‘-yl)carbonyl]-N-ethyl-1 H-indazole-3-carboxamide; 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 Ή5 spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-N-(2-methoxyethyl)-1 H-indazole-3-carboxamide; 6-[(2tert-butyl-7-oxo-2,4,6,7-tetrahydro-1'l-l-spiro[Îndazole-5,4'-piperidin]-1 '-yl)carbonyl]-N-isopropyl-1 Hindazole-3-carboxamide; 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-rH-spÎro[indazole-5,4'-pîperidin]r-yl)carbonyl]-N-propyl-1H4ndazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-rHspiro[Îndazole-5,4'-piperidin]-1'-yl)carbonyl]-N-cyclopropyl-1H-indole-3-carboxamide; 6-[(2-tert10 butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-N-cyclobutyl-1 Hindazole-3-carboxamide; 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-rH-spÎro[indazole-5₁4^,-piperidin]r-yl)carbonyl]-N-oxetan-3-yl-1H-indazole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydrol'H-spiro[indazole-5,4'-piperidin]-1 ’-yl)carbonyl]-N-(2-methoxyethyl)-1 H-indole-3-carboxamide; 5[(2-tert-butyl-7-oxo-2,4_l6_l7-tetrahydro-1'H-spiro[indazole-5,4'-piperidin]-1'-yl)carbonyl]-N-methyl-1H15 indole-3-carboxamide; 5-[(2-tert-butyl-7-oxo-2,4,6_l7-tetrahydro-1 'H-spiro[indazole-5,4‘-piperidin]-1 yl)carbonyl]-N-ethyl-1 H-indole-3-carboxamide; and 6'[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5_t4'-piperidin]-1 '-yl)carbonyl]-N-cyclopropyl-1 H-indole-3-carboxamide; or a pharmaceutically acceptable sait thereof.

Another aspect of the présent invention is a pharmaceutical composition comprising an amount of a compound of Formula (I) as described in any of the embodiments; or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable excipient, diluent, or carrier. Preferably, the composition comprises a therapeutically effective amount of a compound of the présent invention. The composition may also contain at least one additional pharmaceutical agent. Preferred agents include anti-diabetic agents and/or anti-obesity agents.

In yet another aspect of the présent invention is a method for treating a disease, condition, or disorder mediated by the inhibition of acetyl-CoA carboxylase enzyme(s) in a mammal that includes the step of administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the présent invention, or a pharmaceutically acceptable sait thereof or a pharmaceutical composition thereof.

Diseases, disorders, or conditions mediated by inhibitors of acetyl-CoA carboxylases include Type II diabètes and diabetes-related diseases, such as nonalcoholic fatty liver disease (NAFLD), hepatic insulin résistance, hyperglycemia, metabolic syndrome, impaired glucose tolérance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and insulin résistance syndrome. Preferred diseases, disorders, or conditions include Type II diabètes, nonalcoholic fatty liver disease (NAFLD), hepatic insulin résistance, hyperglycemia, impaired glucose tolérance, obesity, and insulin résistance syndrome. More preferred are Type II diabètes, nonalcoholic fatty liver disease (NAFLD), hepatic insulin résistance, hyperglycemia, and obesity. Most preferred is Type II diabètes.

A preferred embodiment is a method fortreating (e.g. delaying the progression or onset of)

Type 2 diabètes and diabetes-related disorders in animais comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof or a composition thereof.

A more preferred embodiment is a method for treating, or delaying the progression or onset of, Type 2 diabètes and diabetes-related disorders in a human comprising the step of administering to the human in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof or a composition thereof.

A most preferred embodiment is a method for treating, or delaying the progression or onset of, Type 2 diabètes in a human comprising the step of administering to the human in need of such 15 treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof or a composition thereof.

Another preferred embodiment is a method for treating obesity and obesity-related disorders in animais comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutically 20 acceptable sait thereof or a composition thereof.

Another preferred embodiment is a method for treating obesity and obesity-related disorders in a human comprising the step of administering to the human in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof or a composition thereof.

Yet another preferred embodiment is a method for treating nonalcoholic fatty liver disease (NAFLD) or hepatic insulin résistance in animais comprising the step of administering to an animal, in particular a human, in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof or a composition thereof.

Yet another preferred embodiment is a method for treating nonalcoholic fatty liver disease (NAFLD) or hepatic insulin résistance in a human comprising the step of administering to the human in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof or a composition thereof.

Compounds of the présent invention may be administered in combination with other pharmaceutical agents (in particular, anti-obesity and anti-diabetic agents described herein below).

The combination therapy may be administered as (a) a single pharmaceutical composition which

comprises a compound of the présent invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the présent invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a 5 second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions may be administered simultaneously or sequentially and in any order.

Another embodiment is the use of a compound of the présent invention in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of 10 acetyl-CoA carboxylase enzyme(s).

Another embodiment is the use of a compound of the présent invention in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) wherein the disease, condition, or disorder is Type 2 diabètes, diabetes-related disorders, nonalcoholic fatty liver disease (NAFLD) or hepatic insulin résistance.

Another embodiment is the use of a compound of the présent invention in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) wherein the disease, condition, or disorder is Type 2 diabètes.

Another embodiment is the use the compound of Example 6,14, or 25 in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of 20 acetyl-CoA carboxylase enzyme(s) wherein the disease, condition, or disorder is Type 2 diabètes, diabetes-related disorders, nonalcoholic fatty liver disease (NAFLD) or hepatic insulin résistance.

Another embodiment is the use of the compound of Example 6,14, or 25 in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) wherein the disease, condition, or disorder is Type 2 diabètes.

Another embodiment is the use of the compound of Example 6 in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) wherein the disease, condition, or disorder is Type 2 diabètes.

Another embodiment is the use of the compound of Example 14 in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of 30 acetyl-CoA carboxylase enzyme(s) wherein the disease, condition, or disorder is Type 2 diabètes.

Another embodiment is the use of the compound of Example 25 in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) wherein the disease, condition, or disorder is Type 2 diabètes.

DETAILED DESCRIPTION OF THE INVENTION

Définitions

The phrase the râpe utically effective amount means an amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof that: (i) treats or prevents the particular disease, condition, or disorder, (ii) atténuâtes, améliorâtes, or éliminâtes one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

The term ‘'animal refers to humans (male or female), companion animais (e.g., dogs, cats and horses), food-source animais, zoo animais, marine animais, birds and other similar animal species. Edible animais” refers to food-source animais such as cows, pigs, sheep and poultry.

The phrase “pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingrédients comprising a formulation, and/or the mammal being treated therewith,

The terms treating”, treat, or “treatment embrace both preventative, i.e., prophylactic, and palliative treatment.

The terms “modulated or modulating”, or “modulate(s), as used herein, unless otherwise indicated, refers to the inhibition of the Acetyl-CoA carboxylases (ACC) enzyme(s) with compounds of the présent invention.

The terms mediated or “mediating or mediate(s), as used herein, unless otherwise indicated, refers to the (i) treatment or prévention the particular disease, condition, or disorder, (ii) atténuation, amelioration, or élimination of one or more symptoms of the particular disease, condition, or disorder, or (iii) prévention or delay of the onset of one or more symptoms of the particular disease, condition, or disorder described herein, by inhibiting the Acetyl-CoA carboxylases (ACC) enzyme (s).

The term “compounds of the présent invention” (unless specifically identified otherwise) refer to compounds of Formula (I) and any pharmaceutically acceptable salts of the compounds, as well as, ail stereoisomers (including diastereoisomers and enantiomers), tautomers, conformational isomers, and isotopically labeled compounds. Hydrates and solvatés of the compounds of the présent invention are considered compositions of the présent invention, wherein the compound is in association with water or solvent, respectively.

The terms (Ci-C₆)alkyr and “(Ci-C₃)alkyl are alkyl groups of the specified number of carbons, from one to six or one to three carbons, respectively, which can be either straight chain or branched. For example, the term (Ci-C₃)alkyr has from one to three carbons and consists of methyl, ethyl, n-propyl and isopropyl. Alkoxy groups with a specified number of carbons are named in an analogous manner.

The term (Ci-C₃)alkylene ara diradical (Ci-C₃)alkyl groups of from one to three carbons which can be either straight chain or branched. Représentative examples of the term “(Ci-C₃)alkylene include, but are not limited to, -CH₂-, -CH₂CH₂-, -CH{CH₃)CH₂-, -CH₂CH₂(CH₃)-, or -CH₂CH₂CH₂-.

The term (C₃-Cz)cycloalkyl·' means a cycloalkyl group with three to seven carbon atoms and consists of cydopropyl, cyclobutyl, cyclopentyl, cydohexyl and cycloheptyl or can be a bicyclo ring system such as bicyde[1.1.1 .jpentanyl. The term “halo means fluoro, chloro, bromo or îodo.

The term four to seven membered heterocyclyl” means a radical of a four to seven membered non-aromatic heterocycle. The point of attachment can be either through a carbon atom or a nitrogen atom. Non-limiting examples of these include oxetanyl, tetrahydrofuranyl, morpholinyl, azetidinyl, pyrrolodinyl, piperidinyl, piperazinyl and the like.

The terms indolyl, indazolyl, pyrrolopyridinyl, pyrazolopyridinyl, quinolinyl or benzoimidazolyl are radicale of the groups shown below and the point of attachment is on a carbon atom of that

l//-pyiTOlo[2,3-h]pyridine

l//-pyrrolo[3,2-£»]pyridine

lW-benzo[t/]irrudazole

3a,7a-dihydro-l//-pyrazolo(4,3-&]pyridine

quinolinc

In one embodiment, the compound of Formula (I) is a N1 ACC inhibitor compound having the following structure:

Compounds of the présent invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Svnthesis. v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie. 4, Aufl. ed. Springer-Verlag, Berlin, including suppléments (also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the présent invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although spécifie starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of dérivatives and/or reaction conditions. In addition, many of the compounds prepared by 10 the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In the préparation of compounds of the présent invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the 15 préparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tbutoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a hydroxy-protecting group refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl-protecting groups (O-Pg) include for example, allyl, acetyl, sllyl, benzyl, para-methoxybenzyl, trityl, and the like. The need for such protection is 20 readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Svnthesis. John Wiley & Sons, New York, 1991.

The following reaction schemes, Reaction Schemes I through Reaction Scheme III, provide représentative procedures that are used to préparé the compounds of Formula (I). It is to be 25 understood that these reaction schemes are to be construed in a non-limiting manner and that reasonable variations of the depicted methods can be used to préparé the compounds of Formula

d).

Réaction Scheme I outlines the general procedures one could use to provide N1

ACC inhibitor compounds of the présent invention having Formula la, which is a compound of

Formula (I) in which R¹ is a (Ci-C0)alkyl or (Ca-Czjcycloalkyl and R² is indolyl, indazolyl, pyrrolopyridinyl, pyrazolopyridinyl, quinolinyl or benzoimidazolyl; wherein each R² group is optionally substituted with one to two substituents independently selected from a cyano, -LC(O)NR⁴R⁵, -L-NR⁴R⁵, (CrC₃)alkyl, (CrC3)alkoxy and halo; R³ is hydrogen; L is a direct bond or XfCrCaJalkylene; X is a direct bond, O or S; and R⁴ and R⁵ are each independently hydrogen, (C;35 C₃)alkyl, (C₃-C₇)cycloalkyl or four to seven membered heterocyclyl wherein said (C_rC₃)alkyl, (C₃16631

C₇)cycloalkyl or four to seven membered heterocyclyl is optionally substituted with one to three fluoro or (Ci-C₃)alkoxy,

REACTION SCHEME I

According to Scheme I, the compound of VIla can be formed by reacting the compound of formula Villa wherein Pg représente an appropriate amine protecting group with tris(dimethylamino)methane in an appropriate solvent. The reaction can be carried out in an appropriate solvent such as toluene at an elevated température, such as reflux, for a period of 1 to 10 24 hours to provide the compound of formula VIla. The compound of formula Via can be formed by reacting the compound of formula VIla with an appropriate alkyl or cycloalkyl hydrazine (RiNHNHz, such as t-butyl hydrazine, isopropyl hydrazine or bicycle[1.1.1 .]pentanyl hydrazine ) in an appropriate solvent such as éthanol. For example, the compound of formula Via can be formed by reacting VIla with an appropriate alkyl hydrazine (R1NHNH2,) optionally in the presence of a base 15 such as potassium carbonate (K₂CO₃) in refluxing éthanol to provide the desired cyclized compound, at a température of about 20°C to about 80°C for about 2 to 24 hours.

The compound of formula Va can be formed by converting the compound of formula Via to the corresponding hydroxy bromide dérivative by reaction with an appropriate brominating reagent and water in an appropriate solvent. For example, the compound of formula Va can be formed by 20 reacting the compound of formula Via with N-bromosuccinimrde (NBS) and water in tetrahydrofuran at room température for 1 hour to provide the corresponding hydroxy bromo dérivative of formula Va. The compound of formula IVa can then be formed by oxidation of the compound of formula Va with an appropriate oxidizing agent in an appropriate solvent. For example, the compound of formula Va can be oxidized by treatment with Jones reagent in acetone at 0°C to room température 25 for a period of 15 minutes to 4 hours followed by extractive workup. The compound of formula IVa can then be debrominated by treatment with aqueous ammonium chloride and zinc métal in an appropriate solvent such as tetrahydrofuran for 15 minutes to 4 hours, typieally at room température.

The compound of formula Ilia can then be deprotected to provide the free spiropiperidine dérivative of formula lia using standard methods which dépend on which protecting group Pg has been employed. For example, when Pg represents BOC, standard strong acid deprotection conditions, such as 4N hydrochloric acid in dioxane or trifluoroacetic acid in an appropriate solvent such as dichloromethane, can be used to remove the BOC group. When Pg represents Cbz, hydrogénation over palladium on carbon in éthanol or treatment with a hydrogen source such as ammonium formate or 1-methyl-1,4-cyclohexadiene in the presence of palladium on carbon in éthanol or ethyl acetate can be employed to carry out the deprotection.

The spiropiperidine dérivative of formula lia can then be acylated by employing standard methods to provide the compound of formula la. For example, the compound (la) may then be formed using a standard peptide coupling reaction with the desired carboxylic acid (R²CO2H). For example, the spiropiperidine intermediate (lia) and carboxylic acid (R²CO2H) may be coupled by forming an activated carboxylic acid ester, such as by contacting the carboxylic acid (R²CO₂H) with a peptide coupling reagent, such as O-(7-azabenzotriazol-1-yl)-N,/\/,N',A/'-tetramethyluronium hexafluorophosphate (HATU”) or 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (“EDCHCI”), in the presence or absence of an activating agent, such as hydroxybenzotriazole (Ή0ΒΓ) and in the presence of a suitable base, such as A/,A/-diisopropylethylamine (DIEA), triethylamine or N-methylmorpholine (NMM), in a suitable solvent such as THF and/or DMF, dimethylacetamide (DMA”) or dichloromethane and then contacting the activated carboxylic acid ester with the spiropiperidine dérivative lia to form a compound of formula la.

Reaction Schéma II outlines the general procedures one could use to provide N2 ACC inhibitor compounds of the présent invention having Formula Ib, in which R’ is a (CrC₆)alkyl or (C₃C₇)cycloalkyl and R² is indolyl, indazolyl, pyrrolopyridinyl, pyrazolopyridinyl, quinolinyl or benzoimîdazolyl; wherein each R² group is optionally substituted with one to two substituents independently selected from a cyano, -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, (Ci-C3)alkyl, (Ci-C3)alkoxy and halo; R³ is hydrogen; L is a direct bond or -X(Ci-C3)alkylene; X is a direct bond, O or S; and R⁴ and R⁵ are each independently hydrogen, (Ci-Ca)alkyl, (C3-C₇)cycloalkyl or four to seven membered heterocyclyl wherein said (Ci-C₃)alkyl, (C₃-C₇)cycloalkyl or four to seven membered heterocyclyl is optionally substituted with one to three fluoro or (C_rC₃)alkoxy.

REACTION SCHEME II

According to Scheme II, reaction of the compound of formula VIIb with an appropriate hydrazine dérivative R¹-NHNH^a provides the compound of formula Vlb. The reaction is typically 5 carried out in an appropriate solvent such as éthanol at an elevated température such as 60^DC to reflux for a period of about 1 to 48 hours to provide the compound of formula Vlb. When the hydrazine dérivative R¹-NHNH² employed is in the form of its corresponding acid addition sait, such as a hydrochloride sait, it is to be appreciated that the compound of formula Vlb formed may also exist as a sait. When the compound of formula Vlb existe as the sait form, it is typically treated with an appropriate base, such as sodium bicarbonate, in an appropriate solvent, such as dichloromethane, for 15 minutes to 4 hours at ambient température prior to conversion to the compound of formula Vb. The compound of formula Vb is formed by first reacting phosphorous oxychloride with dimethylformamide at 0°C then adding the compound of formula Vlb and cyclizing it at an elevated température, such as 80°C for a period of 1 to 24 hours. The compound of formula Vb is then converted to the corresponding methoxy bromo dérivative of formula IVb by reaction with an appropriate brominating agent and methanol in an appropriate solvent such as tetrahydrofuran. For example, reaction of the compound Vb with N-bromosuccinimide in 20% methanol/tetrahydrofuran for 30 minutes to 4 hours at ambient température can provide the compound of formula IVb. Treatment of the compound of formula IVb with an appropriate base, such as potassium t-butoxide, in an appropriate solvent such as tetrahydrofuran for 15 minutes to 2 hours followed by acidification with an appropriate acid, such as 2N hydrochloric acid, can provide the compound of formula IIIb. Deprotection of the compound of formula lllb, followed by coupling with the acid R2CO2H in the manner described previously in Reaction Scheme I provides the compound of formula Ib.

Reaction Scheme III outlines the general procedures one could use to provide N2 ACC inhibitor compounds of the présent invention having Formula le, tn which R¹ and R² are as previously and R3 is an alkyl group.

REACTION SCHEME III

The compound of formula II le may be formed by palladium catalyzed cross-coupling of the bromide of formula IVc with an alkyl or alkenyl tributylstannane such as methyl tri-nbutylstannane or S vinyl tri-nbutylstannane or allyl tri-nbutylstannane or a trialkyl boroxine such as trimethyl boroxine or trivinyl boroxine in the presence of a palladium catalyst such as tetrakis(triphenylphosphine) palladium(0) or a precatalyst and ligand combination such as palladium(ll)acetate and 2dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) and in the presence or absence of a base such as potassium carbonate in a protic solvent such as éthanol or t-amyl alcohol or an aprotic solvent such as tetrahydrofuran or dimethylformamide at a température of about 20°C to about 100°C for about 2 hours to about 18 hours or at a température of about 100°C to about 150°C for about 5 minutes to about 60 minutes under microwave heating. If a alkenyl trialkylstannane or alkenyl boroxine is utilized to install the R³ group, réduction of the resulting olefin may be affected by hydrogénation over palladium on carbon in éthanol or treatment with a hydrogen source such as ammonium formate or 1-methyl-1,4-cyclohexadiene in the presence of palladium on carbon in éthanol or ethyl acetate.

The compound of formula II le may then be deprotected to provide the free spiropiperidine dérivative of formula Ile using standard methods which dépend on which protecting group Pg has been employed. For example, when Pg représente BOC, standard strong acid deprotection conditions, such as 4N hydrochloric acid in dioxane or trifluoroacetic acid in an appropriais solvent such as dichloromethane, can be used to remove the BOC group. When Pg représente Cbz, hydrogénation over palladium on carbon in éthanol or treatment with a hydrogen source such as ammonium formate or 1-methyl-1,4-cyclohexadiene in the presence of palladium on carbon in éthanol or ethyl acetate may be employed to carry out the deprotection.

The spiropiperidine dérivative of formula Ile may then be acylated by employing standard methods to provide the compound of Formula le. For example, the compound le may then be formed using a standard peptide coupling reaction with the desired carboxylic acid (R²CO2H). For example, the spiropiperidine intermediate Ile and carboxylic acid (R^ZCO2H) may be coupled by forming an activated carboxylic acid ester, such as by contacting the carboxylic acid (R^ZCO₂H) with a peptide coupling reagent, such as HATU or EDCHCI, in the presence or absence of an activating agent, such as HOBt and in the presence of a suitable base, such as DIEA, triethylamine or NMM, in a suitable solvent such as THF and/or DMF, DMA or dichloromethane and then contacting the activated carboxylic acid ester with the spiropiperidine dérivative Ile to form a compound of Formula le. Similar methodology can be employed to préparé the corresponding N1 analogues (where R¹ is on N1 of the pyrazole ring rather than on N2 as shown in Reaction Scheme III).

The compounds of the présent invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts. In accordance with the présent invention, compounds with multiple basic nitrogen atoms can form salts with varying number of équivalents (eq.) of acid. It will be understood by practitioners that ail such salts are within the scope of the présent invention.

Pharmaceutically acceptable salts, as used herein In relation to compounds of the présent invention, include pharmaceutically acceptable inorganic and organic salts of the compound. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound thereof, with a suitable organic or inorganic acid and isolating the sait thus formed. Représentative salts include, but are not limited to, the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitate, pamoate, malonate, stéarate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, t art rate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may also include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnésium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tétraméthylammonium, tetraethylammonium, méthylammonium, dimethylammonium, trimethylammonium, triethylammonium, ethylammonium, and the like. For additional examples see, for example, Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

Compounds of the présent invention may exist in more than one crystal form. Polymorphe of compounds of Formula (I) and salts thereof (including solvatés and hydrates) form part of this invention and may be prepared by crystallization of a compound of the présent invention under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different températures; various modes of cooling, ranging from

very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting a compound of the présent invention followed by graduai or fast cooling. The presence of polymorphs may be determined by solid probe nuclear magnetic résonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

This invention also includes isotopically-labeled compounds, which are identical to those described by Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include 10 isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur and fluorine, such as ^ZH, ³H, ¹³C, ¹⁴C, ^1SN, ¹⁰O, ¹⁷O,³⁵S, ³⁶CI, ¹²⁵l, ¹²⁹l, and^1BF respectively. Certain isotopically-labeled compounds of the présent invention, for example those into which radioactive isotopes such as ³H and ’⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³H), and carbon-14 (i.e., ¹⁴C), isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ^ZH), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the présent invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds of the présent invention may contain stereogenic centers. These compounds may exist as mixtures of enantiomers or as pure enantiomers. Wherein a compound includes a stereogenic center, the compounds may be resolved into the pure enantiomers by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of stereoisomeric dérivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; sélective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic estérification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the séparation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, the spécifie stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.

Compounds of the présent invention may exist in different stable conformattonal forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric 5 single bond, for example because of steric hindrance or ring strain, may permit séparation of different conformers. The compounds of the présent invention further include each conformational isomer of compounds of Formula (I) and mixtures thereof.

Compounds of the présent invention are useful for treating diseases, conditions and/or disorders modulated by the inhibition of the acetyl-CoA carboxylases enzyme(s) (in particular, 10 ACC1 and ACC2), Another embodiment of the présent invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the présent invention and a pharmaceutically acceptable excipient, diluent or carrier. The compounds of the présent invention (including the compositions and processes used therein) may also be used in the manufacture of a médicament for the therapeutic applications described herein.

A typical formulation is prepared by mixing a compound of the présent invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include matcrials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobie matériels, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will dépend upon the means and purpose for which 20 the compound of the présent invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, éthanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an élégant présentation of the drug (i.e., a compound of the présent invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical 30 product (i.e., for use in the preparing a médicament).

The formulations may be prepared using conventional dissolution and mixing procedures.

For example, the bulk drug substance (i.e., compound of the présent invention or stabiiized form of the compound (e.g., complex with a cyclodextrïn dérivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.

The dissolution rate of poorly water-soluble compounds may be enhanced by the use of a spray16631 dried dispersion, such as those described by Takeuchi, H., et al. in Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent déposition method and disintegrants J. Pharm. Pharmacol.. 39, 769-773 (1987); and ΕΡ09017Θ6 B1 (US2002/009494), incorporated herein by reference. The compound of the présent invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an élégant and easily handleable product

The pharmaceutical compositions also include solvatés and hydrates of the compounds of the présent invention. The term solvaté refers to a molecular complex of a compound represented by Formula (I) (including pharmaceutically acceptable salts thereof) with one or more 10 solvent molécules. Such solvent molécules are those commonly used in the pharmaceutical art, which are known to be innocuous to the récipient, e.g., water, éthanol, ethylene glycol, and the like, The term hydrate” refers to the complex where the solvent molécule is water. The solvatés and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvatés in the préparation of more désirable solvatés, such as methanol, methyl t-butyl ether, ethyl acetate, 15 methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and the like.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, métal cyllnders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

The présent invention further provides a method of treating diseases, conditions and/or disorders modulated by the inhibition of the acetyl-CoA carboxylases enzyme(s) in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutical composition comprising an effective amount of a compound of the présent invention and a pharmaceutically acceptable excipient, diluent, or carrier. The method is particularly useful for treating diseases, conditions and/or disorders that benefit from the inhibition of acetyl-CoA carboxylases enzyme(s).

One aspect of the présent invention is the treatment of obesity, and obesity-related disorders (e.g., overweight, weight gain, or weight maintenance).

Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimâtes the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m²). Overweight is typically defined as a BMI of

25-29.9 kg/m², and obesity is typically defined as a BMI of 30 kg/m². See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998).

Another aspect of the présent invention is for the treatment (e.g., delaying the progression or onset) of diabètes or diabetes-related disorders including Type 1 (insulin-dependent diabètes mellitus, also referred to as “IDDM¹¹) and Type 2 (noninsulin-dependent diabètes mellitus, also referred to as “NIDDM) diabètes, impaired glucose tolérance, insulin résistance, hyperglycemia, and diabetic complications (such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).

In yet another aspect of the présent invention is the treatment of obesity co-morbiditles, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin résistance, diabètes (e.g., Type 2 diabètes), coronary artery disease and heart failure. For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P.Z., et al., “The Metabolic Syndrome: Perhaps an Etiologie Mystery but Far From a Myth -Where Does the International Diabètes Fédération Stand?. Diabètes & Endocrinoloav. 7(2), (2005); and Alberti, K.G., et al., The Metabolic Syndrome - A New Worldwide Définition,” Lancet, 366, 1059-62 (2005). Preferably, administration of the compounds of the présent invention provides a statistically significant (p<0.05) réduction in at least one cardiovascular disease risk factor, such as lowering of plasma leptin, C-reactive protein (CRP) and/or cholestérol, as compared to a vehicle control containing no drug. The administration of compounds of the présent invention may also provide a statistically significant (p<0.05) réduction in glucose sérum levels.

In yet another aspect of the invention is the treatment of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin résistance.

For a normal adult human having a body weight of about 100 kg, a dosage in the range of from about 0.001 mg to about 10 mg per kilogram body weight is typically sufficient, preferably from about 0.01 mg/kg to about 5.0 mg/kg, more preferably from about 0.01 mg/kg to about 1 mg/kg. However, some variability in the general dosage range may be required depending upon the âge and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like. The détermination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefît of the instant disclosure. It is also noted that the compounds of the présent invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the présent invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be 5 used in combination with the compounds of the présent invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.

Suitable lipid lowering agents that can be combined with the compounds of the présent invention include, for exampie, those described at page 30, line 20 through page 31, line 30 of WO 10 2011005611. The lipid lowering agents include bile acid séquestrants, HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, cholestérol absorption inhibitors, acyl coenzyme Acholesterol acyl transferase (ACAT) inhibitors, CETP inhibitors, squalene synthetase inhibitors, PPAR a agonists, FXR receptor modulators, LXR receptor modulators, lipoprotein synthesis inhibitors, rennin angiotensisn system inhibitors, PPAR d partial agonists, bile acid reabsorption 15 inhibitors, PPAR y agonists, triglycéride synthesis inhibitors, microsomal triglycéride transport inhibitors, transcription modulators, squalene epoxidase inhibitors, low density lipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, niacin bound chromium and other agents that affect lipid composition.

Suitable anti-hypertensive agents that can be combined with the compounds of the présent 20 invention include, for example, those described at page 31, line 31 through page 32, line 1Θ of WO 2011005611. The anti-hypertensive agents include diuretics, beta-adrenergic blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, neutral endopeptidase inhibitors, endothelin antagonists, vasodilators, angiotensin II receptor antagonists, α/β adrenergic blockers, alpha 1 blockers, alpha 2 agonists, aldostérone inhibitors, mineraocorticoid receptor 25 inhibitors, renin inhibitors and angiopoietin-2-binding agents.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in W02009144554, W02003072197, W02009144555 and W02008065508, a diacylglycérol O-acyltransferase 1 (DGAT-1) inhibitor, such as those described in W009016462 or WO2010086820, AZD7687 or LCQ908, diacylglycérol O-acyltransferase 2 (DGAT-2) inhibitor, 30 monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine, camiglibose, 35 emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone,

ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone and troglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such as an agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide, exenatide 5 (Byetta®), albiglutide, taspoglutide, lixisenatide, dulaglutide, semaglutide, NN-9924.TTP-054, a protein tyrosine phosphatase-1B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Todav. 12(9/10), 373-381 (2007)), SIRT1 inhibitor (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (e.g., those in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and 10 saxagliptin), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa) such as those described in WO2010103437, WO2010103438, W02010013161, W02007122482, TTP-399, TTP-355, TTP547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, an insulin mimetic, a glycogen phosphorylase inhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 15 inhibitors, such as those described in E.C. Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin, BI-10733, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 as well as those in WO2010023594, a glucagon receptor modulator such as those described in Demong, D.E. et al. Annual Reports in Médicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described 20 in WO2010140092, WO2010128425, W02010128414, WO2010106457, Jones, R.M. et al. in

Médicinal Chemistry 2009, 44, 149-170 (e.g. ΜΒΧ-29Θ2, GSK1292263, APD597 and PSN821), FGF21 dérivatives or analogs such as those described in Kharitonenkov, A. et al. et al„ Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in 25 Médicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Médina, J.C., Annual Reports in Médicinal Chemistry, 2008, 43, 75-85, including but not limited to ΤΑΚ-Θ75, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further représentative listing of antidiabetic agents that can be combined with the compounds of the présent invention can be found, 30 for example, at page 28, line 35 through page 30, line 19 of WO2011005611. Preferred antidiabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors 35 of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa, PKCb, PKCg), inhibitors of fatty

acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 famlly including ILIbeta, modulators of RXRalpha. In addition 5 suitable antl-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

Suitable anti-obesity agents (some of which may also act as anti-diabetic agents as well) include 11p-hydroxy steroid dehydrogenase-1 (Ιΐβ-HSD type 1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine 10 reuptake inhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5 antagonists such 15 as velneperit), PYY3.36 (including analogs thereof), BRS3 modulator, mixed antagonists of opiod receptor subtypes, thyromimetic agents, déhydroépiandrostérone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, cillary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein 20 (AGRP) inhibitors, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide, JTT130, Usistapide, Sl_x4090), opioid antagonist, mu opioid receptor modulators, including but not limited to GSK1521498, MetAp2 inhibitors, including but not limited to ZGN-433, agents with mixed modulatory activity at 2 or more of glucagon, GIP and GLP1 receptors, such as MAR-701 or 25 ZP2929, norepinephrine transporter inhibitors, cannabinoid-1-receptor antagonist/inverse agonists, ghrelin agonists/antagonists, oxyntomodulin and analogs, monoamine uptake inhibitors, such as but not limited to tesofensine, an orexin antagonist, combination agents (such as bupropion plus zonisamide, pramlintide plus metreleptin, bupropion plus naltrexone, phentermine plus topiramate), and the like.

Preferred anti-obesity agents for use in the combination aspects of the présent invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541-47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1H-indol-3ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropylacetamide described in PCT Publication No. WO 2005/116034 or US Publication No. 200535 0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US

6,818,658), lipase inhibitor (e.g., Cetilistat), PYY3.3S (as used herein ΡΥΥ^ includes analogs, such as peglated PYY3.36 e.g., those described in US Publication 2006/0178501), opioid antagonîsts (e.g., naltrexone), oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), leptin, bromocriptine, orlistat, AOD-9604 (CAS No.

221231-10-3) and sibutramine. Preferably, compounds of the présent invention and combination thérapies are administered in conjunction with exercise and a sensible diet.

Ail of the recited U.S. patents and publications (including ail technical bulletins referenced in the Examples) are incorporated herein by reference in their entireties.

The Examples set forth herein below are for illustrative purposes only, The compositions, methods, and various parameters reflected herein are intended only to exemplify various aspects and embodiments of the invention, and are not intended to limit the scope of the claimed invention in any way.

EXAMPLES

The compounds and intermediates described below were named using the naming convention provided with Chemdraw Ultra, Version 11.0.1 (CambridgeSoft Corp., Cambridge Massachusetts). The naming convention provided with Chemdraw Ultra, Version 11.0.1 are well known by those skilled in the art and it is believed that the naming convention provided with Chemdraw Ultra, Version 11.0.1 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Unless noted otherwîse, ail reactants were obtained commercially. Ail of the references cited herein below are incorporated by reference.

Flash chromatography was performed according to the method described by Still et al., J. Org. Chem., 1978, 43, 2923.

Ail Biotage® purifications, discussed herein, were performed using Biotage® SNAP columns containing KP-SIL silica (40-63 pM, 60 Angstroms) (Biotage AB; Uppsala, Sweden).

Ail Combiflash® purifications, discussed herein, were performed using a CombiFlash® Companion system (Teledyne Isco; Lincoln, Nebraska) utilizing packed RediSep® silica columns Mass Spectra were recorded on a Waters (Waters Corp.; Milford, MA) Micromass Platform

II spectrometer. Unless otherwise specified, mass spectra were recorded on a Waters (Milford, MA) Micromass Platform II spectrometer.

Proton NMR chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on a Varian Unity 300, 400 or 500 MHz (megaHertz) spectrometer (Varian Inc.; Palo Alto, CA). NMR chemical shifts are given in parts per million downfield from tetramethylsilane (for proton) or fluorotrichloromethane (for fluorine).

ï

HPLC rétention times were measured using the following methods: Method A:

column: Waters Atlantis dCl6 4.6x50 mm, 5 pm; mobile phase A: 0.05% TFA in water (v/v); mobile phase B: 0.05% TFA in acetonitrile (v/v); gradient: 95% A/5% B linear to 5% A/95% B in 4.0 minutes, hold at 5% A/95% B for 5.0 minutes; flow rate: 2.0 mL/minute.

The préparations described below were used in the synthesis of compounds exemplified in the following examples.

The following starting materials are available from the corresponding sources

6-bromo-1 H-indole-3-carbonitrile - Indofine Chemical Company, Inc. (Hillsborough, NJ, USA)

5- bromo-1 H-indole-3-carbonitrile - Indofine Chemical Company, Inc. (Hillsborough, NJ, USA)

6- bromo-1H-indole-2-carboxamide-Aurora Fine Chemicals LLC (San Diego, CA, USA) methyl 3-iodo-1H-indazole-5-carboxylate - Anichem LLC (North Brunswick, NJ, USA) 1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid-ACS Scientîfic Inc. (Metuchen, NJ, USA) methyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate - ACS Scientîfic Inc. (Metuchen, NJ, USA) methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate-Anichem LLC (North Brunswick, NJ, USA) 5-(methoxycarbonyl)-1 H-indole-2-carboxylic acid - Bepharm Ltd. (Shanghai, China) methyl 3-bromo-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate - MolBridge (Plainsboro, NJ, USA) ethyl 2-bromo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate-American Custom Chemicals Corp. (San Diego, CA, USA)

5- bromo-1H-indazole-3-carboxylic acid - Anichem LLC (North Brunswick, NJ, USA)

6- methoxyquinoline-3-carboxylic acid -BioBlocks, Inc. (San Diego, CA, USA); prepared as described by A. Hanna-Eiias et al. Austr. J.Chem. 2009, 62, 150-156 2-amînoquinoline-6-carboxylic acid - Princeton Biomolecular Research Inc. (Monmouth Junction, NJ, USA)

5-bromo-2-nitrobenzaldehyde - Oakwood Products, Inc. (West Columbia, SC, USA) ethyl quinoline-7-carboxylate - ASW MedChem, Inc. (New Brunswick, NJ, USA)

Préparation of Intermediates and Starting Materials

Intermediate 1: 1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one, shown below, was prepared as follows:

Step 1. tert-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate

Methyl vinyl ketone (146 mL, 1.78 mol) was added to a solution of tert-butyl 4formylpiperidine-1-carboxylate (375 g, 1.76 mol) in tetrahydrofuran (18 L). The reaction mixture 5 was cooled to -5 °C and a solution of potassium hydroxide in éthanol (3N, 0.243 L) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room température and stirred for 16 hours. Cyclohexane (10 L) was added and the solution was washed with saturated sodium chloride (3x10 L). The organic layer was concentrated to an oil. This oil was dissolved in 2L of 80:20 cyclohexane / ethyl acetate and filtered through Celite® to remove the insoluble material. The filtrate was purified via flash column chromatography (30% ethyl acetate / hexanes) to afford the product as an oil. The oil was triturated in hexanes to afford the title compound as a colorless solid (131 g, 28%).

Step 2. 1 -isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1 H)-one

A solution of tert-butyl 9-oxo-3-azaspiro(5.5]undec-7-ene-3-carboxylate (250 g) and tris (dimethylaminomethane) (325 mL) in toluene (1.9 L) was heated at reflux for 4 hours. The mixture was distilled and concentrated to a minimum stirring volume (110 °C) and then toluene (1.9 L) was added. The reaction was redistilled to a minimum stirring volume and cooled to room température. Toluene (1.8 L) and isopropyl hydrazine hydrochloride (135 g) were added and the solution was 20 heated to reflux for 5 hours. The reaction was cooled to room température and was washed with citric acid (10% aqueous, 2 x 150 mL) and water (200 mL). The organic layer was then distilled to a minimum stirring volume. Methanol (2 L) was added and distilled to a minimum stirring volume.

This was repeated with methanol (2 L). The solution was redissolved in methanol (2.5 L) and Nbromosuccinimide (176 g) was added in one portion. The solution was stirred at 23 °C for 2 hours.

Aqueous sodium thiosulfate solution (5 wt%, 0.5 L) was added and the mixture was stirred for 15 minutes. The reaction mixture was concentrated via distillation (45 °C, 210 mm Hg) to - 0.5 L and then 2-methyl tetrahydrofuran (2.5 L) was added. After stirring for 15 minutes the aqueous layer was discarded. The organic layer was concentrated to - 0.2 L and tetrahydrofuran (0.5 L) was added. To the mixture was added a potassium tert-butoxlde solution in tetrahydrofuran (1.9 L, 1 M 30 solution). The solution was heated to 60 °C and stirred for 1 hour. After cooling to room température, aqueous hydrochloric acid (1 N, 2.2 L) was added over 20 minutes. The mixture was stirred at room température for 20 minutes, and then the layers were allowed to separate. The aqueous layer was removed and back extracted with ethyl acetate (1.75 L). The combined organic layers were washed with water (1 L) and concentrated via distillation (4 L solvent removed). Ethyl acetate (1.8 L) was added and the solution was concentrated to a minimum stirring volume. Ethyl acetate (3 L) and methanol (0.8 L) were added and the solution was cooled to 0 °C. Acetyl chloride (401 mL) was added dropwise over 20 minutes and the solution was stirred at 0 °C for 4 hours. The precipitate was collected by filtration under nitrogen. The filtrate was washed with ethyl acetate (0.5 L) and dried in a vacuum oven at 40 °C to afford the title compound as an off-white solid (241 g). +ESI (M+H) 248.4; Ή NMR (400 MHz, CD₃OD, δ): 7.43 (s, 1 H), 5.32 - 5.42 (m, 1 H), 3.15 - 3.25 (m, 4 H), 2.89 (s, 2 H), 2.64 (s, 2 H), 1.69 - 1.90 (m, 4 H), 1.37 - 1.45 (m, 6 H).

Intermediate 2: 2-tert-butyl-4,6-dihydrospiro[indazole-5,4'-piperidÎn]-7(2H)-one hydrochloride sait, shown below, was prepared as follows:

Step 1. benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate

o

To a benzene (700 mL) solution of benzyl 4-formylpiperidine-1-carboxylate (90.0 g, 364 mmol) in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p-toluenesulfonic acid (6.92 g, 36.4 mmol) with stirring. The reaction was heated to 70 °C, and 3-buten-2-one (61.8 mL, 753 mmol) was added. The mixture was heated at reflux for 24 hours collecting expelled water in the trap. The reaction was cooled to room température and washed with 500 mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The résultant dark brown oil was taken up in 200 mL dichloromethane and filtered through a silica pad (600 mL silica), eluting with 2 L heptane followed by 3 L 50% ethyl acetate/heptane and then 3 L ethyl acetate. Fractions containing clean product were combined and concentrated to yield 68.1 g of the title compound as a thick brown oil. The fractions containing impure product were combined and concentrated and purified by flash column chromatography (10-80% ethyl acetate / heptanes) to yield an additional 23.6 g of the title compound as a thick brown oil. A combined yield of 91.7 g, (94.1%) was realized. Ή NMR (400 MHz, CDCI₃, δ): 7.27 - 7.43 (m, 5 H), 6.79 (d, J =

10.3 Hz, 1 H), 5.95 (d, J =10.3 Hz, 1 H), 5.13 (s, 2 H), 3.56 - 3.71 (m, 2 H), 3.39 - 3.55 (m, 2H),

2.38 - 2.50 (m, 2 H), 1.96 (t, J = 6.7 Hz, 2 H), 1.52 - 1.70 (m, 4 H).

Step 2. (E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3-carboxylate hydrochloride sait

Benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (4.89 g, 16.3 mmol) was dissolved in éthanol (60 mL) and tert-butylhydrazine hydrochloride (2.44 g, 19.6 mmol) was added. The mixture was heated at reflux for 4 hours and then stirred at 60 °C for 48 hours. The reaction was cooled to room température and concentrated under reduced pressure to give a tan oil which solidified upon standing to yield 6.60 g (99%) of the title compound as a tan solid. +ESI (M+H) 370.3; ¹H NMR (400 MHz, CDCI₃, δ): 7.26 - 7.42 (m, 5 H), 6.46 (d, 10.0 Hz, 1 H), 6.26 (br. s., 1

H), 5.08 - 5.16 (m, 2 H), 3.43 - 3.58 (m, 4 H), 3.19 (s, 2 H), 1.78 (s, 2 H), 1.44- 1.63 (m, 4 H), 1.171.30 (m, 9H).

Step 3. benzyl 2-tert-butyl-2,4-dihydrospiro[indazole-5,4'-piperidine]-T-carboxylate

O (E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3-carboxylate hydrochloride sait (8.00 g, 19.7 mmol) was dissolved in dichloromethane (100 mL) and treated with sodium bicarbonate (1.70 g, 19.7 mmol). The solution was stirred for 30 minutes and was then filtered and concentrated under reduced pressure to yield (E)-benzyl 9-(2-tert-butylhydrazono)-3azaspiro[5.5]undec-7-ene-3-carboxylate. A 250 mL round bottom flask was charged with dimethylformamide (80 mL) and cooled to 0 °C. Phosphorous oxychloride (5.51 mL, 59.1 mmol) was added dropwise over 2 minutes, and the solution was stirred for 30 minutes at 0 °C. To this solution was added the (E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3carboxylate in dimethylformamide (15 mL) and the reaction was heated at 80 °C for 18 hours. The reaction was cooled to room température and concentrated under reduced pressure. The résultant oil was dissolved in ethyl acetate (500 mL) and washed with brine (2 x 150 mL). The aqueous layer was extracted with an additional 100 mL ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The résultant oil was purified by flash column chromatography (10-80% ethyl acetate / heptane) to yield 4.89 g (65%) of the title compound as a pale yellow oil. +ESI (M+H) 380.0; Ή NMR (400 MHz, CDCI₃, δ): 7.25 - 7.36 (m, 5 H), 7.18 (s, 1 H), 6.57 (d, J = 10.0 Hz, 1 H), 5.86 (d, J = 10.0 Hz, 1 H), 5.12 (s, 2 H), 3.51 - 3.69 (m, 2 H), 3.36 3.53 (m, 2 H), 2.58 (s, 2 H), 1.59 - 1.74 (m, 2 H), 1.52 - 1.58 (m, 9 H), 1.41 -1.53 (m, 2 H).

Step 4. benzyl 6-bromo-2-tert-butyl-7-methoxy-2,4,6,7-tetrahydrospiro[indazole-5_l4'-piperidine]-1 carboxylate θ'

O

Benzyl 2-tert-butyl-2,4-dihydrospiro[indazole-5,4'-piperidine]-1'-carboxylate (560 mg, 1.4Θ mmol) was dissolved in a 20 % methanol / tetrahydrofuran mixture (25 mL). N-bromosuccinimide (315 mg, 1.77 mmol) was added and the mixture was stirred for 30 minutes. The mixture was concentrated under reduced pressure. The résultant oil was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The résultant oil was purified by flash column chromatography (10-80% ethyl acetate / heptane) to yield 538 mg (73%) of the title compound as a colorless oil. ¹H NMR (400 MHz, CDCIa, δ): 7.27 - 7.43 (m, 6 H), 5.12 (s, 2 H), 4.74 (d, J = 2.7 Hz, 1 H), 4.41 (d, J = 2.5 Hz, 1 H), 3.60 - 3.84 (m, 2 H), 3.54 - 3.61 (m, 3 H), 3.14 - 3.39 (m, 2 H), 2.59 (s, 2 H), 1.86 (br. s„ 1 H), 1.69 (br. s., 3 H), 1.51-1.60 (m, 9 H).

Step 5. benzyl 2-tert-butyl-7-oxo-2,4,6,7-tetrahydrospiro[indazole-5,4’-piperidine]-T-carboxylate

Benzyl 6-bromo-2-tert-butyl-7-methoxy-2,4,6_l7-tetrahydrospiro[indazole-5,4^,-piperidine]-1^lcarboxylate (150 mg, 0.31 mmol) was dissolved in 5 mL tetrahydrofuran and treated with potassium

tert-butoxide (0.61 mL, 0.61 mmol, 1 M tetrahydrofuran) and stirred for 30 minutes. Aqueous 2 N HCl (5 mL) was added and the mixture was stirred for 15 minutes at room température. The mixture was then diluted with 50 mL water and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (10-80% ethyl acetate ! heptanes) to yield 86 mg (71%) of the title compound as a clear oil. +ESI (M+H) 396.5; ’H NMR (400 MHz, CDCI₃, δ): 7.38 (s, 1 H), 7.27 7.35 (m, 5 H), 5.11 (s, 2 H), 3.48 (t, J = 5.8 Hz, 4 H), 2.71 (s, 2 H), 2.57 (s, 2 H), 1.57 - 1.66 (m, 9 H), 1.47-1.59 (m, 4 H).

Step 6. 2-tert-butyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one hydrochloride sait

Benzyl 2-tert-butyl-7-oxo-2,4,6,7-tetrahydrospiro[indazole-5,4'-piperrdine]-r-carboxylate (441 mg, 1.12 mmol) was dissolved in methanol (15 mL) and treated with ammonium formate (217 mg, 3.34 mmol) and palladium on carbon (50 mg, 10% Pd, 50% H₂O). The reaction was stirred 2 hours at room température and the catalyst then removed by filtration. The filtrate was concentrated under reduced pressure, The résultant colorless solid was taken up in ethyl acetate (20 mL) and treated with 0.5 M HCl in diethyl ether (1 mL). The mixture was stirred for 30 minutes and concentrated under reduced pressure. The résultant colorless solid was triturated with heptane (20 mL) to yield 265 mg (80%) of the title compound as a colorless solid. +ESI (M+H) 262.1 ; ’H NMR (400 MHz, CD₃OD, δ): 7.74 (s, 1 H), 3.20 (t, J = 6.1 Hz, 4 H), 2.88 (s, 2 H), 2.64 (s,

2 H), 1.67-1.91 (m, 4 H), 1.55 -1.63 (m, 9 H).

Intermediate 3: 2-(bicyclo[1.1.1]pentan-1-yl)-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one_lshown below, was prepared as follows:

Step 1: dî-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate

Tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(lll) (281 mg, 0.460 mmol) was dîssolved In 2-propanol (100 mL) in a 1 L 3-necked flask equipped with addition funnel, gas inlet, and thermometer. The solution was cooled to -15 °C under nitrogen. Di-tert-butyl azodicarboxylate (8.11 g, 34.5 mmol) and phenylsilane (2.9 mL, 23 mmol) were dissolved in dichloromethane (100 mL) and this resulting orange solution was added to the above cooled solution dropwise over 10 minutes, maintaining the internai température at approximately -10 °C. A solution of [1.1.1]propellane (Journal of the American Chemical Society (2001), 123(15), 3484-3492) (50 mL, 23 mmol, 0.46 M in pentane) was added to the reaction mixture in one portion at -15 °C. The reaction was stirred at -15 °C for 30 minutes. The cold bath was removed and the reaction was allowed to warm to room température and stîr for 4 hours. The reaction was concentrated and purification by flash column chromatography (5-20% ethyl acetate / heptanes) gave the title compound (6.38 g, 93%) as a clear oil which solidifiée) upon standing. -ESI (M-H) 297.4; Ή NMR (400 MHz, CDCI₃₁ δ): 6.26 (br. s„ 1H), 2.37 (s, 1H), 2.02 (s, 6H), 1.45 (s, 18H).

Step 2: bicyclo[1.1.1]pentan-1-ylhydrazine hydrochloride

To a solution of di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate (6.38 g, 21.4 mmol) in ethyl acetate (20 mL) was added 4 N hydrochloric acid in 1,4-dioxane (53.5 mL, 214 mmol). The reaction was stirred at room température for 18 hours. The reaction was concentrated and the solid triturated with heptanes to yield the title compound (3.24 g, 89%) as a white solid. ’H NMR (400 MHz, DMSO-d_e, δ): 2.42 (s, 1 H), 1.80 (s, 6 H).

Step 3: benzyl 2-(bicyclo[1.1.1]pentan-1-yl)-7-oxo-2,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]1 '-carboxylate

O

The title compound was prepared by a method analogous to that described in Steps 1 - 5 of

Intermediate 2, using bicyclo[1.1.1]pentan-1-ylhydrazine hydrochloride in Step 2. +ESI (M+H)

406.1; ’H NMR (400 MHz, CDCI₃, δ): 7.28 - 7.36 (m, 5 H), 7.27 (s, 1 H), 5.10 (s, 2 H), 3.44 - 3.50 (m, 4 H), 2.70 (s, 2 H), 2.62 (s, 1 H), 2.56 (s, 2 H), 2.31 (s, 6 H), 1.53 (d, J= 2.5 Hz, 4H).

Step 4: 2-(bicyclo[1.1.1 ]pentan-1 -yl)-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one

To a solution of benzyl 2-(bicyclo[1.1.1]pentan-1-yl)-7-oxo-2,4,6,7-tetrahydrospiro(indazole5,4‘-piperidine]-r-carboxylate (150 mg, 0.37 mmol) in ethyl acetate (10 mL) was added 10% palladium on carbon (1 mg) and 1-methylcyclohexane-1,4-diene (0.1 mL, 0.9 mmol). The reaction was heated to 80 °C and stirred for 2 hours. The reaction was cooled to room température and filtered through Celite. The filtrate was concentrated to give the title compound (100 mg, 100%) as an oil. +ESI (M+H) 272.4; Ή NMR (400 MHz, CDCI₃, δ): 7.26 (s, 1 H), 2.82 (dd, J = 6.63, 4.49 Hz, 4 H), 2.69 (s, 2 H), 2.60 (s, 1 H), 2.56 (s, 2 H), 2.30 (s, 6 H), 1.47 - 1.55 (m. 4 H).

Intermediate 4: 1-tert-butyl-4,6-dihydrospiro[indazole-5,4^,-piperidin]-7(1H)-one, shown below, was prepared as follows:

NH

Step 1. benzyl 10-({dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate

O

Benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (15.2 g, 51 mmol) was dissolved in toluene (180 mL) and tns(dimethylamino)methane (22.2 g, 27 mmol) was added. The reaction was heated to reflux for 5 hours and then allowed to cool to room température and stir overnight. The reaction solution was concentrated in vacuo to provide the title compound (18.0 g, 100%). +APCI (M+H) 354.6; ¹H NMR (400 MHz, CDCI_a, δ): 7,49 (s, 1 H), 7.28 - 7.40 (m, 5 H), 6.59 (d, J = 10.16

Hz, 1 H), 6.01 (d, J = 9.97 Hz, 1 H), 5.13 (s, 2 H), 3.52 - 3.66 (m, 2 H), 3.39 - 3.52 (m, 2 H), 3.07 (s,

H), 2.74 (s, 2 H), 1.58- 1.73 (m, 2 H), 1.41 -1.58 (m, 2 H).

Step 2. benzyl 1-tert-butyl-1,4-dihydrospiro[indazole-5,4’-piperidine)-1'-carboxylate

-Y

Benzyl 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (59.2 g, 167 mmol) was dissolved in éthanol (Θ35 mL). To the solution was added acetic acid (20 mL, 345 mmol) and tert-butylhydrazine hydrochloride (29.1 g, 234 mmol). The reaction was heated to reflux for 1 hour. The reaction was cooled to room température and concentrated to an orange oil. Purification by flash column chromatography (20-40% ethyl acetate / heptanes) afforded the title compound (50 g, 79%) as a pale yellow solid. +ESI (M+H) 380.5; ’H NMR (400 MHz, CDCh, δ): 7.26-7.40 (m, 5 H), 7.17 (s, 1 H), 6.66 (d, J = 9.95 Hz, 1 H), 5.77 (d, J = 10.15 Hz, 1 H), 5.12 (s, 2 H), 3.38 - 3.64 (m, 4 H), 2,58 (s, 2 H), 1.60 (s, 12 H), 1.50 (br. s., 1 H).

Step 3. benzyl 6-bromo-1 -tert-butyl-7-hydroxy-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 'carboxylate

O

Benzyl l-tert-butyl-M-dihydrospirofindazole-S^'-piperidineJ-r-carboxylate (50 g, 132 mmol) was dissolved in tetrahydrofuran (1 L). Tothe reaction was added A/-bromosuccinimide (24.6 g, 138 mmol) and water (250 mL). The reaction was stirred for 1 hour at room température. The reaction was partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed 2 times with water and once with saturated aqueous sodium chloride. The organic phase was dried over magnésium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from diethylether to afford the title compound (60.7 g, 97%) as a creamcolored solid. +ESI (M+H) 476.5; ¹H NMR (400 MHz, CDCI₃,ô): 7.28 - 7.36 (m, 5 H), 7.27 (s, 1 H), 5.23 (t, J = 4.68 Hz, 1 H), 5.12 (s, 2 H), 4.24 (d, J = 4.49 Hz, 1 H), 3.87 (br. s., 2 H), 3.12 (br. s., 2 H), 2.79 (d, J = 16.00 Hz, 2 H), 2.59 (d, J = 15.80 Hz, 2 H), 1.95 (br. s._r 1 H), 1.66 (s, 11 H), 1.58 (br. s., 1 H).

Step 4. benzyl 6-bromo-1-tert-butyl-7-oxo-1 ,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 carboxylate

O

Benzyl 6-bromo-1-tert-butyl-7-hydroxy-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 carboxylate (57.9 g, 122 mmol) was dissolved in acetone (1 L) and cooled to 0 °C in an ice bath. To the solution was added Jones Reagent (122 mL) (Fillion, E. Tetrahedron Letters 2004,46,10911094). The ice bath was removed and the reaction was allowed to warm to room température and stir for 45 minutes. Saturated aqueous sodium bicarbonate was added until gas évolution ceased and the pH reached 7. The resulting mixture was filtered through a pad of Celite®, rinsing with ethyl acetate. The filtrate layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed twice with water, once with saturated aqueous sodium chloride, dried over magnésium sulfate, filtered and concentrated. The residue was crystallized from ethyl acetate / heptanes to afford the title compound (50.4 g, 87%). +ESI (M+H) 474,5; ¹H NMR (400 MHz, CDCI₃₁ δ): 7.32 (d, J = 9.38 Hz, 6 H), 5.11 (s, 2 H), 4.24 (s, 1 H), 3.58 - 3.84 (m, 2 H), 3.16-3.41 (m, 2 H), 2.67-2.91 (m, 2 H), 1.80 (br. s., 1 H), 1.61 -1.76 (m, 11 H), 1.52-1.61 (m, 1 H).

Step 5. benzyl 1 -tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 '-carboxylate

O

To a solution of benzyl 6-bromo-1-tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'piperidine]-r-carboxylate (50.4 g, 106 mmol) in tetrahydrofuran (600 mL), was added saturated aqueous ammonium chloride (600 mL) and zinc powder (20.8 g, 319 mmol). The reaction was stirred for 30 minutes at room température. The reaction was filtered through Celite®. The phases of the filtrate were separated and the organic phase was washed with water and saturated aqueous sodium chloride. The organics were dried over magnésium sulfate, filtered, and concentrated to

provide a foam. The foam was triturated once with ethyl acetate / heptanes and once with diethylether to afford the title compound (40.4 g, 96%) as a white solid. +ESI (M+H) 396.5; ¹H NMR (400 MHz, CDCIa, δ): 7.24 - 7.38 (m, 6 H), 5.11 (s, 2 H), 3.36 - 3.61 (m, 4 H), 2.74 (s, 2 H), 2.54 (s, 2 H), 1.64 (s, 9 H), 1.51 (br. s., 4 H).

Step 6. 1 -tert-butyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1 H)-one

A solution of benzyl 1-tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5_l4’-piperidine]-rcarboxylate (46.6 g, 118 mmol) in éthanol (730 mL) was added to 10% palladium on carbon (9.4 g). To this mixture was added 1-methyl-1,4-cyclohexadiene (90 mL, 769 mmol). The reaction was stirred at reflux for 2 hours. The reaction was cooled to room température and filtered through Celite®. The filtrate was concentrated in vacuo to give a gray solid. The solid was dissolved in ethyl acetate (150 mL) and to this solution was added 4 M hydrochloric acid in 1,4-dioxane (35 mL). The resulting precipitate was collected by filtration and dried under vacuum to afford the title compound (34 g, 97%) as a white solid. +ESI (M+H) 262.5; ¹H NMR (400 MHz, CD₃OD, δ): 7.34 (s, 1 H) 3.12 - 3.25 (m, 4 H) 2.90 (s, 2 H) 2.66 (s, 2 H) 1.67 - 1.85 (m, 4 H) 1.62 (s, 9 H).

Intermediate 5:1-(bicyclo[1.1,1]pentan-1-yl)-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one hydrochloride, shown below, was prepared as follows:

Step 1: benzyl 1-(bicyclo[1.1.1]pentan-1-yl)-1 _l4-dihydrospiro[indazole-5,4'-piperidine]-1'carboxylate

To a solution of benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (543 mg, 1.81 mmol) in toluene (15 mL) was added tris(dimethylamino)methane (0.47 mL, 2.7 mmol). The reaction was heated to reflux and stirred for 4 hours. The reaction was cooled to room température,

diluted with ethyl acetate (50 mL), and washed with water (50 mL). The organic layer was dried oer sodium sulfate, filtered, and concentrated. The resulting yellow oil was taken up in toluene (15 mL) and bicyclo[1.1.1]pentan-1-ylhydrazine hydrochloride (310 mg, 1.Θ1 mmol) was added. The mixture was heated to reflux and stirred for 1Θ hours. The reaction was cooled to room température, diluted with ethyl acetate (50 mL), washed with water (50 mL) and 1 M aqueous citric acid (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2 regioisomeric products.

benzyl 1 -(bicyclo[1.1.1]pentan-1 -yl)-1,4-dihydrospiro[indazole-5,4‘-piperidine]-1 '-carboxylate (365 mg, 52%): +APCI (M+H) 390.5; Ή NMR (400 MHz, CDCI₃₁ δ): 7.33 - 7.36 (m, 5 H), 7.22 (s, 1 H), 6.51 (d. J = 10.1 Hz, 1 H), 5.81 (d, J = 9.9 Hz, 1 H), 5.12 (s, 2 H), 3.42 - 3.59 (m, 4 H), 2.59 (s, 3 H), 2.35 (s, 6 H), 1.43- 1.68 (m, 4 H).

benzyl 2-(bicyclo[1.1 .llpentan-l-yO^^-dihydrospiroIindazole-S^'-piperidineJ-l'-carboxylate (85 mg, 12%): +APCI (M+H) 390.5; ’H NMR (400 MHz, CDCI₃, δ): 7.33 - 7.36 (m, 5 H), 7.08 (d, J = 0.8 Hz, 1 H), 6.56 (d, J = 10.0 Hz, 1 H), 5.91 (d, J = 10.0 Hz, 1 H), 5.12 (s, 2 H), 3.40 - 3.62 (m, 4 H), 2.57 (s, 3 H), 2.26 (s, 6 H), 1.41 -1.68 (m, 4 H).

Step 2: benzyl 1 -(bicyclo[1.1.1]pentan-1 -yl)-7-oxo-1 Aej-tetrahydrospirolindazole-SX-piperidine]1 '-carboxylate

O

To a solution of benzyl 1-(bicyclo[1.1.1]pentan-1-yl)-1,4-dihydrospiro[indazole-5,4'piperidine]-T-carboxylate (340 mg, 0.87 mmol) in 3:1 tetrahydrofuran : water (10 mL) was added Nbromosuccinimide (155 mg, 0.87 mmol). The reaction was stirred at room température for 45 minutes. The reaction was diluted with ethyl acetate (50 mL), washed with 0.5 N aqueous sodium hydroxide (25 mL) and saturated aqueous sodium thiosulfate (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting oil was taken up in dichloromethane (5 mL) and treated with activated 4A molecular sieves (500 mg) and tetrapropylammonium perruthenate (16 mg, 0.04 mmol). The slurry was treated with N-methylmorpholine-N-oxide (243 mg, 1.75 mmol) in acetonitrile (5 mL). The reaction was stirred at room température for 2 hours. The reaction was filtered through Celite and the filtrate was concentrated. The residue was purified by flash column chromatography (7-60% ethyl acetate / heptanes) to yield a clear oil. The oil was

taken up in tetrahydrofuran (5 mL) and treated with saturated aqueous ammonium chloride (5 mL) and zinc dust (171 mg, 2.62 mmol). The mixture was stirred at room température for 30 minutes. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (7-60% ethyl acetate / heptanes) gave the title compound (148 mg, 42%) as a white solid. ¹H NMR (400 MHz, CDCI₃, δ): 7.34 (m, 6 H), 5.13 (s, 2 H), 3.51 (m, 4 H), 2.75 (s, 2 H), 2.59 (s, 1 H), 2.54 (s, 2 H), 2.41 (s, 6 H), 1.56 (m, 4 H).

Step 3: 1-(bicyclo[1.1.1]pentan-1-yl)-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one hydrochloride

The title compound was prepared by a method analogous to that described in Step 6 of Intermediate 4.

Intermediate 6: 3-carbamoyl-1 H-indazole-6-carboxylic acid, shown below, was prepared as follows:

To a solution of 1H-indazole-6-carboxylic acid (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2,06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room température overnight. The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100% ethyl acetate / heptanes) to afford methyl 1 H-indazole-6-carboxylate as a yellow solid (2.95 g, 90%). Ή NMR (400 MHz, CDCI₃₁ δ): 10.40 (br. s., 1 H), 8.26 (s, 1 H), 8.13 (s, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 3.96 (s, 3 H).

Step 2. methyl 3-iodo-1H-indazole-6-carboxylate

To a solution of methyl 1 H-indazole-6-carboxylate (865 mg, 4.91 mmol) in Ν,Νdimethylformamide (12 mL) was added potassium hydroxide (840 mg, 3.05 mmol) followed by iodine (1.54 g, 5.9 mmol). The mixture was stirred at room température for 3 hours. Sodium bisulfate (30 mL of 5% aqueous) was added and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (5-65% ethyl acetate / heptanes) to afford methyl 3-iodo-1 H-indazole-6-carboxylate as a colorless solid (1.16 g, 78%). ’H NMR (400 MHz, DMSO-d₆, δ): 13.84 (s, 1 H), 8.13 (s, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 3.87 (s, 3 H).

Step 3. methyl 3-cyano-1H-indazole-6-carboxylate

A mixture of methyl 3-iodo-1 H-indazole-6-carboxylate (3.0 g, 9.9 mmol), zinc dust (400 mg, 6.11 mmol), zinc cyanide (2.0 g, 17.0 mmol), [1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (1.15 g, 1.41 mmol), and copper (I) iodide (1.90 g, 9.97 mmol) in dimethylacetamide (55 mL) was purged with nitrogen for 15 minutes. The mixture was stirred at 120 °C for 15 hours. The reaction mixture was cooled, diluted with ethyl acetate (250 mL), and filtered through Celite, rinsing with ethyl acetate (100 mL). To the filtrats was added -400 mL of a solution of saturated aqueous ammonium chloride and concentrated ammonium hydroxide (prepared by adding ammonium hydroxide to a saturated aqueous solution of ammonium chloride until pH = 8). The mixture was stirred for 1 hour. The layers were then separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. To the residue was added methanol (40 mL) and the mixture was stirred overnight. The mixture was filtered and the solid was dried în vacuo to give methyl 3-cyano1 H-indazole-6-carboxylate as a tan solid (1.47 g, 73%). ’H NMR (400 MHz, DMSO-d₆, δ): 13.40 (br. s., 1 H), 8.25 (s, 1 H), 7.94 (d, J = 8.6 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 3.88 (s, 3 H).

Step 4. 3-carbamoyl-1H-indazole-6-carboxylic acid

To a solution of methyl 3-cyano-1 H-indazole-6-carboxylate (254 mg, 1,26 mmol) in methanol (12 mL) at 0 °C was added a cold solution of urea hydrogen peroxide (1.22 g, 12.6 mmol) in sodium hydroxide (12.6 mL 1M in water, 12.6 mmol). The yellow solution was stirred at room température overnight. The mixture was concentrated in vacuo to remove methanol. The pH of the resulting residue was adjusted to ~4 with 1N hydrochloric acid. A precipitate formed. The mixture was filtered and the solid was dried to afford 3-carbamoyl-1 H-indazole-6-carboxylic acid as a brown solid (82 mg, 32%). 1H NMR (400 MHz, DMSO-d_e, δ): 13.84 (s, 1 H), 13.04 (br. s., 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 8.13-8.16 (m, 1 H), 7.77 (br. s., 1 H), 7.74 (dd, J = 8.6, 1.4 Hz, 1 H), 7.38 (br. s„ 1 H).

Intermediate 7: 3-carbamoyl-1 H-indole-6-carboxylic acid, shown below, was prepared as follows:

NH₂

Step 1. 3-cyano-1 H-indole-6-carboxylic acid ethyl ester

To a solution of 6-bromo-1 H-indole-3-carbonitrile (328 mg, 1.48 mmol) in éthanol (5 mL) in a 500 mL Parr bottle was added sodium acetate (370 mg, 4.47 mmol) and [1,1 'bistdiphenylphosphinoJfenOcenejdichloropalladiumfll), complex with dichloromethane (242 mg, 0.297 mmol). The reaction vessel was purged with nitrogen and evacuated three times and then was filled with 30 psi carbon monoxide. The réaction mixture was heated to 70 ’C, increasing the pressure within the vessel to 45 psi. The reaction was agitated at 70 °C for 24 hours. The reaction mixture was cooled to room température. The mixture was filtered through Celite, rinsing with éthanol. The filtrate was concentrated under reduced pressure and diluted with dichloromethane. The remaining solids were filtered off and the filtrate was concentrated. The residue was purified by flash column chromatography (20-80% ethyl acetate / heptanes) to give 3-cyano-1 H-indole-6carboxylic acid ethyl ester (142 mg, 45%). -APCI (M-H) 213.4; ¹H NMR (400 MHz, DMSO-de, δ):

12.50 (br. s., 1 H), 8.45 (s, 1 H), 8.16 (s, 1 H), 7.82 (dd, J = 8.4, 1.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 4.32 (q, J = 7.0 Hz, 2 H), 1.33 (t, J = 7.0 Hz, 3 H).

Step 2. 3-carbamoyl-1H-indole-6-carboxylic acid

A suspension of 3-cyano-1 H-indole-6-carboxylic acid ethyl ester (100 mg, 1.4 mmol) in methanol (1.12mL) was added to a solution of urea hydrogen peroxide (453 mg, 4.67 mmol) in 2.5 M sodium hydroxide (1.12 mL, 2.80 mmol) at 0 °C. The suspension was allowed to warm to room température and was stirred overnight. The reaction was concentrated under reduced pressure. Water was added and the solution was acidified with 3 N aqueous hydrochloric acid to pH = 2. A precipitate formed. The reaction mixture was stirred for 1 minute at room température and was then filtered to give an orange solid. Additional urea hydrogen peroxide (453 mg) in 2.5 M sodium hydroxide and methanol was added and the mixture was stirred for 2 hours. The reaction was concentrated, diluted with water, acidified to pH = 3 and filtered. The solid was washed with water and heptanes and was dried in a vacuum oven to give 3-carbamoyl-1H-indole-6-carboxylic acid as a solid (66.5 mg, 70%). -ESI (M-1) 203.1; Ή NMR (400 MHz, DMSO-d_e, δ): 12.45 (br. s., 1 H), 11.78 (br. s., 1 H), 8.83 (d, J = 1.6 Hz, 1 H), 8.09 (d, J = 2.9 Hz, 1 H), 7.73 (dd, J = 8.6,1.8 Hz, 1 H), 7.51 (br. s., 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 6.89 (br. s., 1 H).

Intermediate 8: 3-carbamoyl-1 H-Îndazole-5-carboxylic acid, shown below, was prepared as follows:

Step 1. methyl 3-cyano-1H-indazole-5-carboxylate

Methyl 3-iodo-1H-indazole-5-carboxylate (30.7 g, 102 mmol), zinc cyanide (20.3 g, 173 mmol), zinc dust (4.05 g, 61.9 mmol), [1,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll), complex with dichloromethane (12 g, 15 mmol), and copper (I) iodide (19.7 g, 103 mmol) were combined in a 1L round bottom flask. N,N-dimethylacetamide (500 mL) was added and the reaction mixture was purged with nitrogen for 10 minutes. The reaction was heated to 120 °C for 1 hour. The reaction was cooled to room température and was diluted with ethyl acetate (1 L), and allowed

to stirfor 20 minutes. The reaction mixture was filtered through a plug of Colite, rinsing with 500 mL ethyl acetate. The filtrate was added to a solution of saturated ammonium chloride and concentrated ammonium hydroxide (2 L) (prepared by adding ammonium hydroxide to a saturated aqueous solution of ammonium chloride until pH = 8) and the biphasic solution was stirred vigorously for 1 hour. The resulting émulsion was filtered through a small pad of Celite. The layers were separated and the aqueous was extracted two additional times with ethyl acetate (1.1 L), each time filtering the resulting émulsion through Celite. The combined organic layers were washed with water (2 x 900 mL) and brine (900 mL), dried over sodium sulfate, filtered and concentrated. To the crude was added methanol (100 mL) and the mixture was stirred for 20 minutes. The resulting precipitate was filtered off and washed with methanol (10 mL). The filtrate was concentrated to give the title compound (13.2 g, 65%) as a solid. -ESl (M-H) 200.0; ¹H NMR (400 MHz, DMSO-d_e, δ):

8.43 - 8.45 (m, 1 H), 8.05 (dd, J = 8.8, 1.6 Hz, 1 H), 7.85 (dd, J = 8.9, 0.9 Hz, 1 H), 3.88 (s, 3 H).

Step 2. 3-carbamoyl-1 H-indazole-5-carboxylic acid

A suspension of methyl 3-cyano-1 H-indazole-5-carboxylate (50.0 g, 249 mmol) in methanol (1 L) was cooled to 10 °C. A solution of urea hydrogen peroxide (241 g, 2.49 mol) in sodium hydroxide (1 L of 2.5 N) and water (100 mL) was added dropwise, maintaining an internai température below 25 °C. When the addition was complété, the ice bath was removed and the reaction was allowed to stir at room température for 16 hours. A small amount of unreacted starting material was observed by HPLC. The réaction was cooled to 15 °C and additional urea hydrogen peroxide (50 g) was added portionwise. Vigorous bubbling was noted. The reaction was allowed to stir for another 2 hours. The crude reaction was filtered to remove the solids présent and the filtrate was concentrated to remove the methanol. The remaining solution was cooled in an ice bath and 6 N hydrochloric acid (420 mL) was added dropwise to adjust the pH to 4. The solution was stirred for

20 minutes and the resulting tan solid was collected by filtration and dried to give 57.2 g of crude product. To the crude was added acetonitrile (700 mL) and dichloromethane (700 mL) and the mixture was stirred at room température for 1 hour. The solid was collected by filtration, washed with 1:1 acetonitrile : dichloromethane (400 mL) and dried to give the title compound (39.5 g, 77%) as a tan solid. +ESI (M+H) 206.1; Ή NMR (DMSO-d₆, δ): 13.81 (s. 1 H), 12.85 (br. s„ 1 H), 8.82 (d, J = 0.8 Hz, 1 H), 7.93 (dd, J = 8.8,1.6 Hz, 1 H), 7.79 - 7.85 (m, 1 H), 7.64 (d, J = 8.6 Hz, 1 H),

7.44 (s, 1 H).

Intermediate 9: 3-carbamoyl-1 H-pyrrolo[3,2-b]pyridine-6-carboxylic acid, shown below, was prepared as follows:

Step 1. benzyl 1 H-pyrrolo[3,2-b]pyridine-6-carboxylate

To a solution of 1 H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (1.37 g, 8.45 mmol) in Ν,Νdimethylformamide (55 mL) was added césium carbonate (2.79 g, 8.56 mmol) and benzyl bromide (1,05 mL, 8.64 mmol). The reaction was allowed to stir at room température for 17 hours. Additional césium carbonate (500 mg, 1.54 mmol) and benzyl bromide (0.186 mL, 1.53 mmol) were added, and the reaction was stirred for another 4 hours. The reaction was then quenched with water and diluted with ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate three times. The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0100% ethyl acetate / heptanes) gave the title compound (1.42 g, 67%). +ESI (M+H) 253.3; ’H NMR (400 MHz, DMSO-dg, δ): 11.68 (br. s., 1 H), 8.93 (d, J = 2.0 Hz, 1 H), 8.33 (dd, J = 2.0, 1.0 Hz, 1 H), 7.93 (t, J = 3.0 Hz, 1 H), 7.51 (m, 2 H), 7.41 (m, 3 H), 6.68 (ddd, J = 3.1,2.0, 1.0 Hz, 1 H), 5.40 (s, 2 H).

Step 2. benzyl 3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carboxylate

To a 0 °C solution of benzyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate (830 mg, 3.29 mmol) in Ν,Ν-dimethylformamide (19 mL) was added N-bromosuccinimide (609 mg, 3.42 mmol). The reaction was allowed to gradually warm to room température and stir over the weekend. The reaction was diluted with ethyl acetate and washed successively with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, water, and brine. The organics were dried over sodium sulfate, filtered, and concentrated to give the title compound (1.08 g, quantitative). +ESI (M+1 +H) 333.0; ¹H NMR (400 MHz, DMSO-d₆₁ δ): 12.06 (br. s„ 1 H), 8.99 (d, J = 1.8 Hz, 1 H), 8.37 (d, J = 2.0 Hz, 1 H), 8.14 (d, J = 2.9 Hz, 1 H), 7.52 (m, 2 H), 7.41 (m, 3 H), 5.41 (s, 2 H).

Step 3. 3-carbamoyl-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid

The title compound was prepared by a method analogous to that described in Stops 3 - 4 for Intermediate 6, using benzyl 3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carboxylate. +ESI (M+H) 206.2; Ή NMR (400 MHz, DMSO-d_e. δ): 12.76 (br.s., 1 H), 8.92 (d, J = 1.6 Hz, 1 H), 8.54-8.64 (m, 2 H), 8.17 (br. s., 1 H), 7.51 (br. s., 1 H).

Intermediate 10: 3-carbamoyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, shown below, was prepared as follows:

Step 1. methyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

To a solution of methyl 1 H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.97 g, 14.0 mmol) in Ν,Νdimethylformamide (30 mL) was added potassium carbonate (5.79 g, 41,9 mmol). Iodine (3.90 g,

15.4 mmol) in N,N-dimethylformamide (5.0 mL) was then added dropwise and the reaction was allowed to stir at room température for 2 hours. Water (150 mL) was then added to the reaction mixture, resulting in the formation of a precipitate. A solution of sodium bisulfite (5.79 g, 41.9 mmol) in water (50 mL) was slowly added, and the mixture was allowed to stir for 1 hour. The resulting solid was filtered and dried under vacuum to give the title compound (3.07 g, 73%). +ESI (M+H) 303.0; ’H NMR (400 MHz, DMSO-d_e, δ): 12.53 (br. s., 1 H), 8.79 (d, J = 2.0 Hz, 1 H), 8.15 (d, J = 2.0 Hz, 1 H), 7.86 (s, 1 H), 3.88 (s, 3 H).

Step 2. 1 -tert-butyl 5-methyl 3-iodo-1 H-pyrrolo(2,3-b]pyridine-1,5-dicarboxylate

To a mixture of methyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (700 mg, 2.32 mmol) in dichlorométhane (10 mL) and tetrahydrofuran (10 mL) was added N,N-diisopropylethylamine (1.21 mL, 6.95 mmol), di-tert-butyldicarbonate (607 mg, 2.78 mmol), and 4-dimethylaminopyridine (28 mg, 23 mmol). The reaction was ailowed to stir at room température for 16 hours. The reaction was concentrated and purification by flash column chromatography (0-50% ethyl acetate / heptanes) gave the title compound (760 mg, 82%) as a solid. +APCI (M+H) 403.3; ’H NMR (400 MHz, DMSO-d_e, δ): 8.93 (d, J = 2.0 Hz, 1 H), 8.16 (d, J = 2.0 Hz, 1 H), 8.14 (s, 1 H), 3.91 (s, 3 H), 1.59 (s, 9 H).

Step 3. 3-carbamoyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid

The title compound was prepared by a method analogous to that described in Steps 3 - 4 for Intermediate 6, using 1-tert-butyl 5-methyl 3-iodo-1 H-pyrrolo[2,3-b]pyridine-1,5-dicarboxylate. APCI (M-H) 204.4.

Intermediate 11: 2-carbamoyl-1 H-indole-5-carboxylic acid, shown below, was prepared as follows:

Step 1. methyl 2-carbamoyl-1 H-indole-5-carboxyiate

To a solution of 5-(methoxycarbonyl)-1 H-indole-2-carboxylic acid (2.50 g, 11.4 mmol) in tetrahydrofuran (20 mL) was added 1,1-carbonyldiimidazole (3.70 g, 22.8 mmol). The yellow suspension was stirred for 2 hours. Then concentrated ammonium hydroxide (20 mL) was added and the mixture was stirred at room température for 5 hours. The pale green suspension was filtered, washed with water and 5 mL of methanol, and air dried to give methyl 2-carbamoyl-1Hindole-5-carboxylate (2.04 g, 82%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d_e, δ): 11.93 (br. s., 1 H), 8.32 (d, J = 1.2 Hz, 1 H), 8.06 (br. s., 1 H), 7.79 (dd, J = 8.6, 1.6 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 1 H), 7.45 (br. s., 1 H), 7.27 (s, 1 H), 3.32 (s, 3 H).

Step 2. 2-carbamoyl-1H-indole-5-carboxylic acid

To a suspension of methyl 2-carbamoyl-1H-indole-5-carboxylate (300 mg, 1.38 mmol) in tetrahydrofuran (4.5 mL) and ethylene glycol (4.5 mL) was added potassium hydroxide (3.16 g,

56.4 mmol). The mixture was heated to reflux and stirred for 2 hours. The reaction was cooled to room température and diluted with water. The tetrahydrofuran was removed under reduced pressure. The solids were filtered off and the filtrate was acidified to pH 4 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give 2-carbamoyl-1H-indole-5-carboxylicacid (230 mg, 82%). ’H NMR (400 MHz, DMSO-d_e, δ): 12.53 (br. s., 1 H), 11.88 (br. s„ 1 H), 8.28 (s, 1 H), 8.04 (br. s., 1 H), 7.77 (d, J = 8.6 Hz, 1 H), 7.46 (m, J = 8.6 Hz, 2 H), 7.25 (s, 1 H).

Intermediate 12: 3-carbamoyl-1H-indole-5-carboxylic acid, shown below, was prepared asfollows:

Step 1. ethyl 3-cyano-1 H-indole-5-carboxylate

To a solution of 5-bromo-1 H-indole-3-carbonitrile (2.61 g, 11.8 mmol) in éthanol (50 mL) in a 500 mL Parr bottle was added sodium acetate (2.90 g, 35.6 mmol) and 1.Γbis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (1.93 g, 2.36 mmol). The reaction mixture was evacuated and back filled with nitrogen three times. The reaction vessel was then pressurized with 25 psi carbon monoxide. The reaction was heated to 70 °C and when the desired température was reached the pressure of the vessel was increased to 40 psi. The reaction was agitated at 70 °C for 24 hours. The mixture was filtered through Celite, rinsing with éthanol. The filtrate was concentrated under reduced pressure and then diluted with dichloromethane. The mixture was filtered to remove the insoluble solids. The filtrate was concentrated and purified by flash column chromatography (20-80% ethyl acetate / heptanes). The resulting solid was triturated with dichloromethane and a small amount of heptanes to give ethyl 3cyano-1H-indole-5-carboxylate (1.05 g, 41%)¹H NMR (400 MHz, DMSO-d_e, δ): 12.54 (br. s., 1 H), 8.41 (d, J = 2.7 Hz, 1 H), 8.25 (d, J =1.6 Hz, 1 H), 7.89 (dd, J = 8.6, 1.6 Hz, 1 H), 7.66 (dd,J = 8.6, 0.6 Hz, 1 H), 4.34 (q, J = 7.0 Hz, 2 H), 1.35 (t, J = 7.1 Hz, 3 H).

Step 2. 3-carbamoyl-1H-indole-5-carboxylic acid

A solution of ethyl 3-cyano-1 H-indole-5-carboxylate (1.05 g, 4.89 mmol) in methanol (12 mL) was added to a 0 °C solution of urea hydrogen peroxide (4.74 g, 48.9 mmol) and sodium hydroxide (11.7 mL of a 2.5 M solution in water, 29.3mmol). The mixture was allowed to warm to room température and stir overnight. An additional 2 mL of a 2.5 M solution of sodium hydroxide was added and the reaction was left stirring 4 hours. The mixture was concentrated and acidified to pH 2 using 6 M hydrochloric acid. The resulting precipitate was filtered off and dried under vacuum at 60 °C to give the title compound (915 mg, 92%). ¹H NMR (400 MHz, DMSO-d_e, δ): 12.46 (br. s., 1 H), 11.84 (s, 1 H), 8.85 (s, 1 H), 8.12 (d, J = 2.5 Hz, 1 H), 7.75 (dd, J = 8.6, 1.6 Hz, 1 H), 7.507.63 (m, 1 H), 7.47 (d, J = 8.6 Hz, 1 H), 6.88 (br. s., 1 H).

Intermediate 13: 2-carbamoyl-1H-indole'6-carboxylic acid, shown below, was prepared asfollows:

O	TV- H	O nh₂
Step 1. ethyl 2-carbamoyl-1 H-lndole-6-carboxylate		0
	H	nh₂
O

The title compound was prepared by a method analogous to that described in Step 1 for Intermediate 12, using 6-bromo-1H-indole-2-carboxamide. +ESI (M+H) 233.2; ¹H NMR (DMSO-d_e, δ): 11.92 (s, 1 H), 8.07 (s, 2 H), 7.65 - 7.71 (m, 1 H), 7.57 - 7.63 (m, 1 H), 7.49 (br. s., 1 H), 7.17 (dd, J = 2.1,1.0 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.31 (t, J = 7.1 Hz, 3 H).

Step 2. 2-carbamoyl-1 H-indole-6-carboxylic acid

To a solution of ethyl 2-carbamoyl-1H-indole-6-carboxylate (3.3 g, 14 mmol) in methanol (50 mL) was added 1 N aqueous sodium hydroxide (71 mL, 71 mmol). The reaction was stirred at room température for 17 hours. Then the reaction was acidified to pH 2-3 using 6 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to afford the title compound (2.97 g, 100%). -APCI (M-H) 203.4.

Intermediate 14: 2-amino-1H-benzo[d]imidazole-5-carboxylic acid, shown below, was prepared as follows:

A solution of cyanogen bromide (5.0 mL, 5 M in acetonitrilo, 25 mmol) was added to a mixture of methyl 3,4-diaminobenzoate (3.0 g, 18 mmol) in water (50 mL). The reaction was stirred at room température overnight. Aqueous ammonia (20 mL) and ethyl acetate (100 mL) were added to the reaction mixture and the layers were separated. The organics were dried over sodium sulfate, filtered, and concentrated. To the crude residue was added 2 N aqueous hydrochloric acid (18 mL, 36.0 mmol) and the mixture was heated at reflux overnight. The reaction was concentrated to give the title compound (2.90 g, 97%). ¹H NMR (400 MHz, DMSO-d_e, δ): 8.75 (s, 2 H), 7.84 (s, 1 H), 7.77 (dd, J = 1.2 Hz, J = 8.4 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H).

Intermediate 15: 3-(methylcarbamoyl)-1H-indazole-5-carboxylic acid, shown below, was prepared as follows:

NH \

Step 1. 5-bromo-N-methyl-1 H-indazole-3-carboxamide

To a solution of 5-bromo-1 H-indazole-3-carboxylic acid (1.2 g, 5.0 mmol) in N,Ndimethylformamîde (20 mL) was added methyl amine (5 mL, 2 M in tetrahydrofuran, 10 mmol), 1, (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.4 g, 7.5 mmol), 1hydroxybenzotriazole hydrate (1.2 g, 7.5 mmol), and N-methylmorpholine (1.0 g, 10 mmol). The reaction was stirred at room température overnight, The reaction was concentrated and purification by flash column chromatography gave the title compound (0.71 g, 56%) as a colorless solid. ’H NMR (400 MHz, DMSO-d₀, δ): 13.8 (br. s., 1 H), 8.41 (m, 1 H), 8.31 (s, 1 H), 7.60 (d, J = 8.8 Hz, 1 H), 7.51 - 7.54 (m, 1 H), 2.80 (d, J = 4.8 Hz, 3 H).

Step 2. methyl 3-(methylcarbamoyl)-1 H-indazole-5-carboxylate

/

N

H

To a solution of 5-bromo-N-methyl-1 H-indazole-3-carboxamide (710 mg, 2.6 mmol) in anhydrous methanol (20 mL) was added 1,T-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (400 mg, 0.56 mmol) and N-methylmorpholine (565 mg, 5.60 mmol). The reaction vessel was evacuated and back filled with nitrogen three times. The vessel was then filled with 30 psi carbon monoxide. The reaction mixture was heated to 70 °C, increasing the pressure within the vessel to 45 psi. The reaction was agitated at 70 °C for 24 hours. The reaction mixture was cooled to room température and was filtered through Celite, rinsing with methanol. The filtrate was concentrated and purification by flash column chromatography gave the title compound (410 mg, 61%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6, δ): 13.9 (s, 1 H),

Θ.88 (s, 1 H), 8.49 (d, J = 4.8, 1 H), 7.95 - 7.98 (m, 1 H), 7.68 - 7.70 (m, 1 H), 3.88 (s, 3 H), 2.82 (d,

J = 4.8 Hz, 3 H).

Step 3. 3-(methylcarbamoyl)-1 H-indazole-5-carboxylic acid

To a solution of methyl 3-(methylcarbamoyl)-1H-indazole-5-carboxylate (400 mg, 1.7 mmol) 15 in methanol (10 mL) and water (10 mL), was added lithium hydroxide monohydrate (0.36 g, 8.5 mmol). The reaction was heated to 60 °C and was stirred overnight. The methanol was removed under reduced pressure and the remaining residue was acidified to pH = 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (350 mg, 94%) as a yellow solid. 'H NMR (400MHz, DMSO-d₀, δ): 13.99 20 (s, 1 H), 8.85 (s, 1 H), 8.47 - 8.48 (m, 1 H), 7.94 - 7.96 (m, 1 H), 7.65 - 7.68 (m, 1 H), 2.82 (d, J =

4.4 Hz, 3 H).

Intermediate 16: 3-(ethylcarbamoyl)-1 H-indazole-5-carboxylic acid, shown below, was prepared as follows:

To a solution of 5-bromo-1H-indazole-3-carboxylic acid (1.2 g, 5.0 mmol) in dichloromethane (20 mL) was added oxalyl chloride (1.26 g, 10 mmol) and 1 drop of N,N-

dimethylformamide. The mixture was stirred at room température under a nitrogen atmosphère ovemight. The reaction was concentrated and the residue was dissolved in dichloromethane (20 mL). Ethylamine (1.1 g, 25 mmol) was added dropwise. The reaction was allowed to stir at room température for 4 hours. The reaction mixture was concentrated to provide the title compound (1.27 g). +ESI (M+H+1) 270.9.

Step 2. ethyl 3-(ethylcarbamoyl)-1 H-indazole-5-carboxylate

To a solution of 5-bromo-N-ethyl-1H-indazole-3-carboxamide (1.1 g, 4.1 mmol) in éthanol (50 mL), was added triethylamine (1.24 g, 12.3 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane complex (300 mg, 0.41 mmol). The reaction vessel was evacuated and back filled with nitrogen three times. The vessel was filled with 50 psi carbon monoxide, heated to 80 °C, and was agitated for 24 hours. The reaction was cooled to room température and filtered on Celite. The filtrate was concentrated to a brown residue. The residue was diluted with ethyl acetate (100 mL) and was washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organics were dried over sodium sulfate, filtered, and concentrated to give the title compound (0.ΘΘ g, 82%) as a brown solid. ’H NMR (400MHz, DMSO-d₆, δ): 13.87 (s, 1 H), 8.88 (s, 1 H), 8.54- 8.57 (m, 1 H), 7.96-7.98 (m, 1 H), 7.68 - 7.70 (m, 1 H), 4.32 - 4.37 (m, 2 H), 3.33 - 3.37 (m, 2 H), 1.35 (t, 3 H), 1.22 (t, 3 H).

Step 3. 3-(ethylcarbamoyl)-1 H-indazole-5-carboxylic acid

The title compound was prepared by a method analagous to that described in Step 3 of Intermediate 15.¹H NMR (400MHz, DMSO-d₆₁ δ): 13.83 (s, 1 H), 12.91 (br. s., 1 H), 8.86 (s, 1 H), 8.51 - 8.54 (m, 1 H), 7.95-7.97 (m, 1 H), 7.65-7.68 (m, 1 H), 3.30-3.36 (m, 2 H), 1.12 - 1.16 (t, 3 H).

Intermediate 17: 3-(2,2,2-trifluoroethylcarbamoyl)-1H-indazole-5-carboxyllcacid, shown below, was prepared as follows:

HO cf₃

The title compound was prepared by a method analogous to that described for Intermediate 16, using 2,2,2-trifluroethylamine in Step 1. ’H NMR (400 MHz, DMSO-d_e, δ): 14.04 (s, 1 H), 13.0 (br. s„ 1 H), 9.12 - 9.15 (m, 1 H), Θ.83 (s, 1 H), 7.97 - 7.99 (m, 1 H), 7.69 - 7.72 (m, 1 H), 4.04 4.13 (m, 2 H).

Intermediate 18: 2-(methylamino)-1H-benzo[d]imidazole-5-carboxylic acid, shown below, was prepared as follows:

Step 1. methyl 2-(methylamino)-1H-benzo[d]imidazole-5-carboxylate

A mixture of 3,4-diaminobenzoic acid (15 g, 0.09 mol) and isothiocyanatomethane (6.6 g, 0.09 mol) was dissolved in tetrahydrofuran (90 mL). The reaction was heated at reflux for 3 hours and was then concentrated. The residue was poured into ice water. The resulting precipitate was filtered, washed with water, and dried under vacuum to give methyl 4-amino-3-(3methylthioureido)benzoate (12.0 g, 56%).

To the solid (12 g, 0.05 mol) was added éthanol (200 mL), followed by methyl iodide (35.5 g, 0.25 mol). The réaction was heated to reflux and stirred overnight. The reaction was concentrated and the residue was basified with ammonium hydroxide. The solids were collected by filtration and washed with water. Purification by column chromatography (9-25% ethyl acetate ! petroleum ether) gave the title compound (2.9 g, 28%) as a yellow solid. ’H NMR (400 MHz, CDCI3, δ): 8.37 (s, 1 H), 7.92 - 7.96 (m, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 3.93 (s, 3 H), 2.81 (s, 3 H).

Step 2. 2-(methylamino)-1H-benzo[d]imidazole-5-carboxylic acid

N Aqueous hydrochloric acid (14 mL, 42 mmol) was added to methyl 2-(methylamino)-1Hbenzo[d]imidazole-5-carboxylate (2.9 g, 14 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated to give the title compound (2.4 g, 90%) as a yellow solid. ’H NMR (400 MHz, CD3OD, δ): 7.96 - 8.00 (m, 2 H), 7.40 (d, J = 8.4 Hz, 1 H), 3.10 (s, 3 H).

Intermediate 19: 3-cyano-1H-indazole-6-carboxylic acid, shown below, was prepared as follows:

Step 1 : methyl 1 H-indazole-6-carboxylate

O

To a solution of 1H-indazole-6-carboxylic acid (3.00 g, 18.5 mmol) in Ν,Ν-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room température overnight. The mixture was poured Into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100% ethyl acetate / heptanes) to afford methyl 1 H-indazole-6-carboxylate as a yellow solid (2.95 g, 90%). ¹H NMR (400 MHz, CDCI₃, δ): 10.40 (br. s., 1 H), 8.26 (s, 1 H), 8.13 (s, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 3.96 (s, 3 H).

Step 2: methyl 3-iodo-1H-indazole-6-carboxylate

To a solution of methyl 1 H-indazole-6-carboxylate (865 mg, 4.91 mmol) in N,Ndlmethylformamide (12 mL) was added potassium hydroxide (840 mg, 3.05 mmol) followed by iodine (1.54 g, 5.9 mmol). The mixture was stirred at room température for 3 hours. Sodium bisulfate (30 mL of 5% aqueous) was added and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (5-65% ethyl acetate / heptanes) to afford methyl 3-iodo-1 H-indazole-6-carboxylate as a colorless solid (1.16 g, 78%). ¹H NMR (400 MHz, DMSO-d₆, δ): 13.84 (s, 1 H), 8.13 (s, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.54 (d, J =8.6 Hz, 1 H), 3.87 (s, 3 H).

Step 3: methyl 3-cyano-1H-indazole-6-carboxylate

A mixture of methyl 3-iodo-1 H-indazole-6-carboxylate (3.0 g, 9.9 mmol), zinc dust (400 mg,

6.11 mmol), zinc cyanide (2.0 g, 17.0 mmol), [1,1’-bis(diphenylphosphîno)ferrocene]5 dichloropalladium(ll), complex with dichloromethane (1.15 g, 1.41 mmol), and copper (I) iodide (1.90 g, 9.97 mmol) in dimethylacetamide (55 mL) was purged with nitrogen for 15 minutes. The mixture was stirred at 120 °C for 15 hours. The reaction mixture was cooled, diluted with ethyl acetate (250 mL), and filtered through Celite, rinsing with ethyl acetate (100 mL). To the filtrate was added -400 mL of a solution of saturated aqueous ammonium chloride and concentrated ammonium hydroxide (prepared by adding ammonium hydroxide to a saturated aqueous solution of ammonium chloride until pH = 8). The mixture was stirred for 1 hour. The layers were then separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. To the residue was added methanol (40 mL) and the mixture was stirred overnight. The mixture was filtered and the solid was dried in vacuo to give methyl 3-cyano15 1 H-indazole-6-carboxylate as a tan solid (1.47 g, 73%). ¹H NMR (400 MHz, DMSO-d₆, δ): 13.40 (br. s., 1 H), 8.25 (s, 1 H), 7.94 (d, J = 8.6 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 3.88 (s, 3 H).

Step 4: 3-cyano-1 H-indazole-6-carboxylic acid

To a solution of methyl 3-cyano-1H-indazole-6'Carboxylate (1.47 g, 7.31 mmol) in methanol (36 mL) and tetrahydrofuran (20 mL) was added 2 N aqueous lithium hydroxide (16 mL, 32 mmol).

The reaction was heated to 50 °C for 72 hours. The reaction was cooled to room température and concentrated. The residue was diluted with water and the pH was adjusted to 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered off, rinsed with water, and dried under vacuum to provide the title compound (500 mg, 37%) as a tan solid. +ESI (M+H) 188.2.

Intermediate 20: 3-chloro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid, shown below, was prepared 25 as follows:

Step 1 : methyl 3-chloro-1 H-pyrrolo[3,2-b]pyridine-6-carboxylate

To a 0 °C solution of methyl 1 H-pyrrolo[3,2-b]pyridine-6-carboxylate (1.00 g, 5.68 mmol) in N,N-dimethylformamide (15 mL) was added N-chlorosuccinîmide (895 mg, 5.96 mmol). The reaction was allowed to gradually warm to room température and stir overnight. The reaction was diluted with water (125 mL) and stirred for 20 minutes. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (1.11 g, 93%) as an orange powder. +ESI (M+H) 211.0; ¹H NMR (400 MHz, DMSO-d_e, δ): 11.99 (br. s., 1 H), 8.92 (d, J = 2.0 Hz, 1 H), 8.31 (d, J = 1.8 Hz, 1 H), 8.08 (d, J = 3.1 Hz, 1 H), 3.88 (s, 3 H).

Step 2: 3-chloro-1 H-pyrrolo[3,2-b]pyridine-6-carboxylic acid

Methyl 3-chloro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (1.10 g, 5.22 mmol) was suspended in 1,4-dioxane (25 mL) and 6 N aqueous hydrochloric acid (8.7 mL) was added. The reaction was allowed to stir at room température overnight. The reaction was then concentrated to give the title compound (1.2 g, 100%). +ESI (M+H) 197.1; ¹H NMR (400 MHz, DMSO-d_e, δ): 12.50 (br. s., 1 H), 8.92 (d, J = 1.6 Hz, 1 H), 8.46 (br. s., 1 H), 8.19 (br. s., 1 H).

Intermediate 21: 3-cyano-1 H-indazole-5-carboxylic acid, shown below, was prepared as follows:

Methyl 3-cyano-1 H-indazole-5-carboxylate (500 mg, 2.5 mmol) was dissolved in methanol (12 mL) and 2 N aqueous lithium hydroxide (3.7 mL, 7 mmol) was added. The reaction was stirred at room température overnight. The reaction mixture was concentrated to remove the methanol and

the residue was acidified to pH = 4 with 1 N aqueous hydrochloric acid. The resulting yellow precipitate was collected by filtration, washed with water, and dried in a vacuum oven to provide the title compound (445 mg, 96%). -ESl (M-H) 1Θ6.4; Ή NMR (400 MHz, DMSO-d_fl, δ): 13.17 (br. s„ 1H), Θ.42 (s, 1H), 8.05 (dd, J = 8.8, 1.6 Hz, 1 H), 7.83 (d, 1H).

Intermediate 22: 6-{2-tert-butoxy-2-oxoethoxy)quinoline-3-carboxylic acid, shown below, was prepared as follows:

Step 1: 2-chloro-6-hydroxyquinoline-3-carbaldehyde

O

To a -78 ^DC mixture of 2-chloro-6-methoxyquinoline-3-carbaldehyde (4.64 g, 20.9 mmol) in dichloromethane (130 mL) was added boron tribromide (4.0 mL, 42 mmol). The mixture was allowed to warm to room température and stir for 4 hours. The reaction was neutralized by the careful addition of saturated aqueous sodium bicarbonate. The mixture was then extracted with 2methyl tetrahydrofuran (3 x). The combined organics were filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate (3 x) and once with brine. The organics were dried over sodium sulfate, filtered, and concentrated to a yellow solid. The solid was partially dissolved in 2methyl tetrahydrofuran and filtered. The filtrate was concentrated to a solid and again partially dissolved in 2-methyl tetrahydrofuran, filtered, and concentrated. Purification by flash column chromatography (10-100% ethyl acetate / heptanes) gave the title compound (2.65 g, 61%) as a pale yellow solid. +ESI (M+H) 208.1; ¹H NMR (400 MHz, CDCI₃, δ): 10.54 (s, 1 H), 8.59 (s, 1 H), 7.98 (d, J = 9.17 Hz, 1 H), 7.47 (dd, J = 9.17, 2.73 Hz, 1 H), 7.25 (d, J = 2.93 Hz, 1 H), 5.57 (br. s., 1 H).

Step 2: tert-butyl 2-(2-chloro-3-formylquinolin-6-yloxy)acetate

To a solution of 2-chloro-6-hydroxyquinoline-3-carbaldehyde (2.35 g, 11.3 mmol) in Ν,Νdimethylformamide (15 mL) was added tert-butyl 2-bromoacetate (2.0 mL, 13.6 mmol) and potassium carbonate (3.13 g, 22.6 mmol). The reaction was stirred at room température for 1.5 hours. The reaction was diluted with water (100 mL) and allowed to stir for 1 hour. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (3.62 g, 99%) as an off-white solid. +ESI (M+H) 322.1; ¹H NMR (400 MHz, CDCI_3l δ): 10.54 (s, 1 H), 8.60 (s, 1 H), 7.99 (d, J = 9.36 Hz, 1 H), 7.59 (dd, J = 9.17, 2.93 Hz, 1 H), 7.11 (d, J = 2.73 Hz, 1 H), 4.65 (s, 2 H), 1.49 (s, 9 H).

Step 3: 6-(2-tert-butoxy-2-oxoethoxy)-2-chloroquinoline-3-carboxylic acid

Cl

HO.

To a suspension of tert-butyl 2-(2-chloro-3-formylquinolin-6-yloxy)acetate (3.6 g, 11 mmol) in tert-butanol (150 mL) was added 2-methyl-2-butene (14.9 mL, 133 mmol) and a solution of sodium chlorite (8.27 g, 73.1 mmol) and sodium dihydrogenphosphate (8.10 g, 58.7 mmol) in water (50 mL). The reaction was allowed to stir at room température for 1 hour. The tert-butanol was removed in vacuo. The mixture was diluted with water (60 mL) and acidified to pH = 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (3.7 g, 100%) as a white solid. +ESI (M+H) 338.1 ; ’H NMR (400 MHz, CD₃OD, δ): 8.69 (s, 1 H), 7.89 (d, J = 9.19 Hz, 1 H), 7.56 (dd, J = 9.19, 2.74 Hz, 1 H), 7.34 (d, J = 2.93 Hz, 1 H), 4.76 (s, 2 H), 1.49 (s, 9 H).

Step 4: 6-(2-tert-butoxy-2-oxoethoxy)quinoline-3-carboxylic acid

Methanol (100 mL) and triethylamine (4.5 mL, 33 mmol) were added to 6-(2-tert-butoxy-2oxoethoxy)-2-chloroquinoline-3-carboxylic acid (1.27 g, 3.76 mmol). 10% Palladium on carbon (350 mg) was added and the reaction was pressurized to 17 psi hydrogen. The reaction was agitated at room température for 3 hours. The reaction mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated to a yellow solid. The solid was diluted with water and the mixture was acidified to pH = 4 with 1 N aqueous hydrochloric acid. The solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (960 mg, 84%) as a pale yellow solid. +ESI (M+H) 304.2; ¹H NMR (400 MHz, CD₃OD, δ): 9.19 (d, J = 2.15 Hz, 1 H),

Θ.87 (d, J = 2.15 Hz, 1 H), 8.01 (d, J = 9.36 Hz, 1 H), 7.59 (dd, J = 9.27, 2.83 Hz, 1 H), 7.38 (d, J =

2.73 Hz, 1 H), 4,78 (s. 2 H), 1.49 (s, 9 H).

Intermediate 23: 6-carbamoylquinoline-3-carboxylic acid, shown below, was prepared as follows: O O

Step 1: ethyl 6-bromoquinoline-3-carboxylate

O

To a solution of 5-bromo-2-nitrobenzaldehyde (2 g, 9 mmol) in éthanol (46 mL) was added tin(ll) chloride dihydrate (7.95 g, 35.2 mmol) and 3,3-diethoxypropionic acid ethyl ester (4.2 mL, 22 mmol). The reaction was heated to 90 °C for 16 hours. The reaction was then allowed to cool to room température and stir overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was poured into saturated aqueous sodium bicarbonate. The resulting émulsion was filtered through Celite, rinsing with ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnésium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate / heptanes) gave the title compound (1.41 g, 60%) as a solid.

Step 2: 6-carbamoylquinoline-3-carboxylic acid

The title compound was prepared by a method analogous to that described in Steps 3 - 4 of Intermediate 6, using ethyl 6-bromoquinoline-3-carboxylate. +ESI (M+H) 217.0; ¹H NMR (400 MHz, DMSO-d₆, δ): 13.58 (br. s., 1 H), 9.34 (d, J = 2.1 Hz, 1 H), 8.97 (d, J = 2.1 Hz, 1 H), 8.67 (d, J = 2.0 Hz, 1 H), 8.25 - 8.31 (m, 1 H), 8.20 (br. s., 1 H), 8.09 - 8.14 (m, 1 H), 7.61 (br. s., 1 H).

Intermediate 24: 7-bromo-6-methoxyquinoline-3-carboxylic acid, shown below, was prepared as follows:

HO

Ο

Step 1: 1-bromo-2-methoxy-4-methyl-5-nitrobenzene O

U

To a solution of 4-methoxy-2-methyl-1-nitrobenzene (2.0 g, 12 mmol) in N,Ndimethylformamide (5 mL) was added N-bromosuccinimide (8.52 g, 47.9 mmol). The reaction was heated to 100 °C for 1.5 hours. The reaction was cooled to room température and diluted with saturated aqueous sodium thiosulfate. The mixture was extracted with ethyl acetate (3 x). The combined organics were washed with water, saturated sodium thiosulfate, and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via flash column chromatography (0-30% ethyl aceate / heptanes) to provide the title compound (2.6 g, -43% pure) as a pale yellow solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.32 (s, 1 H), 6.74 (s, 1 H), 3.97 (s, 3 H), 2.63 (s, 3 H).

Step 2: 4-bromo-5-methoxy-2-nitrobenzaldehyde

O

The crude 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (2.6 g, 11 mmol) was dissolved in N.N-dimethylformamide (15 mL) and N, N-dimethylformamide dimethylacetal (5mL, 38 mmol) was added. The reaction was heated to 120 °C for 18 hours. The reaction was cooled to room température and the mixture was added directly to a 0 °C suspension of sodium periodate (12.2 g, 57.2 mmol) in water (20 mL) and N.N-dimethylformamide (5 mL). The reaction was stirred at 0 °C for 2 hours, then allowed to warm to room température and stir for another 6 hours. The reaction mixture was filtered, rinsing with ethyl acetate, toluene, and water. The frltrate was extracted with ethyl acetate (3 x). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate / heptanes) gave the title compound (550 mg, 19%) as a pale yellow solid. ¹H NMR (400 MHz, CDCIa, δ): 10.47 (s, 1 H), 8.41 (s, 1 H), 7.35 (s, 1 H), 4.05 (s, 3 H).

Step 3: ethyl 7-bromo-6-methoxyquinoline-3-carboxylate

To a suspension of 4-bromo-5-methoxy-2-nitrobenzaldehyde (475 mg, 1.83 mmol) in éthanol (15 mL) was added tin(ll) chloride dihydrate (1.65 g, 7.31 mmol) and ethyl 3,3diethoxypropionate (1.0 mL, 5.1 mmol). The reaction was heated to 90 °C for 3 hours. LCMS showed the reaction to be incomplète. Additional tin(ll) chloride dihydrate (600 mg, 2.7 mmol) and ethyl 3,3-diethoxypropionate (0.35 mL, 1.8 mmol) were added and the reaction was left heating overnight, LCMS showed the reaction to be incomplète. Tin(ll) chloride dihydrate (200 mg, 0.89 mmol) and ethyl 3,3-diethoxypropionate (0.10 mL, 0.51 mmol) were added and the réaction was heated at 90 °C for another 3 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was filtered and extracted again with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via flash column chromatography (0-100% ethyl acetate / heptanes) to give a yellow solid (410 mg) which contained desired product and impurities. This material was taken up in tetrahydrofuran (5 mL) and ethyl 3,3diethoxypropionate (0.17 mL, 0.87 mmol) and p-toluenesulfonic acid monohydrate (12.0 mg, 0.63 mmol) were added. The mixture was heated to 75 °C and stirred for 3 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous was extracted with ethyl acetate (2 x). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-25% ethyl acetate / heptanes) gave the title compound (256 mg, 45%) as a yellow solid. +ESI (M+H+1) 313.3.

Step 4: 7-bromo-6-methoxyquinoline-3-carboxylic acid

To a solution of ethyl 7-bromo-6-methoxyquinoline-3-carboxylate (250 mg, 0.80 mmol) in tetrahydrofuran (5 mL) was added 1 N aqueous lithium hydroxide (1.6 mL, 1.6 mmol). The reaction was stirred at room température overnight. The reaction was concentrated and the residue was taken up in water and 1 N aqueous lithium hydroxide (0.4 mL). The solution was extracted twice with ethyl acetate. The aqueous layer was then acidified to pH = 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (165 mg, 73%) as an off-white solid. +ESI (M+H+1) 284.1; ’H NMR (400 MHz, CD₃OD, δ): 9.19 (d, J = 2.15 Hz, 1 H), 8.89 (d, J = 1.76 Hz, 1 H), 8.30 (s, 1 H), 7.53 (s, 1 H), 4.04 (s, 3 H).

Intermediate 25: 2-(tert-butylamino)quinoline-7-carboxylic acid, shown below, was prepared as follows:

Step 1: 7-(ethoxycarbonyl)quinoline 1-oxide

To a solution of ethyl quinoline-7-carboxylate (1.02 g, 5.05 mmol) in dichloromethane (20 mL) was added peracetic acid (2.13 mL, 10.1 mmol, 32 wt% in acetic acid). The reaction was stirred at room température overnight. The reaction was partitioned between water and dichloromethane. The layers were separated and the aqueous was extracted with dichloromethane (4 x). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The solid was concentrated from heptanes and ethyl acetate several fîmes, then dried under vacuum to give the title compound (1.01 g, 92%) as a yellow solid. +ESI (M+H) 218.2; Ή NMR (400 MHz, CDCI₃₁ δ): 9.40 (s, 1 H), 8.65 (d, J = 6.05 Hz, 1 H), 8.27 (dd, J = 8.58,1.56 Hz, 1 H), 7.95 (d, J = 8.39 Hz, 1 H), 7.82 (d, J = 8.58 Hz, 1 H), 7.42 (dd, J = 8.49, 6.15 Hz, 1 H), 4.47 (q, J = 7.02 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H).

Step 2: 2-(tert-butylamino)quinoline-7-carboxylic acid

To a 0 °C solution of 7-(ethoxycarbonyl)quinoline 1-oxide (500 mg, 2.3 mmol) and tertbutylamine (1.46 mL, 13.8 mmol) in trifluoromethylbenzene (25 mL) was added p-toluenesulfonic anhydride (1.96 g, 5.76 mmol) portion-wise, maintaining the internai reaction température below 5 °C. The reaction was stirred for 1 hour, Saturated aqueous sodium bicarbonate was added and the reaction mixture was allowed to stir for 15 minutes. The phases were then separated and the aqueous was extracted with dichloromethane (2 x). The combined organics were washed with brine, dried over magnésium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 499 mg of a clear oil that solidified upon standing. This material was taken up in tetrahydrofuran (5 mL) and 1 N aqueous lithium hydroxide (3.6 mL, 3.6 mmol) was added. The reaction was stirred at room température overnight. The reaction was concentrated and the residue was diluted with water and acidified to pH = 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered off and dried under vacuum to give the title compound (330 mg,

75%) as a pale yellow powder. -ESI (M-H) 243.1 ; Ή NMR (400 MHz, DMSO-d_e, δ): 12.86 (br. s., 1 H), 8.02 (d, J = 1.56 Hz, 1 H), 7.81 (d, J = 9.03 Hz, 1 H), 7.57 - 7.65 (m, 2 H), 6.83 (d, J = 8.97 Hz, 1 H), 6.81 (br. s., 1 H), 1.46 (s, 9 H).

Intermediate 26: 2-(methylamino)quinoline-7-carboxylic acid, shown below, was prepared as follows:

Step 1 : ethyl 2-(methylamino)quinoline-7-carboxylate

To a -70 °C solution of 7-(ethoxycarbonyl)quinoline 1-oxide (1.67 g, 7.70 mmol) in dichloromethane (80 mL) was added trifluoromethanesulfonic anhydride (1.43 mL, 8.47 mmol) dropwise, under a nitrogen atmosphère. The mixture was stirred at -70 °C for 5 minutes. Then a solution of methylamine in tetrahydrofuran (21 mL, 42 mmol, 2.0 M) was added dropwise at -70 °C. The mixture was stirred for 5 minutes and then the reaction was quenched with water (20 mL). The layers were separated and the aqueous was extracted with dichloromethane (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (720 mg, 41%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.42 (s, 1 H), 7.84 - 7.82 (m, 2 H), 7.63 - 7.61 (m, 1 H), 6.72 6.70 (m, 1 H), 4.92 (br. s., 1 H), 4.44-4.38 (m, 2 H), 3.12-3.11 (m, 3 H), 1.44- 1.40 (m, 3 H).

Step 2: 2-(methylamino)quinoline-7-carboxylic acid

The title compound was prepared by a method analogous to that described in Step 2 of Intermediate 13, using ethyl 2-(methylamino)quinoline-7-carboxylate. ¹H NMR (400 MHz, DMSO, δ): 8.08 (s, 1 H), 7.91 - 7.89 (m, 1 H), 7.71 - 7.62 (m, 2 H), 7.21 (s, 1 H), 6.85 - 6.83 (m, 1 H), 2.91 2.90 (m, 3 H).

Example 1: 6-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 '-yl) carbonyl]-1H-indole-3-carboxamide

nh₂

A mixture of 3-carbamoyl'1H-indole-6-carboxylic acid (25 mg, 0.12 mmol), l-isopropyl-4,6dÎhydrospiro[indazole-5,4'-piperidin]-7(1 H)-one (38 mg, 0.13 mmol), (1H-7-azabenzotriazol-1-yl)1,1,3,3-tetramethyl uronium hexafluorophosphate (46 mg, 0.12 mmol), and diisopropyethylamine (85 μΙ_, 0.49 mmol) in 0.5mL of dimethylformamide was stirred at room température overnight. The reaction was diluted with ethyl acetate and washed with 0.1 N hydrochloric acid. The organic layer was dried over magnésium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC to yield the title compound (14.6 mg, 28%). Analytical LCMS: +ESI (M+H) 434.1 ; rétention time 2.24 minutes (Waters Atlantis C₁₀ 4.6 x 50 mm, 5 μΜ column; 95 % water / acetonitrile linear gradient to 5 % water / acetonitrile over 4.0 minutes, hold at 5 % water / acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mLJminute) (Method A).

Example 2: 5-[(1 -isopropyl-7-οχοΊ ,4,6,7-tetrahydro-1 Ή-spîrofindazole-ô^'-piperidin]-1 *-yl) carbonyl]-1H-indazole-3-carboxamide

To a suspension of 1-isopropyl-4,6-dihydrospiro[indazole-5,4'’piperidin]-7(1H)One (16.8 g, 53.6 mmol) and 3-carbamoyl-1 H-indazole-5-carboxylic acid (10.0 g, 48.7 mmol) in N,Ndimethylformamide (120 mL) was added triethylamine (40 mL, 290 mmol). The mixture was stirred at room température for 5 minutes and was then cooled to 5 °C. 1-Propanephosphonic acid cyclic anhydride (60 mL, 100 mmol, 50 wt% solution in ethyl acetate) was added dropwise over 20 minutes, maintaining and internai température between 5 -10 °C. The reaction was allowed to stir overnight, gradually warming to room température. The reaction mixture was slowly poured into 700 mL of water at 5 °C. The resulting précipitais was filtered off and dried. To the filtrate was added 10% methanol / ethyl acetate (1 L) and the resulting precipitate was filtered off and dried. The solids collected were combined (8.9 g) and were dissolved in N,N-dimethylformamide (34 mL) at 130 °C. The solution was cooled to 100 °C and methanol (65 mL) was added. The solution was allowed to slowly cool to room température. The resulting precipitate was collected by filtration and dried to give the title compound (6.0 g, 28%). +ESI (M+H) 435.1 ; ’H NMR (400 MHz, DMSO-d₆, δ): 13.65 (s, 1 H), 8.15 (s, 1 H), 7.75 (s, 1 H), 7.60 (d, J = 8.6 Hz, 1 H), 7.29 - 7.47 (m, 3 H), 5.24 (m, 1

H), 3.32 - 3.79 (m, 4 H), 2.78 (s, 2 H), 2.59 (s, 2 H), 1.47 (br. s„ 4 H), 1.32 (d, J = 6.7 Hz, 6 H).

Example 3: 6-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 ’H-spiro[indazole-5,4'-piperidin]-1 '-yl) carbonyl]-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

O

To a solution of 1, (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (252 mg, 1.31 mmol) and 1-hydroxybenzotriazole hydrate (199 mg, 1.30 mmol) in dichloromethane (5 mL) was added 3-carbamoyl-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (212 mg, 1.04 mmol). The mixture was stirred at room température for 40 minutes. 1-isopropyl-4,6-dÎhydrospiro[indazole-5,4’piperidin]-7(1 H)-one (312 mg, 1.26 mmol) and triethylamine (0.434 mL, 3.11 mmol) were then added and the reaction was allowed to stir at room température for 16 hours. The reaction was diluted with saturated aqueous ammonium chloride and extracted twice with dichloromethane. The combined organic layers were washed successively with saturated sodium bicarbonate, water, and brine. The organics were dried over sodium sulfate, filtered, and concentrated. Purification via flash column chromatography (0-100% of a 20% methanol / dichloromethane solution) afforded the title compound (254 mg, 57%). +ESI (M+H) 435.5; ¹H NMR (400 MHz, CD_aOD, δ): 8.57 (d, J = 1.8

Hz, 1 H), 8.26 (s, 1 H), 7.98 (d, J = 1.0 Hz, 1 H), 7.43 (s, 1 H), 5.38 (m, 1 H), 3.63 (m, 4 H), 2.90 (s,

H), 2.66 (s, 2 H), 1.66 (m, 4 H), 1.42 (d, J = 6.6 Hz, 6 H).

The compounds listed in Table 1 below were prepared using procedures analogous to those described above for the synthesis of the compounds of Examples 1 -3 using the appropriate starting materials which are available commercially, prepared using préparations well-known to those skilled In the art, or prepared by a route described above. The compounds listed below were isolated initially as the free base and may be converted to a pharmaceutically acceptable sait for testing.

Table 1:

Example		Analytical Data
4	%-νη₂	+ESI (M+H) 435.3; ¹H NMR (400 MHz, DMSO-d_e, δ): 13.64 (s, 1 H). 8.15 (d, J = 8.2 Hz, 1 H), 7.73 (d, J = 0.8 Hz, 1 H), 7.56 (s, 1 H), 7.43 (s, 1 H), 7.33 7.38 (m, 1 H), 7.18 (dd, J =8.3, 0.9 Hz, 1 H), 5.17- 5.32 (m, 1 H), 3.50 - 3.80 (m, 2 H), 3.22 - 3.38 (m, 2 H), 2.78 (br. s., 2 H), 2.59 (s, 2 H), 1.40 -1.61 (m, 4 H), 1.32 (d, J = 6.3 Hz, 6 H).
5	M ^H x-W ₀^nh₂	+ESI (M+H) 435.1; rétention time 2.1 minutes. (Method A)
6	H W	+ESI (M+H) 434.2; Ή NMR (400 MHz, DMSO-d_e, δ): 11.67- 11.72 (m, 1 H), 7.98 (br. s., 1 H), 7.65 (s, 1 H), 7.45 (s, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.38 (br. s„ 1 H), 7.21 (d, J = 0.4 Hz, 1 H), 7.15 (d, J = 2.5 Hz, 1 H), 5.26 (dt, J = 13.3, 6.6 Hz, 1 H), 3.38 3.54 (m, 4 H), 2.80 (s, 2 H), 2.61 (s, 2 H), 1.45-1.54 (m, 4 H), 1.35 (d, J = 6.4 Hz, 6 H).
7	•vOÏ _οΛΝΗ₂	+ESI (M+H) 434.2; ’H NMR (400 MHz, DMSO-d_e, δ): 11.68 (br. s., 1 H), 8.20 (s, 1 H), 8.08 (s, 1 H), 7.41 - 7.47 (m, 3 H), 7.17 (dd, J = 8.3, 1.5 Hz, 1 H), 6.81 (br. s., 1 H), 5.21 - 5.32 (m, 1 H), 3.42 - 3.71 (m, 4 H), 2.81 (s, 2 H), 2.62 (s, 2 H), 1.44 - 1.56 (m, 4 H), 1.36 (d, J =6.6 Hz, 6 H).
8	aOCn^/>NHï	’H NMR (400 MHz, CD₃0D, δ): 8.50 (br. s., 1 H), 7.44 (s, 1 H), 7.37 (d, J = 9.2 Hz, 2 H), 7.26 (d, J = 8 Hz,1 H), 5.37 - 5.44 (m, 1 H), 3.40 - 4.00 (m, 4 H), 2.91 (s, 2 H), 2.66 (s, 2 H), 1.50 - 1.80 (m, 4 H), 1.44 (d, J = 6.8 Hz, 6 H).
9	H il ^K aW Λ~νη 0 \	’H NMR (400 MHz, DMSO-d_e, δ): 13.65 (s, 1 H), 8.35 (m, 1 H), 8.13 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.39 (s, 1 H), 7.35 - 7.37 (m, 1 H), 5.15 - 5.30 (m, 1 H), 3.3 - 3.8 (m, 4 H), 2.75 (m, 5 H), 2.56 (s, 2 H), 1.35 - 1.60 (m, 4 H), 1.29 (d, J = 6.8 Hz, 6 H).

10		Ή NMR (400 MHz, CD₃OD, δ): Θ.43 (m, 1 Η), 8.31 (s, 1 Η), 7.65 (d, J = 8.8 Hz, 1 H), 7.47 (d, J = Θ.Θ Hz, 1 H), 7.43 (s, 1 H), 5.37 - 5.40 (m, 1 H), 3.65 4.00 (m, 2 H), 3.44 - 3.52 (m, 4 H), 2.90 (s, 2 H), 2.66 (s, 2 H), 1.50 - 1.80 (m, 4 H), 1.42 (d, J = 6.4 Hz, 6 H), 1.26 (t, J = 7.2 Hz, 3 H).
11	⁰ y;	Ή NMR (400 MHz, CD₃OD, δ): 8.31 (s, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.43 (s, 1 H), 5.37 - 5.40 (m, 1 H), 4.09 - 4.16 (m, 2 H), 3.65 - 4.00 (m, 2 H), 3.45 - 3.64 (m, 2 H), 2.90 (s, 2 H), 2.66 (s, 2 H), 1.50 - 1.80 (m, 4 H), 1.42 (d, J = 6.4 Hz, 6 H).
12	XXK	+ESI (M+H) 434.3; ¹H NMR (400 MHz, DMSO-d₀, δ): 11.67 (s, 1 H), 7.98 (br. s., 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 7.40 - 7.44 (m, 2 H), 7.36 - 7.40 (m, 1 H), 7.09 - 7.13 (m, 1 H), 7.01 (dd, J = 8.3, 1.5 Hz, 1 H), 5.19 - 5.29 (m, 1 H), 3.31 - 3.70 (m, 4 H), 2.78 (s, 2 H), 2.59 (s, 2 H), 1.38 - 1.54 (m, 4 H), 1.33 (d, J = 6.6 Hz, 6 H).
13	XiX Η	+ESI (M+H) 432.3; HPLC rétention time 2.18 minutes (Method A)
14	ΛΧ	+ESI (M+H) 433.3; HPLC rétention time 2.52 minutes (Method A). Ή NMR (500 MHz, CDCI₃, δ) 8.78 (d, J=2.20 Hz, 1 H), 8.13 (d, J=1.95 Hz, 1 H), 8.03 (d, J=9.27 Hz, 1 H), 7,44 (dd, J=9.03, 2.68 Hz, 1 H), 7.40 (s, 1 H), 7.10 (d, J=2.68 Hz, 1 H), 5.35 5.43 (m, 1 H), 3.96 (s, 3 H), 3.81 (br. s._r 2 H), 3.50 (br. s., 2 H), 2.84 (s, 2 H), 2.63 (s, 2 H), 1.54 -1.79 (m, 4 H), 1.47 (d, J=6.34 Hz, 6 H).
15	χχΧ	+ESI (M+H) 418.2; HPLC rétention time 2.06 minutes (Method A).
16	et Η	+ESI (M+H) 426.1; HPLC rétention time 2.18 minutes (Method A).
17	// ,ΓΊΡν Η	+ESI (M+H) 417.2; ¹H NMR (400 MHz, DMSO-d₆, δ): 7.91 (dd, J = 8.4, 0.8 Hz, 1 H), 7.73 (s, 1 H), 7.42 (s, 1 H), 7.33 (dd, J = 8.4, 1.2 Hz, 1 H), 5.19 5.28 (m, 1 H), 3.49 - 3.78 (m, 4 H), 2.77 (br. s., 2 H), 2.59 (s, 2 H), 1.36 - 1.60 (m, 4 H), 1.33 (m, 6 H).

Example 18: 5-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 yl) carbonyl] -1H -pyrazolo[3,4-b] pyridi ne-3-carboxamide

Step 1. methyl 3-cyano-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Methyl 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.28 g, 5.01 mmol) was combined with N,N-dimethylacetamide (34 mL). To this mixture was added zinc dust (195 mg, 2.90 mmol) and zinc cyanide (1.20 g, 10.2 mmol). Nitrogen was bubbled through the mixture for 30 minutes. Then 1,1'-bis(diphenylphosphino)ferrocene-palladium (11) dichloride dichloromethane complex (611 mg, 0.749 mmol) was added and the reaction vessel was sealed. The reaction was heated to 120 °C for 65 hours. The reaction was diluted with 20% methanol / ethyl acetate and filtered through Celite. The filtrate was diluted with water and transferred to a separatory funnel. The phases were separated, and the organics were washed again with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-75% ethyl acetate / heptanes) gave the title compound (390 mg, 39%). +ESI (M+H) 203.1.

Step 2. 5-(1 -isopropyl-7-oxo-1 Aej-tetrahydrospirofindazole-S^'-piperidine]-! ’-ylcarbonyl)-1 Hpyrazolo[3,4-b]pyridine-3-carbonrtrile

Methyl 3-cyano-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (390 mg, 1.93 mmol) was dissolved in methanol (20 mL). Aqueous 1 N sodium hydroxide (11 mL, 10 mmol) was added and the reaction was allowed to stir at room température for 22 hours. The crude was concentrated to

remove the methanol and was then washed once with dichloromethane. The aqueous layer was acidified to pH = 2 with 6 N aqueous hydrochloric acid and the resulting solids were collected by filtration (172 mg).

To the carboxylic acid (170 mg, 0.91 mmol) was added 4-dimethylaminopyridine (27.6 mg, 0.22 mmol), 2-propanephosphonic acid cyclic anhydride (0.65 mL, 1.1 mmol), and dichloromethane (3 mL). The mixture was stirred at room température for 1 hour. Triethylamine (0.51 mL, 3.6 mmol) and 1-isopropyl-4,6-dihydrospiro(indazole-5,4'-piperidin]-7(1H)-one (293 mg, 0.913 mmol) were then added and the reaction was stirred for 17 hours. Additional triethylamine (0.30 mL, 2.2 mmol) was added and the reaction was stirred for another 24 hours. The reaction was diluted with water and the layers were separated. The aqueous was extracted twice with dichloromethane. The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-100% of a 10% methanol in dichloromethane solution / dichloromethane) gave the title compound (177 mg, 47%). +ESI (M+H) 418.3; ¹H NMR (500 MHz, CHLOROFORM-d, δ): 13.59 (br. s.. 1 H), 8.81 (d, J = 2.0 Hz, 1 H), 8.38 (d, J = 1.7 Hz, 1 H), 7.44 (s, 1 H), 5.40 (m, 1 H), 3.77 - 3.98 (m, 2 H), 3.44 - 3.63 (m, 2 H), 2.86 (s, 2 H), 2.66 (s, 2 H), 1.54 1.85 (m, 4 H), 1.47 (d, J = 6.6 Hz, 6 H).

Step 3. 5-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-rH-spiro[indazole-5,4'-piperidin]-1'-yl)carbonyl]1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A solution of 5-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-rylcarbonyl)-1 H-pyrazolo[3,4-b]pyridine-3-carbonitrile (177 mg, 0.424 mmol) in methanol (2 mL) was added to a 0 ’C solution of urea hydrogen peroxide (552 mg, 5.70 mmol) in 1 N aqueous sodium hydroxide (4.24 mL, 4.24 mmol). The reaction was allowed to warm to room température and stir for 22 hours. The methanol was removed under reduced pressure and the residue was diluted with water and saturated aqueous ammonium chloride. The mixture was extracted with dichloromethane (3x). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by reversed-phase HPLC gave the title compound. Analytical LCMS: +ESI (M+H) 436.2; rétention time 2.11 minutes (Method A).

Example 19: 5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro[indazole-5,4'-piperïdin]-1 yl)carbonyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Step 1, ethyl 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylate

The title compound was prepared by a method analogous to that described in Step 1 of

Example 18, using ethyl 2-bromo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. +ESI (M+H) 216.3; ¹H

NMR (400 MHz, METHANOL-d₄, δ): 9.02 (d, J = 2.1 Hz, 1 H), 8.73 (d, J = 2.0 Hz, 1 H), 7.35 (s, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.1 Hz, 3 H).

Step 2. 5-(1 -isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 '-ylcarbonyl)-1 Hpyrrolo[2,3-b]pyridine-2-carbonitrile

To ethyl 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (36 mg, 0.17 mmol) was added methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL), followed by 2 N aqueous lithium hydroxide (0.17 mL, 0.33 mmol). The reaction was stirred at room température overnight and was then concentrated. The crude was taken up in water and the pH was adjusted to 4 using 1 N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3x). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide the 2-cyano-1 Hpyrrolo[2,3-b]pyridine-5-carboxylic acid. The title compound was then prepared by a method analogous to that described in Example 1, using 2-cyano-1 H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, -ESI (M-H) 415.1.

Step 3. 5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 Ή-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonylj1 H-pyrrolo[2,3 - b] py ri d i ne-2-carboxam id e

The title compound was prepared by a method analogous to that described in Step 3 of Example 18. Analytical LCMS: +ESI (M+H) 435.1; rétention time 2.17 minutes (Method A).

Example 20:1 -isopropyl-14[2-(methylamino)-1H-benzimidazol-5-yl]carbonyl}-1,4dihydrospîro[indazole-5,4'-piperidin]-7(6H)-one

Step 1. 1 '-(3,4-diaminobenzoyl)-1 -isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin)-7(1 H)-one

The title compound was prepared by a method analogous to that described for Example 3, using 3,4-diaminobenzoic acid. ¹H NMR (400 MHz, DMSO-d6, δ): 7.45 (s, 1 H), 6.60 (s, 1 H), 6.46 (s, 1 H), 5.76 (s, 1 H), 5.24 - 5.30 (m, 1 H), 4.78 (s, 2 H), 4.56 (s, 2 H), 3.35 - 3.55 (m, 4 H), 2.79 (s, 2 H), 2.59 (s, 2 H), 2.40-2.50 (m, 1 H), 1.42 - 1.46 (m, 3 H), 1.35 (d, J = 6.8 Hz, 6 H).

Step 2. 1 -isopropyl-1 '-{[2-(methylamino)-1 H-benzimidazol-5-yl]carbonyl}-1,4-dihydrospiro[indazole5,4'-piperidin]-7(6H)-one

A mixture of 1'-(3,4-diaminobenzoyl)-1 -isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidîn]7(1H)-one (0.1 g, 0.3 mmol) and isothiocyanatomethane (19 mg, 0.3 mmol) was dissolved in tetrahydrofuran (3 mL). The reaction was heated to reflux and stirred for 6 hours. The reaction mixture was concentrated, and the residue was poured into cold water. The solution was extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide 1-(2-amino-4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4‘piperidine]-1’-ylcarbonyl)phenyl)-3-methylthiourea (37 mg, 27%).

The crude product was dissolved in éthanol (2 mL) and methyl iodide (147 mg, 1.0 mmol) was added. The reaction was heated to reflux and stirred ovemight. The reaction was concentrated and the residue was basified to pH = 9 with ammonium hydroxide. The mixture was extracted with dichloromethane (3 x 20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by reversed-phase HPLC gave the title compound (28 mg, 83%) as an off white solid. ¹H NMR (400 MHz, CDCI₃, δ): 7.39 (s, 1 H), 7.13 (s, 1 H), 7.05 - 7.07 (m, 1 H), 6.99 - 7.01 (m, 1 H), 5.33 - 5.43 (m, 1 H), 3.44 - 3.89 (m, 4 H), 2.91 (s, 3 H), 2.86 (s, 2 H), 2.60 (s, 2 H), 1.50 - 1.80 (m, 4 H), 1.46 (d, J = 6.8 Hz, 6 H).

Example 21: 5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 yl)carbonyl]-1H-benzimidazole-2-carboxamide

A mixture of 1'-(3,4-diaminobenzoyi)-1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]7(1H)-one (500 mg, 1.3 mmol), 2-chloroacetamide (200 mg, 2.1 mmol), sulfur (200 mg, 6.3 mmol), and triethylamine (1 mL, 7 mmol) in Ν,Ν-dimethylformamide (5 mL) was stirred at 65 °C overnight. The reaction mixture was cooled to 0 °C, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave the title compound (252 mg, 44%) as a yellow solid. Ή NMR (400 MHz, CD_aOD, δ): 7.60 - 7.90 (m, 2 H), 7.30 - 7.50 (m, 2 H), 5.37 - 5.40 (m, 1 H), 3.40 - 4.00 (m, 4 H), 2.89 (s, 2 H), 2.65 (s, 2 H), 1.50 - 1.80 (m, 4 H), 1.42 (d, J = 6.4 Hz, 6 H).

Example 22: 3-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spirotindazole-S^'-piperidin]-! yl)carbonyl]-6-methoxyquinoline-7-carboxamide

Step 1: 1 '-(7-bromo-6-methoxyquinoline-3-carbonyl)-1 -isopropyl-4,6-dihydrospiro[indazole-5₁4'piperidinl-7(1H)-one

The title compound was prepared by a method analogous to that described for Example 2, using 7-bromo-6-methoxyquinoline-3-carboxylic acid. +ESI (M+H+1) 513.2; ¹H NMR (400 MHz, CDCIg, δ): 8.71 (d, J = 2.15 Hz, 1 H), 8.29 (s, 1 H), 8.05 (d, J = 2.15 Hz, 1 H), 7.32 (s, 1 H), 7.05 (s, 1 H), 5.25 - 5.37 (m, 1 H), 3.96 (s, 3 H), 3.65 - 3.91 (m, 2 H), 3.37 - 3.58 (m, 2 H), 2.77 (s, 2 H), 2.55 (s, 2 H), 1.59 - 1.73 (m, 2 H), 1.46 - 1.59 (m, 2 H), 1.39 (d, J = 6.44 Hz, 6 H).

Step 2: 3-(1 -isopropyl-7-oxo-1 ^.e.Z-tetrahydrospirofindazole-S^'-piperidineJ-l '-ylcarbonyl)-6methoxyquinoline-7-carbonitrile

The title compound was prepared by a method analogous to that described for Intermediate 6, using 1 '-(7-bromo-6-methoxyquinoline-3-carbonyl)-1 -isopropyl-4,6-dihydrospiro[indazole-5,4'piperidin]-7(1H)-one. +ESI (M+H) 458.4; ¹H NMR (400 MHz, CDCI₃, δ): 8.82 (d, J = 1.95 Hz, 1 H), 8.37 (s, 1 H), 8.10 (d, J = 1.56 Hz, 1 H), 7.35 (s, 1 H), 7.14 (s, 1 H), 5.33 (m, 1 H), 4.02 (s, 3 H), 3.70 - 3.91 (m, 2 H), 3.36 - 3.54 (m, 2 H), 2.80 (s, 2 H), 2.58 (s, 2 H), 1.65 -1.77 (m, 2 H). 1.51 1.62 (m, 2 H), 1.42 (d, J = 4.49 Hz, 6 H).

Step 3; 3-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-r-yl)carbonyl]-6methoxyquinoline-7-carboxamide

The title compound was prepared by a method analogous to that described in Step 4 of Intermediate 6, using 3-(1-isopropyl-7-oxo-1 Ae.y-tetrahydrospirotindazole-S^'-piperidineJ-l ylcarbonyl)-6-methoxyquinoline-7-carbonitrile. +ESI (M+H) 476.4; ¹H NMR (400 MHz, CD₃OD, δ): 8.77 (s, 1 H), 8.52 (s, 1 H), 8.36 (s, 1 H), 7.55 (s, 1 H), 7.42 (s, 1 H), 5.31 - 5.43 (m, 1 H), 4.08 (s, 3 H), 3.84 - 4.00 (m, 1 H), 3.69 - 3.83 (m, 1 H), 3.48 - 3.58 (m, 2 H), 2.90 (s, 2 H), 2.65 (br. s., 2 H), 1.53-1.78 (m, 4H), 1.35- 1.45 (m, 6H).

Example 23: 6-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4’-piperidin]-1 'yl)carbonyll-1H-pyrrolo[3,2-blpyridine-3-carbonitrile

Step 1: 1 '-(3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carbonyl)-1 -isopropyl-4,6-dihydrospiro[indazole5,4'-piperidin]-7(1 H)-one

The title compound was prepared by a method analogous to that described for Example 3, using 3-bromo-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid. +ESI (M+H+1) 472.1; ’H NMR (400 MHz, DMSO-d_e. δ): 11.85 (br. s., 1 H), 8.39 (d, J = 1.8 Hz, 1 H), 7.93 (s, 1 H), 7.81 (d, J = 1.8 Hz, 1 H), 7.43 (s, 1 H), 5.24 (m, 1 H), 3.68 (m, 1 H), 3.40 (m, 3 H), 2.79 (s, 2 H), 2.60 (s, 2 H), 1.49 (m, 4 H), 1.33 (d, J = 6.6 Hz, 6 H).

Step2: e-KI-isopropyl-Z-oxo-IAej-tetrahydro-l'H-spirotindazole-S^'-piperidinj-l'-yQcarbonyl]1H-pyrrolo[3,2-b]pyridine-3-carbonitrile

To a mixture of 1-(3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carbonyl)-1-isopropyl-4,6dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one (500 mg, 1.1 mmol), zinc dust (70 mg, 1.1 mmol), and zinc cyanide (187 mg, 1.60 mmol) was added N,N-dimethylacetamide (9 mL). The reaction vial was capped and nitrogen gas was bubbled through the mixture for 15 minutes. Meanwhïle, a mixture of palladium(ll) acetate (24 mg, 0.11 mmol), 4,5-bis(diphenylphosphino)-9,9dimethylxanthene (68 mg, 0.12 mmol), and zinc powder (7 mg, 0.13 mmol) in N,Ndimethylacetamide (1.5 mL) was heated to 80 °C for 15 minutes to give a reddish brown solution. This palladium solution was then added via syringe to the substrate mixture. The reaction was heated to 100 °C and stirred for 3 days. The reaction was cooled to room température and diluted with ethyl acetate (100 mL). The solution was filtered through Celite and the filtrate was concentrated. 50 mg of the crude residue was subjected to purification by reversed-phase HPLC to give the title compound (25.8 mg). +ES1 (M+H) 417.1; HPLC rétention time 2.32 minutes (Method A).

Example 24: 2-({3-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro[indazole-5,4'-piperidin]-1 yl)carbonyl]quinolin-6-yl}oxy)acetamide

nh₂

Step 1: 2-(2-chloro-3-(1 -isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 ylcarbonyl)quinolin-6-yloxy)acetamide

6-(2-tert-butoxy-2-oxoethoxy)-2-chloroquinoline-3-carboxylic acid and 1-ïsopropyl-4,6dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one were coupled by a method analogous to that described for Example 1 to give tert-butyl 2-(2-chloro-3-(1-isopropyl-7-oxo-1,4,6,7tetrahydrospiro[indazole-5,4'-piperidine]-1 '-ylcarbonyl)quinolin-6-yloxy)acetate. This material (30 mg, 0.053 mmol) was suspended in ammonia (2 mL, 10 mmol, 7 M in methanol) and stirred at room température for 1Θ hours. The reaction was concentrated to give the title compound (27 mg, 100%).+ESI (M+H) 510.4.

Step 2: 2-({3-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 Ή-spiro[indazole-5,4'-piperidin]-1 ’yl)carbonyl]quinolin-6-yl}oxy)acetamide

Methanol (1.5 mL) and ethyl acetate (1.5 mL) were added to 2-(2-chloro-3-(1-isopropyl-7oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-pipendine]-r-ylcarbonyl)quinolin-6-yloxy)acetamide (27 mg, 0.053 mmol). Palladium hydroxide (15 mg) was then added and the reaction was pressurized to 40 psi hydrogen and agitated at room température for 20 hours. The reaction mixture was filtered through Celite and concentrated. Purification via reversed-phase HPLC gave the title compound (2.1 mg, 8%). +ESI (M+H) 476.2; HPLC rétention time 2.11 minutes (Method A).

Example 25: 1 '-[(2-aminoquinolin-7-yl)carbonyl]-1 -isopropyl-1,4-dihydrospiro[indazole-5,4'piperidinl-7(6H)-one

Step 1: 1 ’-(2-(tert-butylamino)quinoline-7-carbonyl)-1 -isopropyl-4,6-dihydrospiro[indazole-5,4' piperidin]-7(1H)-one

The title compound was prepared by a method analogous to that described for Example 3, using 2-(tert-butylamino)quinoline-7-carboxylic acid. +APCI (M+H) 474.6; ’H NMR (400 MHz, CDCI₃, δ): 7.72 (d, J = 8.Θ Hz, 1 H), 7.64 (s, 1 H), 7.55 (d, J = 8.2 Hz, 1 H), 7.36 (s, 1 H), 7.16 (dd, J =8.1, 1.3 Hz, 1 H), 6.59 (d, J = 9.2 Hz, 1 H), 5.36 (quin, J = 6.6 Hz, 1 H), 3.31 - 3.96 (m, 4 H), 2.79 (s, 2 H), 2.58 (s, 2 H), 1.55- 1.75 (m, 4 H), 1.52 (s, 9 H), 1.44 (d, J = 6.4 Hz, 6 H).

Step 2: 1 '-[(2-aminoquinolin-7-yl)carbonyl]-1 -isopropyl-1,4-dihydrospiro[indazole-5,4’-piperidin]7(6H)-one Trifluoroacetate Sait

Trifluoroacetic acid (0.90 mL, 12 mmol) was added to r-(2-(tert-butylamino)quinoline-7carbonyl)-1-isopropyl-4,6-dÎhydrospiro[indazole-5,4'-piperidin]-7(1H)-one (50 mg, 0.11 mmol). The reaction was heated to 70 °C for 3 hours, then cooled to room température and left stirring overnight. The reaction was concentrated to dryness and purification by reversed-phase HPLC gave the title compound (41 mg, 93%). +ESI (M+H) 418.2; HPLC rétention time 2.11 minutes (Method A). ¹H NMR (500 MHz, CD₃OD. δ) 8.36 (d, J=9.27 Hz, 1 H), 7.97 (d, J=8.05 Hz, 1 H), 7.66 (s, 1 H), 7.53 (dd, J=8.17, 1.34 Hz, 1 H), 7.44 (s, 1 H), 7.12 (d, J=9.27 Hz, 1 H), 5.39 (quint, J=13.23, 6.68 Hz, 1 H), 3.91 (br. s., 1 H), 3.76 (br. s., 1 H), 3.46 (br. s., 2 H), 2.92 (s, 2 H), 2.67 (d, J=7.81 Hz, 2 H), 1.74 (br. s., 2 H), 1.59 (br. s., 2 H), 1.43 (br. s., 6 H).

The compounds listed in Table 2 below were prepared using procedures analogous to those described above for the synthesis of the compounds of Examples 1-3 using the appropriate starting materials which are available commercially, prepared using préparations well-known to those skilled in the art, or prepared by a route described above. The compounds listed below were

isolated initially as the free base and may be converted to a pharmaceutically acceptable sait for testing.

Table 2:

Example	-R^a	Analytical Data
26	H ÎT;n _oYnh₂	+APCI (M+H) 449.5; ¹H NMR (400 MHz, DMSO-d_e, δ): 13.66 (br. s., 1 H), 8.17 (s, 1 H), 7.77 (br. s„ 1 H), 7.59 - 7.64 (m, 1 H), 7.35 - 7.43 (m, 3 H), 3.33 3.83 (m, 4 H), 2.82 (br. s., 2 H), 2.62 (s, 2 H), 1.56 (s, 9 H), 1.33- 1.53 (m, 4 H).
27	M ^H x-W	+ESI (M+H) 449.2; rétention time 2.31 minutes. (Method A)

The compounds listed in Table 3 below were prepared using procedures analogous to those described above for the synthesis of the compounds of Examples 1-3 using the appropriate starting materials which are available commercially, prepared using préparations well-known to those skilled in the art, or prepared by a route described above. The compounds listed below were isolated initially as the free base and may be converted to a pharmaceutically acceptable sait for testing.

Table 3

O

⁰

Example	-----ΠΥ-----	Analytical Data
28	°y-NH₂ H	+ESI (M+H) 448.2; ¹H NMR (400 MHz, DMSO-d₆δ): 11.65 (br. s., 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.08 (d, J = 2.2 Hz, 1 H), 7.81 (s, 1 H), 7.43 (s, 1 H), 7.36 (br. s., 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.79 (br. s„ 1 H), 3.34 - 3.67 (m, 4 H), 2.77 (s, 2 H), 2.55 (s,

		2 H), 1.51 (s, 9 H), 1.42- 1.50 (m, 4 H).
29	0. %-νη₂	+ESI (M+H) 449.2; Ή NMR (400 MHz, DMSO-d₆, Ô): 13.63 (s, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.78 (s, 1 H), 7.73 (s, 1 H), 7.55 (s, 1 H), 7.34 (s, 1 H), 7.18 (dd, J = 8.3, 1.3 Hz, 1 H), 3.50 - 3.72 (m, 2 H), 3.21 - 3.39 (m, 2 H), 2.74 (s, 2 H), 2.53 (s, 2 H), 1.49 (s, 9 H), 1.22-1.61 (m, 4 H).
30	-vû> _o?-NH₂	+ESI (M+H) 449.2; HPLC rétention time 1.99 minutes. (Method A)
31	M ^H ί T ;n Λ'ΝΗ, 0 ²	+ESI (M+H) 449.3; ¹H NMR (400 MHz, DMSO-d_e, δ): 13.67 (s, 1 H), 8.17 (s, 1 H), 7.81 (s, 1 H), 7.75 7.79 (m, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7,41 (dd, J = 8.6, 1.6 Hz, 2 H), 3.31 - 3.71 (m, 4 H), 2.77 (br. s._r2 H), 2.55 (s, 2 H), 1.52 (s, 9 H), 1.39 - 1.50 (m, 4 H).
32	λΟζΓ	+ESI (M+H) 448.2; 'H NMR (400 MHz, DMSO-d₀, δ): 11.70 (d, J = 1.4 Hz, 1 H), 7.99 (br. s., 1 H), 7.82 (s, 1 H), 7.66 (s, 1 H), 7.42 (d, J = 8.6 Hz, 1 H), 7.39 (br. s., 1 H), 7.21 (dd, J = 8.4, 1.6 Hz, 1 H), 7.16 (d, J= 1.4 Hz, 1 H), 3.49 (br. s„ 4 H), 2.78 (s, 2 H), 2.56 (s, 2 H), 1.50 (s, 9 H), 1.48 (br. s., 4 H).
33	-yCÔ ₀Λ-νη₂	-ESI (M-H) 446.2; ¹H NMR (400 MHz, DMSO-d₀, δ): 11.68 (br. s., 1 H), 8.20 (d, J = 0.8 Hz, 1 H), 8.07 (d, J = 2.7 Hz, 1 H), 7.82 (s, 1 H), 7.46 (br. S„ 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.17 (dd, J = 8.3,1.7 Hz, 1 H), 6.82 (br. s., 1 H), 3.50 (br. s., 4 H), 2.78 (s, 2 H), 2.55 (s, 2 H), 1.53 (s, 9 H), 1.48 (br. s., 4 H).
34	ΧΟΓ H	+ESI (M+H) 448.4; 'H NMR (400 MHz, DMSO-d₀₁δ): 11.67 (d, J = 1.6 Hz, 1 H), 7.98 (br. s., 1 H), 7.79 (s, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 7.41 (s, 1 H), 7.36 - 7.40 (m, 1 H), 7.09 - 7.13 (m, 1 H), 7.02 (dd, J = 8.3, 1.5 Hz, 1 H), 3.43 (br. s., 4 H), 2.75 (s, 2 H), 2.52 (s, 2 H), 1.37 - 1.55 (m, 13 H).
35	aCXn^^NHî	’H NMR (400 MHz, CD_aOD, δ): 8.36 (br. s., 1 H), 7.75 (s, 1 H), 7.34 - 7.36 (m, 2 H), 7.24 - 7.26 (m, 1 H), 3.50 - 3.88 (m, 4 H), 2.91 (s, 2 H), 2.68 (s, 2 H), 1.62 (s, 9 H), 1.56- 1.70 (m, 4 H).

36	xkjf ANH ⁰	’H NMR {400 MHz, CD₃OD, δ): 8.42 - 8.45 (m, 1 H), 8.31 (s, 1 H), 7.74 (s, 1 H), 7.65 (d, J = 8.8 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 3.65 - 4.00 (m, 2 H), 3.44 - 3.60 (m, 4 H), 2.90 (s, 2 H), 2.66 (s, 2 H), 1.50 - 1.80 (m, 4 H), 1.60 (s, 9 H), 1.26 (t, J = 7.2 Hz, 3 H).
37	aCXⁿ o \	’H NMR (400 MHz, DMSO-d_e, δ): 13.70 (s, 1 H), 8.40 - 8.41 (m, 1 H), 8.19 (s, 1 H), 7.83 (s, 1 H), 7.63 (d, J = 8.8 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 3.40 - 3.80 (m, 4 H), 2.81 (d, J=4.4 Hz, 3 H), 2.80 (s, 2 H), 2.57 (s, 2 H), 1.40 -1.60 (m, 13 H).
38	,\W	’H NMR (400 MHz, CD₃OD, δ): 8.31 (s, 1 H), 7.74 (s, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 4.10 - 4.17 (m, 2 H), 3.65 - 4.00 (m, 2 H), 3.40 - 3.65 (m, 2 H), 2.90 (s, 2 H), 2.67 (s, 2 H), 1.50 - 1.80 (m, 4H), 1.60 (s, 9 H).
39		’H NMR (400 MHz, CD₃OD, δ): 8.30 (s, 1 H), 7.73 (s, 1 H), 7.31 (d, J = 9.6 Hz, 2 H), 7.18 - 7.20 (m, 1 H), 3.40 - 3.95 (m, 4 H), 3.04 (s, 3 H), 2.88 (s, 2 H), 2.65 (s, 2 H), 1.60 (s, 9 H), 1.45 - 1.80 (m, 4 H).
40	xa 1	+ESI (M+H) 446.3; HPLC rétention time 2.07 minutes (Method A).
41	// χχ> λ-W-N	+ESÎ (M+H) 431.2; ’H NMR (400 MHz, CD₃OD, δ): 7.93 (d, 1 H), 7.74 (d, 2 H), 7.40 (dd, 1 H), 3.70 4.00 (m, 2 H), 3.40 - 3.50 (m, 2 H), 2.89 (s, 2 H), 2.66 (s, 2 H), 1.65 - 1.80 (m, 2 H), 1.60 (s, 9 H), 1.50 - 1.65 (m, 2 H).
42	Cl H	+ESI (M+H) 440.1 ; HPLC rétention time 2.06 minutes (Method A).
43	H ÎT;ⁿ	+ESI (M+H) 431.3; ’H NMR (400 MHz, DMSO-d_e, δ): 7.89 - 7.92 (m, 1 H), 7.83 (s, 1 H), 7.81 (dd, J = 8.61,0.78 Hz, 1 H), 7.54 (dd, J = 8.71, 1.47 Hz, 1 H), 3.36 - 3.78 (m, 4 H), 2.79 (s, 2 H), 2.58 (s, 2 H), 1.53 (s, 9 H), 1.41 -1.52 (m, 4 H).
44	\-ί>Ογ^ΝΗ2 o	+ESI (M+H) 460.2; Ή NMR (400 MHz, DMSO-d₆, δ): 8.94 (d, J = 2.1 Hz, 1 H), 8.56 (d, J = 2.0 Hz, 1 H), 8.47 (d, J - 2.1 Hz, 1 H), 8.18 - 8.24 (m, 2 H), 8.07 (d, J = 8.78 Hz, 1H), 7.81 (s, 1 H), 7.57 (s, 1 H), 3.57 - 3.77 (m, 2 H), 3.33 - 3.44 (m, 2 H), 2.77

(s, 2 H), 2.56 (s, 2 H), 1.53 -1.61 (m, 2 H), 1.50 (s, 9 H), 1.45-1.50 (m, 2H).

Example 45: 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 '-yl) carbonyl]-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

Step 1. methyl 3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carboxylate

The title compound was prepared by a method analogous to that described in Step 2 for Intermediate 9, using methyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate. +ESI (M+H) 257.1; ¹H NMR (DMSO-de, δ): 12.08 (br. s.. 1 H), 8.92 (d, J = 1.8 Hz, 1 H), 8.30 (d, J = 2.0 Hz, 1 H), 8.10 (d, J = 2.9 Hz, 1 H), 3.88 (s, 3 H).

Step 2. 3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carboxylic acid hydrochloride

.HCl

To a solution of methyl 3-bromo-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (2.90 g, 11.4 mmol) in 1,4-dioxane (30 mL) was added 6 N aqueous hydrochloric acid (18.9 mL, 114 mmol). The reaction was heated to 90 °C and stirred overnight. The reaction was cooled to room température and concentrated to dryness to afford the title compound (2.76 g, quantitative). ’H NMR (400 MHz, DMSO-de, δ): 12.31 (br. s., 1 H), 8.91 (d. J =1.8 Hz, 1 H), 8.37 (s, 1 H), 8.14 (d, J = 1.6 Hz, 1 H).

Step 3.1 '-(3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carbonyl)-2-tert-butyl-4,6-dihydrospiro[indazole5,4'-piperidin]-7(2H)-one ✓

To a suspension of 3-bromo-1 H-pyrrolo[3,2-b]pyridine-6-carboxylic acid hydrochloride (2.75 g, 9.91 mmol) and 2-tert-butyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one hydrochloride sait (2.95 g, 9.91 mmol) in dichloromethane (30 mL) was added triethylamine (5.52 mL, 39.6 mmol). Ν,Ν-dimethylformamide (5 mL) was then added, followed by 1-hydroxybenzotriazole (1.61 g, 11.9 mmol) and 1, (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.28 g, 11.9 mmol). The reaction was allowed to stir at room température for 60 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnésium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-10% methanol / ethyl acetate) gave the title compound (3.39 g, 71%) as a pale brown solid. +ESI (M+1+H) 4Θ6.2; ¹H NMR (400 MHz, CDCI₃, δ): 10.05 (br. s„ 1 H), 8.57 (d, J = 1.8 Hz, 1 H), 7.Θ7 (d, J = 1.8 Hz, 1 H), 7.61 (d, J = 2.7 Hz, 1 H), 7.44 (s, 1 H), 3.78 (br. s., 2 H), 3.51 (br. s., 2 H), 2.81 (s, 2 H), 2.65 (s, 2 H), 1.63 (s, 13 H).

Step 4. 6-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 ’-yl)carbonyl]-1 Hpyrrolo[3,2-b]pyridine-3-carboxamide

A round bottom flask was charged with 1'-(3-bromo-1H-pyrrolo[3,2-b]pyridine-6-carbonyl)-2tert-butyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one (1.25 g, 2.58 mmol), zinc cyanide (454 mg, 3.Θ7 mmol), zinc dust (169 mg, 2.58 mmol), and lastly dîmethylacetamide (22 mL). Nitrogen was bubbled through the mixture for 5 minutes. Copper (I) iodide (494 mg, 2.58 mmol) and [1,1 'bis(diphenylphosphlno)ferrocene]dichloropalladium(ll), complex with dichloromethane (189 mg, 0.258 mmol) were added and the reaction was heated to 120 °C overnight. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with sodium bicarbonate (7% aqueous) and brine. The organics were dried over magnésium sulfate, filtered, and concentrated. The crude residue was triturated with methyl tert-butyl ether and the resulting orange powder was filtered off and dried.

The powder (550 mg) was suspended in dichloromethane (20 mL) and concentrated sulfuric acid (1 mL) was added. The reaction was stirred vigorously for 3 hours, then the upper dichloromethane layer was decanted and set aside. To the remaining brown syrup was added 50 g ice and the pH was adjusted to 7 using 5 N aqueous sodium hydroxide. The mixture was combined with the previously separated dichloromethane layer and transferred to a separatory tunnel. The

phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organics were washed with brine, dried over magnésium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-10% methanol / dichloromethane) gave the title compound (420 mg, 73%) as an off-white solid. +ESI (M+H) 449.3; 'H NMR (400 MHz, DMSO-d_ei δ): 12.09 (br. s., 1 H), 8.49 (d, J = 1.Θ Hz, 1 H), 8.24 (s, 1 H), 8.12 (br. s„ 1 H), 7.93 (d, J = 1.8 Hz, 1 H), 7.83 (s, 1 H), 7.39 (d, J = 2.7 Hz, 1 H), 3.62 (br. s., 2 H), 3.43 (br. s„ 2 H), 2.79 (s, 2 H), 2.58 (s, 2 H), 1.53 (s, 13 H).

Example 46: 2-({3-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 'yl)carbonyl]quinolin-6-yl}oxy)acetamide

Step 1: tert-butyl 2-(3-(2-tert-butyl-7-oxo-2,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-rylcarbonyl)quinolin-6-yloxy)acetate

The title compound was prepared by a method analogous to that described for Example 3, using 6-(2-tert-butoxy-2-oxoethoxy)quinoline-3-carboxylîc acid and 2-tert-butyl-4,6dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one hydrochloride sait. +ESI (M+H) 547.3; ¹H NMR (400 MHz, CDCI₃₁ δ): 8.77 (d, J = 2.0 Hz, 1 H), 8.10 (d, J = 1.6 Hz, 1 H), 8.06 (d, J = 9.2 Hz, 1 H), 7.50 (dd, J = 9.3, 2.8 Hz 1 H), 7.41 (s, 1 H), 7.02 (d, J = 2.7 Hz, 1 H), 4.64 (s, 2 H),3.68 - 3.93 (m, 2 H), 3.41-3.51 (m, 2 H), 2.78 (s, 2 H). 2.65 (s, 2 H), 1.53-1.76 (m, 4 H), 1.61 (s, 9 H), 1.49 (s, 9 H).

Step 2: 2-(3-(2-tert-butyl-7-oxo-2,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 'ylcarbonyl)quinolin-6-yloxy)aceticacid

Hydrochloric acid (10 mL, 40 mmol, 4 M in 1,4-dioxane) was added to tert-butyl 2-(3-(2-tertbutyl-7-oxo-2,4,6₁7-tetrahydrospiro[indazole-5,4'-piperidine]-r-ylcarbonyl)quinolin-6-yloxy)acetate (470 mg, 0.860 mmol). The reaction was stirred vigorously at room température for 1 hour. The reaction was concentrated. The residue was coevaporated with ethyl acetate and heptanes several times, and then dried under vacuum to provide the title compound (422 mg, 100%). +ESI (M+H) 491.4; ¹H NMR (400 MHz, DMSO-d_e, δ): 8.76 (d, J = 2.0 Hz, 1 H), 8.35 (d, J = 1.4 Hz, 1 H), 7.9Θ (d, J = 9.2 Hz, 1 H), 7.81 (s, 1 H), 7.52 (dd, J = 9.3, 2.8 Hz, 1 H), 7.42 (d, J = 2.9 Hz, 1 H), 4.82 (s, 2 H), 3.57 - 3.73 (m, 2 H), 3.34 - 3.50 (m, 2 H), 2.77 (s, 2 H), 2.56 (s, 2 H), 1.50 (s, 9 H), 1.44 -1.58 (m, 4 H).

Step 3: 2-({3-[(2-tert-butyl-7-oxo-2,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 yl)carbonyl]quinolin-6-yl}oxy)acetamide

To a suspension of 2-(3-(2-tert-butyl-7-oxo-2,4_l6,7-tetrahydrospÎro[Îndazole-5,4'-piperidine]1 ’-ylcarbonyl)quinolin-6-yloxy)acetic acid (290 mg, 0.59 mmol) in dichloromethane (6 mL) was added ammonia (2.36 mL, 1.18 mmol, 0.5 M in 1,4-dioxane) and (1H-7-azabenzotriazol-1-yl)1,1,3,3-tetramethyl uranium hexafluorophosphate (225 mg, 0.591 mmol). The reaction was stirred at room température overnight. The reaction was concentrated and purified by flash column chromatography (0-10% methanol / dichloromethane). The resulting material was dissolved in ethyl acetate, washed with water and brine, dried over magnésium sulfate, filtered, and concentrated to give the title compound (280 mg, 97%). +ESI (M+H) 490.4; ¹H NMR (400 MHz, CDCl₃, δ): 8.81 (d, J = 2.1 Hz, 1 H), 8.11 (d, J = 2.1 Hz, 1 H), 8.06 (d, J = 9.2 Hz, 1 H), 7.46 (dd, J = 9.3, 2.8 Hz, 1 H), 7.41 (s, 1 H), 7.11 (d, J = 2.7 Hz, 1 H), 6.54 (br. s., 1 H), 5.66 (br. s., 1 H), 4.63 (s, 2 H), 3.68 - 3.96 (m, 2 H), 3.41 - 3.51 (m, 2 H), 2.78 (s, 2 H), 2.65 (s, 2 H), 1.66-1.76 (m, 2 H), 1.61 (s, 9 H), 1.50 1.60 (m, 2H).

Example 47: 1 '-[(2-aminoquinolin-7-yl)carbonyl]-2-tert-butyl-2,4-dihydrospira[indazole-5,4'piperidin]-7(6H)-one

The title compound was prepared by a method analogous to that described for Example 25, using 2-tert-butyl-4₁6-dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one hydrochloride sait. +ESI (M+H) 432.3; ¹H NMR (400 MHz, CDCI₃, δ): 8.10 (d, J = 9.21 Hz, 1 H), 7.82 (s, 1 H), 7.76 (dd, J = 7.95

Hz, 1 H), 7.49 (dd, 1 H), 7.43 (s, 1 H), 6.87 (d, J = 9.33 Hz, 1 H), 3.95 (m, 1 H), 3.64 (m, 1 H), 3.26 3.46 (m, 2 H), 2.79 (s, 2 H), 2.66 (s, 2 H), 1.57 - 1.80 (m, 4 H), 1.61 (s, 9 H).

Example 48: 2-bicyclo[1.1.1]pent-1-yl-1'-(1H-indazol·5-ylcarbonyl)-2,4-dihydrospiro[indazolθ-5,4^,piperidin]-7(6H)-one

The title compound was prepared by a method analogous to that described in Example 1, using 2-(bicyclo[1.1.1]pentan-1-yl)-4_l6-dihydrospiro[indazole-5,4'-piperidin]-7(2H)-one and 1Hindazole-5-carboxylic acid. +ESI (M+H) 416.2; HPLC rétention time 2.32 minutes (Method A).

Example 49: 5-[(1 -bicyclo[1.1.1 ]pent-1 -yl-7-oxo-1,4,6,7-tetrahydro-1 'H-spirotindazole-S^' piperidin]-1 '-yl)carbonyl]-1 H-indazole-3-carboxamide

The title compound was prepared by a method analogous to that described for Example 2, using 1 -(bicyclo[1.1.1 ]pentan-1 -yl)-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1 H)-one hydrochloride and 3-carbamoyl-1H-indazole-5-carboxylic acid. +APCI (M+H) 459.5; ¹H NMR (400 MHz, CDCI₃, δ): 8.42 (s, 1 H), 7.50 (s, 2 H), 7.35 (s, 1 H). 6.93 (br. s., 1 H), 5.47 (br. s., 1 H), 3.32 - 3.93 (m, 4 H), 2.79 (s, 2 H), 2.58 (s, 2 H), 2.56 (s, 1 H), 2.39 (s, 6 H), 1.45 - 1.76 (m, 4 H).

The following compounds shown in Table 4 can be prepared in a manner analogous to the foregoing examples.

Table 4:

° N 0 Example 50: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-ryl)carbonyl]-1 H-pyrrolo[3,2b]pyridine-3-carbonitrile	k^N.A^kkjz o \\ N Example 51: 5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-ryl)carbonyl]-1 H-pyrrolo[2,3b]pyridine-3-carbonitrile	0 y-XH γυ'υ' 0 Example 52:1 ‘-[(2aminoquinolin-6-yl)carbonyl]-2tert-butyl-2,4dihydrospfro[indazole-5,4'piperidin]-7(6H)-one
0 „-Z~NH 0 \ Example 53: 5-[(1 -isopropyl-7oxo-1,4,6,7-tetrahydro-1 Ήspirotindazole-S^’-piperidinJ-Tyl)carbonyl]-N-methyl-1H-indole3-carboxamide	°_V'h Jk-^l YY-Ç o Example 54: 6-[(1 -isopropyl-7oxo-1,4,6,7-tetrahydro-l ΉspirO[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-methyl-1H-indole3-carboxamide	0 Y-NH ⁰ b. Example 55: 5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-cyclopropyl-1 Hî n dazole-3-carboxam ide
xŸk X o Xnh ⁰ Λ Example 56:5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5_t4'-piperidin]-ryl)carbonyl]-N-isopropyl-1 Hindazole-3-carboxamîde	0 \/ JkrA h ' '—' 1 Γ F n L___N.Yk^Jk-ÿ' o „J-nh ⁰ k Example 57: 5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-ryl)carbonyl]-N-propyl-1 Hindazole-3-carboxamide	0 Xnh ⁰ s 0- Example 5Θ: 5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-(2-methoxyethyl)1 H-indazole-3-carboxamide
Example 59: 5-[(2-tert-butyl-7oxo-2,4,6_l7-tetrahydro-1 ΉspiroIindazole-S.A'-piperidinJ-Tyl)carbonyl]-N-cyclobutyl-1 Hindazole-3-carboxamide	Example 60: 5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-oxetan-3-yl-1 Hindazole-3-carboxamide	Y/ 0 Example 61: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1 yl)carbonyl]-N-cyclopropyl-1 Hindazole-3-carboxamide

Example 63: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-ethyl-1 Hi ndazo I e-3-carboxam id e

Example 62: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-ryl)carbonyl]-N-methyl-1 Hindazole-3-carboxamide

oExample 64: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-Tyl)carbonyl]-N-(2-methoxyethyl)1 H-indazole-3-carboxamide

o

Example 65: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-ryl)carbonyl]-N-isopropyl-1 Hindazole-3-carboxamide

Example 66: 6-[(2-tert-butyl-7-

Example 67: 5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-cyclopropyl-1 Hindole-3-carboxamide oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1 ' yl)carbonyl]-N-propyl-1 H indazole-3-carboxamtde

o

Example 66: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 ’Hspiro[indazole-5,4'-piperidin]-1 yl)carbonyl]-N-cyclobutyl-1 Hindazole-3-carboxamîde

o

Example 69: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidïn]-1'yl)carbonyl]-N-oxetan-3-yl-1 Hindazole-3-carboxamide

oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1 yl)carbonyl]-N-(2-methoxyethyl)1 H-indole-3-carboxamide

Example 71:5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 ’Hspiro[indazole-5,4'-piperidin]-1 yl)carbonyl]-N-methyl-1 H-indole3-carboxamide o

Example 72: 5-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-ethyl-1H-indole-3carboxamide

o

Example 73: 6-[(2-tert-butyl-7oxo-2,4,6,7-tetrahydro-1 Ήspiro[indazole-5,4'-piperidin]-1'yl)carbonyl]-N-cyclopropyl-1 Hindole-3-carboxamide

PHARMACOLOGICAL DATA

Biological Protocols

The utility of the compounds of présent invention, in the treatment of diseases (such as are detailed herein) in animais, particularly mammals (e.g., humans) may be demonstrated by the 5 activity thereof in conventional assays known to one of ordinary skill in the art, including the in vitro and in vivo assays described below. Such assays also provide a means whereby the activities of the compound of the présent invention can be compared with the activities of other known compounds.

Direct Inhibition of the Activities of ACC1 and ACC2

The ACC inhibitory activity of the compound of the présent invention was demonstrated by methods based on standard procedures. For example direct inhibition of ACC activity, for the compound of Formula (I) was determined using préparations of recombinant human ACC1 (rhACCI) and recombinant human ACC2 (rhACC2). Représentative sequences of the recombinant human ACC1 and ACC2 that can be used in the assay are provided herein as SEQ ID NO. 1 and

SEQ. ID NO. 2, respectively.

[1] Préparation of rhACCI. Two liters of SF9 cells, infected with recombinant baculovirus containing full length human ACC1 cDNA, were suspended in ice-cold lysis buffer (25 mM Tris, pH 7.5; 150 mM NaCI; 10% glycerol; 5 mM imidazole (EMD Bioscience; Gibbstown, NJ); 2mM TCEP (BioVectra; Charlottetown, Canada); Benzonase nuclease (10000U/100 g cell paste; Novagen;

Madison, Wl); EDTA-free protease inhibitor cocktail (1 tab/50 mL; Roche Diagnostics; Mannheim, Germany). Cells were lysed by 3 cycles of freeze-thaw and centrifuged at 40,000 X g for 40 minutes (4 °C). Supernatant was directly loaded onto a HisTrap FF crude column (GE Healthcare; Piscataway, NJ) and eluted with an imidazole gradient up to 0.5 M over 20 column volumes (CV). ACC1-containing fractions were pooled and diluted 1:5 with 25 mM Tris, pH 7.5, 2mM TCEP, 10% glycerol and direct loaded onto a CaptoQ (GE Healthcare) column and eluted with an NaCI gradient up to 1 M over 20 CV’s. Phosphate groups were removed from purified ACC1 by incubation with lambda phosphatase (100U/10 μΜ target protein; New England Biolabs; Beverly, MA) for 14 hours at 4 °C; okadaic acid was added (1 μΜ final concentration; Roche Diagnostics) to inhibit the phosphatase . Purified ACC1 was exchanged into 25 mM Tris, pH 7.5, 2 mM TCEP, 10% glycerol,

0.5 M NaCI by 6 hour dialysis at 4 °C. Aliquots were prepared and frozen at -80 °C.

[2] Measurement of rhACCI inhibition. hACCl was assayed in a Costar #3676 (Costar, Cambridge, MA) 384-well plate using the Transcreener ADP détection FP assay kit (Bellbrook Labs, Madison, Wisconsin) using the manufacturer's recommended conditions for a 50 μΜ ATP reaction. The final conditions for the assay were 50 mM HEPES, pH 7.2,10 mM MgCI₂, 7.5 mM tripotassium citrate, 2 mM DTT, 0.1 mg/mL BSA, 30 μΜ acetyl-CoA, 50 μΜ ATP, and 10 mM

KHCOa. Typically, a 10 μΙ reaction was run for 120 min at 25 °C, and 10 μΙ of Transcreener stop and detect buffer was added and the combination incubated at room temp for an additional 1 hour. The data was acquired on a Envision Fluorescence reader (Perkinelmer) using a 620 excitation Cy5 FP general dual mirror, 620 excitation Cy5 FP filter, 688 émission (S) and a 688 (P) émission filter.

[3] Préparation of rhACC2. Human ACC2 inhibition was measured using purified recombinant human ACC2 (hrACC2). Briefly, a full length Cytomax clone of ACC2 was purchased from Cambridge Bioscience Limited and was sequenced and subcloned into PCDNA5 FRT TOTOPO (Invitrogen, Carlsbad, CA). The ACC2 was expressed in CHO cells by tétracycline induction and harvested in 5 liters of DMEM/F12 with glutamine, biotin, hygromycin and blasticidin withl pg/mL tétracycline (Invitrogen, Carlsbad, CA). The conditioned medium containing ACC2 was then applied to a Softlink Soft Release Avidin column (Promega, Madison, Wisconsin) and eluted with 5 mM biotin. 4 mgs of ACC2 were eluted at a concentration of 0.05 mg/mL (determined by A280) with an estimated purity of 95% (determined by A280). The purified ACC2 was dialyzed in 50 mM Tris, 200 mM NaCI, 4 mM DTT, 2 mM EDTA, and 5% glycerol. The pooled protein was frozen and stored at -80 °C, with no loss of activity upon thawing. For measurement of ACC2 activity and assessment of ACC2 inhibition, test compounds were dissolved in DMSO and added to the rhACC2 enzyme as a 5x stock with a final DMSO concentration of 1%.

[4] Measurement of human ACC2 inhibition. hACC2 was assayed in a Costar #3676 (Costar, Cambridge, MA) 384-well plate using the Transcreener ADP détection FP assay kit (Bellbrook Labs, Madison,Wisconsin) using the manufacturées recommended conditions for a 50 uM ATP reaction, The final conditions for the assay were 50 mM HEPES, pH 7.2, 5 mM MgCI₂, 5 mM tripotassium citrate, 2 mM DTT, 0.1 mg/mL BSA, 30 μΜ acetyl-CoA, 50 μΜ ATP, and 8 mM KHCO3. Typically, a 10 μΙ reaction was run for 50 min at 25°C, and 10 μΙ of Transcreener stop and detect buffer was added and the combination incubated at room temp for an additional 1 hour. The data was acquired on an Envision Fluorescence reader (Perkinelmer) using a 620 excitation Cy5 FP general dual mirror, 620 excitation Cy5 FP filter, 688 émission (S) and a 688 (P) émission filter.

The results using the recombinant hACC1 and recombinant hACC2 Transcreener assays described above are summarized in the table below for the Compounds of Formula (I) exemplified in the Examples above.

Example	hACCl IC50 (nM)	n	hACC2 IC50 (nM)	n
1	6.0	6	1.4	6

2	7.9	12	3.1	12
3	32	6	13	6
4	6.5	7	2.9	7
5	17	4	5.8	4
6	11	4	2.9	4
7	5.6	4	1.6	4
8	17	3	3.3	3
9	8.4	3	2.9	3
10	6.1	3	2.7	3
11	14	3	5.5	3
12	13	5	3.0	5
13	2.4	3	1.5	3
14	5.0	5	2.1	5
15	14	3	2.6	3
16	6.7	3	3.1	3
17	19	3	11	3
18	33	3	22	3
19	63	3	15	3
20	13	4	3.0	4
21	47	4	6.7	4
22	30	3	6.9	3

23	32	3	15	3
24	43	1	20	1
25	12	2	10	1
26	7.4	3	2.1	3
27	5.5	3	3.5	3
28	6.5	5	1.3	5
29	8.6	6	1.7	7
30	9.4	4	2.6	4
31	3.8	4	1.3	4
32	8.1	4	1.5	4
33	3.1	4	1.0	4
34	8.1	3	2.8	3
35	12	4	1.4	4
36	4.0	5	1.7	5
37	2.9	7	1.3	7
38	4.3	3	1.1	3
39	9.8	3	1.5	3
40	2.2	3	1.3	3
41	18	7	3.7	7
42	6.6	3	1.8	3
43	6.4	4	2.8	4

44	31	3	5.4	3
45	23	4	2.8	4
46	14	3	3.8	3
47	5.3	4	1.3	4
48	32	3	5.6	3
49	12	3	8.4	3

SEQ. ID NO. 1 provides a sequence of recombinant human ACC1 (SEQ. ID NO. 1) that can be employed in the Transcreener in vitro assay.

Sequence of hACC1

SEQ. IDNO. 1:

MAHHHHHHDEVDDEPSPLAQPLELNQHSRFIIGSVSEDNSEDEISNLVKLDLLEKEGSLSPASVGS DTLSDLGISSLQDGLALHIRSSMSGLHLVKQGRDRKKIDSQRDFTVASPAEFVTRFGGNKVIEKVLI ANNGIAAVKCMRSIRRWSYEMFRNERAIRFWMVTPEDLKANAEYIKMADHYVPVPGGPNNNNYA NVELILDIAKRIPVQAVWAGWGHASENPKLPELLLKNGIAFMGPPSQAMWALGDKIASSIVAQTAGI PTLPWSGSGLRVDWQENDFSKRILNVPQELYEKGYVKDVDDGLQAAEEVGYPVMIKASEGGGGK GIRKVNNADDFPNLFRQVQAEVPGSPIFVMRLAKQSRHLEVQILADQYGNAISLFGRDCSVQRRH QKIIEEAPATIATPAVFEHMEQCAVKLAKMVGYVSAGTVEYLYSQDGSFYFLELNPRLQVEHPCTE MVADVNLPAAQLQIAMGIPLYRIKDIRMMYGVSPWGDSPIDFEDSAHVPCPRGHVIAARITSENPDE GFKPSSGTVQELNFRSNKNVWGYFSVAAAGGLHEFADSQFGH CFSWGENREEAISNMWALKELSIRGDFRTTVEYLIKLLETESFQMNRIDTGWLDRLIAEKVQAERP DTMLGWCGALHVADVSLRNSVSNFLHSLERGQVLPAHTLLNTVDVELIYEGVKYVLKVTRQSPNS YWIMNGSCVEVDVHRLSDGGLLLSYDGSSYTTYMKEEVDRYRITIGNKTCVFEKENDPSVMRSPS AGKLIQYIVEDGGHVFAGQCYAEIEVMKMVMTLTAVESGCIHYVKRPGAALDPGCVLAKMQLDNP SKVQQAELHTGSLPRIQSTALRGEKLHRVFHYVLDNLVNVMNGYCLPDPFFSSKVKDWVERLMKT LRDPSLPLLELQDIMTSVSGRIPPNVEKSIKKEMAQYASNITSVLCQFPSQQIANILDSHAATLNRKS EREVFFMNTQSIVQLVQRYRSGIRGHMKAWMDLLRQYLRVETQFQNGHYDKCVFALREENKSD MNTVLNYIFSHAQVTKKNLLVTMLIDQLCGRDPTLTDELLNILTELTQLSKTTNAKVALRARQVLIAS HLPSYELRHNQVESIFLSAIDMYGHQFCIENLQKLILSETSIFDVLPNFFYHSNQWRMAALEVYVRR AYIAYELNSVQHRQLKDNTCWEFQFMLPTSHPNRGNIPTLNRMSFSSNLNHYGMTHVASVSDVL LDNSFTPPCQRMGGMVSFRTFEDFVRIFDEVMGCFSDSPPQSPTFPEAGHTSLYDEDKVPRDEPI HILNVAIKTDCDIEDDRLAAMFREFTQQNKATLVDHGIRRLTFLVAQKDFRKQVNYEVDRRFHREFP KFFTFRARDKFEEDRIYRHLEPALAFQLELNRMRNFDLTAIPCANHKMHLYLGAAKVEVGTEVTDY RFFVRAIIRHSDLVTKEASFEYLQNEGERLLLEAMDELEVAFNNTNVRTDCNHIFLNFVPTVIMDPSK IEESVRSMVMRYGSRLWKLRVLQAELKINIRLTPTGKAIPIRLFLTNESGYYLDISLYKEVTDSRTAQI MFQAYGDKQGPLHGMLINTPYVTKDLLQSKRFQAQSLGTTYIYDIPEMFRQSLIKLWESMSTQAFL PSPPLPSDMLTYTELVLDDQGQLVHMNRLPGGNEIGMVAWKMTFKSPEYPEGRDIIVIGNDITYRIG

SFGPQEDLLFLRASELARAEGIPRIYVSANSGARIGLAEEIRHMFHVAWVDPEDPYKGYRYLYLTPQ DYKRVSALNSVHCEHVEDEGESRYKITDIIGKEEGIGPENLRGSGMIAGESSLAYNEIITISLVTCRAI GIGAYLVRLGQRTIQVENSHLILTGAGALNKVLGREVYTSNNQLGGIQIMHNNGVTHCTVCDDFEG VFTVLHWLSYMPKSVHSSVPLLNSKDPIDRIIEFVPTKTPYDPRWMLAGRPHPTQKGQWLSGFFD YGSFSEIMQPWAQTVWGRARLGGIPVGWAVETRTVELSIPADPANLDSEAKIIQQAGQVWFPDS AFKTYQAIKDFNREGLPLMVFANWRGFSGGMKDMYDQVLKFGAYIVDGLRECCQPVLVYIPPQAE LRGGSWWIDSSINPRHMEMYADRESRGSVLEPEGTVEIKFRRKDLVKTMRRVDPVYIHLAERLGT PELSTAERKELENKLKEREEFLIPIYHQVAVQFADLHDTPGRMQEKGVISDILDWKTSRTFFYWRLR RLLLEDLVKKKIHNANPELTDGQIQAMLRRWFVEVEGTVKAYVWDNNKDLAEWLEKQLTEEDGVH SVIEENIKCISRDYVLKQIRSLVQANPEVAMDSIIHMTQHISPTQRAEVIRILSTMDSPST

SEQ. ID NO. 2 provides a sequence of recombinant human ACC2 (SEQ. ID NO. 2) that can be employed in the Transcreener in vitro assay.

Sequence of hACC2

SEQ. ID NO. 2:

MVLLLCLSCLIFSCLTFSWLKIWGKMTDSKPITKSKSEANLIPSQEPFPASDNSGETPQRNGEGHTL PKTPSQAEPASHKGPKDAGRRRNSLPPSHQKPPRNPLSSSDAAPSPELQANGTGTQGLEATDTN GLSSSARPQGQQAGSPSKEDKKQANIKRQLMTNFILGSFDDYSSDEDSVAGSSRESTRKGSRASL GALSLEAYLTTGEAETRVPTMRPSMSGLHLVKRGREHKKLDLHRDFTVASPAEFVTRFGGDRVIE KVLIANNGIAAVKCMRSIRRWAYEMFRNERAIRFWMVTPEDLKANAEYIKMADHYVPVPGGPNNN NYANVELIVDIAKRIPVQAVWAGWGHASENPKLPELLCKNGVAFLGPPSEAMWALGDKIASTWAQ TLQVPTLPWSGSGLTVEWTEDDLQQGKRISVPEDVYDKGCVKDVDEGLEAAERIGFPLMIKASEG GGGKGIRKAESAEDFPILFRQVQSEIPGSPIFLMKLAQHARHLEVQILADQYGNAVSLFGRDCSIQR RHQKIVEEAPATIAPLAIFEFMEQCAIRLAKTVGYVSAGTVEYLYSQDGSFHFLELNPRLQVEHPCT EMIADVNLPAAQLQIAMGVPLHRLKDIRLLYGESPWGVTPISFETPSNPPLARGHVIAARITSENPDE GFKPSSGTVQELNFRSSKNVWGYFSVAATGGLHEFADSQFGHCFSWGENREEAISNMWALKEL SIRGDFRTTVEYLINLLETESFQNNDIDTGWLDYLIAEKVQAEKPDIMLGWCGALNVADAMFRTCM TDFLHSLERGQVLPADSLLNLVDVELIYGGVKYILKVARQSLTMFVLIMNGCHIEIDAHRLNDGGLLL SYNGNSYTTYMKEEVDSYRITIGNKTCVFEKENDPTVLRSPSAGKLTQYTVEDGGHVEAGSSYAE MEVMKMIMTLNVQERGRVKYIKRPGAVLEAGCWARLELDDPSKVHPAEPFTGELPAQQTLPILGE KLHQVFHSVLENLTNVMSGFCLPEPVFSIKLKEWVQKLMMTLRHPSLPLLELQEIMTSVAGRIPAPV EKSVRRVMAQYASNITSVLCQFPSQQIATILDCHAATLQRKADREVFFINTQSIVQLVQRYRSGIRG YMKTWLDLLRRYLRVEHHFQQAHYDKCVINLREQFKPDMSQVLDCIFSHAQVAKKNQLVIMLIDEL CGPDPSLSDELISILNELTQLSKSEHCKVALRARQILIASHLPSYELRHNQVESIFLSAIDMYGHQFC PENLKKLILSETTIFDVLPTFFYHANKWCMASLEVYVRRGYIAYELNSLQHRQLPDGTCWEFQFM LPSSHPNRMTVPISITNPDLLRHSTELFMDSGFSPLCQRMGAMVAFRRFEDFTRNFDEVISCFANV PKDTPLFSEARTSLYSEDDCKSLREEPIHILNVSIQCADHLEDEALVPILRTFVQSKKNILVDYGLRRI TFLIAQEKEFPKFFTFRARDEFAEDRIYRHLEPALAFQLELNRMRNFDLTAVPCANHKMHLYLGAAK VKEGVEVTDHRFFIRAIIRHSDLITKEASFEYLQNEGERLLLEAMDELEVAFNNTSVRTDCNHIFLNF VPTVIMDPFKIEESVRYMVMRYGSRLWKLRVLQAEVKINIRQTTTGSAVPIRLFITNESGYYLDISLY KEVTDSRSGNIMFHSFGNKQGPQHGMLINTPYVTKDLLQAKRFQAQTLGTTYIYDFPEMFRQALFK LWGSPDKYPKDILTYTELVLDSQGQLVEMNRLPGGNEVGMVAFKMRFKTQEYPEGRDVIVIGNDIT FRIGSFGPGEDLLYLRASEMARAEGIPKIYVAANSGARIGMAEEIKHMFHVAWVDPEDPHKGFKYL YLTPQDYTRISSLNSVHCKHIEEGGESRYMITDIIGKDDGLGVENLRGSGMIAGESSLAYEEIVTISLV

TCRAIGIGAYLVRLGQRVIQVENSHIILTGASALNKVLGREVYTSNNQLGGVQIMHYNGVSHITVPD DFEGVYTILEWLSYMPKDNHSPVPIITPTDPIDREIEFLPSRAPYDPRWMLAGRPHPTLKGTWQSG FFDHGSFKEIMAPWAQTWTGRARLGGIPVGVIAVETRTVEVAVPADPANLDSEAKIIQQAGQVWF PDSAYKTAQAIKDFNREKLPLMIFANWRGFSGGMKDMYDQVLKFGAYIVDGLRQYKQPILIYIPPYA 5 ELRGGSWWIDATINPLCIEMYADKESRGGVLEPEGTVEIKFRKKDLIKSMRRIDPAYKKLMEQLGE

PDLSDKDRKDLEGRLKAREDLLLPIYHQVAVQFADFHDTPGRMLEKGVISDILEWKTARTFLYWRL RRLLLEDQVKQEILQASGELSHVHIQSMLRRWFVETEGAVKAYLWDNNQVWQWLEQHWQAGD GPRSTIRENITYLKHDSVLKTIRGLVEENPEVAVDCVIYLSQHISPAERAQWHLLSTMDSPAST

Acute in vivo Assessment of ACC Inhibition In Experimental Animais

The ACC inhibitory activity of the compounds of the présent invention can be confirmed in vivo by évaluation of their ability to reduce malonyl-CoA levels in liver and muscle tissue from treated animais.

Measurement of malonyl-CoA production inhibition in experimental animais can be determined using the following methodology.

In this method, male Sprague-Dawley Rats, maintained on standard chow and water ad libitum (225-275g), were randomized prior to the study. Animais were either fed, or fasted for 1Θ hours prior to the beginning of the experiment. Two hours into the light cycle the animais were orally dosed with a volume of 5 mL/kg, (0.5% methyl cellulose; vehicle) or with the appropriate 20 compound (prepared in vehicle). Fed vehicle controls were included to détermine baseline tissue malonyl-CoA levels while fasted animais were included to détermine the effect fasting had on malonyl-CoA levels. One hour after compound administration the animais were asphyxiated with CO₂and the tîssues were removed. Specifically, blood was collected by cardiac puncture and placed into BD Microtainer tubes containing EDTA (BD Biosciences, NJ), mixed, and placed on ïce.

Plasma was used to détermine drug exposure. Liver and quadriceps were removed, immediately freeze-clamped, wrapped in foil and stored in liquid nitrogen.

Tissues were pulverized under liquid N₂ to ensure uniformity in sampling. Malonyl-CoA was extracted from the tissue (150-200 mg) with 5 volumes 10% tricarboxylic acid in Lysing Matrix A (MP Biomedicals, PN 6910) in a FastPrep FP120 (Thermo Scientific, speed=5.5; for 45 seconds).

The supernatant containing malonyl-CoA was removed from the cell débris after centrifugation at 15000 x g for 30 minutes (Eppendorf Centrifuge 5402). Samples were stably frozen at -80C until analysis was completed.

Analysis of malonyl CoA levels in liver and muscle tissue can be evaluated using the following methodology.

The method utilized the following matériels: Malonyl-CoA tetralithium sait and malonyl-¹³C₃CoA trilithium sait which were purchased from Isotec (Miamisburg, OH, USA), sodium perchlorate (Sigma, cat no. 410241), trichloroacetic acid (ACROS, cat no. 42145), phosphoric acid (J.T. Baker, cat no. 0260-01), ammonium formate (Fluka, cat no. 17843), methanol (HPLC grade, J.T. Baker, cat no. 9093-33), and water (HPLC grade, J.T. Baker, 4218-03) were used to make the necessary mobile phases. Strata-X on-line solid phase extraction columns, 25 pm, 20 mm x 2.0 mm I.D (cat no. 00M-S033-B0-CB) were obtained from Phenomenex (Torrance, CA, USA). SunFire C18 reversed-phase columns, 3.5 pm, 100 mm x 3.0 mm I.D. (cat no.186002543) were purchased from Waters Corporation (Milford, MA, USA).

This method may be performed utilizing the following equipment. Two-dimensional chromatography using an Agilent 1100 binary pump, an Agilent 1100 quaternary pump and two Valco Cheminert 6-port two position valves. Samples were întroduced via a LEAP HTC PAL auto sampler with Peltier cooled stack maintained at 10°C and a 20 pL sampling loop. The needle wash solutions for the autosampler were 10% trichloroacetic acid in water (w/v) for Wash 1 and 90:10 methanokwater for Wash 2. The analytical column (Sunfire) was maintained at 35°C using a MicroTech Scientific Micro-LC Column Oven. The eluent was analyzed on an ABI Sciex API3000 triple quadrupole mass spectrometer with Turbo Ion Spray.

Two-dimensional chromatography was performed in parallel using distinct gradient elution conditions for on-line solid phase extraction and reversed-phase chromatography. The general design of the method was such that the first dimension was utilized for sample clean-up and capture of the analyte of Interest followed by a brief coupling of both dimensions for elution from the first dimension onto the second dimension. The dimensions were subsequently uncoupled allowing for gradient elution of the analyte from the second dimension for quantification while simultaneously preparing the first dimension for the next sample in the sequence. When both dimensions were briefly coupled together, the flow of the mobile phase in the first dimension was reversed for analyte elution on to the second dimension, allowing for optimal peak width, peak shape, and elution time.

The first dimension of the HPLC system utilized the Phenomenex strata-X on-line solid phase extraction column and the mobile phase consisted of 100 mM sodium perchlorate ! 0.1% (v/v) phosphoric acid for solvent A and methanol for solvent B.

The second dimension of the HPLC system utilized the Waters SunFire C18 reversedphase column and the mobile phase consisted of 100 mM ammonium formate for solvent A and methanol for solvent B. The initial condition of the gradient was maintained for 2 minutes and during this time the analyte was transferred to the analytical column. It was important that the initial condition was at a sufficient strength to elute the analyte from the on-line SPE column while retaining it on the analytical. Afterwards, the gradient rose linearly to 74.5% A in 4.5 minutes before a wash and re-equilibration step.

Mass spectrometry when coupled with HPLC can be a highly sélective and sensitive method for quantitatively measuring analytes in complex matrices but is still subject to interférences

and suppression. By coupling a two dimensional HPLC to the mass spectrometer, these interférences were significantly reduced. Additionally, by utilizïng the Multiple Reaction Monitoring (MRM) feature of the triple quadrupole mass spectrometer, the signal-to-noise ratio was significantly improved.

For this assay, the mass spectrometer was operated in positive ion mode with a TurbolonSpray voltage of 2250V. The nebulizing gas was heated to 450°C. The Declustering Potential (DP), Focusing Potential (FP), and Collision Energy (CE) were set to 60, 340, and 42 V, respectively. Quadrupole 1 (Q1) resolution was set to unit resolution with Quadrupole 3 (Q3) set to low. The CAD gas was set to 8. The MRM transitions monitored were for malonyl CoA: 854.1 -*347.0 m/z (L. Gao et al. (2007) J. Chromatogr. B 853,303^313); and for malonyl-¹³C₃-CoA: 857.1-*350.0 m/z with dwell times of 200 ms. The eluent was diverted to the mass spectrometer near the expected elution time for the analyte, otherwise it was diverted to waste to help preserve the source and improve robustness of the instrumentation. The resulting chromatograms were integrated using Analyst software (Applied Biosystems). Tissue concentrations for malonyl CoA were calculated from a standard curve prepared in a 10% solution of trichloroacetic acid in water.

Samples comprising the standard curve for the quantification of malonyl-CoA in tissue extracts were prepared in 10% (w/v) trichloroacetic acid (TCA) and ranged from 0.01 to 1 pmol/pL. Malonyl-¹³C₃-CoA (final concentration of 0.4 pmol/pL) was added to each standard curve component and sample as an internai standard.

Six intra-assay quality controls were prepared; three from a pooled extract prepared from fasted animais and three from a pool made from fed animais. These were run as independent samples spiked with 0, 0.1 or 0.3 pmol/pL ^l2C-malonyl-CoA as well as malonyl-¹³C3-CoA (0.4 pmol/pL). Each intra-assay quality control contained 85% of aqueous tissue extract with the remaining portion contributed by internai standard (0.4 pmol/pL) and ¹²C-malonyl-CoA. Inter assay controls were included in each run; they consist of one fasted and one fed pooled sample of quadriceps and/or one fasted and one fed pooled sample of liver. Ail such controls are spiked with malonyl-¹³C3-CoA (0.4 pmol/pL).

Ail publications, including but not limited to issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the spécifie experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following daims.

Claims

What is claimed is:

1. A compound of Formula (I)

Formula (I) or a pharmaceutically acceptable sait thereof; wherein G is

R¹ is a (Ci-C₆)alkyl or (C₃-C₇) cylcoalkyl;

R² is indolyl, indazolyl, pyrrolopyridlnyl, pyrazolopyridînyl, quinolinyl or benzoimidazolyl; wherein each R² group is optionally substituted with one to two substituents independently selected from a cyano, -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, (C_rC₃)alkyl, (C,-C₃)alkoxy and halo;

R³ is hydrogen or (Ci-C₃)alkyl;

L is a direct bond or -X(Ci-C₃)alkylene;

X is a direct bond, O or S;

R⁴ and R⁵ are each independently hydrogen, (CrC₃)alkyl, (C₃-C₇)cycloalkyl or four to seven membered heterocyclyl wherein said (Ci-C3)alkyl, (C₃-C₇)cycloalkyl or four to seven membered heterocyclyl is optionally substituted with one to three fluoro or (CrC₃)alkoxy.
2. The compound of claim 5 wherein

G is or a pharmaceutically acceptable sait thereof.
3. The compound of claim 2 wherein R³ is hydrogen; or a pharmaceutically acceptable sait thereof.
4. The compound of claim 3 wherein R² is wherein each R² is substituted with one substitutent that is -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, or (CrCaJalkoxy; R³ is hydrogen; L is a direct bond or -X(Ci-C₃)alkylene; X is a direct bond, O or S;

10 and R⁴ and R⁵ are each independently hydrogen or (Ct-Cgjalkyl; or a pharmaceutically acceptable sait thereof.
5. The compound of claim 3 wherein R² is one substituent that is -L-C(O)NR⁴R⁵, -L-NR⁴R⁵, or (CrC^alkoxy; L is a direct bond; and R⁴ and

R⁵ are hydrogen; or a pharmaceutically acceptable sait thereof.

100
6. The compound of claim 3 wherein R² is wherein each R² is substituted with one substituent that is -L-NR⁴R⁵ or (Ci-C₃)alkoxy; L is a direct bond; and R⁴ and R⁶ are hydrogen; or a pharmaceutically acceptable sait thereof.
7. A compound selected from the group consisting of

6-[(1 -isopropyl-7-oxo-1 ,4,6,7-tetrahydro-rH-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-1 Hindole-3-carboxamide;

5- ((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 ’H-spirofindazol e-5,4'-pi peridin] -1 '-yl) carbonyl]-1Hi ndazole-3-carboxam i de ;

6- ((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1’H-spiro[indazole-5,4'-pi peridin]-1 ’-yl) carbonyl]-1Hpyrrolo[3,2-b]pyridine-3-carboxamide;

6-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 '-yljcarbonyl]-1Hindazole-3-carboxamide;

5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-1 Hpyrrolo[2,3-b]pyridine-3-carboxamide;

5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 ’-ylJcarbonyl] -1Hindole-2-carboxamide;

5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperÎdin]-1 ’-yl) carbonyl]-1Hindole-3-carboxamide;

1 *-[(2-amino-1 H-benzimidazol-5-yl)carbonyl]-1 -isopropyl-1,4-dihydrospiro(indazole-5,4'piperidin]-7(6H)-one;

5-((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l Ή-spirofî ndazole-5,4'-pipe ridin] -1 '-yl)carbonyl]-Nmethyl-1H-indazole-3-carboxamide;

N-ethyl-5-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 'yl)carbonyl]-1H-indazole-3-carboxamide;

5- ((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro[indazole-5,4'-piperidin]-T-yl)carbonyl]-N(2,2_l2-trifluoroethyl)-1H-indazole-3-carboxamide;

6- ((1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-l 'H-spiro[indazole-5,4'-piperidin]-1 ’-yl) carbonyl]-1Hindole-2-carboxamide;

101

5-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-1 Hpyrazolo[3,4-b]pyridine-3-carboxamide;

5-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spirolindazola-S^'-piperidinl-l '-yl) carbonyl]-1Hpyrrolo[2,3-b]pyridine-2-carboxamide;

1-isopropyl-r-{[2-(methylamino)-1H-benzimidazol-5-yl]carbonyl)-1.4-dihydrospiro[indazole5,4'-piperidin]-7(6H)-ono;

5-[(1 -isopropyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spÎro[indazole-5,4'-piperidin]-1 '-yl) carbonyl]-1Hbenzimidazole-2-carboxamÎde;

5-[(1 -tert-butyl-7-oxo-1,4,6,7-tetrahydro-1 'H-spiro[indazole-5,4'-piperidin]-1 -yl) carbonyl]-1Hindazole-3-carboxamide;

5-[(1 -tert-butyl-7-oxo-1,4,6,7-tetrahydro-1 ’H-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-1 Hpyrrolo[2,3-b]pyridine-3-carboxamide; or a pharmaceutically acceptable sait thereof.
8. A compound of structure

O or a pharmaceutically acceptable sait thereof.
9. A compound of structure

O or a pharmaceutically acceptable sait thereof.
10. A compound of structure

O or a pharmaceutically acceptable sait thereof.

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11. A pharmaceutical composition comprising a compound of any one of daims 1-9, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.
12. The use of a compound of any one of daims 1 -9 in the manufacture of a médicament for treating a disease, condition or disorder that is modulated by the inhibition of acetyl-CoA carboxylase enzyme(s).

10
13. The use of claim 12 wherein the disease, condition, or disorder is Type 2 diabètes, diabetes-related disorders, nonalcoholic fatty liver disease (NAFLD) or hepatic insulin résistance.
14. The use of claim 12 wherein the disease, condition, or disorder is Type 2 diabètes.
15 15. A compound of structure or a pharmaceutically acceptable sait thereof.

ABSTRACT

The invention provides a compound of Formula (I)

5 Formula (I) or a pharmaceutically acceptable sait thereof; wherein G is

R¹, R² and R³ are as described herein; pharmaceutical compositions thereof; and the

10 use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase enzyme(s) in an animal.