WO2022155419A1 - Indazoles and azaindazoles as lrrk2 inhibitors - Google Patents

Indazoles and azaindazoles as lrrk2 inhibitors Download PDF

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Publication number
WO2022155419A1
WO2022155419A1 PCT/US2022/012437 US2022012437W WO2022155419A1 WO 2022155419 A1 WO2022155419 A1 WO 2022155419A1 US 2022012437 W US2022012437 W US 2022012437W WO 2022155419 A1 WO2022155419 A1 WO 2022155419A1
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Prior art keywords
indazol
methyl
pyrazol
carbonitrile
alkyl
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PCT/US2022/012437
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French (fr)
Inventor
Albert W. Garofalo
Jacob Bradley Schwarz
Fabio Maria Sabbatini
Marco Migliore
Silvia BERNARDI
Federica BUDASSI
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ESCAPE Bio, Inc.
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Publication of WO2022155419A1 publication Critical patent/WO2022155419A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
  • Parkinson’s disease is the most common form of parkinsonism, a movement disorder, and the second most common, age-related neurodegenerative disease estimated to affect 1-2% of the population over age 65.
  • PD is characterized by tremor, rigidity, postural instability, impaired speech, and bradykinesia. It is a chronic, progressive disease with increasing disability and diminished quality of life.
  • parkinsonism is exhibited in a range of conditions such as progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies.
  • LRRK2 Leucine-rich repeat kinase 2
  • dardarin Leucine-rich repeat kinase 2
  • LRRK2 expression in the brain is highest in areas impacted by PD (Eur. J. Neurosci. 2006, 23(3):659) and LRRK2 has been found to localize in Lewy Bodies, which are intracellular protein aggregates considered to be a hallmark of the disease.
  • Patients with point mutations in LRRK2 present disease that is indistinguishable from idiopathic patients.
  • LRRK2 While more than 20 LRRK2 mutations have been associated with autosomal-dominantly inherited parkinsonism, the G2019S mutation located within the kinase domain of LRRK2 is by far the most common. This particular mutation is found in >85% of LRRK2 -linked PD patients. It has been shown that the G2019S mutation in LRRK2 leads to an enhancement in LRRK2 kinase activity and inhibition of this activity is a therapeutic target for the treatment of PD.
  • LRRK2 has been linked to other diseases such as cancer, leprosy, and Crohn’s disease (Sci. Signal., 2012, 5(207), pe2).
  • diseases such as cancer, leprosy, and Crohn’s disease (Sci. Signal., 2012, 5(207), pe2).
  • LRRK2 inhibitors As there are presently limited therapeutic options for treating PD and other disorders associated with aberrant LRRK2 kinase activity, there remains a need for developing LRRK2 inhibitors.
  • the present invention is directed to a compound of F ormula I A or IB ’ : or a pharmaceutically acceptable salt thereof, wherein constituent members are defined herein.
  • the present invention is directed to a compound of Formula IA or IB: or a pharmaceutically acceptable salt thereof, wherein constituent members are defined herein.
  • the present invention is further directed to a pharmaceutical composition comprising a compound of Formula IA, IB, or IB’, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention is further directed to a method of inhibiting LRRK2 activity, comprising contacting a compound of Formula I A, IB, or IB’, or a pharmaceutically acceptable salt thereof, with LRRK2.
  • the present invention is further directed to a method of treating a disease or disorder associated with elevated expression or activity of LRRK2, or a functional variant thereof, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB, or IB’, or a pharmaceutically acceptable salt thereof.
  • the present invention is further directed to a method for treating a neurodegenerative disease in a patient comprising administering to the patient a therapeutically effective amount of the compound of Formula IA, IB, or IB’, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides uses of the compounds described herein in the manufacture of a medicament for use in therapy.
  • the present disclosure also provides the compounds described herein for use in therapy.
  • the present invention is directed to an inhibitor of LRRK2 which is a compound of
  • L is -O- or -NH-
  • Ring B is phenyl or 6-membered heteroaryl
  • Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ; wherein not more than two of X 2 , X 3 , and X 4 are simultaneously N;
  • Cy 1 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl- C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b
  • R 2 , R 3 , and R 4 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR
  • the present invention is further directed to an inhibitor of LRRK2 which is a compound of Formula IA or IB: or a pharmaceutically acceptable salt thereof, wherein:
  • L is -O- or -NH-
  • Ring B is phenyl or 6-membered heteroaryl
  • Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ; wherein not more than two of X 2 , X 3 , and X 4 are simultaneously N;
  • Cy 1 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b
  • R 2 , R 3 , and R 4 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR
  • n 1, 2, or 3 and R 1 is a group other than H.
  • the compound has Formula IA:
  • the compound has Formula IB: In some embodiments, the compound has Formula IB’:
  • X 2 is CR 2 . In some embodiments, X 2 is CH.
  • X 2 is N.
  • X 3 is CR 3 . In some embodiments, X 3 is CH.
  • X 3 is N.
  • X 4 is CR 4 . In some embodiments, X 4 is CH.
  • X 4 is N.
  • R 2 , R 3 , and R 4 are each independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 .
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, CN, OR 32 , and halo.
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, and halo.
  • R 2 , R 3 , and R 4 are each independently selected from H and halo.
  • R 2 and R 3 are each H, and R 4 is H or Cl.
  • R 2 , R 3 , and R 4 are each H.
  • R 2 and R 3 are each H, and R 4 is H, methyl, or Cl.
  • R 2 is selected firom H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OR 32 , SR 32 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 .
  • R 2 is H or halo. In some embodiments, R 2 is H.
  • R 3 is selected firom H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OR 32 , SR 32 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR 32 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 .
  • R 3 is H or halo. In some embodiments, R 3 is H, F, or Cl. In some embodiments, R 3 is halo. In some embodiments, R 3 is F or Cl. In some embodiments, R 3 is H.
  • R 4 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OR a2 , SR 32 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 .
  • R 4 is H, C 1-6 alkyl, or halo.
  • R 4 is selected from H, C 1-6 alkyl, CN, OR a2 , and halo. In some embodiments, R 4 is selected from H, methyl, methoxy, CN, F, and Cl. In some embodiments, R 4 is selected from C 1-6 alkyl, CN, OR 32 , and halo.
  • R 4 is H, methyl, or Cl.
  • R 4 is H or halo. In some embodiments, R 4 is H.
  • A is Cy 1 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -4 alkenyl-, Cy 1 -C 1-4 alkyl-, Cy 1 -C 2 -4 alkenyl, -CN, C(O)NR c R d , C(O)OR a , S(O) 2 R b , or S(O) 2 NR c R d , wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .
  • A is Cy 1 , C 1-6 alkyl, C 1-6 haloalkyl, CN, C(O)NR c R d , C(O)OR a , S(O) 2 R b , or S(O) 2 NR c R d , wherein said C 1-6 alkyl is optionally substituted with 1, 2,
  • substituents independently selected from halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .
  • A is Cy 1 or C 1-6 alkyl. In some embodiments, A is Cy 1 . In some embodiments, A is C 1-6 alkyl. In some embodiments, A is methyl.
  • A is Cy 1 , C 1-6 alkyl, C 2 -4 alkenyl-, Cy 1 -C 1-4 alkyl- or Cy 1 -C 2 -4 alkenyl-, wherein said C 1-6 alkyl and C 2 -4 alkenyl are each optionally substituted with 1, 2, 3,
  • substituents independently selected from halo, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .
  • A is Cy 1 , C 1-6 alkyl, C 2 -4 alkenyl-, Cy 1 -C 1-4 alkyl- or Cy 1 -C 2 -4 alkenyl-.
  • A is C 2 -4 alkenyl-, Cy J -C 1-4 alkyl- or Cy 1 -C 2 -4 alkenyl-.
  • A is selected from prop-l-en-l-yl, 2-(pyridin-4-yl)vinyl, 2- (oxazol-4-yl)vinyl, 2-(l -methyl- lH-pyrazol-4-yl)vinyl, 2-(2,6-dimethylpyridin-4-yl)vinyl, 2- (2-methylpyridin-4-yl)vinyl, 3-(3-methoxyazeti din-1 -yl)prop-l -en-1 -yl, 3-(4- methylpiperazin-l-yl)prop-l-en-l-yl, (1-methylazeti din-3 -yl)methyl, 3-(3,3- difluoropy rrolidin- 1 -y l)prop- 1 -en- 1 -en- 1
  • A is selected from 2-(pyridin-4-yl)vinyl, 2-(oxazol-4-yl)vinyl, 2-(l -methyl- lH-pyrazol-4-yl)vinyl, 2-(2,6-dimethylpyridin-4-yl)vinyl, 2-(2-methylpyridin-4- yl)viny 1, 3 -(3 -methoxy azeti din- 1 -y l)prop- 1 -en- 1 -y 1, 3 -(4-methy Ipiperazin- 1 -y l)prop- 1 -en- 1 - yl, (l-methylazetidin-3-yl)methyl, 3-(3,3-difluoropyrrolidin-l-yl)prop-l-en-l-yl, 3- (pyrrolidin-l-yl)prop-l-en-l-yl, 3-(4-methylpiperazin-l-yl)-3-o
  • Cy 1 is C 3-10 cycloalkyl or 5-14 membered heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR
  • Cy 1 is C 3-10 cycloalkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl- C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C
  • Cy 1 is 5-14 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(
  • Cy 1 is C 3-6 cycloalkyl or 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, 4-6 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R
  • Cy 1 is C 3-6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-Ci- 4 alkyl, 4-6 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)
  • Cy 1 is 5-6 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-Ci- 4 alkyl, 4-6 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)
  • Cy 1 is C 3-10 cycloalkyl or 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C3- 10 cycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , NR c C(O)R b , S(O) 2 R b , and S(O) 2 NR c R d
  • Cy 1 is C 3-10 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , NR c C(O)R b , S(O) 2 R b , and S(O) 2 NR c R d
  • Cy 1 is 5-14 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , NR c C(O)R b , S(O) 2 R b , and S(O) 2 NR c R d
  • Cy 1 is C 3-6 cycloalkyl or 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C3- 10 cycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , NR c C(O)R b , S(O) 2 R b , and S(O) 2 NR c R d
  • Cy 1 is C 3-6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , NR c C(O)R b , S(O) 2 R b , and S(O) 2 NR c R d
  • Cy 1 is 5-6 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 3-10 cycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d , NR c C(O)R b , S(O) 2 R b , and S(O) 2 NR c R d
  • Cy 1 is C 3-6 cycloalkyl or 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C 1-6 alkyl and C 3-10 cycloalkyl.
  • Cy 1 is C 3-6 cycloalkyl. In some embodiments, Cy 1 is cyclopropyl. In some embodiments, Cy 1 is 5-6 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from C 1-6 alkyl and C 3-10 cycloalkyl. In some embodiments, Cy 1 is 5-6 membered heteroaryl substituted by C 1-6 alkyl or C 3-10 cycloalkyl.
  • Cy 1 is pyrazolyl or cyclopropyl, wherein said pyrazolyl is optionally substituted with cyclopropyl or methyl. In some embodiments, Cy 1 is pyrazolyl optionally substituted with cyclopropyl or methyl. In some embodiments, Cy 1 is pyrazolyl substituted with cyclopropyl or methyl.
  • Cy 1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d]oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, triazolyl, cyclopropyl, and phenyl, wherein each Cy 1 group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl- C 1-4 alkyl, 4-10 membered heterocycloalkyl-C
  • Cy 1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d] oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, and triazolyl, wherein each Cy 1 group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2
  • Cy 1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d] oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, triazolyl, cyclopropyl, and phenyl, wherein each Cy 1 group is optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d ,
  • Cy 1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d]oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, and triazolyl, wherein each Cy 1 group is optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c
  • Cy 1 is 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, or 1- methyl-lH-pyrazol-4-yl. In some embodiments, Cy 1 is l-cyclopropyl-lH-pyrazol-4-yl or 1- methyl-lH-pyrazol-4-yl. In some embodiments, Cy 1 is l-cyclopropyl-lH-pyrazol-4-yl. In some embodiments, Cy 1 is l-methyl-lH-pyrazol-4-yl.
  • Cy 1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, l-methyl-lH-pyrazol-4-yl,l-(bicyclo[l. 1. 1] pentan- l-yl)-17/-pyrazol-4-yl, 1- (difluoromethyl)-17/-pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1-cyclopentyl- 17/-pyrazol-4-yl, benzo
  • oxazol-2-yl 4- phenyloxazol-2-yl, 4,5-dimethyloxazol-2-yl, 5-methyloxazol-2-yl, 4-methyloxazol-2-yl, 2- methylthiazol-5-yl, pyrimidin-5-yl, 2-methy Ipyrimi din-5 -yl, 3-methylpyridin-4-yl, 1-methyl- 17/-imidazol-4-yl, l-pyrazin-2-yl, pyridazin-3-yl, 2-(pyrrolidin- l-yl)pyrimi din-5 -yl, 1- methyl-17/-l,2,3-triazol-4-yl, 4-methylpyrimidin-2-yl, 2-morpholinopyridin-4-yl, 2- (trifhioromethyl)pyrimidin-5-yl, 1 -isopropyl- 17/-pyrazol-4-yl, l,3-dimethyl-17/-pyrazol
  • Cy 1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, 1-methyl- lH-pyrazol-4-yl,l-(bicyclo[l.l. l]pentan-l-yl)-17/-pyrazol-4-yl, 1 -(difluoromethyl)- 1H- pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1 -cyclopentyl- l//-pyrazol-4-yl.
  • Cy 1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, l-methyl-lH-pyrazol-4-yl,l-(bicyclo[l.1.1] pentan- l-yl)-17/-pyrazol-4-yl, 1- (difluoromethyl)-17/-pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1-cyclopentyl- 17/-pyrazol-4-yl, benzo [t/
  • Cy 1 is selected from pyridazin-4-yl, l-(2-hydroxy-2- methylpropyl)-lH-pyrazol-4-yl, 2-(methoxymethyl)pyridin-4-yl, 1 -(1,1 -Dioxidothi etan-3 -yl)- lH-pyrazol-4-yl, 2-chloropyridin-4-yl, 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl, 2- (3-hydroxyazetidin-l-yl)pyridin-4-yl, 2-methylpyridin-4-yl, l-(oxetan-3-ylmethyl)-lH- py razol-4-y 1, 2-(4-(dimethy Iphosphory l)piperidin- 1 -y l)py ridin-4-y 1, 2-((2-oxa-6- azaspiro[3.3]
  • H-py razol-4-yl 2- methoxypyrimidin-4-yl, 1 -methy l-6-oxo-l,6-dihydropyri din-3 -yl, 3-fluoro-l-methyl-lH- pyrazol-4-yl, 5-fluoro-l -methyl- lH-pyrazol-4-yl, l-(2-cyanopropan-2-yl)-lH-pyrazol-4-yl, l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl, 2-(2-oxaspiro[3.3]heptan-6-yl)pyridin-4-yl, 2- (6-oxa-3-azabicyclo[3. 1. l]heptan-3-yl)pyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl,
  • L is -O-. In some embodiments, L is -NH-.
  • Ring B is phenyl
  • Ring B is 6-membered heteroaryl.
  • Ring B is pyridinyl
  • Ring B is pyrazinyl or pyridinyl.
  • Ring B is phenyl or pyridinyl.
  • Ring B is phenyl, pyrazinyl, or pyridinyl.
  • Ring C is phenyl
  • Ring C is 6-membered heteroaryl.
  • Ring C is pyridinyl
  • Ring C is phenyl or pyridinyl.
  • Ring C is phenyl, pyridinyl, pyrazinyl, or pyridazinyl.
  • Ring C is pyridinyl, pyrazinyl, or pyridazinyl.
  • m is 0.
  • m is 1.
  • each R 1 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, CN, NO 2 , OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R bl , OC(O)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(O)OR al , NR cl C(O)NR cl R dl , NR cl S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • each R 1 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, CN, NO 2 , OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R bl , OC(O)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(O)OR al , NR cl C(O)NR cl R dl , NR cl S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , and S(O) 2 NR cl R dl , wherein said C 1-6 al
  • each R 1 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R bl , OC(O)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(O)OR al , NR cl C(O)NR cl R dl , NR cl S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • each R 1 is independently selected from halo, C 3-6 cycloalkyl
  • each R 1 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and OR al .
  • each R 1 is independently selected from halo and C 1-6 alkyl.
  • each R 1 is independently selected from C 1-6 alkyl.
  • each R 1 is independently selected from methyl, isopropyl, ethyl, prop-l-en-2-yl, chloro, fluoro, bromo, iodo, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, trifluoromethoxy, CN, methoxymethyl, vinyl, but-2-en-2-yl, sec-butyl, l,l,l-trifluoropropan-2-yl, methylsulfonyl, and oxetan-3-yloxy.
  • each R 1 is independently selected from methyl, isopropyl, ethyl, prop-l-en-2-yl, chloro, fluoro, bromo, iodo, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, and trifluoromethoxy.
  • each R 1 is independently selected from methyl, isopropyl, and chloro. In some embodiments, each R 1 is methyl.
  • n 0.
  • n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • n 0, 1, or 2.
  • each R 5 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, CN, NO 2 , OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R bl , OC(O)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(O)OR al , NR cl C(O)NR cl R dl , NR cl S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • each R 5 is independently selected from C 1-6 alkyl and halo. In some embodiments, R 5 is methyl.
  • each R 1 is independently selected from methyl and F.
  • p is 0.
  • p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.
  • p is 0, 1, or 2.
  • each R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.
  • each R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, and halo.
  • each R a3 , R b3 , R c3 , and R d3 is independently selected from H and C 1-6 alkyl.
  • a compound of Formula I A or IB’ or a pharmaceutically acceptable salt thereof, wherein:
  • A is Cy 1 or C 1-6 alkyl
  • L is -O- or -NH-
  • Ring B is phenyl, pyridinyl, or pyrazinyl
  • Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
  • X 2 is CR 2 or N
  • X 3 is CR 3 ;
  • X 4 is CR 4 or N
  • Cy 1 is selected from C 3-10 cycloalkyl, C 6-10 aryl, and 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4- 14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d ,
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, and halo; n is 0, 1, 2, or 3; m is 0 or 1; and p is 0, 1, or 2; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R 1 is a group other than H.
  • A is Cy 1 or C 1-6 alkyl
  • L is -O- or -NH-
  • Ring B is phenyl or pyridinyl
  • Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • X 4 is CR 4 ;
  • Cy 1 is selected from C 3-10 cycloalkyl and 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C 1-6 alkyl and C 3-10 cycloalkyl; each R 1 is independently selected from halo and C 1-6 alkyl;
  • R 2 , R 3 , and R 4 are each independently selected from H and halo; n is 0, 1, 2, or 3; and m is 0 or 1; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3, and R 1 is a group other than H.
  • a compound of Formula IA or IB’ or a pharmaceutically acceptable salt thereof, wherein:
  • A is Cy 1 or C 1-6 alkyl
  • L is -O- or -NH-
  • Ring B is phenyl, pyridinyl, or pyrazinyl
  • Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • X 4 is CR 4 ;
  • Cy 1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d]oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, and triazolyl, wherein each Cy 1 group is optionally substituted by 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, and halo; n is 0, 1, 2, or 3; m is 0 or 1; and p is 0, 1, or 2; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R 1 is a group other than H.
  • a compound of Formula IA or a pharmaceutically acceptable salt thereof, wherein:
  • Ring B is phenyl or 6-membered heteroaryl
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ; wherein not more than two of X 2 , X 3 , and X 4 are simultaneously N;
  • Cy 1 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , 0R a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R
  • R 2 , R 3 , and R 4 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR
  • a compound of Formula IA or a pharmaceutically acceptable salt thereof, wherein:
  • A is Cy 1 or C 1-6 alkyl
  • Ring B is phenyl or pyridinyl
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • X 4 is CR 4 ;
  • Cy 1 is selected from C 3-6 cycloalkyl and 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C 1-6 alkyl and C 3-6 cycloalkyl; each R 1 is independently selected from halo and C 1-6 alkyl;
  • R 2 , R 3 , and R 4 are each independently selected from H and halo; n is 0, 1, 2, or 3; and m is 0 or 1; wherein when ring B is phenyl, then: n is 1, 2, or 3 and R 1 is a group other than H.
  • L is -O- or -NH-
  • Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ; wherein not more than two of X 2 , X 3 , and X 4 are simultaneously N;
  • Cy 1 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b
  • R 2 , R 3 , and R 4 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR
  • a compound of Formula IB or a pharmaceutically acceptable salt thereof, wherein:
  • A is Cy 1 ;
  • L is -O- or -NH-
  • Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
  • X 2 is CR 2 ;
  • X 3 is CR 3 ;
  • X 4 is CR 4 ;
  • Cy 1 is 5-6 membered heteroaryl, optionally substituted by 1 or 2 substituents independently selected from C 1-6 alkyl and C 3-6 cycloalkyl; each R 1 is independently selected from halo and C 1-6 alkyl;
  • R 2 , R 3 , and R 4 are each independently selected from H and halo; n is 0, 1, 2, or 3; and m is 0 or 1.
  • the compound has Formula Ila: a, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • the compound has Formula lib
  • the compound has Formula lie lie, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • the compound has Formula lid or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • the compound has Formula Illa:
  • the compound has Formula Illb: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • the compound has Formula IIIc: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • the compound has Formula Illd: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • the compound has Formula Ille: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
  • a compound selected from the following: 5-Cyano-/V-(l-(l-cyclopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-3,4- dimethylpicolinamide;
  • a compound is selected from:
  • a compound is selected from:
  • n-membered typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • each linking substituent include both the forward and backward forms of the linking substituent.
  • -NR(CR'R")n- includes both -NR(CR'R")n- and -(CR'R") n NR- and is intended to disclose each of the forms individually.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the "alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • substituted refers to any level of substitution, e.g, mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
  • optionally substituted means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • Cn-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include Cm, C 1-6 and the like.
  • alkyl employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched.
  • Cn-m alkyl refers to an alkyl group having n to m carbon atoms.
  • An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, /c/V-butyl. isobutyl, sec-butyl; higher homologs such as 2- methyl-1 -butyl, n-pentyl, 3-pentyl, w-hexyl. 1 ,2,2-trimethylpropyl and the like.
  • alkenyl employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds.
  • An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound.
  • Cn-m alkenyl refers to an alkenyl group having n to m carbons.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n- butenyl, scc-butenyl and the like.
  • alkynyl employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds.
  • An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • Cn-m alkynyl refers to an alkynyl group having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group.
  • An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound.
  • Cn-m alkylene refers to an alkylene group having n to m carbon atoms.
  • alkylene groups include, but are not limited to, ethan-l,2-diyl, ethan- 1,1 -diyl, propan-1, 3-diyl, propan- 1,2-diyl, propan- 1,1 -diyl, butan-l,4-diyl, butan-l,3-diyl, butan-1,2- diyl, 2-methyl-propan- 1,3 -diyl and the like.
  • alkoxy employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above.
  • Cn-m alkoxy refers to an alkoxy group, the alkyl group of which has n to m carbons.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., w-propoxy and isopropoxy), /-butoxy and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m dialkoxy refers to a linking group of formula -O-(Cn-m alkyl)-O-, the alkyl group of which has n to m carbons.
  • Example dialkyoxy groups include -OCH 2 CH 2 O- and OCH 2 CH 2 CH 2 O-.
  • the two O atoms of a C n-m dialkoxy group may be attached to the same B atom to form a 5- or 6- membered heterocycloalkyl group.
  • amino refers to a group of formula -NH 2 .
  • halo refers to fluoro, chloro, bromo and iodo.
  • halo refers to a halogen atom selected from F, Cl, or Br.
  • halo groups are F.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom.
  • Cn-m haloalkyl refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to ⁇ 2(n to m)+l ⁇ halogen atoms, which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CC1 3 , CHC1 2 , C 2 C I5 and the like.
  • the haloalkyl group is a fluoroalkyl group.
  • haloalkoxy employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above.
  • C n-m haloalkoxy refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons.
  • Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • oxo refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an JV-oxide group.
  • oxidized in reference to a ring-forming N atom refers to a ring-forming N-oxide.
  • oxidized in reference to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized it (pi) electrons where n is an integer).
  • aryl employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g, having 2 fused rings).
  • C n-m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g, phenyl, naphthyl, and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl.
  • heteroaryl or “heteroaromatic,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen.
  • the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring.
  • Example heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, and the like.
  • a five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g, 1, 2 or 3) ring atoms are independently selected fromN, O and S.
  • Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • a six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g, 1, 2 or 3) ring atoms are independently selected fromN, O and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.
  • cycloalkyl employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.
  • C n-m cycloalkyl refers to a cycloalkyl that has n to m ring member carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic (e.g, having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C 3-7 ).
  • the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C 3-6 monocyclic cycloalkyl group. Ringforming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g, benzo or thienyl derivatives of cyclopentane, cyclohexane and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, bicyclofl. l.l]pentanyl, bicyclo[2.1.1]hexanyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g, having two fused or bridged rings) or spirocyclic ring systems.
  • the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g, C(O), S(O), C(S) or S(O) 2 , A-oxide etc.) or a nitrogen atom can be quatemized.
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ringforming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (/. e. , having a bond in common with) to the heterocycloalkyl ring, e.g. , benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the definitions or embodiments refer to specific rings (e.g, an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azeti din-3 -yl ring is attached at the 3-position.
  • the compounds described herein can be asymmetric (e.g, having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as p- camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g, dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g, dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds of the invention have the (//(-configuration. In other embodiments, the compounds have the ( ⁇ -configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (/?) or (S), unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g, 1H- and 377-imidazole, 1H-, 2H- and 47/- 1,2,4- triazole, 177- and 2H- isoindole and 177- and 277-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • the compound includes at least one deuterium atom.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
  • the compound includes two or more deuterium atoms.
  • the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms.
  • Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton- Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • the term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
  • All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • solvents e.g., hydrates and solvates
  • the compounds described herein and salts thereof may occur in various forms and may, e.g, take the form of solvates, including hydrates.
  • the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, e.g, a composition enriched in the compounds of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g, a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g, a temperature from about 20 °C to about 30 °C.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1 ). 1-19 and in Stahl et al., Handbook of Pharmaceutical
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., J H or 13 C), infrared spectroscopy, spectrophotometry (e.g, UV -visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., J H or 13 C), infrared spectroscopy, spectrophotometry (e.g, UV -visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • a general synthesis of compounds of Formula IA comprises a procedure as shown in General Scheme 1 above.
  • Bromide 1-1 can be coupled with benzophenone imine using a Pd reagent (e.g., Pd2(dba)3) in the presence of a base (e.g., a sodium alkoxide base such as NaOtBu) to provide imine 1-2.
  • a base e.g., a sodium alkoxide base such as NaOtBu
  • Imine 1-2 can be treated with acid (e.g., HC1) to provide amine 1-3.
  • acid e.g., HC1
  • Combining amine 1-3 and carboxylic acid 1-4 under amide coupling conditions leads to compounds of Formula IA.
  • Compounds of Formula IA can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, chiral phase HPLC, as well as other purification methods such as crystallization.
  • General Scheme 2
  • Products of type 2-3 may be prepared using the procedure as shown in General Scheme 2. Alcohol 2-1 can be coupled with a compound 2-2 (e.g., in the presence of tributylphosphine and 1,1 -(azodi carbonyl)dipiperi dine) to provide an ether of type 2-3. Products of type 2-3 can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, chiral phase HPLC, as well as other purification methods such as crystallization.
  • Products of type 3-2 may be prepared using the procedure as shown in General Scheme 3.
  • Amine 1-3 (as prepared according to General Scheme 1) can be treated with a compound 3-1 in the presence of a hydride reducing agent (e.g., NaCNBHs) to provide a product of type 3-2.
  • Products of type 3-2 can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, chiral phase HPLC, as well as other purification methods such as crystallization.
  • LRRK2 kinase activity is a mechanism in alpha-synuclein related neurodegeneration, and is implicated in diseases that are characterized by the formation of Lewy bodies.
  • Compounds as described herein e.g., compounds of Formula IA, IB, or IB’, exhibit inhibitory activity against LRRK2 kinase, including LRRK2 mutant kinase, such as mutant G2019S.
  • Kinase activity can be determined using a kinase assay, which typically employs a kinase substrate and a phosphate group donor, such as ATP (or a derivative thereol).
  • An exemplary kinase assay is described in Example A.
  • the present disclosure provides methods of modulating (e.g., inhibiting) LRRK2 activity, by contacting LRRK2 with a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the contacting can be administering to a patient, in need thereof, a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure, or pharmaceutically acceptable salts thereof are useful for therapeutic administration to treat neurodegenerative disease.
  • a method of treating a disease or disorder associated with inhibition of LRRK2 interaction can include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including neurodegenerative diseases.
  • any of the compounds of the disclosure including any of the embodiments thereof, may be used.
  • Compounds and compositions as described herein, e.g, compounds of Formula IA, IB, or IB’ are useful in the treatment and/or prevention of LRRK2 kinase mediated disorders, including LRRK2 kinase mutant mediated diseases.
  • LRRK2 kinase mutant G2019S mediated diseases include, but are not limited to, neurological diseases such as Parkinson's disease and other Lewy body diseases such as Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies (e.g., diffuse Lewy body disease (DLBD), Lewy body dementia, Lewy body disease, cortical Lewy body disease or senile dementia of Lewy type), Lewy body variant of Alzheimer's disease (i.e., diffuse Lewy body type of Alzheimer's disease), combined Parkinson's disease and Alzheimer's disease, as well as diseases associated with glial cortical inclusions, such as syndromes identified as multiple system atrophy, including striatonigral degeneration, olivopontocerebellar atrophy, and Shy- Drager syndrome, or other diseases associated with Parkinsonism, such as Hallervorden- Spatz syndrome (also referred to as Hallervorden-Spatz disease), frontotemporal dementia, Sandhoff disease, progressive supranuclear pal
  • a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB, or IB’ or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Shy- Drager syndrome, Hallervorden-Spatz syndrome, frontotemporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, postural hypotension, orthostatic hypotension, cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity, bradykinesia, akinesia, postural instability, melanoma, acute mye
  • the disease is selected
  • a method of treating a neurological disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, wherein the neurological disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Shy -Drager syndrome, Hallervorden-Spatz syndrome, frontotemporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, postural hypotension, orthostatic hypotension, cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity, bradykinesia, akinesia, and postural instability.
  • the neurological disease is selected from the group consist
  • a method of treating a neurological disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I A, IB or IB’, or a pharmaceutically salt thereof, wherein the neurological disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risksyndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy -Drager syndrome.
  • a method of treating Parkinson's disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof.
  • a method of treating a cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma, and papillary thyroid carcinoma.
  • a method of treating an autoimmune disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is selected from Crohn's disease and ulcerative colitis.
  • a method of treating leprosy comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, or a composition comprising such compound or salt thereof.
  • the compounds as described herein are inhibitors of LRRK2 kinase activity.
  • the compounds as described herein, e.g. compounds of Formula IA, IB, or IB’ are inhibitors of LRRK2 mutant kinase activity.
  • the compounds as described herein, e.g. compounds of Formula IA, IB or IB’ are inhibitors of LRRK2 mutant G2019S kinase activity.
  • Compounds as described herein e.g., compounds of Formula IA, IB or IB’, exhibit cellular biological activities, including but not limited to reduction in phosphorylation of ser910 or ser935 in HEK-293 cells transfected with either wild-type LRRK2 or LRRK2 G2019S mutant.
  • compounds of Formula IA, IB or IB’ are selective LRRK2 G2019S mutant inhibitors as compared to wild-type LRRK2.
  • the term “contacting” refers to the bringing together of the indicated moieties in an in vitro system or an in vivo system such that they are in sufficient physical proximity to interact.
  • mice preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the term "selective” or “selectivity” as it relates to kinase activity means that a compound as described herein, e.g. a compound of Formula I A, IB or IB’, is a more potent inhibitor of a particular kinase, such as LRRK2 kinase, when compared to another kinase. While LRRK2 has other enzymatic activities, it is understood that when inhibitory activity or selectivity of LRRK2, or any mutation thereof, is mentioned, it is the LRRK2 kinase activity that is being referred to, unless clearly stated otherwise.
  • selectivity of LRRK2 relative to another kinase indicates a comparison of the ICso of a compound on the kinase activity of LRRK2 to the ICso of the compound on the kinase activity of another kinase.
  • a compound as described herein is selective for a LRRK2 mutant over wild type LRRK2.
  • Selectivity of LRRK2 mutants relative to wild type LRRK2 indicates a comparison of the ICso of a compound on the kinase activity of the mutant LRRK2 to the ICso of the compound on the kinase activity of wild type LRRK2.
  • a compound provided herein is greater than 1 fold selective, greater than 2 fold selective, greater than 5 fold selective, greater than 10 fold selective, greater than 25 fold selective, or greater than 50 fold selective for LRRK2 mutant kinase over wild type LRRK2.
  • the LRRK2 mutant is LRRK2 G2019S.
  • LRRK2-mediated condition means any disease or other condition in which LRRK2, including any mutations thereof, is known to play a role, or a disease state that is associated with elevated activity or expression of LRRK2, including any mutations thereof.
  • a “LRRK2 -mediated condition” may be relieved by inhibiting LRRK2 kinase activity.
  • Such conditions include certain neurodegenerative diseases, such as Lewy body diseases, including, but not limited to, Parkinson's disease, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, dementia with Lewy bodies, diffuse Lewy body disease, as well as any syndrome identified as multiple system atrophy; certain cancers, such as melanoma, papillary renal cell carcinoma and papillary thyroid carcinoma; certain autoimmune diseases, such as inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis); and leprosy.
  • Lewy body diseases including, but not limited to, Parkinson's disease, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, dementia with Lewy bodies, diffuse Lewy body disease, as well as any syndrome identified as multiple system atrophy
  • certain cancers such as melanoma, papillary renal cell carcinoma and papillary thyroid carcinoma
  • certain autoimmune diseases such as inflammatory bowel disease (e.g. Crohn's disease and ulcerative co
  • neurodegenerative diseases includes any disease or condition characterized by problems with movements, such as ataxia, and conditions affecting cognitive abilities (e.g., memory) as well as conditions generally related to all types of dementia.
  • “Neurodegenerative diseases” may be associated with impairment or loss of cognitive abilities, potential loss of cognitive abilities and/or impairment or loss of brain cells.
  • Exemplary “neurodegenerative diseases” include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Down syndrome, dementia, multi-infarct dementia, mild cognitive impairment (MCI), epilepsy, seizures, Huntington's disease, neurodegeneration induced by viral infection (e.g. AIDS, encephalopathies), traumatic brain injuries, as well as ischemia and stroke.
  • Neurodegenerative diseases also includes any undesirable condition associated with the disease.
  • a method of treating a neurodegenerative disease includes methods of treating or preventing loss of neuronal function characteristic of neurodegenerative disease.
  • the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • One or more additional pharmaceutical agents or treatment methods can be used in combination with a compound of Formula IA, IB or IB’ for treatment of LRRK2-associated diseases, disorders, or conditions, or diseases or conditions as described herein.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • the additional pharmaceutical agent is a dopamine precursor, including, for example, levodopa, melevodopa, and etilevodopa.
  • the additional pharmaceutical agent is a dopamine agonist, including, for example, pramipexole, ropinorole, apomorphine, rotigotine, bromocriptine, cabergoline, and pergolide.
  • the additional pharmaceutical agent is a monamine oxidase B (“MAO B”) inhibitor, including, for example, selegiline and rasagiline.
  • the additional pharmaceutical agent is a catechol O-methyltransferase (“COMT”) inhibitor, including, for example, tolcapone and entacapone.
  • the additional pharmaceutical agent is an anticholinergic agent including, for example, benztropine, trihexyphenidyl, procyclidine, and biperiden.
  • the additional pharmaceutical agent is a glutamate (“NMD A”) blocking drug, including, for example, amantadine.
  • NMD A glutamate
  • the additional pharmaceutical agent is an adenosine A2A antagonist, including, for example, istradefylline and preladenant.
  • the additional pharmaceutical agent is a 5-HT1 a antagonist, including, for example, piclozotan and pardoprunox.
  • the additional pharmaceutical agent is an alpha 2 antagonist, including, for example, atipamezole and fipamezole.
  • the compounds of the present disclosure can be administered in the form of pharmaceutical compositions.
  • a composition comprising a compound of Formula IA, IB or IB’ or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier.
  • These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is indicated and upon the area to be treated.
  • Administration may be topical (including transdermal, epidermal, ophthalmic, and to mucous membranes including intranasal, vaginal, and rectal delivery), pulmonary (e.g, by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers.
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g).
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.
  • the therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers.
  • Step 1 6-Bromo-l-(l-cyclopropyl-lH-pyrazol-4-yl)-lH-indazole
  • 6-bromo-1H- indazole 50 mg, 253.77 umol
  • toluene 1 mL
  • Cs 2 CO 3 165.36 mg, 507.53 umol
  • 3,4,7,8-tetramethyl-1,10-phenanthroline 6.00 mg, 25.38 umol
  • 1-cyclopropyl-4- iodo-pyrazole 71.27 mg, 304.52 umol
  • (Bu 4 NCuI) 2 56.83 mg, 50.75 umol
  • Step 2 N-(1-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-1,1-diphenylmethanimine
  • 6-bromo-1-(1- cyclopropyl-1H-pyrazol-4-yl)-1H-indazole 75 mg, 247.40 umol
  • t-Bu Xphos 10.51 mg, 24.74 umol
  • NaOtBu 47.55 mg, 494.79 umol
  • benzophenone imine 58.29 mg, 321.62 umol
  • Pd 2 (dba) 3 22.65 mg, 24.74 umol
  • Step 3 1-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-amine
  • N-(1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-1,1- diphenylmethanimine 160 mg, 396.55 umol
  • 1 M HCl 396.55 uL, 396.55 umol
  • Step 1 5-((l-(l-Cyclopropyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile
  • Step 2 5-( (1-(1 -Cyclopropyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2 rac-5-((l-(l -Cyclopropyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)armno)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method E to afford 5-((l-(l-cy clopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (2.76 mg, 60%).
  • Step 3 6-Bromo-5-chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazole .01 umol), 6-bromo- 5-chloro-1H-indazole (100 mg, 432.01 umol), Cs2CO3 (281.51 mg, 864.02 umol), 3,4,7,8- tetramethyl-1,10-phenanthroline (10.21 mg, 43.20 umol) and (Bu 4 NCuI) 2 (96.68 mg, 86.40 umol) in toluene (4 mL) was degassed and purged with N2 (3x) at 20 °C.
  • Step 4 N-(5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-5-cyano-3,4- dimethylpicolinamide
  • 6-bro razol-4-yl)-1H-indazole 100 mg, 296.21 umol
  • 5-cyano-3,4-dimethylpicolinamide 51.89 mg, 296.21 umol
  • 4,5- bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene 51.42 mg, 88.86 umol
  • Pd2(dba)3 27.12 mg, 29.62 umol
  • Cs 2 CO 3 (289.53 mg, 888.62 umol) in 1,4-dioxane (10 mL) was degassed and purged with N2 (3x) at 20 °C.
  • Example 4 5-((5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2 ) in a microwave reactor tube was added NH 4 OAc (675.37 mg, 8.76 mmol) and the mixture was stirred at 20 °C for 10 min.
  • NaBH3CN 146.83 mg, 2.34 mmol
  • the reaction mixture was filtered and the filtrate was concentrated under vacuum.
  • Step 2 rac-5-((5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile
  • Step 3 5-((5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2 -5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method F to afford 5-((5-chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (3.28 mg, 36%) as a pale yellow solid.
  • Step 1 l-Cyclopropyl-6-nitro-lH-indazole
  • Step 3 6-Chloro-5-cyano-N-(1-cyclopropyl-1H-indazol-6-yl)-3,4-dimethylpicolinamide 6- chloro-5-cyano-3,4-dimethylpicolinic acid (85.12 mg, 404.12 umol) in DMF (2 mL) were added DIEA (156.69 mg, 1.21 mmol) and HATU (199.76 mg, 525.36 umol). The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction mixture was diluted with water, some yellow solid formed, it was filtered, the cake was washed with H 2 O, collected and dried under vacuum to give a residue.
  • Example 7 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
  • Step 1 6
  • 4-iodo-1-methyl-1H-pyrazole 791.75 mg, 3.81 mmol
  • 3,4,7,8-tetramethyl-1,10-phenanthroline 59.97 mg, 253.77 umol
  • Cs2CO3 (1.65 g, 5.08 mmol
  • (Bu 4 NCuI) 2 568.25 mg, 507.53 umol).
  • the mixture was degassed, purged with N2 (3x), and then stirred at 120 °C for 5 hrs in a microwave reactor under an N2 atmosphere.
  • the reaction mixture was diluted with H 2 O and extracted with EtOAc (5x).
  • the combined organic layers were washed with brine, dried over Na2SO4, and filtered.
  • the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (280 mg, 39%) as a white solid.
  • Step 2 1-(1-Methyl-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole
  • 6-bromo -4-yl)-1H-indazole 200 mg, 721.71 umol
  • dioxane 3 mL
  • bis(pinacolato)diboron 219.93 mg, 866.05 umol
  • AcOK 212.49 mg, 2.17 mmol
  • Pd(dppf)Cl2 52.81 mg, 72.17 umol
  • Step 3 1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-ol
  • l-(l-methyl-17/-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-17/-indazole 200 mg, 616.93 umol
  • H2O 3 mL
  • NaBOs FLO 284.76 mg, 1.85 mmol
  • Step 4 rac-5-( ⁇ 1-(1 -Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
  • Step 5 5-((l-(l -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8- rac-5-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method I to afford 5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (4 mg, 89%) as a white solid.
  • Example 8 8-((l-(l-MethyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
  • Step 2 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-amine
  • Step 3 rac-8-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
  • Step 4 8-( (1-(1 -Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2 rac-8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral separation using Method F to afford 8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (4 mg, 86%) as a pale yellow solid.
  • Step 1 8-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahydroquinoline- 3-carbonitrile Two same scale reactions were carried out in parallel (each for 25 mg, total 50 mg starting material).
  • Step 2 8-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahydroquinoline- 3-carbonitrile, enantiomer 1 and 2 rac-8-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral separation using Method L to afford 8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3- carbonitrile, enantiomer 1 (4 mg, 86%) as a yellow solid.
  • Step 1 Sodium (2-oxocyclohexylidene)methanolate
  • Step 3 2-Chloro-5,6, 7,8-tetrahydroquinoline-3-carbonitrile
  • Step 4 2-Chloro-3-cyano-5, 6, 7, 8-tetrahydroquinoline 1 -oxide
  • Step 7 rac-2-Chloro-8-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
  • Step 8 2-Chloro-8-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2 rac-2-Chloro-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral separation using Method N to afford 2-chloro-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (3 mg, 68%) as a yellow solid.
  • Step 4 3-Cyano-N-( 1-(1 -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-2-(prop-l-en-2- yl)benzamide
  • Step 5 3-Cyano-2-isopropyl-N-( 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)benzamide
  • Step 4 7 -Hydroxy-6, 7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile
  • Step 5 rac-7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-6, 7-dihydro-5H- cyclopenta[b ]pyridine-3-carboni trite
  • Example 14 7-((l-(l-MethyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)amino)-6,7-dihydro-5/7- cyclopenta[b]pyridine-3-carbonitrile, enantiomer 1 and 2
  • 6-bromo-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazole 150 mg, 541.28 umol
  • tert-butyl carbamate 76.09 mg, 649.54 umol
  • Pd2(dba)3 49.57 mg, 54.13 umol
  • 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl 22.99 mg, 54.13 umol
  • t-BuONa 104.04 mg, 1.08 mmol
  • Step 2 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-amine
  • Step 3 N-(3-Bromo-6, 7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-l -(1 -methyl- lH-pyrazol-4- yl)-lH-indazol-6-amine
  • Step 4 rac-7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-6, 7-dihydro-5H- cyclopenta [b ]pyridine-3-carboni trile
  • Step 5 7-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-6, 7-dihydro-5H- rac-7-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile was subjected to chiral separation using Method R to afford 7-(( 1 -(1 -methyl- 17/-py razol -4-y 1)- I //-indazol -6- l)amino)-6,7-dihy dro-57/- cyclopenta[b]pyridine-3-carbonitrile, enantiomer 1 (2.75 mg, 61%) as a blue solid.
  • Example 15 4-Cyano-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6-yl)-3-(prop-l-en-2- yl)picolinamide
  • Step 1 l-(l-Methyl-lH-pyrazol-4-yl)-6-nitro-lH-indazole
  • the suspension was filtered through a Celite pad and the combined organic layers were evaporated to obtain a residue which was taken up in aqueous citrate buffer (pH 3) and stirred for 30 minutes.
  • the solid was filtered under vacuum, washed with H2O, and dried to obtain a dark residue which was dissolved in DCM and passed through an alumina pad.
  • the filtrate was evaporated to obtain a light orange solid that was triturated with Et2O and dried to afford the title compound (3.2 g, 44%) as a yellow solid.
  • Step 2 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-amine
  • Step 9 4-Cyano-3-(prop-l-en-2-yl)picolinic acid
  • Step 10 4-Cyano-N-(l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-3-(prop-l-en-2- yl)picolinamide
  • Step 3 5-Cyano-6-(difluoromethyl)-3,4-dimethyl-N-(5-methyl-l-(l-methyl-lH-pyrazol-4-yl)- lH-indazol-6-yl)picolinamide
  • Example 18 5-Cyaiio-6-(difliioromethyl)-3,4-dimethyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)- l//-indazol-6-yl)picolinamide
  • Step 6 5-Cyano-6-(difluoromethyl)-3, 4-dimethyl-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH- indazol-6-yl)picolinamide
  • Step 8 5-Cyano-3,4-dimethyl-6-(prop-l-en-2-yl)picolinic acid
  • Step 9 5-Cyano-3, 4-dimethyl-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)-6-(pr op-1- en-2-yl)picolinamide
  • Step 6 Methyl 5-cyano-3,4-dimethyl-6-(trifluoromethyl)picolinate 0.0 mg, 2.84 mmol) and zinc trifluoromethanesulfinate (1881.82 mg, 5.68 mmol) in DMSO (8 mL) was cooled in ice H2O. The mixture was stirred vigorously while adding 2-hydropperoxy-2-methylpropane (0.82 mL, 5.9 mmol, 70% solution in H 2 O). The solution was then allowed to reach room temperature and warmed at 50 °C for 2 hrs.
  • Step 7 5-Cyano-3,4-dimethyl-6-(trifluoromethyl)picolinic acid
  • MeOH MeOH
  • a 1 N aqueous solution of sodium hydroxide 0.39 mL, 0.39 mmol
  • Volatiles were removed under reduced pressure to afford the title compound (105 mg) which was used without further purification.
  • 'H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm 2.50 (s., 3 H) 2.26 (s, 3 H).
  • MS- ESI (m/z) calc’d for C10H8F3N2O2 [M+H] + : 245.0. Found 244.9.
  • Step 8 5-Cyano-3, 4-dimethyl-N-(5 -methyl- 1-( I -methyl- IH-pyr azol-4-yl)-l H-indazol-6-yl)-6- (trifluoromethyl)picolinamide
  • Step 2 Methyl 5-cyano-2-(prop-1-en-2-yl)benzoate (240.05 mg, 1 mmol), 4,4,5,5- tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (0.28 mL, 1.5 mmol), Pd(dppf)Cl2 (109.76 mg, 0.15 mmol) and potassium carbonate (276.42 mg, 2 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was stirred under N2 at 100 °C for 3 hrs. The mixture was diluted with H 2 O and extracted with EtOAc (3x).
  • Step 3 Methyl 5-cyano-2-(prop-1-en-2-yl)benzoate and Methyl 5-cyano-2-isopropylbenzoate
  • m ate 17.36 mg, 0.01 mmol
  • ammonium formate 111 mg, 1.76 mmol
  • the mixture was stirred at 65 °C for 2 hrs.
  • the mixture was diluted with H 2 O and extracted with DCM (3x).
  • the combined organic layers were passed through a phase separator and evaporated to afford a mixture of the title compounds (170 mg, 95%) as a yellow oil.
  • Step 5 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-(prop-1-en-2- yl)benzamide
  • 22a Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide, using 5-cyano-2-(prop-1-en-2-yl)benzoic acid in place of 4-cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (42.5 mg, 53%) as a white solid.
  • Step 6 5-Cyano-2-isopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide
  • 22b Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide, using 5-cyano-2-isopropylbenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (5 mg, 7%) as a white solid.
  • Example 23 3-Cyano-2,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide 15 g, 5 mmol) in DMF (16.67 mL) was added iodomethane (622.54 uL, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) and the mixture was stirred at 25 °C for 2 hrs. The mixture was then poured into H 2 O and extracted with Et2O (3x). The combined organic layers were washed with H2O (3x), dried over Na 2 SO 4 , and evaporated to afford the title compound (1.19 g, 98%) as a clear oil.
  • Step 2 3-Bromo-2,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide
  • 1-(1- mine 42.65 mg, 0.20 mmol
  • methyl 3-bromo-2,6-dimethylbenzoate 48.62 mg, 0.20 mmol
  • toluene 2 mL
  • 2 M trimethylaluminum 0.3 mL, 0.60 mmol
  • Tetrakis(triphenylphosphine) palladium(0) (0.29 g, 0.250 mmol) was added and the mixture was stirred at 100 °C under N 2 for 3 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-10% EtOAc/cyclohexane gradient eluent to afford the title compound (1.06 g, 100%) as a clear oil.
  • Step 2 5-Bromo-3,6-dimethylpicolinic acid
  • acetone 25 mL
  • potassium permanganate 1.74 g, 11 mmol
  • H2O 25 mL
  • the excess permanganate was quenched by addition of formic acid, then the solid was removed by filtration.
  • the filtrate was evaporated and the residue was taken up in H 2 O and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (900 mg, 78%) as a white solid.
  • Step 3 Methyl 5-bromo-3,6-dimethylpicolinate To a solution of 5-bromo-3,6 ic acid (900.0 mg, 3.91 mmol) in DMF (6.52 mL) was added potassium carbonate (1.62 g, 11.74 mmol) and iodomethane (0.49 mL, 7.82 mmol) and then the mixture was stirred at 80 °C for 1 hr. The mixture was then poured into H 2 O (150 mL) and stirred for 10 minutes. The solid that formed was filtered and dried under vacuum to afford the title compound (833 mg, 87%) as a brown liquid.
  • Step 4 Methyl 3,6-dimethyl-5-vinylpicolinate A solution of methyl 5-bromo-3 ate (0.83 g, 3.41 mmol) and tributyl(ethenyl)stannane (1.99 mL, 6.83 mmol) in 1,4-dioxane (34.13 mL) was purged with N2 for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.24 g, 0.340 mmol) was added and the mixture was stirred at 100 °C under N 2 for 2 hrs.
  • Step 5 Methyl 5-formyl-3,6-dimethylpicolinate To a solution of methyl 3,6- colinate (460.0 mg, 2.41 mmol) in 1,4- dioxane (12 mL) was added a solution of sodium periodate (1.03 g, 4.81 mmol) in water (12 mL) and the mixture was stirred at 25 °C for 5 minutes. Osmium tetroxide (766 uL, 0.12 mmol) was added and the reaction was then stirred for 1 hr. The mixture was partitioned between DCM and H 2 O and the layers were separated.
  • Step 6 Methyl 5-cyano-3,6-dimethylpicolinate To a solution of methyl 5-fo picolinate (464.75 mg, 2.41 mmol) in DMSO (2.406 mL) was added hydroxylamine hydrochloride (183.88 mg, 2.65 mmol) and the mixture was stirred at 90 °C for 4 hrs. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with H2O (3x), passed through a phase separator, and evaporated to afford the title compound (380 mg, 83%) as a purple solid.
  • Step 8 5-Cyano-3, 6-dimethyl-N-(l-(l -methyl- IH-pyr azol-4-yl)-l H-indazol-6- yl)picolinamide
  • Example 28 2-Bromo-6-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)nicotinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 2-bromo-6-cyanonicotinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (70 mg, 83%) as a white solid.
  • Example 30 5-Cyano-3-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide
  • -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyanopyrazine-2-carboxylic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (39 mg, 54%) as a yellow solid.
  • Example 31 6-Cyano-4-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)nicotinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 6-cyano-4-methylnicotinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (39 mg, 54%) as a yellow solid.
  • Example 32 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)picolinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyanopicolinic acid in place of 4-cyano-3-(prop- 1-en-2-yl)picolinic acid to afford the title compound (55 mg, 80%) as a yellow solid.
  • Example 34 4-Cyano-2-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 4-cyano-2-methoxybenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (57 mg, 76%) as a beige solid.
  • Example 35 3-Chloro-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 3-chloro-5-cyanopicolinic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (62.5 mg, 84%) as a beige solid.
  • Example 36 2-Chloro-4-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 2-chloro-4-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (62.5 mg, 84%) as a beige solid.
  • Example 37 5-Cyano-3,4,6-trimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide ylpyridine-3-carbonitrile (150.0 mg, 0.76 mmol), potassium carbonate (210.87 mg, 1.53 mmol) and trimethylboroxine (0.21 mL, 1.53 mmol) in 1,4-dioxane (2 mL) and H 2 O (1 mL) was degassed with N 2 for 15 min. Then tetrakis(triphenylphosphine) palladium(0) (176.3 mg, 0.15 mmol) was added and the mixture was stirred at 90 °C for 6 hrs.
  • Step 3 5-Cyano-3,4,6-trimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide
  • -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyano-3,4,6-trimethylpicolinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (63 mg, 84%) as a beige solid.
  • Example 38 5-Cyano-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyano-6-methylpicolinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (36 mg, 50%) as a yellow solid.
  • Example 39 4-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- (trifluoromethyl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 4-cyano-2-(trifluoromethyl)benzoic acid in place of 4-cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (28 mg, 34%) as a white solid.
  • Example 44 2-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)isonicotinamide Prepared as describe -(1-(1-methyl-1H-pyrazol-4- yl)-1H-indazol-6-yl)benzamide, using methyl 2-cyanoisonicotinate in place of methyl 3- cyano-6-chloro-2-fluorobenzoate. The material was purified via prep-HPLC (Method Z) to afford the title compound (26 mg, 37%) as a yellow solid.
  • Example 46 5-Cyano-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)nicotinamide Prepared as describe -(1-(1-methyl-1H-pyrazol-4- yl)-1H-indazol-6-yl)benzamide, using methyl 5-cyanonicotinate in place of methyl 3-cyano- 6-chloro-2-fluorobenzoate. The material was purified via prep-HPLC using Method X to afford the title compound (48.6 mg, 68%) as a yellow solid.
  • Example 47 2-Bromo-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 2-bromo-5-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (48 mg, 57%) as a beige solid.
  • Example 48 3-Cyano-2,6-difluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyano-2,6-difluorobenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (57.7 mg, 76%) as a beige solid.
  • Example 49 2-Bromo-3-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 2-bromo-3-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (52 mg, 62%) as a beige solid.
  • Example 50 3-Cyano-2-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyano-2-fluorobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (57 mg, 79%) as a beige solid.

Abstract

The present invention is directed to indazole and azaindazole derivatives of formulae as shown below which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders such as Parkinson's disease.

Description

INDAZOLES AND AZAINDAZOLES AS LRRK2 INHIBITORS
FIELD OF THE INVENTION
The present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
BACKGROUND OF THE INVENTION
Parkinson’s disease (“PD”) is the most common form of parkinsonism, a movement disorder, and the second most common, age-related neurodegenerative disease estimated to affect 1-2% of the population over age 65. PD is characterized by tremor, rigidity, postural instability, impaired speech, and bradykinesia. It is a chronic, progressive disease with increasing disability and diminished quality of life. In addition to PD, parkinsonism is exhibited in a range of conditions such as progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies.
Current therapeutic strategies for PD are primarily palliative and focus on reducing the severity of symptoms using supplemental dopaminergic medications. At present, there is no disease-modifying therapy that addresses the underlying neuropathological cause of the disease, thus constituting a significant unmet medical need.
It has long been known that family members of PD patients have an increased risk of developing the disease compared to the general population. Leucine-rich repeat kinase 2 (“LRRK2,” also known as dardarin) is a 286 kDa multi-domain protein that has been linked to PD by genome-wide association studies. LRRK2 expression in the brain is highest in areas impacted by PD (Eur. J. Neurosci. 2006, 23(3):659) and LRRK2 has been found to localize in Lewy Bodies, which are intracellular protein aggregates considered to be a hallmark of the disease. Patients with point mutations in LRRK2 present disease that is indistinguishable from idiopathic patients. While more than 20 LRRK2 mutations have been associated with autosomal-dominantly inherited parkinsonism, the G2019S mutation located within the kinase domain of LRRK2 is by far the most common. This particular mutation is found in >85% of LRRK2 -linked PD patients. It has been shown that the G2019S mutation in LRRK2 leads to an enhancement in LRRK2 kinase activity and inhibition of this activity is a therapeutic target for the treatment of PD.
In addition to PD, LRRK2 has been linked to other diseases such as cancer, leprosy, and Crohn’s disease (Sci. Signal., 2012, 5(207), pe2). As there are presently limited therapeutic options for treating PD and other disorders associated with aberrant LRRK2 kinase activity, there remains a need for developing LRRK2 inhibitors.
SUMMARY OF THE INVENTION The present invention is directed to a compound of F ormula I A or IB ’ :
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein constituent members are defined herein.
The present invention is directed to a compound of Formula IA or IB:
Figure imgf000003_0002
or a pharmaceutically acceptable salt thereof, wherein constituent members are defined herein.
The present invention is further directed to a pharmaceutical composition comprising a compound of Formula IA, IB, or IB’, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present invention is further directed to a method of inhibiting LRRK2 activity, comprising contacting a compound of Formula I A, IB, or IB’, or a pharmaceutically acceptable salt thereof, with LRRK2.
The present invention is further directed to a method of treating a disease or disorder associated with elevated expression or activity of LRRK2, or a functional variant thereof, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB, or IB’, or a pharmaceutically acceptable salt thereof.
The present invention is further directed to a method for treating a neurodegenerative disease in a patient comprising administering to the patient a therapeutically effective amount of the compound of Formula IA, IB, or IB’, or a pharmaceutically acceptable salt thereof.
The present disclosure also provides uses of the compounds described herein in the manufacture of a medicament for use in therapy. The present disclosure also provides the compounds described herein for use in therapy.
DETAILED DESCRIPTION
The present invention is directed to an inhibitor of LRRK2 which is a compound of
Formula I A or IB’:
Figure imgf000004_0001
IA
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1, Cy1-C1-4 alkyl-, Cy1-C2-4 alkenyl-, Cy1-C2-4 alkynyl-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, C(=NRe)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
L is -O- or -NH-;
Ring B is phenyl or 6-membered heteroaryl;
Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4; wherein not more than two of X2, X3, and X4 are simultaneously N;
Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl- C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 and R5 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R1 and R5 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl;
R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R2, R3 and R4 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, OR32, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, R32, Rb2, Rc2, Rd2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, Ra2, Rb2, Rc2, and Rd2 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl. C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or RC1 and Rdl together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; each Re, Rel, Re2, and Re3 is independently selected from H, C1-4 alkyl, and CN; n is 0, 1, 2, or 3; m is 0 or 1; and p is 0, 1, 2, or 3; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H.
The present invention is further directed to an inhibitor of LRRK2 which is a compound of Formula IA or IB:
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1, Cy1-C1-4 alkyl-, Cy1-C2-4 alkenyl-, Cy1-C2-4 alkynyl-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, C(=NRe)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
L is -O- or -NH-;
Ring B is phenyl or 6-membered heteroaryl;
Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4; wherein not more than two of X2, X3, and X4 are simultaneously N;
Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 is independently selected firom H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl;
R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R2, R3 and R4 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, OR32, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, R32, Rb2, Rc2, Rd2 is independently selected from
H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, Ra2, Rb2, Rc2, and Rd2 is optionally substituted with
I, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or RC1 and Rdl together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalky 1, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalky 1, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; each Re, Rel, Re2, and Re3 is independently selected from H, C1-4 alkyl, and CN; n is 0, 1, 2, or 3; and m is 0 or 1.
In some embodiments, in Formula I A when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H.
In some embodiments, the compound has Formula IA:
Figure imgf000011_0001
IA.
In some embodiments, the compound has Formula IB:
Figure imgf000011_0002
In some embodiments, the compound has Formula IB’:
Figure imgf000012_0001
In some embodiments, X2 is CR2. In some embodiments, X2 is CH.
In some embodiments, X2 is N.
In some embodiments, X3 is CR3. In some embodiments, X3 is CH.
In some embodiments, X3 is N.
In some embodiments, X4 is CR4. In some embodiments, X4 is CH.
In some embodiments, X4 is N.
In some embodiments, R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
In some embodiments, R2, R3, and R4 are each independently selected from H, C1-6 alkyl, CN, OR32, and halo.
In some embodiments, R2, R3, and R4 are each independently selected from H, C1-6 alkyl, and halo.
In some embodiments, R2, R3, and R4 are each independently selected from H and halo.
In some embodiments, R2 and R3 are each H, and R4 is H or Cl.
In some embodiments, R2, R3, and R4 are each H.
In some embodiments, R2 and R3 are each H, and R4 is H, methyl, or Cl.
In some embodiments, R2 is selected firom H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, OR32, SR32, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
In some embodiments, R2 is H or halo. In some embodiments, R2 is H.
In some embodiments, R3 is selected firom H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, OR32, SR32, C(O)Rb2, C(O)NRc2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
In some embodiments, R3 is H or halo. In some embodiments, R3 is H, F, or Cl. In some embodiments, R3 is halo. In some embodiments, R3 is F or Cl. In some embodiments, R3 is H.
In some embodiments, R4 is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa2, SR32, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
In some embodiments, R4 is H, C1-6 alkyl, or halo.
In some embodiments, R4 is selected from H, C1-6 alkyl, CN, ORa2, and halo. In some embodiments, R4 is selected from H, methyl, methoxy, CN, F, and Cl. In some embodiments, R4 is selected from C1-6 alkyl, CN, OR32, and halo.
In some embodiments, R4 is H, methyl, or Cl.
In some embodiments, R4 is H or halo. In some embodiments, R4 is H.
In some embodiments, A is Cy1, C1-6 alkyl, C1-6 haloalkyl, C2-4 alkenyl-, Cy1-C1-4 alkyl-, Cy1-C2-4 alkenyl, -CN, C(O)NRcRd, C(O)ORa, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments, A is Cy1, C1-6 alkyl, C1-6 haloalkyl, CN, C(O)NRcRd, C(O)ORa, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl is optionally substituted with 1, 2,
3, 4, or 5 substituents independently selected from halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments, A is Cy1 or C1-6 alkyl. In some embodiments, A is Cy1. In some embodiments, A is C1-6 alkyl. In some embodiments, A is methyl.
In some embodiments, A is Cy1, C1-6 alkyl, C2-4 alkenyl-, Cy1-C1-4 alkyl- or Cy1-C2-4 alkenyl-, wherein said C1-6 alkyl and C2-4 alkenyl are each optionally substituted with 1, 2, 3,
4, or 5 substituents independently selected from halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments, A is Cy1, C1-6 alkyl, C2-4 alkenyl-, Cy1-C1-4 alkyl- or Cy1-C2-4 alkenyl-.
In some embodiments, A is C2-4 alkenyl-, CyJ-C1-4 alkyl- or Cy1-C2-4 alkenyl-. In some embodiments, A is selected from prop-l-en-l-yl, 2-(pyridin-4-yl)vinyl, 2- (oxazol-4-yl)vinyl, 2-(l -methyl- lH-pyrazol-4-yl)vinyl, 2-(2,6-dimethylpyridin-4-yl)vinyl, 2- (2-methylpyridin-4-yl)vinyl, 3-(3-methoxyazeti din-1 -yl)prop-l -en-1 -yl, 3-(4- methylpiperazin-l-yl)prop-l-en-l-yl, (1-methylazeti din-3 -yl)methyl, 3-(3,3- difluoropy rrolidin- 1 -y l)prop- 1 -en- 1 -y 1, 3 -(py rrolidin- 1 -y l)prop- 1 -en- 1 -y 1, 3-(4- methylpiperazin-l-yl)-3-oxoprop-l-en-l-yl, 2-(l-methyl-lH-pyrazol-3-yl)vinyl, and 2- (oxetan-3-yl)vinyl.
In some embodiments, A is selected from 2-(pyridin-4-yl)vinyl, 2-(oxazol-4-yl)vinyl, 2-(l -methyl- lH-pyrazol-4-yl)vinyl, 2-(2,6-dimethylpyridin-4-yl)vinyl, 2-(2-methylpyridin-4- yl)viny 1, 3 -(3 -methoxy azeti din- 1 -y l)prop- 1 -en- 1 -y 1, 3 -(4-methy Ipiperazin- 1 -y l)prop- 1 -en- 1 - yl, (l-methylazetidin-3-yl)methyl, 3-(3,3-difluoropyrrolidin-l-yl)prop-l-en-l-yl, 3- (pyrrolidin-l-yl)prop-l-en-l-yl, 3-(4-methylpiperazin-l-yl)-3-oxoprop-l-en-l-yl, 2-(l- methyl-lH-pyrazol-3-yl)vinyl, and 2-(oxetan-3-yl)vinyl.
In some embodiments, Cy1 is C3-10 cycloalkyl or 5-14 membered heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-10 cycloalkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(0)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is 5-14 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-6 cycloalkyl or 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(0)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5- 6 membered heteroaryl-C1-4 alkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1 or 2 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-Ci- 4 alkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5- 6 membered heteroaryl-C1-4 alkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1 or 2 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is 5-6 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-Ci- 4 alkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5- 6 membered heteroaryl-C1-4 alkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1 or 2 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-10 cycloalkyl or 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C3- 10 cycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, NRcC(O)Rb, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-10 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C3-10 cycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, NRcC(O)Rb, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is 5-14 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C3-10 cycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, NRcC(O)Rb, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-6 cycloalkyl or 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C3- 10 cycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, NRcC(O)Rb, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C3-10 cycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, NRcC(O)Rb, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is 5-6 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C3-10 cycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, NRcC(O)Rb, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is C3-6 cycloalkyl or 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C1-6 alkyl and C3-10 cycloalkyl.
In some embodiments, Cy1 is C3-6 cycloalkyl. In some embodiments, Cy1 is cyclopropyl. In some embodiments, Cy1 is 5-6 membered heteroaryl optionally substituted by 1 or 2 substituents independently selected from C1-6 alkyl and C3-10 cycloalkyl. In some embodiments, Cy1 is 5-6 membered heteroaryl substituted by C1-6 alkyl or C3-10 cycloalkyl.
In some embodiments, Cy1 is pyrazolyl or cyclopropyl, wherein said pyrazolyl is optionally substituted with cyclopropyl or methyl. In some embodiments, Cy1 is pyrazolyl optionally substituted with cyclopropyl or methyl. In some embodiments, Cy1 is pyrazolyl substituted with cyclopropyl or methyl.
In some embodiments, Cy1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d]oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, triazolyl, cyclopropyl, and phenyl, wherein each Cy1 group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments, Cy1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d] oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, and triazolyl, wherein each Cy1 group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments, Cy1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d] oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, triazolyl, cyclopropyl, and phenyl, wherein each Cy1 group is optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d]oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, and triazolyl, wherein each Cy1 group is optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
In some embodiments, Cy1 is 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, or 1- methyl-lH-pyrazol-4-yl. In some embodiments, Cy1 is l-cyclopropyl-lH-pyrazol-4-yl or 1- methyl-lH-pyrazol-4-yl. In some embodiments, Cy1 is l-cyclopropyl-lH-pyrazol-4-yl. In some embodiments, Cy1 is l-methyl-lH-pyrazol-4-yl.
In some embodiments, Cy1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, l-methyl-lH-pyrazol-4-yl,l-(bicyclo[l. 1. 1] pentan- l-yl)-17/-pyrazol-4-yl, 1- (difluoromethyl)-17/-pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1-cyclopentyl- 17/-pyrazol-4-yl, benzo |<7|oxazol-2-yl. l-(2,2,2-trifluoroethyl)-17/-pyrazol-4-yl, l-(2- methoxyethyl)- l//-pyrazol-4-yl. 3-methoxy-l -methyl- IT/-pyrazol-4-yl. oxazol-2-yl, 4- phenyloxazol-2-yl, 4,5-dimethyloxazol-2-yl, 5-methyloxazol-2-yl, 4-methyloxazol-2-yl, 2- methylthiazol-5-yl, pyrimidin-5-yl, 2-methy Ipyrimi din-5 -yl, 3-methylpyridin-4-yl, 1-methyl- 17/-imidazol-4-yl, l-pyrazin-2-yl, pyridazin-3-yl, 2-(pyrrolidin- l-yl)pyrimi din-5 -yl, 1- methyl-17/-l,2,3-triazol-4-yl, 4-methylpyrimidin-2-yl, 2-morpholinopyridin-4-yl, 2- (trifhioromethyl)pyrimidin-5-yl, 1 -isopropyl- 17/-pyrazol-4-yl, l,3-dimethyl-17/-pyrazol-4-yl,
1 -benzyl- 17/-pyrazol-4-yl, 1 -phenyl- 17/-pyrazol-4-yl, 1 -(tert-butyl)- I T/-pyrazol-4-yl. 1,5- dimethyl- l//-pyrazol-4-yl. l-(oxetan-3-yl)-17/-pyrazol-4-yl, l-(pyridin-2-yl)-17/-pyrazol-4- yl, l -(tetrahydro-27/-pyran-4-yl)- l//-pyrazol-4-yl. 1 -ethyl- 17/-pyrazol-4-yl, 5-methylthiazol-
2-yl, 1 -methyl- 17/-pyrazol-3-yl, 2-methyloxazol-5-yl, 4-methylthiazol-5-yl, pyrazolo[l,5- o|pyri din-3 -yl, 2-methoxy-6-methylpyridin-4-yl, 3-morpholinophenyl, and 1 -(pyrimidin-2- yl)-17/-pyrazol-4-yl.
In some embodiments, Cy1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, 1-methyl- lH-pyrazol-4-yl,l-(bicyclo[l.l. l]pentan-l-yl)-17/-pyrazol-4-yl, 1 -(difluoromethyl)- 1H- pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1 -cyclopentyl- l//-pyrazol-4-yl. benzo \d\ oxazol-2-y 1, 1 -(2,2,2-trifluoroethy 1)- 17/-py razol-4-y 1, 1 -(2-methoxy ethyl)- 1H- pyrazol-4-yl, 3-methoxy-l -methyl- 17/-pyrazol-4-yl, oxazol-2-yl, 4-phenyloxazol-2-yl, 4,5- dimethyloxazol-2-yl, 5-methyloxazol-2-yl, 4-methyloxazol-2-yl, 2-methylthiazol-5-yl, py rimi din-5 -yl, 2-methylpyrimidin-5-yl, 3-methylpyridin-4-yl, 1 -methyl- 17/-imidazol-4-yl, 1- pyrazin-2-yl, pyridazin-3-yl, 2-(pyrrohdin-l-yl)pyrimidin-5-yl, l-methyl-17/-l,2,3-triazol-4- yl, 4-methylpyrimidin-2-yl, 2-morpholinopyridin-4-yl, 2-(trifluoromethyl)pyrimidin-5-yl, 1- isopropyl-17/-pyrazol-4-yl, l,3-dimethyl-17/-pyrazol-4-yl, 1 -benzyl- 17/-pyrazol-4-yl, 1- phenyl-17/-pyrazol-4-yl, 1 -(tert-butyl)- IT/-pyrazol-4-yl. 1,5 -dimethyl- 17/-pyrazol-4-yl, 1- (oxetan-3-yl)- IT/-pyrazol-4-yl. 1 -(pyridin-2-yl)- 17V-pyrazol-4-yl. l-(tetrahydro-27/-pyran-4- yl)-17/-pyrazol-4-yl, 1 -ethyl- 17/-pyrazol-4-yl, 5-methylthiazol-2-yl, 1 -methyl- 17/-pyrazol-3- yl, 2-methyloxazol-5-yl, 4-methylthiazol-5-yl, pyrazolo[l,5-a]pyridin-3-yl, 2-methoxy-6- methylpyridin-4-yl, and l-(pyrimidin-2-yl)-17/-pyrazol-4-yl.
In some embodiments, Cy1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, l-methyl-lH-pyrazol-4-yl,l-(bicyclo[l.1.1] pentan- l-yl)-17/-pyrazol-4-yl, 1- (difluoromethyl)-17/-pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1-cyclopentyl- 17/-pyrazol-4-yl, benzo [t/|oxazol-2-yl, l-(2,2,2-trifluoroethyl)-17/-pyrazol-4-yl, l-(2- methoxyethyl)- l//-pyrazol-4-yl. 3-methoxy-l -methyl- 17/-pyrazol-4-yl, oxazol-2-yl, 4- phenyloxazol-2-yl, 4,5-dimethyloxazol-2-yl, 5-methyloxazol-2-yl, 4-methyloxazol-2-yl, 2- methylthiazol-5-yl, pyrimidin-5-yl, 2-methy Ipy rimi din-5 -yl, 3-methylpyridin-4-yl, 1-methyl- 17/-imidazol-4-yl, l-pyrazin-2-yl, pyridazin-3-yl, 2-(pyrrolidin- l-yl)py rimi din-5 -yl, 1- methyl-17/-l,2,3-triazol-4-yl, 4-methylpyrimidin-2-yl, 2-morpholinopyridin-4-yl, 2- (trifhioromethyl)pyrimidin-5-yl, 1 -isopropyl- 17/-pyrazol-4-yl, l,3-dimethyl-17/-pyrazol-4-yl,
1 -benzyl- 17/-pyrazol-4-yl, 1 -phenyl- 17/-pyrazol-4-yl, 1 -(tert-butyl)- 17/-pyrazol-4-yl, 1,5- dimethyl- l//-pyrazol-4-yl. l-(oxetan-3-yl)-17/-pyrazol-4-yl, l-(pyridin-2-yl)-17/-pyrazol-4- yl, l-(tetrahydro-27/-pyran-4-yl)- IT/-pyrazol-4-yl. 1 -ethyl- 17/-pyrazol-4-yl, 5-methylthiazol-
2-yl, 1 -methyl- 17/-pyrazol-3-yl, 2-methyloxazol-5-yl, 4-methylthiazol-5-yl, pyrazolo[l,5- o|pyri din-3 -yl, 2-methoxy-6-methylpyridin-4-yl, 3-morpholinophenyl, 1 -(pyrimidin-2-yl)- 17/-pyrazol-4-yl, pyridazin-4-yl, l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl, 2- (methoxymethyl)pyridin-4-yl, l-(l,l-Dioxidothietan-3-yl)-lH-pyrazol-4-yl, 2-chloropyridin- 4-yl, 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl, 2-(3-hydroxyazetidin-l-yl)pyridin-4- yl, 2-methylpyridin-4-yl, l-(oxetan-3-ylmethyl)-lH-pyrazol-4-yl, 2-(4- (dimethylphosphoryl)piperidin-l-yl)pyridin-4-yl, 2-((2-oxa-6-azaspiro[3.3]heptan-6- yl)methyl)pyridin-4-yl, 2-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl, 2-(l- (hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl, 6-methylpyridazin-4-yl, 6- methoxypyridazin-4-yl, 2-methoxythiazol-5-yl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-3- yl, 2-isopropylthiazol-5-yl, 5-methyl-l,3,4-oxadiazol-2-yl, 2-methylthiazol-4-yl, pyrimidin-4- yl, l-(2-fluoroethyl)-lH-pyrazol-4-yl, 2-methoxypyrimidin-4-yl, l-methyl-6-oxo-l,6- dihydropyri din-3 -y 1, 3-fluoro- 1 -methyl- 1 H-py razol-4-y 1, 5 -fluoro- 1 -methy 1- IH-py razol-4-y 1, l-(2-cyanopropan-2-yl)-lH-pyrazol-4-yl, l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl, 2- (2-oxaspiro[3.3]heptan-6-yl)pyridin-4-yl, 2-(6-oxa-3-azabicyclo[3.1. l]heptan-3-yl)pyridin-4- yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, l-(2-morpholinoethyl)-lH-pyrazol-4-yl, 1-((1- methylpiperidin-4-yl)methyl)-lH-pyrazol-4-yl, 2-(4-methylmorpholin-2-yl)pyridin-4-yl, 2- (4-methylmorpholin-3-yl)pyridin-4-yl, 6-(3-(2-hydroxypropan-2-yl)pyrrolidin-l- yl)pyrimidin-4-yl, 6-(3-(2-Hydroxy propan-2 -yl)pyrrolidin-l-yl)pyrimidin-4-yl, 2-(pyridin-4- yl)cyclopropyl, 2-(2-methoxy ethoxy )-6-methylpyridin-4-yl, 2-(2-oxa-5- azabicyclo[2.2. l]heptan-5-yl)pyridin-4-yl, 2,6-dimethoxypyridin-4-yl, 4-oxospiro[2.5]oct-5- en-6-yl, 6-(4-methylpiperazin-l-yl)pyridazin-4-yl, 3-oxocyclohex-l-en-l-yl, 2- (morpholinomethyl)pyridin-4-yl, l-((l-methylazetidin-3-yl)methyl)-lH-pyrazol-4-yl, 1'- methyl-l',2',3',6'-tetrahydro-[2,4'-bipyridin]-4-yl, and 3-oxocyclopent-l-en-l-yl.
In some embodiments, Cy1 is selected from pyridazin-4-yl, l-(2-hydroxy-2- methylpropyl)-lH-pyrazol-4-yl, 2-(methoxymethyl)pyridin-4-yl, 1 -(1,1 -Dioxidothi etan-3 -yl)- lH-pyrazol-4-yl, 2-chloropyridin-4-yl, 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl, 2- (3-hydroxyazetidin-l-yl)pyridin-4-yl, 2-methylpyridin-4-yl, l-(oxetan-3-ylmethyl)-lH- py razol-4-y 1, 2-(4-(dimethy Iphosphory l)piperidin- 1 -y l)py ridin-4-y 1, 2-((2-oxa-6- azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl, 2-((2-oxa-6-azaspiro[3.3]heptan-6- yl)methyl)pyridin-4-yl, 2-(l-(hydroxymethyl)-3-azabicyclo[3.1 ,0]hexan-3-yl)pyridin-4-yl, 6- methylpyridazin-4-yl, 6-methoxypyridazin-4-yl, 2-methoxythiazol-5-yl, 4, 5,6,7- tetrahydropyrazolo[l,5-a]pyridin-3-yl, 2-isopropylthiazol-5-yl, 5-methyl-l,3,4-oxadiazol-2- yl, 2-methylthiazol-4-yl, pyrimidin-4-yl, 1 -(2 -fluoroethyl)-! H-py razol-4-yl, 2- methoxypyrimidin-4-yl, 1 -methy l-6-oxo-l,6-dihydropyri din-3 -yl, 3-fluoro-l-methyl-lH- pyrazol-4-yl, 5-fluoro-l -methyl- lH-pyrazol-4-yl, l-(2-cyanopropan-2-yl)-lH-pyrazol-4-yl, l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl, 2-(2-oxaspiro[3.3]heptan-6-yl)pyridin-4-yl, 2- (6-oxa-3-azabicyclo[3. 1. l]heptan-3-yl)pyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl,
1-(2-morpholinoethyl)-lH-pyrazol-4-yl, 1-((1 -methy lpiperidin-4-yl)methyl)-lH-pyrazol -4-yl,
2-(4-methylmorpholin-2-yl)pyridin-4-yl, 2-(4-methylmorpholin-3-yl)pyridin-4-yl, 6-(3-(2- hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl, 6-(3-(2-Hydroxypropan-2-yl)pyrrolidin-
1-yl)pyrimidin-4-yl, 2-(pyridin-4-yl)cyclopropyl, 2-(2-methoxyethoxy)-6-methylpyridin-4-yl,
2-(2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)pyridin-4-yl, 2,6-dimethoxypyridin-4-yl, 4- oxospiro[2.5] oct-5 -en-6-y 1, 6-(4-methy Ipiperazin- 1 -y l)py ridazin-4-y 1, 3 -oxocyclohex- 1 -en- 1 - yl, 2-(morpholinomethyl)pyridin-4-yl, l-((l-methylazetidin-3-yl)methyl)-lH-pyrazol-4-yl, 1'- methyl-r,2',3',6'-tetrahydro-[2,4'-bipyridin]-4-yl, and 3-oxocyclopent-l-en-l-yl.
In some embodiments, L is -O-. In some embodiments, L is -NH-.
In some embodiments, Ring B is phenyl.
In some embodiments, Ring B is 6-membered heteroaryl.
In some embodiments, Ring B is pyridinyl.
In some embodiments, Ring B is pyrazinyl or pyridinyl.
In some embodiments, Ring B is phenyl or pyridinyl.
In some embodiments, Ring B is phenyl, pyrazinyl, or pyridinyl.
In some embodiments, Ring C is phenyl.
In some embodiments, Ring C is 6-membered heteroaryl.
In some embodiments, Ring C is pyridinyl.
In some embodiments, Ring C is phenyl or pyridinyl.
In some embodiments, Ring C is phenyl, pyridinyl, pyrazinyl, or pyridazinyl.
In some embodiments, Ring C is pyridinyl, pyrazinyl, or pyridazinyl.
In some embodiments, m is 0.
In some embodiments, m is 1.
In some embodiments, each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl.
In some embodiments, each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C3-7 cycloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl, wherein said C1-6 alkyl and C2-6 alkenyl or R1 are each optionally substituted with a substituent selected from CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl.
In some embodiments, each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl. In some embodiments, each R1 is independently selected from halo, C3-6 cycloalkyl, C1-6 alkyl, C1-6 haloalkyl, and ORal.
In some embodiments, each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and ORal.
In some embodiments, each R1 is independently selected from halo and C1-6 alkyl.
In some embodiments, each R1 is independently selected from C1-6 alkyl.
In some embodiments, each R1 is independently selected from methyl, isopropyl, ethyl, prop-l-en-2-yl, chloro, fluoro, bromo, iodo, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, trifluoromethoxy, CN, methoxymethyl, vinyl, but-2-en-2-yl, sec-butyl, l,l,l-trifluoropropan-2-yl, methylsulfonyl, and oxetan-3-yloxy.
In some embodiments, each R1 is independently selected from methyl, isopropyl, ethyl, prop-l-en-2-yl, chloro, fluoro, bromo, iodo, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, and trifluoromethoxy.
In some embodiments, each R1 is independently selected from methyl, isopropyl, and chloro. In some embodiments, each R1 is methyl.
In some embodiments, n is 0.
In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
In some embodiments, n is 0, 1, or 2.
In some embodiments, each R5 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl.
In some embodiments, each R5 is independently selected from C1-6 alkyl and halo. In some embodiments, R5 is methyl.
In some embodiments, each R1 is independently selected from methyl and F.
In some embodiments, p is 0.
In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.
In some embodiments, p is 0, 1, or 2.
In some embodiments, each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
In some embodiments, each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, and halo.
In some embodiments, each Ra3, Rb3, Rc3, and Rd3 is independently selected from H and C1-6 alkyl.
In some embodiments, provided herein is a compound of Formula I A or IB’, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1 or C1-6 alkyl;
L is -O- or -NH-;
Ring B is phenyl, pyridinyl, or pyrazinyl;
Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is CR2 or N;
X3 is CR3;
X4 is CR4 or N;
Cy1 is selected from C3-10 cycloalkyl, C6-10 aryl, and 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4- 14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and ORal; each R5 is independently selected from C1-6 alkyl and halo;
R2, R3, and R4 are each independently selected from H, C1-6 alkyl, and halo; n is 0, 1, 2, or 3; m is 0 or 1; and p is 0, 1, or 2; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H. In some embodiments, provided herein is a compound of Formula IA or IB, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1 or C1-6 alkyl;
L is -O- or -NH-;
Ring B is phenyl or pyridinyl;
Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is CR2;
X3 is CR3;
X4 is CR4;
Cy1 is selected from C3-10 cycloalkyl and 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C1-6 alkyl and C3-10 cycloalkyl; each R1 is independently selected from halo and C1-6 alkyl;
R2, R3, and R4 are each independently selected from H and halo; n is 0, 1, 2, or 3; and m is 0 or 1; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3, and R1 is a group other than H.
In some embodiments, provided herein is a compound of Formula IA or IB’, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1 or C1-6 alkyl;
L is -O- or -NH-;
Ring B is phenyl, pyridinyl, or pyrazinyl;
Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is CR2;
X3 is CR3;
X4 is CR4;
Cy1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo [d]oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, and triazolyl, wherein each Cy1 group is optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd each R1 is independently selected from halo, C3-6 cycloalkyl, C1-6 alkyl, C1-6 haloalkyl, and ORal; each R5 is independently selected from C1-6 alkyl and halo;
R2, R3, and R4 are each independently selected from H, C1-6 alkyl, and halo; n is 0, 1, 2, or 3; m is 0 or 1; and p is 0, 1, or 2; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H.
In some embodiments, provided herein is a compound of Formula IA, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1, Cy1-C1-4 alkyl-, Cy1-C2-4 alkenyl-, Cy1-C2-4 alkynyl-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa C(O)Rb, C(O)NRcRd, C(O)ORa, C(=NRe)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
Ring B is phenyl or 6-membered heteroaryl;
== represents a single bond or a double bond;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4; wherein not more than two of X2, X3, and X4 are simultaneously N;
Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, 0Ra, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(0)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 is independently selected firom H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl;
R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R2, R3 and R4 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, OR32, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, R32, Rb2, Rc2, Rd2 is independently selected from
H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, Ra2, Rb2, Rc2, and Rd2 is optionally substituted with
I, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or RC1 and Rdl together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalky 1, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; each Re, Rel, Re2, and Re3 is independently selected from H, C1-4 alkyl, and CN; n is 0, 1, 2, or 3; and wherein when ring B is phenyl, then: n is 1, 2, or 3, and R1 is a group other than H.
In some embodiments, provided herein is a compound of Formula IA, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1 or C1-6 alkyl;
Ring B is phenyl or pyridinyl;
== represents a single bond or a double bond;
X2 is CR2;
X3 is CR3;
X4 is CR4;
Cy1 is selected from C3-6 cycloalkyl and 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C1-6 alkyl and C3-6 cycloalkyl; each R1 is independently selected from halo and C1-6 alkyl;
R2, R3, and R4 are each independently selected from H and halo; n is 0, 1, 2, or 3; and m is 0 or 1; wherein when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H. Provided herein is a compound of Formula IB, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1, Cy1-C1-4 alkyl-, Cy1-C2-4 alkenyl-, Cy1-C2-4 alkynyl-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa C(O)Rb, C(O)NRcRd, C(O)ORa, C(=NRe)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
L is -O- or -NH-;
Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4; wherein not more than two of X2, X3, and X4 are simultaneously N;
Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl;
R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R2, R3 and R4 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, OR32, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, R32, Rb2, Rc2, Rd2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, Ra2, Rb2, Rc2, and Rd2 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or RC1 and Rdl together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalky 1, and C1-6 haloalkoxy; each Re, Rel, Re2, and Re3 is independently selected fromH, C1-4 alkyl, and CN; n is 0, 1, 2, or 3; and m is 0 or 1.
In some embodiments, provided herein is a compound of Formula IB, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1;
L is -O- or -NH-;
Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is CR2;
X3 is CR3;
X4 is CR4;
Cy1 is 5-6 membered heteroaryl, optionally substituted by 1 or 2 substituents independently selected from C1-6 alkyl and C3-6 cycloalkyl; each R1 is independently selected from halo and C1-6 alkyl;
R2, R3, and R4 are each independently selected from H and halo; n is 0, 1, 2, or 3; and m is 0 or 1.
In some embodiments, the compound has Formula Ila:
Figure imgf000033_0001
a, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula lib
Figure imgf000034_0001
Uh, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula lie
Figure imgf000034_0002
lie, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula lid
Figure imgf000034_0003
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula Illa:
Figure imgf000034_0004
Illa, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula Illb:
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula IIIc:
Figure imgf000035_0002
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula Illd:
Figure imgf000035_0003
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
In some embodiments, the compound has Formula Ille:
Figure imgf000035_0004
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
Provided herein is a compound selected from the following: 5-Cyano-/V-(l-(l-cyclopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-3,4- dimethylpicolinamide;
5-((l-(l-Cyclopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
/V-(5-Chloro-l-(l-cyclopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-5-cyano-3,4- dimethylpicolinamide;
5-((5-Chloro-l-(l-cyclopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
6-Chloro-5-cyano-3,4-dimethyl-N-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)picolinamide;
6-Chloro-5-cyano-/V-(l-cyclopropyl-17/-indazol-6-yl)-3,4-dimethylpicolinamide;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-
3-carbonitrile;
2-Chloro-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
6-Chloro-5-cyano-3,4-dimethyl-N-(l-methyl-lH-indazol-6-yl)picolinamide;
3-Cyano-2-isopropyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
7-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile;
7-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt of any of the aforementioned.
Also provided herein is a compound is selected from:
4-Cy ano-/V-( 1 -( 1 -methyl- 17/-py razol -4-y I )- 1 //-indazol -6-y l)-3-(prop- 1 -en-2- yl)picolinamide;
3-Cyano-2-iodo-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
5-Cyano-6-(difluoromethyl)-3,4-dimethyl-JV-(5-methyl-l-(l-methyl-17/-pyrazol-4- yl)- 17/-indazol-6-y l)picolinamide; 5-Cyano-6-(difluoromethyl)-3,4-dimethyl-7V-(l-(l-methyl-177-pyrazol-4-yl)-177- indazol-6-yl)picolinamide;
5-Cyano-3,4-dimethyl-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)-6-(prop-l- en-2-yl)picolinamide;
5-Cyano-6-isopropyl-3,4-dimethyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)picolinamide;
5-Cyano-3,4-dimethyl-7V-(5-methyl-l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)- 6-(trifluoromethyl)picolinamide;
5-Cy ano-/V-( 1 -( 1 -methyl- 17/-py razol -4-y I )- 1 //-indazol -6-y l)-2-(prop- 1 -en-2- yl)benzamide;
5-Cyano-2-isopropyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2,6-dimethyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-cy cl opropyl-/V-(l -(1 -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6- yl)benzamide;
2-Chloro-4-cyano-6-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
5-Cyano-3,6-dimethyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)picolinamide;
6-Cyano-2-methyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)nicotinamide;
2-Bromo-6-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)ni cotinamide;
5-Cyano-/V-(l-(l-methyl-77/-pyrazol-4-yl)-17/-indazol-6-yl)pyrazine-2-carboxamide;
5-Cyano-3-fluoro-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)picolinamide;
6-Cyano-4-methyl-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)nicotinamide;
5-Cyano-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)picolinamide;
4-Cyano-2-methyl-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)benzamide;
4-Cyano-2-methoxy-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)benzamide;
3-Chloro-5-cyano-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)picolinamide;
2-Chloro-4-cyano-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)benzamide;
5-Cyano-3,4,6-trimethyl-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6- yl)picolinamide;
5-Cyano-6-methyl-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)picolinamide;
4-Cyano-7V-(l-(l-methyl-177-pyrazol-4-yl)-177-indazol-6-yl)-2-
(trifluoromethyl)benzamide; 6-Chloro-3-cyano-2-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
6-Cyano-3-methyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
5-Cyano-2-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
2-Chloro-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)ni cotinamide;
2-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)isoni cotinamide;
5-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)nicotinamide;
5-Cyano-6-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)nicotinamide;
2-Bromo-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2,6-difluoro-iV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
2-Bromo-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Bromo-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
4-Cyano-6-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
5-Cyano-2-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
2-Chloro-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-methoxy-/V-[l-(l-methylpyrazol-4-yl)indazol-6-yl]benzamide;
2-Chloro-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
5-Cyano-3,4-dimethyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6-
(trifluoromethyl)picolinamide;
4-Cyano-3-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
6-Chloro-l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile;
5-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-pyrazolo [4, 3-6]pyridin-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(Bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
8-((l-(l-(Bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6- yl)oxy)-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile; 5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-pyrazolo [3, 4-b]pyridin-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-pyrazolo [4, 3-c]pyridin-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(Difluoromethyl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
7-Methyl-l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile;
4-Methyl-8-((5-methyl-l-(l -methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
7-Fluoro-l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile;
2-Methyl-8-((5-methyl-l-(l -methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(l -(Difluoromethyl)- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Methyl-17/-imidazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(Thiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
4-Methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
1-Methyl-5-((l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
3-Methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-Chloro-4-cyano-2,3-dimethyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
2-Chloro-7-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile;
5-((l-(l -Cyclopentyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; 5-((l-(Benzo[r/|oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(l-(2,2,2-Trifluoroethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(2-Methoxyethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(3-Methoxy-l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Cyclopentyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
7-Methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(Oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(4-Phenyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(4,5-Dimethyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile;
5-((l-(5-Methyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(4-Methyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(2-Methylthiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(Pyrimidin-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(2-Methylpyrimidin-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile;
5-((l-(3-Methylpyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(l -Methyl-17/-imidazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l -Pyrazin-2-yl)- IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2- carbonitrile; 5-((l-(Pyridazin-3-yl)-177-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(2-(Pyrrolidin-l-yl)pyrimidin-5-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-Methyl-177-l,2,3-triazol-4-yl)-177-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(4-Methylpyrimi din-2 -yl)-17/-indazol-6-yl)oxy)-5, 6,7, 8-tetrahy dronaphthalene- 2-carbonitrile;
5-((l-(2-Morpholinopyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(Trifluoromethyl)pyrimi din-5-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Isopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l,3-Dimethyl-17/-pyrazol-4-yl)-77/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-Benzyl-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Phenyl- 177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(tert-Butyl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l,5-Dimethyl-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(Oxetan-3-yl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(Pyri din-2-yl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(Tetr ahydro-2ff-pyran-4-yl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Ethyl- 177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahy dronaphthalene- 2-carbonitrile;
5-((l-(5-Methylthiazol-2-yl)-177-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahy dronaphthal ene-2- carbonitrile; 5-((l-(l-Methyl-177-pyrazol-3-yl)-177-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Methyloxazol-5-yl)-177-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
3-Cyano-2-isopropyl-7V-(l-(l-(2-methoxyethyl)-177-pyrazol-4-yl)-177-indazol-6- yl)benzamide;
3-Cyano-7V-(l-(4,5-dimethyloxazol-2-yl)-177-indazol-6-yl)-2-isopropylbenzamide;
3-Cyano-7V-(l-(l-cyclopentyl-177-pyrazol-4-yl)-177-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-7V-(l-(oxazol-2-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(4-phenyloxazol-2-yl)-177-indazol-6-yl)benzamide;
7V-(l-(Benzo[<7]oxazol-2-yl)-177-indazol-6-yl)-3-cyano-2-isopropylbenzamide;
3-Cyano-2-isopropyl-7V-(l-(2-methylthiazol-5-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(4-methylthiazol-5-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(pyrimidin-5-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(2-methylpyrimidin-5-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(3-methylpyridin-4-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(pyridazin-3-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(2-(pyrrolidin-l-yl)pyrimidin-5-yl)-177-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(pyrazolo[l,5-a]pyridin-3-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(l-isopropyl-777-pyrazol-4-yl)-177-indazol-6- yl)benzamide;
3-Cyano-7V-(l-(l,3-dimethyl-177-pyrazol-4-yl)-177-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-7V-(l-(l-phenyl-177-pyrazol-4-yl)-177-indazol-6-yl)benzamide;
7V-(l-(l-(/er/-Butyl)-177-pyrazol-4-yl)-177-indazol-6-yl)-3-cyano-2- isopropylbenzamide;
3-Cyano-2-isopropyl-7V-(l-(l-(oxetan-3-yl)-177-pyrazol-4-yl)-177-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(l-methyl-177-pyrazol-3-yl)-177-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(2-methoxy-6-methylpyridin-4-yl)-177-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(3-morpholinophenyl)-777-indazol-6-yl)benzamide; 3-Cyano-2-isopropyl-/V-(l-(5-methylthiazol-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(pyrazin-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-methyl-17/-l,2,3-triazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-(pyrimidin-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cy ano-2-isopropyl-/V-(l-(l-(pyri din-2 -yl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-/V-(l-(l-ethyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-isopropylbenzamide;
3-Cy ano-N-( 1 -(1 -(difluoromethyl)- 17/-py razol-4-y 1)- 1 //-indazol -6-y l)-2- isopropylbenzamide;
3-Cy ano-/V-( 1 -( 1 -methyl- 17/-py razol -4-y I )- 1 //-indazol -6-y l)-2-(prop- 1 -en-2- yl)benzamide;
3-Cyano-2-fluoro-6-methyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cy ano-2-methoxy-6-methy l-JV-( 1 -( 1 -methyl- 17/-py razol-4-y 1)- 17/-indazol-6- yl)benzamide;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- (trifluoromethoxy)benzamide;
3-Cyano-2-ethyl-6-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
5-((l-(3-Morpholinophenyl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- (trifluoromethyl)benzamide;
5-((l -(1 -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahy dronaphthalene- 1 -carbonitrile;
4-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
4-Cy ano-/V-( 1 -( 1 -methyl- 17/-py razol -4-y 1 )- 1 //-indazol -6-y l)-2-(prop- 1 -en-2- yl)benzamide;
5-((l-(l-(Pyrimidin-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; and
8,8-Difluoro-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, or pharmaceutically acceptable salts of any of the aforementioned.
Also provided herein is a compound is selected from:
2-Methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
4-Methyl-8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile; l-Methoxy-5-((l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Methoxy-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Chloro-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
6-Methyl-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; l-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile;
3-Fluoro-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
3-Methoxy-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((4-Fluoro-l -(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroisoquinoline-3-carbonitrile; l-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/-indene-5- carbonitrile;
5-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline- 2-carbonitrile;
4-Methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitril e; 8-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4- (trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile; l-Methoxy-5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57/- cyclopenta|6|pyrazme-2-carbonitrile;
1-Fluoro-5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(Pyridazin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
4-(Difluoromethyl)-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl-3-d)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
2-(Difluoromethyl)-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
2-(Difluoromethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
6-((6-Cy ano- 1 ,2,3,4-tetrahy dronaphthalen- 1 -yl)oxy)- 1 -(1 -methyl-l//-pyrazol-4-yl)- 17/-indazole-5-carbonitrile;
8-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Fluoro- 1 -(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Fluoro- 1 -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
2-Chloro-8-((5-methyl-l -(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
4-(Difluoromethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
4-Methyl-7-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7- dihydro-57/-cyclopenta[b]pyridine-3-carbonitrile; 8-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydrocinnoline-
3-carbonitrile;
5-((l-(l-(2-Hydroxy-2-methylpropyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(Methoxymethyl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(l,l-Dioxidothietan-3-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((l-(2-Chloropyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3- carbonitrile;
8-((l -(6-(2-Oxa-6-azaspiro [3.3]heptan-6-yl)pyri din-3 -y 1)- 17/-indazol-6-y l)oxy )- 5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((l -(2-(3-Hydroxyazeti din- l-yl)pyri din-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(2-Methylpyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahy droquinoline-3- carbonitrile;
8-((l-(l -(Oxetan-3-ylmethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
4-Methoxy-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(4-(Dimethylphosphoryl)piperidin-l-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)- 5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((l-(2-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
8-((l-(2-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
4-(Methoxymethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(l-(Hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
5-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6- (trifluoromethyl)picolinamide;
4-Cyano-3-isopropyl-/V-(l-(l-methyl-lH-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-vinylbenzamide; 3-Cyano-2-ethyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(pyridazin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(6-methylpyridazin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(6-methoxypyridazin-4-yl)-17/-indazol-6-yl)benzamide;
2-(But-2-en-2-yl)-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
2-(sec-Butyl)-3-cyano-/V-(l-(l-rnethyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzarnide;
5-Cyano-4-isopropyl-N-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)nicotinamide;
5-((l-(4-Methylthiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l -(2 -Methoxy thiazol-5-yl)- IT/-indazol-6-yl)oxy)-5.6,7, 8-tetrahy dronaphthal ene-2- carbonitrile;
5-((l -(4,5,6, 7-Tetrahydropyrazolo[l,5-a]pyridin-3-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Isopropylthiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile;
5-((l-(Pyrazolo[l, 5-a]pyridin-3-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(5-Methyl-l,3,4-oxadiazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Methylthiazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahy dronaphthal ene-2- carbonitrile;
5-((l-(2-Morpholinopyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(Pyrimidin-4-yl)-17/-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahy dronaphthalene-2- carbonitrile;
3-Cyano-2-(prop-l-en-2-yl)-N-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-N-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-/V-(l-(l-(2-fluoroethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methoxypyrimidin-4-yl)-17/-indazol-6-yl)benzamide; 3-Cyano-2-isopropyl-/V-(l-(3-methoxy-l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-/V-(l-(l,5-dimethyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-/V-(l-(5-methyloxazol-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-morpholinopyridin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-(2,2,2-trifluoroethyl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l -(4,5,6, 7-tetrahy dropyrazolo[l, 5-a]pyridin-3-yl)-17/- indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-isopropylthiazol-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-(trifluoromethyl)pyrimidin-5-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-N-(l-(4-methyloxazol-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methylthiazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropenyl-6-methyl-JV-[l-(l-methylpyrazol-4-yl)indazol-6- yl]benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-(pyridin-4-yl)vinyl)-17/-indazol-6-yl)benzamide;
3-Cyano-/V-(l-(3-fluoro-l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
4-Cyano-2-isopropyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-/V-(5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-(prop-l-en- 2-yl)benzamide;
3-Cyano-2-isopropyl-/V-(5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide; l-Methoxy-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile; l-Isopropyl-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l -( 1 -Methyl- 17/-py razol-4-y 1)- 1 //-indazol -6-y l)amino)- 1 -(trifluoromethyl)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
3-Cyano-/V-(l-(5-fluoro-l-methyl-lH-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cy ano-6-fluoro-/V-( 1 -( 1 -methy 1- 17/-py razol-4-y 1)- 17/-indazol-6-y l)-2-(prop- 1 -en-2- yl)benzamide;
3-Cyano-6-fluoro-2-isopropyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-/V-(l-(l-(2-cyanopropan-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-/V-(l-(l-methyl-17/-imidazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-(tetrahydro-27/-pyran-4-yl)-17/-pyrazol-4-yl)-17/- indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methyloxazol-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(4-methylpyrimidin-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(5-methyl-l,3,4-oxadiazol-2-yl)-17/-indazol-6- yl)benzamide;
JV-(l-(l-Benzyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-3-cyano-2-isopropylbenzamide;
5-((l-(l-(2-Cyanopropan-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(5-Fluoro-l -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-Methyl-6-oxo-l,6-dihydropyridin-3-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(2-Oxaspiro[3.3]heptan-6-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(6-Oxa-3-azabicyclo[3. 1. l]heptan-3-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
5-((l -( 1 -Methyl- 17/-py razol-4-y 1)- 1 //-indazol -6-y l)amino)- 1 -(prop- 1 -en-2-yl)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
3-Cyano-2-isopropyl-/V-[l-[2-(4-methylpiperazin-l-yl)-4-pyridyl]indazol-6- yl]benzamide;
3-Cyano-2-isopropyl-/V-(l-methyl-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-(2-morpholinoethyl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-((l-methylpiperidin-4-yl)methyl)-17/-pyrazol-4-yl)-17/- indazol-6-yl)benzamide; 3-Cyano-2-isopropyl-/V-(l-(2-(4-methylmorpholin-2-yl)pyridin-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-(4-methylmorpholin-3-yl)pyridin-4-yl)-17/-indazol-6- yl)benzamide;
Cyano-/V-(l-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/- indazol-6-yl)-2-isopropylbenzamide;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-(l,l,l-trifluoropropan- 2-yl)benzamide;
5-((l-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-l-carbonitrile;
5-((l-(6-((7?)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-l-carbonitrile;
3-Cyano-/V-(l-(l-(difluoromethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6-fluoro-2- (prop- 1 -en-2-y l)benzamide;
3-Cyano-/V-(l-(l-(difluoromethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6-fluoro-2- isopropylbenzamide;
2-Cyano-/V-(l-(2-methoxy-6-methylpyridin-4-yl)-17/-indazol-6-yl)-3-(prop-l-en-2- yl)isonicotinamide;
2-Cyano-3-isopropyl-/V-(l-(2-methoxy-6-methylpyridin-4-yl)-17/-indazol-6- yl)isonicotinamide;
2-Cyano-3-(prop-l-en-2-yl)-JV-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)isonicotinamide;
2-Cyano-3-isopropyl-N-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)isonicotinamide;
3-Cyano-2-isopropyl-/V-(l-(2-(pyridin-4-yl)cyclopropyl)-17/-indazol-6-yl)benzamide;
3-cyano-/V-(l-(2-(2,6-dimethylpyridin-4-yl)vinyl)-17/-indazol-6-yl)-2- isopropylbenzamide;
5-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahy dronaphthalene- 1 -carbonitrile;
1-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-2,3-dihydro- 17/-indene-5 -carbonitrile;
3-Cyano-2-isopropyl-/V-(l-(2-(2-methoxyethoxy)-6-methylpyridin-4-yl)-17/-indazol- 6-yl)benzamide;
2-Cyano-3-isopropyl-/V-(l-(2-(oxazol-4-yl)vinyl)-17/-indazol-6-yl)isonicotinamide; 2-Cyano-3-isopropyl-/V-(l-(2-(l-methyl-17/-pyrazol-4-yl)vinyl)-lH-indazol-6- yl)isonicotinamide;
5-((l-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-l -carbonitrile;
5-((l-(6-((7?)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-5, 6, 7, 8-tetr ahy dronaphthalene- 1 -carbonitrile;
5-((l-(2-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)- 5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile;
5-(( 1 -(6-(3 -(2-Hy droxy propan-2-y l)py rrolidin- 1 -y l)py rimidin-4-y 1)- 17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; l-((l-(2-(3-(2-Hydroxypropan-2-yl)azetidin-l-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-
2.3-dihydro- IT/-indene-5-carbonitrile; l-((l-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile;
1-((1 -(6-((7?)-3-(2-hy droxypropan-2-yl)pyrroli din-1 -yl)pyrimi din-4-yl)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile;
8-((l-(2-(2-Methylpyridin-4-yl)vinyl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-[l-(2,6-Dimethoxy-4-pyridyl)indazol-6-yl]oxy-5,6,7,8-tetrahydroquinoline-3- carbonitrile;
8-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4- (trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
(£)-2-Cyano-3-isopropyl-/V-(l-(2-(2-methylpyridin-4-yl)vinyl)-17/-indazol-6- yl)isonicotinamide;
8-((5 -Methyl- 1 -(2-(l-methyl-lH-pyrazol-4-yl)vinyl)-lH-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l -(3-(3-Methoxyazetidin-l-yl)prop-l-en-l-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((l-(4-Oxospiro[2.5]oct-5-en-6-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Methyl- 1 -(3-(4-methy Ipiperazin- 1 -y l)prop- 1 -en- 1 -y 1)- lH-indazol-6-y l)oxy )-
5 , 6, 7 , 8 -tetr ahy droquinoline-3 -carbonitrile; 8-((5-Methyl-l-(l-((l-methylazetidin-3-yl)methyl)-lH-pyrazol-4-yl)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
8-((5-Chloro-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(6-(4-Methylpiperazin-l-yl)pyridazin-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Chloro- 1 -( 1 -methyl- 1 H-pyrazol-4-y 1)- lH-indazol-6-y l)oxy )-4-(trifluoromethy 1)- 5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
5-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-l- (methylsulfonyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
8-((l-(3-(3,3-Difluoropyrrolidin-l-yl)prop-l-en-l-yl)-5-methyl-lH-indazol-6-yl)oxy)- 5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((l -(Prop-1 -en-l-yl)-lH-indazol-6-yl)oxy )-4-(trifluoromethyl)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
4-Methoxy-8-((5-methyl- l-(2-(l -methyl- lH-pyrazol-4-yl)vinyl)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
5-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-l-(oxetan-3- yloxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
4-Ethyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(3-Oxocy clohex-l-en-1 -yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((5 -Methyl- 1 -(3-(pyrrolidin-l-yl)prop-l-en-l-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
6-((6-Cyano-l,2,3,4-tetrahydronaphthalen-l-yl)oxy)-N-methyl-lH-indazole-l- carboxamide;
4-Methoxy-8-((5-methyl-l-(2-methylpyri din-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Methyl- 1 -(3-(4-methy Ipiperazin- 1 -y 1) -3 -oxoprop- 1 -en- 1 -y 1)- 1 H-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(4-Methylpiperazin-l-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile; 8-((l-(2-(Morpholinomethyl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(l-Methyl-lH-pyrazol-3-yl)vinyl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(l-((l-Methylazetidin-3-yl)methyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
8-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline- 3, 4-di carbonitrile;
6-((6-Cy ano- 1 ,2,3,4-tetrahy dronaphthalen- 1 -yl)oxy)-N-phenyl- IH-indazole- 1 - carboxamide;
8-((l-(r-Methyl-r,2',3',6'-tetrahydro-[2,4'-bipyridin]-4-yl)-lH-indazol-6-yl)oxy)-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((l-(3-Oxocyclopent-l-en-l-yl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;
8-((l-(2-(2-Methylpyridin-4-yl)vinyl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitril e;
8-((l-(2-(Oxetan-3-yl)vinyl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile; and
7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-4-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile, or pharmaceutically acceptable salts of any of the aforementioned.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Thus, it is contemplated as features described as embodiments of the compounds of Formula IA, IB, or IB’ can be combined in any suitable combination. At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-6 alkyl" is specifically intended to individually disclose (without limitation) methyl, ethyl, Cs alkyl, C4 alkyl, C5 alkyl and Ce alkyl.
The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
At various places in the present specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R")n- includes both -NR(CR'R")n- and -(CR'R")nNR- and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.
The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any level of substitution, e.g, mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.
The term "Cn-m" indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include Cm, C1-6 and the like.
The term "alkyl" employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. The term "Cn-m alkyl", refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, /c/V-butyl. isobutyl, sec-butyl; higher homologs such as 2- methyl-1 -butyl, n-pentyl, 3-pentyl, w-hexyl. 1 ,2,2-trimethylpropyl and the like.
The term "alkenyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term "Cn-m alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n- butenyl, scc-butenyl and the like.
The term "alkynyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term "Cn-m alkynyl" refers to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
The term "alkylene", employed alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-l,2-diyl, ethan- 1,1 -diyl, propan-1, 3-diyl, propan- 1,2-diyl, propan- 1,1 -diyl, butan-l,4-diyl, butan-l,3-diyl, butan-1,2- diyl, 2-methyl-propan- 1,3 -diyl and the like.
The term "alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term "Cn-m alkoxy" refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., w-propoxy and isopropoxy), /-butoxy and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “C n-m dialkoxy” refers to a linking group of formula -O-(Cn-m alkyl)-O-, the alkyl group of which has n to m carbons. Example dialkyoxy groups include -OCH2CH2O- and OCH2CH2CH2O-. In some embodiments, the two O atoms of a C n-m dialkoxy group may be attached to the same B atom to form a 5- or 6- membered heterocycloalkyl group.
The term "amino" refers to a group of formula -NH2.
The term "carbonyl", employed alone or in combination with other terms, refers to a -C(=O)- group, which also may be written as C(O).
The term "cyano" or "nitrile" refers to a group of formula -C=N, which also may be written as -CN.
The terms "halo" or "halogen", used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, halo groups are F.
The term "haloalkyl" as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term "Cn-m haloalkyl" refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m)+l } halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CC13, CHC12, C2CI5 and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.
The term "haloalkoxy", employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "Cn-m haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an JV-oxide group. In some embodiments, heterocyclic groups may be optionally substituted by 1 or 2 oxo (=O) substituents.
The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when attached to carbon.
The term “oxidized” in reference to a ring-forming N atom refers to a ring-forming N-oxide.
The term “oxidized” in reference to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl. The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized it (pi) electrons where n is an integer).
The term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g, having 2 fused rings). The term "Cn-maryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g, phenyl, naphthyl, and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl.
The term "heteroaryl" or "heteroaromatic," employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, and the like.
A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g, 1, 2 or 3) ring atoms are independently selected fromN, O and S. Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g, 1, 2 or 3) ring atoms are independently selected fromN, O and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.
The term "cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term "Cn-m cycloalkyl" refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g, having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C3-7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ringforming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g, benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, bicyclofl. l.l]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g, having two fused or bridged rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g, C(O), S(O), C(S) or S(O)2, A-oxide etc.) or a nitrogen atom can be quatemized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ringforming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (/. e. , having a bond in common with) to the heterocycloalkyl ring, e.g. , benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
At certain places, the definitions or embodiments refer to specific rings (e.g, an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azeti din-3 -yl ring is attached at the 3-position.
The compounds described herein can be asymmetric (e.g, having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as p- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g, dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
In some embodiments, the compounds of the invention have the (//(-configuration. In other embodiments, the compounds have the (^-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (/?) or (S), unless otherwise indicated.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g, 1H- and 377-imidazole, 1H-, 2H- and 47/- 1,2,4- triazole, 177- and 2H- isoindole and 177- and 277-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton- Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays. The term, "compound," as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g, take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g, a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g, a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g, a temperature from about 20 °C to about 30 °C.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1 ). 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N- oxide forms.
Synthesis
Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below.
The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006). Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., JH or 13C), infrared spectroscopy, spectrophotometry (e.g, UV -visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.
General Scheme 1
Figure imgf000063_0001
Formula IA
A general synthesis of compounds of Formula IA comprises a procedure as shown in General Scheme 1 above. Bromide 1-1 can be coupled with benzophenone imine using a Pd reagent (e.g., Pd2(dba)3) in the presence of a base (e.g., a sodium alkoxide base such as NaOtBu) to provide imine 1-2. Imine 1-2 can be treated with acid (e.g., HC1) to provide amine 1-3. Combining amine 1-3 and carboxylic acid 1-4 under amide coupling conditions (e.g., in the presence of HATU and DIEA) leads to compounds of Formula IA. Compounds of Formula IA can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, chiral phase HPLC, as well as other purification methods such as crystallization. General Scheme 2
Figure imgf000064_0001
Products of type 2-3 may be prepared using the procedure as shown in General Scheme 2. Alcohol 2-1 can be coupled with a compound 2-2 (e.g., in the presence of tributylphosphine and 1,1 -(azodi carbonyl)dipiperi dine) to provide an ether of type 2-3. Products of type 2-3 can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, chiral phase HPLC, as well as other purification methods such as crystallization.
General Scheme 3
Figure imgf000064_0002
Products of type 3-2 may be prepared using the procedure as shown in General Scheme 3. Amine 1-3 (as prepared according to General Scheme 1) can be treated with a compound 3-1 in the presence of a hydride reducing agent (e.g., NaCNBHs) to provide a product of type 3-2. Products of type 3-2 can be purified by silica gel chromatography, preparative reverse-phase HPLC, SFC, chiral phase HPLC, as well as other purification methods such as crystallization. Methods of Use
Over-activation of LRRK2 kinase activity, e.g., in kinase mutant G2019S, is a mechanism in alpha-synuclein related neurodegeneration, and is implicated in diseases that are characterized by the formation of Lewy bodies. Compounds as described herein, e.g., compounds of Formula IA, IB, or IB’, exhibit inhibitory activity against LRRK2 kinase, including LRRK2 mutant kinase, such as mutant G2019S. Kinase activity can be determined using a kinase assay, which typically employs a kinase substrate and a phosphate group donor, such as ATP (or a derivative thereol). An exemplary kinase assay is described in Example A.
The present disclosure provides methods of modulating (e.g., inhibiting) LRRK2 activity, by contacting LRRK2 with a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting can be administering to a patient, in need thereof, a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to treat neurodegenerative disease. For example, a method of treating a disease or disorder associated with inhibition of LRRK2 interaction can include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including neurodegenerative diseases. For the uses described herein, any of the compounds of the disclosure, including any of the embodiments thereof, may be used.
Compounds and compositions as described herein, e.g, compounds of Formula IA, IB, or IB’ are useful in the treatment and/or prevention of LRRK2 kinase mediated disorders, including LRRK2 kinase mutant mediated diseases. LRRK2 kinase mutant G2019S mediated diseases include, but are not limited to, neurological diseases such as Parkinson's disease and other Lewy body diseases such as Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies (e.g., diffuse Lewy body disease (DLBD), Lewy body dementia, Lewy body disease, cortical Lewy body disease or senile dementia of Lewy type), Lewy body variant of Alzheimer's disease (i.e., diffuse Lewy body type of Alzheimer's disease), combined Parkinson's disease and Alzheimer's disease, as well as diseases associated with glial cortical inclusions, such as syndromes identified as multiple system atrophy, including striatonigral degeneration, olivopontocerebellar atrophy, and Shy- Drager syndrome, or other diseases associated with Parkinsonism, such as Hallervorden- Spatz syndrome (also referred to as Hallervorden-Spatz disease), frontotemporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, autonomic dysfunctions (e.g., postural or orthostatic hypotension), cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity (e.g., joint stiffness, increased muscle tone), bradykinesia, akinesia and postural instability (failure of postural reflexes, along other disease related factors such as orthostatic hypotension or cognitive and sensory changes, which lead to impaired balance and falls); cancers, including melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma, and papillary thyroid carcinoma; autoimmune diseases such as inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis); and leprosy.
In some embodiments, a method of treating a disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB, or IB’ or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Shy- Drager syndrome, Hallervorden-Spatz syndrome, frontotemporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, postural hypotension, orthostatic hypotension, cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity, bradykinesia, akinesia, postural instability, melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma, papillary thyroid carcinoma, Crohn's disease, ulcerative colitis, and leprosy.
In some embodiments, a method of treating a neurological disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, wherein the neurological disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Shy -Drager syndrome, Hallervorden-Spatz syndrome, frontotemporal dementia, Sandhoff disease, progressive supranuclear palsy, corticobasal degeneration, postural hypotension, orthostatic hypotension, cerebellar dysfunctions, ataxia, movement disorders, cognitive deterioration, sleep disorders, hearing disorders, tremors, rigidity, bradykinesia, akinesia, and postural instability.
In some embodiments, a method of treating a neurological disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I A, IB or IB’, or a pharmaceutically salt thereof, wherein the neurological disease is selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risksyndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy -Drager syndrome.
In some embodiments, a method of treating Parkinson's disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof.
In some embodiments, a method of treating a cancer is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from melanoma, acute myelogenous leukemia, breast carcinoma, lung adenocarincoma, prostate adenocarcinoma, renal cell carcinoma, and papillary thyroid carcinoma.
In some embodiments, a method of treating an autoimmune disease is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is selected from Crohn's disease and ulcerative colitis.
In some embodiments, a method of treating leprosy is provided comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IA, IB or IB’, or a pharmaceutically acceptable salt thereof, or a composition comprising such compound or salt thereof.
In some embodiments, the compounds as described herein, e.g., compounds of Formula IA, IB or IB’, are inhibitors of LRRK2 kinase activity. In some embodiments, the compounds as described herein, e.g. compounds of Formula IA, IB, or IB’, are inhibitors of LRRK2 mutant kinase activity. In some embodiments, the compounds as described herein, e.g. compounds of Formula IA, IB or IB’, are inhibitors of LRRK2 mutant G2019S kinase activity.
Compounds as described herein, e.g., compounds of Formula IA, IB or IB’, exhibit cellular biological activities, including but not limited to reduction in phosphorylation of ser910 or ser935 in HEK-293 cells transfected with either wild-type LRRK2 or LRRK2 G2019S mutant.
In some embodiments, compounds of Formula IA, IB or IB’ are selective LRRK2 G2019S mutant inhibitors as compared to wild-type LRRK2.
As used herein, the term “contacting” refers to the bringing together of the indicated moieties in an in vitro system or an in vivo system such that they are in sufficient physical proximity to interact.
The terms "individual" or "patient," used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
The phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
As used herein, the term "treating" or "treatment" refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
As used herein, the term "selective" or "selectivity" as it relates to kinase activity, means that a compound as described herein, e.g. a compound of Formula I A, IB or IB’, is a more potent inhibitor of a particular kinase, such as LRRK2 kinase, when compared to another kinase. While LRRK2 has other enzymatic activities, it is understood that when inhibitory activity or selectivity of LRRK2, or any mutation thereof, is mentioned, it is the LRRK2 kinase activity that is being referred to, unless clearly stated otherwise. As such, selectivity of LRRK2 relative to another kinase indicates a comparison of the ICso of a compound on the kinase activity of LRRK2 to the ICso of the compound on the kinase activity of another kinase. For example, a compound that is 10 fold selective for LRRK2 kinase activity relative to another kinase activity will have a ratio of ICso(other kinase) + IC5O(LRRK2) = 10 (or a ratio of IC5o(LRRK2) - IC5o(other kinase) = 0.1).
In some embodiments, a compound as described herein, e.g, a compound of Formula IA, IB or IB’, is selective for a LRRK2 mutant over wild type LRRK2. Selectivity of LRRK2 mutants relative to wild type LRRK2 indicates a comparison of the ICso of a compound on the kinase activity of the mutant LRRK2 to the ICso of the compound on the kinase activity of wild type LRRK2. For example, a compound that is 10 fold selective for LRRK2 mutant kinase activity relative to wild type LRKK2 kinase activity will have a ratio of ICso(wild type LRRK2) + ICso(mutant LRRK2) = 10. In some embodiments, a compound provided herein is greater than 1 fold selective, greater than 2 fold selective, greater than 5 fold selective, greater than 10 fold selective, greater than 25 fold selective, or greater than 50 fold selective for LRRK2 mutant kinase over wild type LRRK2. In some embodiments, the LRRK2 mutant is LRRK2 G2019S.
The term "LRRK2-mediated condition", "Leucine-rich repeat kinase 2 mediated disorder" or any other variation thereof, as used herein means any disease or other condition in which LRRK2, including any mutations thereof, is known to play a role, or a disease state that is associated with elevated activity or expression of LRRK2, including any mutations thereof. For example, a "LRRK2 -mediated condition" may be relieved by inhibiting LRRK2 kinase activity. Such conditions include certain neurodegenerative diseases, such as Lewy body diseases, including, but not limited to, Parkinson's disease, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, dementia with Lewy bodies, diffuse Lewy body disease, as well as any syndrome identified as multiple system atrophy; certain cancers, such as melanoma, papillary renal cell carcinoma and papillary thyroid carcinoma; certain autoimmune diseases, such as inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis); and leprosy.
The term "neurodegenerative diseases" includes any disease or condition characterized by problems with movements, such as ataxia, and conditions affecting cognitive abilities (e.g., memory) as well as conditions generally related to all types of dementia. "Neurodegenerative diseases" may be associated with impairment or loss of cognitive abilities, potential loss of cognitive abilities and/or impairment or loss of brain cells. Exemplary "neurodegenerative diseases" include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Down syndrome, dementia, multi-infarct dementia, mild cognitive impairment (MCI), epilepsy, seizures, Huntington's disease, neurodegeneration induced by viral infection (e.g. AIDS, encephalopathies), traumatic brain injuries, as well as ischemia and stroke.
"Neurodegenerative diseases" also includes any undesirable condition associated with the disease. For instance, a method of treating a neurodegenerative disease includes methods of treating or preventing loss of neuronal function characteristic of neurodegenerative disease.
In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
Combination Therapies
One or more additional pharmaceutical agents or treatment methods can be used in combination with a compound of Formula IA, IB or IB’ for treatment of LRRK2-associated diseases, disorders, or conditions, or diseases or conditions as described herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, the additional pharmaceutical agent is a dopamine precursor, including, for example, levodopa, melevodopa, and etilevodopa. In some embodiments, the additional pharmaceutical agent is a dopamine agonist, including, for example, pramipexole, ropinorole, apomorphine, rotigotine, bromocriptine, cabergoline, and pergolide. In some embodiments, the additional pharmaceutical agent is a monamine oxidase B (“MAO B”) inhibitor, including, for example, selegiline and rasagiline. In some embodiments, the additional pharmaceutical agent is a catechol O-methyltransferase (“COMT”) inhibitor, including, for example, tolcapone and entacapone. In some embodiments, the additional pharmaceutical agent is an anticholinergic agent including, for example, benztropine, trihexyphenidyl, procyclidine, and biperiden. In some embodiments, the additional pharmaceutical agent is a glutamate (“NMD A”) blocking drug, including, for example, amantadine. In some embodiments, the additional pharmaceutical agent is an adenosine A2A antagonist, including, for example, istradefylline and preladenant. In some embodiments, the additional pharmaceutical agent is a 5-HT1 a antagonist, including, for example, piclozotan and pardoprunox. In some embodiments, the additional pharmaceutical agent is an alpha 2 antagonist, including, for example, atipamezole and fipamezole. Formulations, Dosage Forms, and Administration
When employed as pharmaceuticals, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. Thus the present disclosure provides a composition comprising a compound of Formula IA, IB or IB’ or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is indicated and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic, and to mucous membranes including intranasal, vaginal, and rectal delivery), pulmonary (e.g, by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers. In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient
The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g). The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.
The therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers.
EXAMPLES
Experimental procedures for compounds of the invention are provided below. Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is stated that compounds were prepared analogously to earlier examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents and temperature can be modified for each specific reaction and that it may be necessary or desirable to employ different work-up or purification techniques. Where reactions are carried out using microwave irradiation, the microwave used is a Biotage Initiator. The actual power supplied varies during the course of the reaction in order to maintain a constant temperature.
All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen.
Liquid chromotography conditions are described below.
Liquid Chromatography Methods
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Example 1: 5-Cyano-A-(l-(l-cyclopropyl-LH-pyrazol-4-yl)-Lff-indazol-6-yl)-3,4- dimethylpicolinamide
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Step 1: 6-Bromo-l-(l-cyclopropyl-lH-pyrazol-4-yl)-lH-indazole
Figure imgf000112_0002
Eight same-scale reactions were conducted in parallel. To a solution of 6-bromo-1H- indazole (50 mg, 253.77 umol) in toluene (1 mL) were added Cs2CO3 (165.36 mg, 507.53 umol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (6.00 mg, 25.38 umol), 1-cyclopropyl-4- iodo-pyrazole (71.27 mg, 304.52 umol), and (Bu4NCuI)2 (56.83 mg, 50.75 umol) at 20 °C. The mixture was then stirred at 120 °C for 12 hrs under an Ar atmosphere. The reaction mixture was filtered and filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-14% EtOAc/petroleum ether gradient eluent to afford the title compound (150 mg, 14%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.82 (d, J=8.55 Hz, 1H), 7.38 (d, J=8.55 Hz, 1H), 3.82 (tt, J=3.73, 7.34 Hz, 1H), 1.14- 1.19 (m, 2H), 0.98-1.06 (m, 2H). MS-ESI (m/z) calc’d for C13H12BrN4 [M+H]+: 303.0, 305.0. Found 303.2, 305.2. Step 2: N-(1-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-1,1-diphenylmethanimine
Figure imgf000113_0001
Two same-scale reactions were conducted in parallel. To a solution of 6-bromo-1-(1- cyclopropyl-1H-pyrazol-4-yl)-1H-indazole (75 mg, 247.40 umol) in toluene (4 mL) were added t-Bu Xphos (10.51 mg, 24.74 umol), NaOtBu (47.55 mg, 494.79 umol), benzophenone imine (58.29 mg, 321.62 umol), and Pd2(dba)3 (22.65 mg, 24.74 umol) at 20 °C. The mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere and then concentrated. The material was diluted with H2O and extracted with EtOAc (5x). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was combined with another 38 mg batch and purified by preparative-TLC (SiO2, petroleum ether/EtOAc = 3/1) to afford the title compound (160 mg, 53%) as a pale yellow solid. MS-ESI (m/z) calc’d for C26H22N5 [M+H]+: 404.2. Found 404.3. Step 3: 1-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-amine
Figure imgf000114_0001
To a solution of N-(1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-1,1- diphenylmethanimine (160 mg, 396.55 umol) in THF (4 mL) was added 1 M HCl (396.55 uL, 396.55 umol) at 20 °C. The mixture was stirred at 20 °C for 20 minutes and then concentrated to give a residue. The residue was diluted with H2O and extracted with EtOAc (5x). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (65 mg, 68%) as a pale yellow solid.1H NMR (400 MHz, DMSO- d6) δ 8.17 (s, 1 H), 7.91 (d, J=0.75 Hz, 1 H), 7.75 (s, 1 H), 7.43 (d, J=8.63 Hz, 1 H), 6.67 (s, 1 H), 6.56 (dd, J=8.57, 1.69 Hz, 1 H), 5.42 (br s, 2 H), 3.79 - 3.81 (m, 1 H), 1.10 - 1.14 (m, 2 H), 0.97 - 1.02 (m, 2 H). MS-ESI (m/z) calc’d for C13H14N5 [M+H]+: 240.1. Found 240.2. Step 4: 5-Cyano-N-(1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-3,4- dimethylpicolinamide
Figure imgf000114_0002
To a solution of 5-cyano-3,4-dimethyl-pyridine-2-carboxylic acid (26.51 mg, 150.45 umol) in DMF (3 mL) were added HATU (57.21 mg, 150.45 umol) and DIEA (48.61 mg, 376.14 umol) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. Then 1-(1-cyclopropyl- 1H-pyrazol-4-yl)-1H-indazol-6-amine (30 mg, 125.38 umol) was added and the reaction mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated to give a residue that was purified by preparative-HPLC using Method B and further subjected to chiral separation using Method C to afford the title compound (2.21 mg, 4%) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.89 (br s, 1H), 8.89 (s, 1H), 8.30 (d, J=11.25 Hz, 2H), 8.22 (s, 1H), 7.77-7.86 (m, 2H), 7.53 (d, J=9.04 Hz, 1H), 3.86 (td, J=3.67, 7.44 Hz, 1H), 2.55 (s, 3H), 2.43 (s, 3H), 1.15 (br d, J=3.09 Hz, 2H), 0.99-1.05 (m, 2H). MS-ESI (m/z) calc’d for C22H20N7O [M+H]+: 398.2. Found 398.1.
Example 2: 5-((l-(l-Cyclopropyl-lH-pyrazol-4-yI)-lH-indazol-6-yI)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000115_0001
Step 1: 5-((l-(l-Cyclopropyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000115_0002
Four same-scale reactions were conducted in parallel. To a solution of 6-bromo-l-(l- cyclopropyl-17/-pyrazol-4-yl)-17/-indazole (25 mg, 82.47 umol) in 1,4-dioxane (2 mL) were added Xantphos (14.31 mg, 24.74 umol) and CS2CO3 (80.61 mg, 247.40 umol) followed by 5-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (14.20 mg, 82.47 umol) and Pd2(dba)s (7.55 mg, 8.25 umol) at 20 °C. The mixture was then stirred at 100 °C for 3 hrs under an N2 atmosphere. The four parallel reactions were combined with another 10 mg scale reaction before work-up. The final mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative TLC (petroleum ether/EtOAc=2/l, Rf=0.3) and further purified by preparative-HPLC using Method D to afford the title compound (12 mg, 7%) as a white solid. MS-ESI (m/z) calc’d for C24H23N6 [M+H]+: 395.2. Found 395.1.
Step 2: 5-( (1-(1 -Cyclopropyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000115_0003
rac-5-((l-(l -Cyclopropyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)armno)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method E to afford 5-((l-(l-cy clopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (2.76 mg, 60%). 1H NMR (400 MHz, DMSO-de) 8 8.19 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.55-7.60 (m, 1H), 7.48 (dd, J=4.52, 8.27 Hz, 2H), 6.65-6.74 (m, 2H), 6.43 (d, J=8.82 Hz, 1H), 4.86 (br d, J=7.28 Hz, 1H), 3.79 (tt, J=3.78, 7.36 Hz, 1H), 2.76-2.86 (m, 2H), 1.79-2.00 (m, 4H), 1.08-1.13 (m, 2H), 0.96-1.02 (m, 2H). MS-ESI (m/s) calc’d for C24H23N6 [M+H]+: 395.2. Found 395.2. A later eluting fraction was also isolated to afford 5-(( I -( I -cyclopropyl- 17/-pyrazol-4-yl)- 17/- indazol-6-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (3.16 mg, 69%). 'H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.53-7.60 (m, 1H), 7.48 (dd, J=4.30, 8.27 Hz, 2H), 6.65-6.75 (m, 2H), 6.43 (d, J=8.82 Hz, 1H), 4.86 (br d, J=7.50 Hz, 1H), 3.79 (tt, J=3.80, 7.33 Hz, 1H), 2.74-2.88 (m, 2H), 1.80-2.00 (m, 4H), 1.08-1.13 (m, 2H), 0.95-1.03 (m, 2H). MS-ESI (m/z) calc’d for C24H23N6 [M+H]+: 395.2. Found 395.2.
Example 3: /V-(5-ChIoro-l-(l-cyclopropyl-lH-pyrazol-4-yI)-lH-indazol-6-yI)-5-cyano- 3,4-dimethyIpicolinamide
Figure imgf000116_0001
Step 1: 5-Cyano-3,4-dimethylpicolinoyl chloride
Figure imgf000116_0002
To a solution of 5-cyano-3,4-dimethylpicolinic acid (300 mg, 1.70 mmol) in DCM (6 mL) were added oxalyl chloride (432.28 mg, 3.41 mmol) and DMF (12.45 mg, 170.29 umol) at 0 °C under an N2 atmosphere. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was then evaporated to afford the title compound (430 mg, 90%) as a red oil which was used without further purification. Step 2: 5-Cyano-3,4-dimethylpicolinamide To a solution of 5-cyano-3,4
Figure imgf000117_0001
l chloride (430 mg, 2.21 mmol) in DCM (16 mL) was added to NH4OH (4.30 mL, 27.91 mmol) at 0 °C. The mixture was stirred at 20 °C for 20 minutes and then concentrated to give a residue. The residue was diluted with a mixture of DCM/i-PrOH (10:1); some yellow solid formed that was collected by filtration and washed with the DCM/i-PrOH (10:1) solution (2x). The filtrate was evaporated to afford the title compound (300 mg, 70%) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C9H10N3O [M+H]+: 176.1. Found 176.0. Step 3: 6-Bromo-5-chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazole
Figure imgf000117_0002
.01 umol), 6-bromo- 5-chloro-1H-indazole (100 mg, 432.01 umol), Cs2CO3 (281.51 mg, 864.02 umol), 3,4,7,8- tetramethyl-1,10-phenanthroline (10.21 mg, 43.20 umol) and (Bu4NCuI)2 (96.68 mg, 86.40 umol) in toluene (4 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 120 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated to give a residue that was diluted with H2O and extracted with EtOAc (4x). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative-TLC (SiO2, petroleum ether/EtOAc (2:1), Rf = 0.69) to afford the title compound (120 mg, 41%) as a pale yellow oil. MS-ESI (m/z) calc’d for C13H11BrClN4 [M+H]+: 337.0, 339.0. Found 337.1, 339.1. Step 4: N-(5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-5-cyano-3,4- dimethylpicolinamide A mixture of 6-bro
Figure imgf000118_0001
razol-4-yl)-1H-indazole (100 mg, 296.21 umol), 5-cyano-3,4-dimethylpicolinamide (51.89 mg, 296.21 umol), 4,5- bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (51.42 mg, 88.86 umol), Pd2(dba)3 (27.12 mg, 29.62 umol) and Cs2CO3 (289.53 mg, 888.62 umol) in 1,4-dioxane (10 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 100 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated under vacuum to give a residue that was diluted with DMF and MeOH and filtered. The solid was washed with H2O (4x) and dried under vacuum to afford the title compound (15 mg, 40%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1 H), 8.93 (s, 1 H), 8.45 (s, 1 H), 8.39 (s, 1 H), 8.27 (s, 1 H), 8.12 (s, 1 H), 7.88 (s, 1 H), 3.87 (td, J=3.6, 7.4 Hz, 1 H), 2.62 (s, 3 H), 2.57 (s, 3 H), 1.18 - 1.14 (m, 2 H), 1.06 - 1.01 (m, 2 H). MS-ESI (m/z) calc’d for C22H19ClN7O [M+H]+: 432.1. Found 432.1. Example 4: 5-((5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000118_0002
) in a microwave reactor tube was added NH4OAc (675.37 mg, 8.76 mmol) and the mixture was stirred at 20 °C for 10 min. NaBH3CN (146.83 mg, 2.34 mmol) was then added and the tube was sealed and heated at 90 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was diluted with H2O and acidified with 1 N HCl to pH = 3. Then the aqueous phase was extracted with EtOAc (3x) and the organic phase was discarded. The aqueous phase was basified by addition of NaHCO3 solid to pH = 8 and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to afford the title compound (55 mg, 39%) as a yellow solid which was used without further purification.1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=8.00 Hz, 1 H), 7.35-7.41 (m, 1 H), 7.31 (s, 1 H), 3.92 (t, J=5.94 Hz, 1 H), 2.64-2.82 (m, 2 H), 1.96-2.02 (m, 1 H), 1.84-1.92 (m, 1 H), 1.73-1.78 (m, 1 H), 1.57-1.65 (m, 1 H). MS-ESI (m/z) calc’d for C11H13N2 [M+H]+: 173.1. Found 173.1. Step 2: rac-5-((5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile A mixture of 6-bro
Figure imgf000119_0001
yrazol-4-yl)-1H-indazole (70 mg, 207.34 umol), 5-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (35.71 mg, 207.34 umol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (35.99 mg, 62.20 umol), Pd2(dba)3 (18.99 mg, 20.73 umol) and Cs2CO3 (202.67 mg, 622.03 umol) in 1,4-dioxane (2 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by preparative-TLC (SiO2, petroleum ether /EtOAc = 2 / 1, Rf = 0.39) and further purified by preparative-HPLC using Method U to afford the title compound (20 mg, 22%) as a white solid. MS-ESI (m/z) calc’d for C24H22ClN6 [M+H]+: 429.2. Found 429.2. Step 3: 5-((5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000120_0001
-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method F to afford 5-((5-chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (3.28 mg, 36%) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1 H), 8.02 (s, 1 H), 7.84 (s, 1 H), 7.79 (s, 1 H), 7.68 (s, 1 H), 7.59 (d, J=8.00 Hz, 1 H), 7.46 (d, J=8.00 Hz, 1 H), 6.74 (s, 1 H), 5.88 (d, J=8.75 Hz, 1 H), 5.01-5.11 (m, 1 H), 3.80 (tt, J=3.75, 7.32 Hz, 1 H), 2.86 (br t, J=6.00 Hz, 2 H), 1.82-2.07 (m, 4 H), 1.08-1.14 (m, 2 H), 0.99-1.07 (m, 2 H). MS-ESI (m/z) calc’d for C24H22ClN6 [M+H]+: 429.2. Found 429.1. A later eluting fraction was also isolated to afford 5-((5-chloro- 1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 2 (2.99 mg, 32%) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1 H), 8.02 (s, 1 H), 7.84 (s, 1 H), 7.79 (s, 1 H), 7.68 (s, 1 H), 7.57-7.61 (m, 1 H), 7.46 (d, J=8.00 Hz, 1 H), 6.74 (s, 1 H), 5.88 (d, J=8.63 Hz, 1 H), 5.02-5.11 (m, 1 H), 3.80 (tt, J=3.75, 7.32 Hz, 1 H), 2.86 (br t, J=6.00 Hz, 2 H), 1.80-2.08 (m, 4 H), 1.09-1.15 (m, 2 H), 0.99-1.05 (m, 2 H). MS-ESI (m/z) calc’d for C24H22ClN6 [M+H]+: 429.2. Found 429.1. Example 5: 6-Chloro-5-cyano-3,4-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H- indazol-6-yl)picolinamide To a solution of 6-ch
Figure imgf000120_0002
ic acid (24.69 mg, 117.24 umol) in DMF (1.5 mL) were added HATU (53.49 mg, 140.69 umol) and DIEA (45.46 mg, 351.72 umol). The mixture was stirred at 20 °C for 0.5 hr. Then 1-(1-methyl-1H-pyrazol-4- yl)-1H-indazol-6-amine (25 mg, 117.24 umol) was added. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated to give a residue. The residue was purified by preparative-TLC (SiO2, EtOAc/petroleum ether = 2/1, Rf=0.4) to afford the title compound (9.41 mg, 19%) as ayellow solid. H NMR (400 MHz, DMSO-de) 8 10.93 (s, 1 H), 8.22 - 8.26 (m, 3 H), 7.81 - 7.85 (m, 2 H), 7.45 (dd, J=8.78, 1.63 Hz, 1 H), 3.95 (s, 3 H), 2.59 (s, 3 H), 2.38 (s, 3 H). MS-ESI (m/z) calc’d for C20H17CIN7O [M+H]+: 406.1. Found 406.3.
Example 6: 6-Chloro-5-cyano-/V-(l -cyclop ropy 1-17/-indazol-6-y l)-3, 4- diniethylpicolinamide
Figure imgf000121_0001
Step 1: l-Cyclopropyl-6-nitro-lH-indazole
Figure imgf000121_0002
To a solution of 6-nitro-l/f-indazole (500 mg, 3.06 mmol), cyclopropylboronic acid (526.55 mg, 6.13 mmol), Na2COs (649.71 mg, 6.13 mmol) in DCE (30 mL) were added CU(OAC)2 (556.70 mg, 3.06 mmol) and 2-(2-pyridyl)pyridine (478.70 mg, 3.06 mmol). The mixture was stirred at 70 °C for 3 hrs. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (500 mg, 80%) as ayellow solid. 'H NMR (400 MHz, CDCh) 8 8.53 (s, 1 H) 7.98 - 8.05 (m, 2 H) 7.80 (d, J=8.77 Hz, 1 H) 3.63 - 3.72 (m, 1 H) 1.23 - 1.28 (m, 4 H). MS-ESI (m/z) calc’d for C10H10N3O2 [M+H]+: 204.1. Found 204.2.
Step 2: l-Cyclopropyl-lH-indazol-6-amine
Figure imgf000121_0003
To a solution of l-cyclopropyl-6-nitro-17/-indazole (200 mg, 984.27 umol) in H2O (2 mL) and EtOH (2 mL) were added Fe (274.83 mg, 4.92 mmol) and NH4CI (263.25 mg, 4.92 mmol). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by preparative- TLC (SiO2, petroleum ether / EtOAc = 1/1, Rf = 0.38) to afford the title compound (80 mg, 47%) as a brown oil. MS-ESI (m/z) calc’d for C10H12N3 [M+H]+: 174.1. Found 174.3. Step 3: 6-Chloro-5-cyano-N-(1-cyclopropyl-1H-indazol-6-yl)-3,4-dimethylpicolinamide
Figure imgf000122_0001
6- chloro-5-cyano-3,4-dimethylpicolinic acid (85.12 mg, 404.12 umol) in DMF (2 mL) were added DIEA (156.69 mg, 1.21 mmol) and HATU (199.76 mg, 525.36 umol). The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction mixture was diluted with water, some yellow solid formed, it was filtered, the cake was washed with H2O, collected and dried under vacuum to give a residue. The residue was purified by preparative-HPLC using Method G to afford the title compound (53 mg, 35%) as a yellow solid.1H NMR (400MHz, DMSO-d6) δ 10.93 (s, 1H), 8.35 (s, 1H), 7.98 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.35 (dd, J=1.6, 8.7 Hz, 1H), 3.74 - 3.67 (m, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 1.17 - 1.09 (m, 4H). MS-ESI (m/z) calc’d for C19H17ClN5O [M+H]+: 366.1. Found 366.2. Example 7: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2 Step 1: 6
Figure imgf000122_0002
Figure imgf000122_0003
To a solution of 6-bromo-1H-indazole (500 mg, 2.54 mmol) in DMA (4 mL) in a microwave reaction vial were added 4-iodo-1-methyl-1H-pyrazole (791.75 mg, 3.81 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (59.97 mg, 253.77 umol), Cs2CO3 (1.65 g, 5.08 mmol), and (Bu4NCuI)2 (568.25 mg, 507.53 umol). The mixture was degassed, purged with N2 (3x), and then stirred at 120 °C for 5 hrs in a microwave reactor under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (5x). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (280 mg, 39%) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1 H) 7.86 (s, 1 H) 7.79 (s, 1 H) 7.74 (s, 1 H) 7.66 (d, J=8.56 Hz, 1 H) 7.34 (dd, J=8.56, 1.47 Hz, 1 H) 4.04 (s, 3 H). MS-ESI (m/z) calc’d for C11H10BrN4 [M+H]+: 277.0, 279.0. Found 277.1, 279.1. Step 2: 1-(1-Methyl-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole To a solution of 6-bromo
Figure imgf000123_0001
-4-yl)-1H-indazole (200 mg, 721.71 umol) in dioxane (3 mL) were added bis(pinacolato)diboron (219.93 mg, 866.05 umol), AcOK (212.49 mg, 2.17 mmol) and Pd(dppf)Cl2 (52.81 mg, 72.17 umol) at 20 °C, the mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. The reaction mixture was concentrated to give a residue. The residue was purified by preparative-TLC (petroleum ether/EtOAc=1/1, Rf = 0.29) to afford the title compound (200 mg, 85%) as a white solid. MS-ESI (m/z) calc’d for C17H22BN4O2 [M+H]+: 325.2. Found 325.3. Step 3: 1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-ol
Figure imgf000123_0002
To a solution of l-(l-methyl-17/-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-17/-indazole (200 mg, 616.93 umol) in THF (3 mL) and H2O (3 mL) was added NaBOs FLO (284.76 mg, 1.85 mmol). The mixture was stirred at 50 °C for 1 hr. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative-TLC (SiO2, 100% EtOAc, Rf = 0.42) to afford the title compound (90 mg, 68%) as a white solid. MS-ESI (m/z) calc’d for C11H11N4O [M+H]+: 215.1. Found 215.2.
Step 4: rac-5-( <1-(1 -Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000124_0001
To a solution of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol (50 mg, 233.40 umol) and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40.43 mg, 233.40 umol) in toluene (1 mL) were added l,l-(azodicarbonyl)dipiperidine (118 mg, 466.80 umol) and tributylphosphine (94 mg, 466.80 umol) at 0 °C. The mixture was stirred at 90 °C for 2 hrs under an N2 atmosphere and then concentrated to give a residue. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 1/3, Rf = 0.48) and further purified by preparative-HPLC using Method S to afford the title compound (15 mg, 17%) as a white solid. MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.3.
Step 5: 5-((l-(l -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-
Figure imgf000124_0002
rac-5-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method I to afford 5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (4 mg, 89%) as a white solid. JH NMR (400 MHz, DMSO-de) 8 8.31 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.64 (br d, J=7.9 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.27 (s, 1H), 6.95 (dd, J=2.0, 8.8 Hz, 1H), 5.78 (t, J=4.6 Hz, 1H), 3.92 (s, 3H), 2.94 - 2.84 (m, 1H), 2.83 - 2.73 (m, 1H), 2.02 (q, J=5.1 Hz, 2H), 1.93 - 1.74 (m, 2H). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.2. A later eluting fraction was also isolated to afford 5-((l-(l-methyl-17/-pyrazol- 4-yl)- IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (4 mg, 77%) as a white solid. 'H NMR (400 MHz, DMSO-de) 8 8.31 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.64 (br d, J=7.9 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.27 (s, 1H), 6.95 (dd, J=2.0, 8.8 Hz, 1H), 5.78 (t, J=4.6 Hz, 1H), 3.92 (s, 3H), 2.94 - 2.84 (m, 1H), 2.83 - 2.73 (m, 1H), 2.02 (q, J=5.1 Hz, 2H), 1.93 - 1.74 (m, 2H). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.2.
Example 8: 8-((l-(l-MethyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000125_0001
To a solution of 6-bromo-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazole (640 mg, 2.31 mmol) in toluene (5 mL) were added t-Bu XPhos (98.07 mg, 230.95 umol), t-BuONa (443.90 mg, 4.62 mmol), diphenylmethanimine (502.26 mg, 2.77 mmol), and Pd2(dba)3 (211.48 mg, 230.95 umol) at 20 °C. The mixture was then stirred at 90 °C for 3 hrs under an N2 atmosphere. The mixture was filtered and the filtrate was diluted with H2O and extracted with EtOAc (5x). The combined organic layers were dried over Na2SC>4 and concentrated to give a residue. The residue was purified by silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (332 mg, 38%) as a yellow solid. MS-ESI (m/z) calc’d for C24H20N5 [M+H]+: 378.2. Found
378.3.
Step 2: 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-amine
Figure imgf000126_0001
To a solution of /V-(diphenylmethylene)-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- amine (328.5 mg, 872.72 umol) in THF (5 rnL) was added HC1 (1 M, 2.62 mL) at 20 °C. The mixture was then stirred at 20 °C for 20 minutes. The reaction mixture was evaporated to give a residue that was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-81% EtOAc/petroleum ether gradient eluent to afford the title compound (128 mg, 69%) as a brown solid. 1 H NMR (400 MHz, DMSO-de) 8 8.12 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.43 (d, J=8.63 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J=1.44, 8.57 Hz, 1H), 5.43 (br s, 2H), 3.92 (s, 3H). MS-ESI (m/z) calc’d for C11H12N5 [M+H]+: 214.1. Found 214.2.
Step 3: rac-8-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
Figure imgf000126_0002
To a solution of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (50 mg, 234.48 umol) and 8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (40.37 mg, 234.48 umol) in MeOH (1 mL) was added AcOH (1.41 mg, 23.45 umol) to adjust to pH = 5. The mixture was stirred at 20 °C for 2 hrs, then NaBHsCN (44.21 mg, 703.44 umol) was added. The resulting mixture was stirred at 20 °C for 2 hrs and concentrated to give a residue. The residue was purified by preparative-HPLC using Method K to afford the title compound (18 mg, 15%) as a pale yellow solid. MS-ESI (m/z) calc’d for C21H20N7 [M+H]+: 370.2. Found 370.4. Step 4: 8-( (1-(1 -Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000127_0001
rac-8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral separation using Method F to afford 8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (4 mg, 86%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-de) 8 8.81 (d, J=1.98 Hz, 1H), 8.18 (s, 1H), 8.13 (d, J=1.76 Hz, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.46 (d, J=8.60 Hz, 1H), 6.76 (s, 1H), 6.70 (dd, J=1.54, 8.82 Hz, 1H), 6.41 (d, J=7.94 Hz, 1H), 4.80-4.87 (m, 1H), 3.91 (s, 3H), 2.76-2.93 (m, 2H), 1.77-2.07 (m, 4H). MS-ESI (m/z) calc’d for C21H20N7 [M+H]+: 370.2. Found 370.2. A later eluting fraction was also isolated to afford 8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (4 mg, 86%) as a pale yellow solid. 'H NMR (400 MHz, DMSO-de) 8 8.81 (d, J=1.76 Hz, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.46 (d, J=8.82 Hz, 1H), 6.76 (s, 1H), 6.70 (dd, J=1.54, 8.82 Hz, 1H), 6.41 (d, J=7.72 Hz, 1H), 4.79-4.88 (m, 1H), 3.91 (s, 3H), 2.78-2.92 (m, 2H), 1.79- 2.05 (m, 4H). MS-ESI (m/z) calc’d for C21H20N7 [M+H]+: 370.2. Found 370.2.
Example 9: 8-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000127_0002
Step 1: 8-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahydroquinoline- 3-carbonitrile
Figure imgf000127_0003
Two same scale reactions were carried out in parallel (each for 25 mg, total 50 mg starting material). To a solution of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol (25 mg, 116.70 umol) and 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (20.33 mg, 116.70 umol) in toluene (4 mL) were added tributylphosphine (47.22 mg, 233.40 umol) and 1,1- (azodicarbonyl)dipiperidine (58.89 mg, 233.40 umol) at 0 °C. The mixture was stirred at 90 °C for 1 hr. The reaction mixture was combined with an additional, identical reaction mixture and the combined mixture was concentrated to give a residue. The residue was purified by preparative-HPLC using Method T to afford the title compound (26 mg, 30%) as a white solid. MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.2. Found 371.1.
Step 2: 8-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahydroquinoline- 3-carbonitrile, enantiomer 1 and 2
Figure imgf000128_0001
rac-8-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral separation using Method L to afford 8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3- carbonitrile, enantiomer 1 (4 mg, 86%) as a yellow solid. JH NMR (400 MHz, DMSO-de) 8 8.86 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.72 (d, J=9.04 Hz, 1H), 7.34 (s, 1H), 6.94 (dd, J=1.87, 8.71 Hz, 1H), 5.71-5.78 (m, 1H), 3.92 (s, 3H), 2.89-3.01 (m, 1H), 2.83 (br dd, J=10.36, 16.32 Hz, 1H), 2.24 (br d, J=14.55 Hz, 1H), 1.98-2.07 (m, 1H), 1.76-1.96 (m, 2H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.2. Found 371.2. A later eluting fraction was also isolated to afford 8-(( I -( I -methyl- IT/-pyrazol-4- l)-l7/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (4 mg, 95%) as a yellow solid. 'H NMR (400 MHz, DMSO-de) 8 8.87 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.16 (d, J=0.88 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J=8.60 Hz, 1H), 7.35 (s, 1H), 6.95 (dd, J=2.09, 8.93 Hz, 1H), 5.76 (s, 1H), 3.93 (s, 3H), 2.90-3.03 (m, 1H), 2.77-2.88 (m, 1H), 2.25 (br d, J=13.67 Hz, 1H), 2.02 (br d, J=13.67 Hz, 1H), 1.91 (br s, 1H), 1.84 (br s, 1H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.2. Found 371.2.
Example 10: 2-ChIoro-8-((l-(l-methyI-lH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000129_0001
Step 1: Sodium (2-oxocyclohexylidene)methanolate
Figure imgf000129_0002
Na (5.39 g, 234.35 mmol) was dissolved in MeOH (44 mL) at 25 °C and the mixture was stirred for 0.5 h. A mixture of cyclohexanone (20 g, 203.79 mmol) in methyl formate (12.24 g, 203.79 mmol) was then added to the solution dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 0.5 h; some yellow solid formed. The reaction mixture was filtered and the solid was washed with EtOAc (3x) to afford the title compound (30 g, 99%) as a light yellow solid which was used without further purification.
Step 2: 2-Hydr oxy-5, 6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000129_0003
To a solution of sodium (2-oxocyclohexylidene)methanolate (30 g, 202.52 mmol) in H2O (200 mL) was added 2-cyanoacetamide (18.73 g, 222.77 mmol) followed by addition of freshly prepared piperidine acetate (18 mL) (prepared using 4.2 mL AcOH, 10 mL H2O, 7.2 mL piperidine) at 20 °C. The mixture was then stirred at 100 °C for 12 hrs. AcOH (18 mL) was added to the mixture; the resulting mixture was cooled to 0 °C and filtered. The solid was collected by filtration and dried under vacuum to afford the title compound (14 g, 38%) as a yellow solid. 'H NMR (400 MHz, DMSO-de) 8 7.89 (s, 1 H) 2.56 (br t, J=6 Hz, 2 H) 2.43 (br t, J=6 Hz, 2 H) 1.59 - 1.74 (m, 4 H). MS-ESI (m/z) calc’d for C10H11N2O [M+H]+: 175.1. Found 175.2.
Step 3: 2-Chloro-5,6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000129_0004
A solution of 2-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (2 g, 11.48 mmol) in POCh (17.60 g, 114.81 mmol) was stirred at 100 °C for 12 hrs. The mixture was concentrated to give a residue. The residue was adjusted to pH=8 with 2 M aqueous NaOH and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (2 g, 99%) as a yellow solid which was used without further purification. JH NMR (400MHz, DMSO-de) 8 8.17 (s, 1H), 2.93 - 2.69 (m, 4H), 1.87 - 1.66 (m, 4H). MS-ESI (m/z) calc’d for C10H10CIN2 [M+H]+: 193.1. Found 193.1.
Step 4: 2-Chloro-3-cyano-5, 6, 7, 8-tetrahydroquinoline 1 -oxide
Figure imgf000130_0001
To a solution of 2-chloro-5,6,7,8-tetrahydroquinoline-3-carbonitrile (400 mg, 2.08 mmol) in DCM (6 mL) was added m-CPBA (632.31 mg, 3.11 mmol) at 0 °C, and the mixture was stirred at 50 °C for 12 hrs. The reaction was cooled to 0 °C, and 5 mL of 10% aqueous Na2SOs was added dropwise. The mixture was stirred at 20 °C for 10 minutes and extracted with EtOAc (3x). The combined organic layers were washed with saturated aqueous NaiCOs (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (617 mg) as ayellow solid. MS-ESI (m/z) calc’d for C10H10CIN2O [M+H]+: 209.0. Found 209.2.
Figure imgf000130_0002
A solution of 2-chloro-3-cyano-5, 6, 7, 8-tetrahydroquinoline 1 -oxide (567 mg, 2.72 mmol) in TFAA (5 mL) was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give the title compound (900 mg) as a white solid which was used without further purification. MS-ESI (m/z) calc’d for C12H9CIF3N2O2 [M+H]+: 305.0. Found 305.0. Step 6: 2-Chloro-8-hydr oxy-5, 6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000131_0001
A solution of 2-chloro-3-cyano-5,6,7,8-tetrahydroquinolin-8-yl 2,2,2-trifluoroacetate (900 mg, 2.95 mmol) in aqueous NaOH (2 M, 5 mL) was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O and extracted with EtOAc (4x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (56 mg, 9%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.03 (s, 1 H) 4.69 (t, J=5.32 Hz, 1 H) 2.71 - 2.96 (m, 2 H) 1.93 - 2.16 (m, 3 H) 1.75 - 1.89 (m, 1 H). MS-ESI (m/z) calc’d for C10H10CIN2O [M+H]+: 209.0. Found 209.1.
Step 7: rac-2-Chloro-8-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
Figure imgf000131_0002
To a solution of 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (25 mg, 119.82 umol) and 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol (25.67 mg, 119.82 umol) in toluene (2 mL) were added tributylphosphine (48.48 mg, 239.64 umol) and 1,1- (azodicarbonyl)dipiperidine (60.46 mg, 239.64 umol) at 0 °C. The mixture was then stirred at 90 °C for 2.5 hrs under N2. The reaction mixture was evaporated and purified by preparative-HPLC using Method M to afford the title compound (14 mg, 28%) as a yellow oil. MS-ESI (m/z) calc’d for C21H18CIN6O [M+H]+: 405.1. Found 405.1.
Step 8: 2-Chloro-8-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000132_0001
rac-2-Chloro-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral separation using Method N to afford 2-chloro-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (3 mg, 68%) as a yellow solid. 1 H NMR (400 MHz, DMSO-de) 8 8.41 (s, 1 H) 8.32 (s, 1 H) 8.17 (s, 1 H) 7.92 (s, 1 H) 7.74 (d, J=8.80 Hz, 1 H) 7.36 (s, 1 H) 6.94 (dd, J=8.80, 2.08 Hz, 1 H) 5.71 (t, J=3.85 Hz, 1 H) 3.89 - 3.99 (m, 3 H) 2.89 - 2.99 (m, 1 H) 2.73 - 2.85 (m, 1 H) 2.17 - 2.26 (m, 1 H) 1.96 - 2.06 (m, 1 H) 1.77 - 1.95 (m, 2 H). MS-ESI (m/z) calc’d for C2iHisClNeO [M+H]+: 405.1. Found 405.2. A later eluting fraction was also isolated to afford 2-chloro-8-(( I -(I -methyl- l//-pyrazol-4- l)-l//- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (3 mg, 60%) as a yellow solid. 'H NMR (400 MHz, DMSO-de) 8 8.41 (s, 1 H) 8.32 (s, 1 H) 8.17 (s, 1 H) 7.92 (s, 1 H) 7.74 (d, J=8.80 Hz, 1 H) 7.37 (s, 1 H) 6.95 (dd, J=8.80, 2.08 Hz, 1 H) 5.71 (t, J=3.79 Hz, 1 H) 3.93 (s, 3 H) 2.95 (dt, J=17.55, 4.62 Hz, 1 H) 2.75 - 2.85 (m, 1 H) 2.17 - 2.26 (m, 1 H) 1.96 - 2.07 (m, 1 H) 1.76 - 1.96 (m, 2 H). MS-ESI (m/z) calc’d for C2iHisClNeO [M+H]+: 405.1. Found 405.2.
Example 11: 6-Chloro-5-cyano-3,4-dimethyl-A-(l-methyl-l/7-indazol-6- yl)picolinamide, hydrochloride
Figure imgf000132_0002
To a solution of 1 -methyl- 17/-indazol-6-amine (100 mg, 679.45 umol), 6-chloro-5- cyano-3,4-dimethylpicolinic acid (143.10 mg, 679.45 umol) in DMA (1 mL) were added HATU (335.85 mg, 883.29 umol) and DIEA (263.44 mg, 2.04 mmol) at 20 °C. The mixture was stirred at 80 °C for 2 hrs. The reaction was filtered and the solid was washed with H2O
(3x), collected, and suspended in 4 M HCl/MeOH (20 mL). The suspension was stirred at 20 °C for 10 minutes and concentrated under reduced pressure to afford the title compound (114 mg, 44%) as ayellow solid. 'H NMR (400 MHz, DMSO-de) 8 10.92 (s, 1H), 8.24 (s, 1H), 8.02 (d, J=0.75 Hz, 1H), 7.76 (d, J=8.63 Hz, 1H), 7.31 (dd, J=1.56, 8.69 Hz, 1H), 4.03 (s, 3H), 2.62 (s, 3H), 2.41 (s, 3H). MS-ESI (m/z) calc’d for C17H15CIN5O [M+H]+: 340.1. Found 340.1.
Example 12: 3-Cyaiio-2-isopropyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6- yl)benzamide
Figure imgf000133_0001
Step 1: Ethyl 3-cyano-2-iodobenzoate
Figure imgf000133_0002
To a solution of ethyl 3-cyanobenzoate (100 mg, 570.83 umol) in THF (2 mL) was added 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (162.24 mg, 669.30 umol) at 0 °C and the mixture was stirred at 20 °C for 1 hr. A solution of h (173.86 mg, 685.00 umol) in THF (2 mL) was then added dropwise at 0 °C and the mixture was stirred at 20°C for 2 hrs. The mixture was combined with 2 additional, identical reaction mixtures and the combined mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography (ISCO; 4 g SepaFlash column) using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (225 mg, 43%) as a pale yellow solid. 'H NMR (400 MHz, CDCh) 8 7.87 (dd, J=7.78, 1.63 Hz, 1 H), 7.70 (dd, J=7.78, 1.63 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 4.40 - 4.48 (m, 2 H), 1.43 (t, J=7.09 Hz, 3 H).
Step 2: Ethyl 3-cyano-2-(prop-l-en-2-yl)benzoate
Figure imgf000133_0003
To a solution of ethyl 3-cyano-2-iodobenzoate (140 mg, 464.99 umol) and 4, 4,5,5- tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (117.21 mg, 697.49 umol) in EtOH (3 mL) and H2O (0.3 mL) were added Pd(Amphos)C12 (32.92 mg, 46.50 umol) and KO Ac (136.90 mg, 1.39 mmol) at 20 °C. The mixture was then stirred at 50 °C for 12 hrs under N2. The reaction mixture was concentrated and purified by preparative-TLC (SiO2, petroleum ether/EtOAc = 5/1, Rf = 0.63) to afford the title compound (58 mg, 58%) as ayellow liquid.
Step 3: 3-Cyano-2-(prop-l-en-2-yl)benzoic acid
Figure imgf000134_0001
To a solution of ethyl 3-cyano-2-(prop-l-en-2-yl)benzoate (106 mg, 492.46 umol) in THF (2 mL) and H2O (2 mL) was added LiOFEFLO (41.33 mg, 984.91 umol) at 20 °C. The mixture was stirred at 20 °C for 3 hrs and then extracted with EtOAc (2x). The organic layer was discarded. The aqueous layer was then acidified with 1 M HC1 to pH = 5 and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound (77 mg, 80%) as a pale yellow solid. MS-ESI (m/z) calc’d for C11H8NO2 [M-H]’: 186.1. Found 186.2.
Step 4: 3-Cyano-N-( 1-(1 -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-2-(prop-l-en-2- yl)benzamide
Figure imgf000134_0002
To a solution of 3-cyano-2-(prop-l-en-2-yl)benzoic acid (20 mg, 106.84 umol) and 1- (1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (22.78 mg, 106.84 umol) in DMF (2 mL) were added EDCI (24.58 mg, 128.21 umol), HOBt (17.32 mg, 128.21 umol) and triethylamine (32.43 mg, 320.52 umol) and the mixture was stirred at 20 °C for 12 hrs. The reaction mixture was combined with an additional, identical reaction mixture and the combined mixture was evaporated to dryness. The residue was purified by preparative-TLC (100% EtOAc, Rf = 0.48) to afford the title compound (38 mg, 46%) as a pale yellow liquid. MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.2. Found 383.3.
Step 5: 3-Cyano-2-isopropyl-N-( 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)benzamide
Figure imgf000135_0001
To a solution of 3-cyano-A-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-(prop- l-en-2-yl)benzamide (19 mg, 49.68 umol) in THF (3 mL) and MeOH (1.5 mL) was added 10% Pd/C (10 mg) at 20 °C. The mixture was then stirred at 20 °C for 15 minutes under an H2 (15 psi) atmosphere. The reaction mixture was combined with an additional, identical reaction mixture and the combined mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative-HPLC using Method O to afford the title compound (11 mg, 28%) as a colorless gum. JH NMR (400 MHz, DMSO-de) 8 10.80 (s, 1 H), 8.29 (s, 1 H), 8.22 (s, 2 H), 7.94 (d, J=6.39 Hz, 1 H), 7.77 - 7.85 (m, 2 H), 7.74 (d, J=6.62 Hz, 1 H), 7.53 (t, J=7.72 Hz, 1 H), 7.38 (dd, J=8.60, 1.54 Hz, 1 H), 3.95 (s, 3 H), 3.34 - 3.39 (m, 1 H), 1.42 (d, J=7.06 Hz, 6 H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2.
Example 13: 7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-6,7-dihydro-5ZZ- cyclopenta[b]pyridine-3-carbonitrile, enantiomer 1 and 2
Figure imgf000135_0002
To a mixture of AlCh (27.97 g, 209.80 mmol) in 6,7-dihydro-57/- cyclopenta[b]pyridine (10 g, 83.92 mmol) was added Bn (15.56 g, 97.35 mmol) slowly at 100 °C. The mixture was stirred at 100 °C for 1 hr. The reaction mixture was poured into ice water and adjusted to pH = 8 with 2 M aqueous NaOH. The mixture was filtered and the filtrate was extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (ISCO; 40 g SepaFlash column) using a 0-1% EtOAc/petroleum ether gradient eluent to afford the title compound (3 g, 18%) as a pale yellow solid. 'H NMR (400 MHz, CDCh) 8 8.31 - 8.47 (s, 1 H), 7.60 (s, 1 H), 2.94 (q, J=8.33 Hz, 4 H), 2.09 - 2.21 (m, 2 H). MS-ESI (m/z) calc’d for CsFLBrN [M+H]+: 198.0/200.0.
Found 198.0/200.1.
Figure imgf000136_0001
To a solution of 3-bromo-6,7-dihydro-57/-cyclopenta[b]pyridine (2 g, 10.10 mmol) in DMA (20 mL) were added Zn(CN)2 (2.37 g, 20.20 mmol), Zn (1.32 g, 20.20 mmol), 1,1- bis(diphenylphosphino)ferrocene (1.12 g, 2.02 mmol), and Pd2(dba)s (1.85 g, 2.02 mmol) at 20 °C. The mixture was stirred at 100 °C for 2 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-6% EtOAc/petroleum ether gradient eluent to afford the title compound (680 mg, 46%) as a white solid. JH NMR (400 MHz, CDCh) 8 8.63 (s, 1 H), 7.73 (s, 1 H), 3.10 (t, J=7.78 Hz, 2 H), 3.01 (t, J=7.53 Hz, 2 H), 2.20 (quin, J=7.65 Hz, 2 H). MS-ESI (m/z) calc’d for C9H9N2 [M+H]+: 145.1. Found 145.2.
Step 3: 3-Cyano-6, 7-dihydro-5H-cyclopenta[b]pyridine 1 -oxide
Figure imgf000136_0002
To a solution of 6,7-dihydro-57/-cyclopenta[b]pyridine-3-carbonitrile (800 mg, 5.55 mmol) in DCM (20 mL) was added m-CPBA (1.69 g, 8.32 mmol) and the mixture was stirred at 20 °C for 3 hrs. The reaction mixture was quenched by addition of 10% aqueous Na2SCh (9 mL) and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (880 mg, 100%) as a white solid. MS-ESI (m/z) calc’d for C9H9N2O [M+H]+: 161.1. Found 161.1.
Step 4: 7 -Hydroxy-6, 7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile
Figure imgf000137_0001
To a solution of 3-cyano-6,7-dihydro-57/-cyclopenta[b]pyridine 1-oxide (500 mg, 3.12 mmol) in DCM (15 mL) was added TFAA (3.93 g, 18.73 mmol) and the mixture was stirred at 20 °C for 12 hrs. The mixture was adjusted to pH = 8 with saturated aqueous NaHCOs. stirred at 20 °C for 10 minutes, and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0- 55% EtOAc/petroleum ether gradient eluent to afford the title compound (350 mg, 70%) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 8.73 (s, 1 H), 7.84 (d, J=0.75 Hz, 1 H), 5.26 (t, J=7.15 Hz, 1 H), 3.11 (ddd, J=16.75, 8.97, 3.64 Hz, 1 H), 2.91 (dt, J=16.56, 8.16 Hz, 1 H), 2.64 (dtd, J=13.36, 7.94, 7.94, 3.76 Hz, 1 H), 2.05 - 2.18 (m, 1 H). MS-ESI (m/z) calc’d for C9H9N2O [M+H]+: 161.1. Found 161.1.
Step 5: rac-7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-6, 7-dihydro-5H- cyclopenta[b ]pyridine-3-carboni trite
Figure imgf000137_0002
To a solution of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol (55 mg, 256.74 umol) and 7 -hydroxy-6.7-dihydro-57/-cyclopenta|b|pyridme-3-carbonitrile (49.35 mg, 308.09 umol) in toluene (5 mL) were added l,l-(azodicarbonyl)dipiperidine (129.56 mg, 513.48 umol) and tributylphosphine (103.89 mg, 513.48 umol) at 0 °C under an N2 atmosphere. The mixture was stirred at 90 °C for 2 hrs and concentrated to give a residue. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by preparative-HPLC using Method K to afford the title compound (9 mg, 7%) as a white solid. MS-ESI (m/z) calc’d for C20H17N6O [M+H]+: 357.1. Found 357.2.
Figure imgf000137_0003
cyclopenta[b]pyridine-3-carbonitrile, enantiomer 1 and 2
Figure imgf000138_0001
rac-7-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile was subjected to chiral separation using Method P. Product-containing fractions were evaporated and further purified by preparative-HPLC using Method Q to afford 7-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7- dihydro-5//-cyclopenta|b|pyridme-3-carbonitrile. enantiomer 1 (0.81 mg, 18%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.80 (s, 1 H) 8.12 - 8.17 (m, 2 H) 8.09 (s, 1 H) 7.91 (s, 1 H) 7.70 (d, J=8.88 Hz, 1 H) 7.39 (s, 1 H) 6.96 (dd, J=8.82, 2.06 Hz, 1 H) 5.93 (dd, J=6.94, 4.31 Hz, 1 H) 4.00 (s, 3 H) 3.19 - 3.26 (m, 1 H) 3.02 - 3.11 (m, 1 H) 2.68 - 2.78 (m, 1 H) 2.28 - 2.37 (m, 1 H). MS-ESI (m/z) calc’d for C20H17N6O [M+H]+: 357.1. Found 357.1. A later eluting fraction from the initial chiral separation was also isolated, evaporated and further purified by preparative-HPLC using Method Q to afford 7-((l-(l-methyl-17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-6,7-dihydro-57/-cyclopenta[b]pyridine-3-carbonitrile, enantiomer 2 (0.84 mg, 18%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.80 (s, 1 H) 8.12 - 8.17 (m, 2 H) 8.09 (s, 1 H) 7.91 (s, 1 H) 7.70 (d, J=8.88 Hz, 1 H) 7.39 (s, 1 H) 6.96 (dd, J=8.82, 2.06 Hz, 1 H) 5.93 (dd, J=6.94, 4.31 Hz, 1 H) 4.00 (s, 3 H) 3.19 - 3.26 (m, 1 H) 3.02 - 3.11 (m, 1 H) 2.68 - 2.78 (m, 1 H) 2.28 - 2.37 (m, 1 H). MS-ESI (m/z) calc’d for C20H17N6O [M+H]+: 357.1. Found 357.1.
Example 14: 7-((l-(l-MethyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)amino)-6,7-dihydro-5/7- cyclopenta[b]pyridine-3-carbonitrile, enantiomer 1 and 2
Figure imgf000138_0002
To a solution of 6-bromo-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazole (150 mg, 541.28 umol) and tert-butyl carbamate (76.09 mg, 649.54 umol) in toluene (5 mL) were added Pd2(dba)3 (49.57 mg, 54.13 umol), 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (22.99 mg, 54.13 umol) and t-BuONa (104.04 mg, 1.08 mmol) at 20 °C. The mixture was stirred at 90 °C for 3 hrs under N2 atmosphere. The reaction mixture was combined with an additional, identical reaction mixture and the combined mixture was concentrated to give a residue. The residue was purified by silica gel chromatography (ISCO; 20 g SepaFlash column) using a 0-45% EtOAc/petroleum ether gradient eluent to afford the title compound (329 mg, 96%) as a brown oil. MS-ESI (m/z) calc’d for C16H20N5O2 [M+H]+: 314.2. Found 314.3.
Step 2: 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-amine
Figure imgf000139_0001
To a solution of tert-butyl (l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)carbamate (328 mg, 1.05 mmol) in EtOAc (2 mL) was added a 4 M solution of HC1 in EtOAc (10 mL) at 20 °C. The mixture was then stirred at 20 °C for 12 hrs. The reaction mixture was adjusted to pH=8 with saturated aqueous NaHCCL. then diluted with H2O, and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated to afford the title compound (200 mg, 90%) as a brown solid. JH NMR (400 MHz, DMSO-de), 8 8.12 (s, 1 H), 7.90 (s, 1 H), 7.75 (s, 1 H), 7.43 (d, J=8.63 Hz, 1 H), 6.66 (s, 1 H), 6.57 (dd, J=8.57, 1.69 Hz, 1 H), 5.42 (s, 2 H), 3.91 (s, 3 H). MS-ESI (m/z) calc’d for C11H12N5 [M+H]+: 214.1. Found 214.2.
Step 3: N-(3-Bromo-6, 7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-l -(1 -methyl- lH-pyrazol-4- yl)-lH-indazol-6-amine
Figure imgf000139_0002
To a solution of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (50 mg, 234.48 umol) in MeOH (3 mL) were added AcOH (28.16 mg, 468.96 umol) and 3-bromo-57/- cyclopenta[b]pyridin-7(677)-one (74.58 mg, 351.72 umol) at 20 °C and the mixture was stirred at 20 °C for 3 hrs. Then NaBHsCN (44.20 mg, 703.44 umol) was added and the mixture was stirred at 20 °C for an additional 12 hrs. The reaction mixture was concentrated and purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 1/3, Rf = 0.5) to afford the title compound (51 mg, 53%) as a brown oil. MS-ESI (m/z) calc’d for CisHisBrNe. [M+H]+: 409.1, 411.1. Found 409.2, 411.2.
Step 4: rac-7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-6, 7-dihydro-5H- cyclopenta [b ]pyridine-3-carboni trile
Figure imgf000140_0001
To a solution of /V-(3-bromo-6,7-dihydro-57/-cyclopenta[b]pyridin-7-yl)-l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (50 mg, 122.17 umol) in DMA (3 mL) were added Zn(CN)2 (28.69 mg, 244.33 umol), Zn (15.98 mg, 244.33 umol), 1,1- bis(diphenylphosphino)ferrocene (13.55 mg, 24.43 umol), and Pd2(dba)s (22.37 mg, 24.43 umol) at 20 °C. The mixture was stirred at 100 °C for 2 hr under an N2 atmosphere in a microwave reactor. The reaction mixture was then concentrated to give a residue that was purified by preparative-HPLC using Method K to afford the title compound (9 mg, 15%) as a white solid. MS-ESI (m/z) calc’d for C20H18N7 [M+H]+: 356.2. Found 356.3.
Step 5: 7-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-6, 7-dihydro-5H-
Figure imgf000140_0002
rac-7-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile was subjected to chiral separation using Method R to afford 7-(( 1 -(1 -methyl- 17/-py razol -4-y 1)- I //-indazol -6- l)amino)-6,7-dihy dro-57/- cyclopenta[b]pyridine-3-carbonitrile, enantiomer 1 (2.75 mg, 61%) as a blue solid. 'H NMR (400 MHz, DMSO-de) 8 8.83 (d, J=1.88 Hz, 1 H), 8.21 - 8.23 (m, 1 H), 8.17 (s, 1 H), 7.95 (d, J=0.75 Hz, 1 H), 7.82 (s, 1 H), 7.48 (d, J=8.63 Hz, 1 H), 6.84 (s, 1 H), 6.72 (dd, J=8.69, 1.81 Hz, 1 H), 6.46 (d, J=7.50 Hz, 1 H), 5.17 (q, J=7.42 Hz, 1 H), 3.91 (s, 3 H), 3.02 - 3.10 (m, 1 H), 2.89 - 2.99 (m, 1 H), 2.61 - 2.70 (m, 1 H), 1.96 (dq, J=12.74, 8.09 Hz, 1 H). MS-ESI (m/z) calc’d for C20H18N7 [M+H]+: 356.2. Found 356.1. A later eluting fraction was also isolated to afford 7-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile, enantiomer 2 (2.4 mg, 53%) as a blue solid. 'H NMR (400 MHz, DMSO-de) 8 8.83 (d, J=1.88 Hz, 1 H), 8.21 - 8.23 (m, 1 H), 8.17 (s, 1 H), 7.95 (d, J=0.75 Hz, 1 H), 7.82 (s, 1 H), 7.48 (d, J=8.63 Hz, 1 H), 6.84 (s, 1 H), 6.72 (dd, J=8.69, 1.81 Hz, 1 H), 6.46 (d, J=7.50 Hz, 1 H), 5.17 (q, J=7.42 Hz, 1 H), 3.91 (s, 3 H), 3.02 - 3.10 (m, 1 H), 2.89 - 2.99 (m, 1 H), 2.61 - 2.70 (m, 1 H), 1.96 (dq, J=12.74, 8.09 Hz, 1 H). MS-ESI (m/z) calc’d for C20H18N7 [M+H]+: 356.2. Found 356. E
Example 15: 4-Cyano-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6-yl)-3-(prop-l-en-2- yl)picolinamide
Figure imgf000141_0001
Step 1: l-(l-Methyl-lH-pyrazol-4-yl)-6-nitro-lH-indazole
Figure imgf000141_0002
A mixture of 6-nitro-17/-indazole (4.89 g, 30 mmol), 4-iodo-l-methylpyrazole (9.36 g, 45 mmol), (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (2.13 g, 15 mmol), cuprous iodide (1.14 g, 6 mmol) and potassium phosphate (19.08 g, 90 mmol) in dry DMSO (10 mL) was stirred at 100 °C for 24 hrs. The mixture was then diluted with H2O and extracted with EtOAc (3x). The suspension was filtered through a Celite pad and the combined organic layers were evaporated to obtain a residue which was taken up in aqueous citrate buffer (pH 3) and stirred for 30 minutes. The solid was filtered under vacuum, washed with H2O, and dried to obtain a dark residue which was dissolved in DCM and passed through an alumina pad. The filtrate was evaporated to obtain a light orange solid that was triturated with Et2O and dried to afford the title compound (3.2 g, 44%) as a yellow solid. 'H NMR (400 MHz, DMSO-de) 6 8.54 (d, J = 1.0 Hz, 1H), 8.47 (dt, J = 1.9, 0.9 Hz, 1H), 8.45 (d, J = 0.8 Hz, 1H), 8.13 (dd, J = 8.8, 0.7 Hz, 1H), 8.05 (dd, J = 8.8, 1.9 Hz, 1H), 7.96 (d, J = 0.9 Hz, 1H), 3.97 (s, 3H). MS-ESI (m/z) calc’d for C11H10N5O2 [M+H]+: 244.2. Found 244.2.
Step 2: 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-amine
Figure imgf000142_0001
To a suspension of l-(l-methyl-17/-pyrazol-4-yl)-6-nitro-17/-indazole (3.2 g, 13.16 mmol) in methanol (65.78 mL) was added 10% palladium on carbon (0.7 g, 0.66 mmol) and ammonium formate (2.49 g, 39.47 mmol), then the mixture was stirred at 65 °C for 5 hrs. After cooling, the catalyst was removed by filtration under vacuum and the filtrate was evaporated. The residue was taken up in H2O and the solid that formed was filtered under vacuum, washed with H2O, and dried to afford the title compound (2.5 g, 90%) as a beige solid. 'H NMR (400 MHz, DMSO-de) 6 8.12 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 5.41 (s, 2H), 3.92 (s, 3H). MS-ESI (m/z) calc’d for C11H12N5 [M+H]+: 214.2. Found 214.1.
Step 3: 2, 3-Dichloroisonicotinamide
Figure imgf000142_0002
A suspension of 2,3-dichloropyridine-4-carboxylic acid (3.84 g, 20 mmol) in thionyl chloride (40 mL) was stirred at 79 °C for 10 hrs. After cooling the solvent was evaporated under reduced pressure and the residue was carefully added to 28% NH4OH. The solid that formed was filtered and dried to afford the title compound (3.21 g, 84%) as a white solid. 'H NMR (400 MHz, DMSO-de) 6 8.44 (d, J = 4.8 Hz, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H). MS-ESI (m/z) calc’d for C6H5CI2N2O [M+H]+: 191.0, 193.0. Found 190.9, 192.9.
Step 4: 2,3-Dichloroisonicotinonitrile
Figure imgf000143_0001
A suspension of 2,3-dichloroisonicotinamide (3.21 g, 16.81 mmol) in phosphoryl chloride (20 mL) was stirred at 100 °C for 1 hr. The solvent was evaporated under reduced pressure and the residue was carefully quenched by addition of saturated aqueous NaHCOs and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain the title compound (2.75 g, 95%) as a beige solid. 'H NMR (400 MHz, DMSO-de) 6 8.63 (d, J = 4.9 Hz, 1H), 8.07 (d, J = 4.9 Hz, 1H). MS-ESI (m/z) calc’d for C6H3CI2N2 [M+H]+: 173.0, 175.0. Found 172.9; 174.8.
Step 5: 3-Chloro-2-vinylisonicotinonitrile
Figure imgf000143_0002
To a solution of 2,3-dichloroisonicotinonitrile (2.75 g, 15.9 mmol) in toluene (52.99 mL) was added tributyl(vinyl)stannane (4.65 mL, 15.9 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.12 g, 1.59 mmol), then the suspension was stirred at 100 °C under N2 for 3 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (2.6 g, 100%) as a pale yellow solid. JH NMR (400 MHz, DMSO-de) 6 8.76 (d, J = 4.8 Hz, 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.24 (dd, J = 16.9, 10.6 Hz, 1H), 6.51 (dd, J = 16.9, 2.0 Hz, 1H), 5.78 (dd, J = 10.7, 2.0 Hz, 1H). MS-ESI (m/z) calc’d for CsHeC [M+H]+: 165.0. Found 164.9.
Step 6: 3-Chloro-4-cyanopicolinic acid
Figure imgf000143_0003
To a solution of 3-chloro-2-vinylisonicotinonitrile (2.62 g, 15.9 mmol) in acetone (39.74 mL) and H2O (39.74 mL) was added KMnOi (8.79 g, 55.64 mmol) and the mixture was stirred at 25 °C for 3 hrs. The mixture was filtered through a Celite pad and washed with H2O and acetone. The filtrate was diluted with H2O and washed with Et2O (2x), the aqueous layer was acidified by addition of 37% HC1 and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (2.25 g, 78%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 14.33 (s, 1H), 8.81 (d, J = 4.9 Hz, 1H), 8.16 (d, J = 4.9 Hz, 1H). MS-ESI (m/z) calc’d for C7H4CIN2O2 [M+H]+: 183.0. Found 182.9.
Step 7: Methyl 3-chloro-4-cyanopicolinate
Figure imgf000144_0001
To a solution of 3-chloro-4-cyanopicolinic acid (2.25 g, 12.32 mmol) in DMF (61.62 mL) was added potassium carbonate (3.41 mL, 24.65 mmol) and iodomethane (1.53 mL, 24.65 mmol), then the mixture was stirred at 25 °C for 1 hr. Water was added and the solution was extracted with Et20 (3x), the combined organic layers were washed with H2O (2x), passed through a phase separator and evaporated to afford the title compound (570 mg, 24%) as an off-white solid. 'H NMR (400 MHz, DMSO- e) 6 8.84 (d, J = 4.9 Hz, 1H), 8.23 (d, J = 4.8 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for CsHeC Ch [M+H]+: 197.0. Found 197.9.
Figure imgf000144_0002
To a solution of methyl 3-chloro-4-cyanopicolinate (570.0 mg, 2.9 mmol) in 1,4- dioxane (14.5 mL) was added 4,4,5,5-tetramethyl-2-(l-methylethenyl)-l,3,2-dioxaborolane (1.63 mL, 8.7 mmol), potassium carbonate (0.4 mL, 2.9 mmol) and XPhos Pd G1 (214.49 mg, 0.290 mmol). The mixture was stirred at 100 °C under N2 for 2 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (327 mg, 56%) as an orange oil. 'H NMR (400 MHz, DMSO- e) 6 8.81 (d, J = 4.9 Hz, 1H), 8.10 (d, J = 4.9 Hz, 1H), 5.44 (p, J = 1.5 Hz, 1H), 5.02 (p, J = 1.0 Hz, 1H), 3.85 (s, 3H), 2.10 (dd, J = 1.6, 1.0 Hz, 3H). MS- ESI (m/z) calc’d for C11H11N2O2 [M+H]+: 203.2. Found 203.0.
Step 9: 4-Cyano-3-(prop-l-en-2-yl)picolinic acid
Figure imgf000145_0001
To a solution of methyl 4-cyano-3-(prop-l-en-2-yl)picolinate (327.0 mg, 1.62 mmol) in ethanol (4.04 mL) and H2O (4.04 mL) was added LiOH’TbO (67.85 mg, 1.62 mmol) and the mixture was stirred at 25 °C for 1 hr. The mixture was then diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4 and evaporated to afford the title compound (225 mg, 74%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 13.73 (s, 1H), 8.78 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 5.0 Hz, 1H), 5.43 (p, J = 1.5 Hz, 1H), 5.04 (p, J = 1.0 Hz, 1H), 2.11 (t, J = 1.3 Hz, 3H). MS-ESI (m/z) calc’d for C10H9N2O2 [M+H]+: 189.1 Found 189.0.
Step 10: 4-Cyano-N-(l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-3-(prop-l-en-2- yl)picolinamide
Figure imgf000145_0002
To a mixture of l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-amine (254.96 mg, 1.2 mmol), methyl 4-cyano-3-(prop-l-en-2-yl)picolinate (225.0 mg, 1.2 mmol), and triethylamine (0.17 mL, 1.2 mmol) in MeCN (12 mL) was added HATU (454.63 mg, 1.2 mmol) and the reaction was stirred at 25 °C for 3 hrs. Water was then added and the solid formed was filtered under vacuum, washed with H2O, and dried to afford the title compound (263 mg, 57%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.85 (s, 1H), 8.87 (d, J = 5.0 Hz, 1H), 8.22 (d, J = 2.6 Hz, 3H), 8.11 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 9.1, 1.3 Hz, 1H), 5.40 (p, J = 1.4 Hz, 1H), 5.05 (q, J = 1.0 Hz, 1H), 3.95 (s, 3H), 2.14 (t, J = 1.2 Hz, 3H). MS-ESI (m/z) calc’d for C21H18N7O [M+H]+: 384.4. Found 384.2.
Example 16 : 3-Cyano-2-iodo-/V-(l -(1 -methyl- 1 H-py razol-4-y 1)- lff-indazol-6- yl)benzamide
Figure imgf000146_0001
Prepared as described for 4-cyano-N-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide using 3-cyano-2-iodobenzoic acid in place of 4-cyano-3- (prop-l-en-2-yl)picolinic acid to afford the title compound (7 mg, 2%) as an off white solid. 'H NMR (400 MHz, DMSO- e) 6 10.78 (s, 1H), 8.24 (d, J = 1.5 Hz, 1H), 8.23 (d, J = 1.0 Hz, 1H), 8.21 (s, 1H), 7.94 (dd, J = 7.6, 1.7 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.78 (dd, J = 7.7, 1.7 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.37 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H14IN6O [M+H]+: 469.3. Found 469.0.
Example 17 : 5-Cyano-6-(difliioromethyl)-3,4-dimethyl-/V-(5-methyl-l -(1 -methyl-1//- pyrazol-4-yl)- l//-iiidaz()l-6-yl)picolinainide
Figure imgf000146_0002
A mixture of 5-methyl-6-nitro-17/-indazole (2.0 g, 11.29 mmol), 4-iodo-l- methylpyrazole (3.52 g, 16.93 mmol), (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (802.89 mg, 5.64 mmol), copper (I) iodide (430.01 mg, 2.26 mmol) and tripotassium phosphate (7.18 g, 33.87 mmol) in dry 1,4-dioxane (80 mL) was heated and stirred at 100 °C for 24 hrs. Additional copper (I) iodide (430.01 mg, 2.26 mmol) and (1R,2R)-N1,N2- dimethylcyclohexane-l,2-diamine (802.89 mg, 5.64 mmol) were added and stirring was continued at 100 °C for an additional 42 hrs. The mixture was diluted with H2O and extracted with EtOAc (3x), filtered, and the combined organic layers were evaporated to obtain a residue which was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (1.5 g, 52%) as a dark yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 8.34 - 8.47 (2 H, m) 8.30 (1 H, s) 7.95 (2 H, dd, J=2.42, 0.66 Hz) 3.91 - 4.00 (3 H, m) 2.56 (3 H, s). MS-ESI (m/z) calc’d for C12H12N4NO2 [M+H]+: 258.2 Found 258.1.
Figure imgf000147_0001
A mixture of iron (1.63 g, 29.15 mmol), ammonium chloride (311.9 mg, 5.83 mmol) and 5 -methyl-l-(l -methyl- I //-pyrazol-4-yl)-6-nitro- 1 //-indazole (1.5 g, 5.83 mmol) was heated at 80 °C for 1.5 hrs. After cooling, the mixture was filtered through a Buchner funnel and the filtrate was evaporated to dryness. The residue was taken up in water and extracted with EtOAc (3x), the combined organic layers were dried over Na2SC>4 and evaporated to afford the title compound (1.3 g, 98%) as a dark yellow solid. 'H NMR (400 MHz, DMSO- tZe) 8 8.03 - 8.15 (1 H, m) 7.83 - 7.93 (1 H, m) 7.71 - 7.80 (1 H, m) 7.28 - 7.41 (1 H, m) 6.77 - 6.88 (1 H, m) 5.06 - 5.26 (2 H, m) 3.89 - 3.96 (3 H, m) 2.12 - 2.22 (3 H, m). MS-ESI (m/z) calc’d for C12H14N5 [M+H]+: 228.3. Found 228.1.
Step 3: 5-Cyano-6-(difluoromethyl)-3,4-dimethyl-N-(5-methyl-l-(l-methyl-lH-pyrazol-4-yl)- lH-indazol-6-yl)picolinamide
Figure imgf000147_0002
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide using 5-cyano-6-(difluoromethyl)-3,4-dimethylpyridine- 2-carboxylic acid in place of 4-cyano-3-(prop-l-en-2-yl)picolinic acid and 5-methyl-l-(l- methyl-17/-pyrazol-4-yl)-17/-indazol-6-amine in place of l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-amine to afford the title compound (56.7 mg, 65%) as an off white solid. 'H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.27 (s, 1H), 8.20 (d, J = 1.0 Hz, 1H), 8.03 (s, 1H), 7.85 (d, J = 0.9 Hz, 1H), 7.74 (s, 1H), 7.20 (t, J = 53.2 Hz, 1H), 3.95 (s, 3H), 2.64 (s, 3H), 2.57 (s, 3H), 2.41 (s, 3H). MS-ESI (m/z) calc’d for C22H20F2N7O [M+H]+: 436.4. Found 436.2. Example 18: 5-Cyaiio-6-(difliioromethyl)-3,4-dimethyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)- l//-indazol-6-yl)picolinamide
Figure imgf000148_0001
To a solution of 6-chloro-5-cyano-3,4-dimethylpyridine-2-carboxylic acid (698.0 mg, 3.31 mmol) in DMF (11.05 mL) was added potassium carbonate (0.92 g, 6.63 mmol) and iodomethane (0.41 mL, 6.63 mmol) then the mixture was stirred at 80 °C for 15 minutes. The mixture was diluted with H2O and extracted with EtOAc (3x), the combined organic layers were passed through a phase separator and evaporated to afford the title compound (744.5 mg, 100%) as a dark oil. 'H NMR (400 MHz, DMSO- e) 6 3.92 (s, 3H), 2.56 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc’d for C10H10CIN2O2 [M+H]+: 225.0. Found 225.0.
Figure imgf000148_0002
To a solution of methyl 6-chloro-5-cyano-3,4-dimethylpicolinate (320.0 mg, 1.42 mmol) in toluene (14.25 mL) was added tributyl(vinyl)stannane (0.46 mL, 1.57 mmol) and bis(triphenylphosphine)palladium(II) dichloride (100.27 mg, 0.14 mmol), then the mixture was stirred at 100 °C for 1 hr. The solvent was evaporated, the residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (230 mg, 75%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.07 (dd, J = 16.8, 10.6 Hz, 1H), 6.47 (dd, J = 16.8, 1.7 Hz, 1H), 5.77 (dd, J = 10.7, 1.8 Hz, 1H), 3.93 (s, 3H), 2.52 (s, 3H), 2.30 (s, 3H) MS-ESI (m/z) calc’d for C12H13N2O2 [M+H]+: 217.4. Found 217.0.
Figure imgf000149_0003
To a solution of methyl 5-cyano-3,4-dimethyl-6-vinylpicolinate (230.0 mg, 1.06 mmol) in 1,4-dioxane (5.32 mL) and H2O (5.32 mL) was added sodium periodate (455.0 mg, 2.13 mmol) and 4% osmium tetroxide (0.34 mL, 0.050 mmol), then the mixture was stirred at 25 °C for 1 hr. The mixture was diluted with H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (232 mg, 100%) as a dark solid. JH NMR (400 MHz, DMSO- e) 6 9.89 (s, 1H), 3.96 (s, 3H), 2.60 (s, 3H), 2.44 (s, 3H). MS-ESI (m/z) calc’d for C11H11N2O3 [M+H]+: 219.1. Found 219.0.
Figure imgf000149_0001
To a solution of methyl 5-cyano-6-formyl-3, 4-dimethylpicolinate (232.1 mg, 1.06 mmol) in DCM (10.54 mL) and EtOH (0.1 mL) was added Deoxo-Fluor (1.14 mL, 4.25 mmol) and the mixture was stirred at 25 °C for 24 hours. The solvent was evaporated, the residue was purified by silica gel column chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (132 mg, 52%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.14 (t, J = 53.1 Hz, 1H), 3.94 (s, 3H), 2.60 (s, 3H), 2.40 (s, 3H). MS-ESI (m/z) calc’d for C11H11F2N2O2 [M+H]+: 241.2. Found 241.0.
Figure imgf000149_0002
To a solution of methyl 5-cyano-6-(difluoromethyl)-3,4-dimethylpicolinate (132.0 mg, 0.55 mmol) in EtOH (5 mL) and H2O (2 mL) was added LiOEMEO (23.06 mg, 0.55 mmol) and the mixture was stirred at 25 °C for 1 hr. The mixture was then diluted with water and extracted with EtOAc(3x). The combined organic layers were dried over Na2SO4 and evaporated to afford the title compound (107 mg, 86%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 14.15 (s, 1H), 7.12 (t, J = 53.2 Hz, 1H), 2.58 (s, 3H), 2.39 (d, J = 1.4 Hz, 3H). MS-ESI (m/z) calc’d for C10H9F2N2O2 [M+H]+: 227.2. Found 227.0.
Step 6: 5-Cyano-6-(difluoromethyl)-3, 4-dimethyl-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH- indazol-6-yl)picolinamide
Figure imgf000150_0001
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide, using 5-cyano-6-(difluoromethyl)-3,4-dimethylpicolinic acid in place of 4-cyano-3-(prop-l-en-2-yl)picolinic acid to afford the title compound (47.9 mg, 57%) as ayellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.95 (s, 1H), 8.27 (dd, J = 1.7, 0.9 Hz, 1H), 8.24 (d, J = 1.0 Hz, 2H), 7.86 - 7.80 (m, 2H), 7.44 (dd, J = 8.7, 1.7 Hz, 1H), 7.19 (t, J = 53.2 Hz, 1H), 3.95 (s, 3H), 2.63 (s, 3H), 2.46 (s, 4H). MS-ESI (m/z) calc’d for C21H18F2N7O [M+H]+: 422.4. Found 422.2.
Example 19: 5-Cyano-3,4-dimethyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6-yl)-6-
(prop-l-en-2-yl)picolinamide
Figure imgf000150_0002
To a solution of 3-methyl-2,4-pentanedione (25.0 g, 219.03 mmol) and 2- cyanoacetamide (18.42 g, 219.03 mmol) was added piperidine (21.64 mL, 219.03 mmol) and the mixture was stirred at 75 °C for 22 hrs. The solvent was concentrated to half volume and H2O was added. The solid that formed was filtered under vacuum and dried to afford the desired compound (26 g, 73%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.93 (s, 3H). MS-ESI (m/z) calc’d for C9H9N2O [M-H]’: 163.1. Found 163.0.
Step 2: 2-Chloro-4,5,6-trimethylnicotinonitrile
Figure imgf000151_0001
A suspension of 4,5,6-trimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (26.0 g, 160.31 mmol) in phosphorus(V) oxychloride (100.0 mL, 1069.6 mmol) was heated at 100 °C for 15 hrs. The solution was concentrated and then poured into H2O (1 L) and the pH was adjusted to ~7 by addition of Na2CO3. The solid was filtrated and dried under vacuum to afford the title compound (28.95 g, 99%) as a white solid. 'H NMR (400 MHz, DMSO- de 8 2.51 (s, 3H), 2.47 (s, 3H), 2.22 (s, 3H). MS-ESI (m/z) calc’d for C9H10CIN2 [M+H]+: 181.0. Found 181.0.
Figure imgf000151_0002
To a solution of 2-chloro-4,5,6-trimethylnicotinonitrile (3.9 g, 21.59 mmol) in trifluoroacetic acid (107.96 mL) was added hydrogen peroxide (6.61 mL, 64.77 mmol) and the mixture was stirred at 75 °C for 15 hrs. Water was added and the solution was neutralized by addition of solid K2CO3 and then extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (3.73 g, 88%) as a beige solid. 'H NMR (400 MHz, DMSO-d6) δ 2.51 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc’d for C9H10CIN2O [M+H]+: 197.0. Found 197.0.
Step 4: 2-Chloro-6-(hydroxymethyl)-4, 5-dimethylnicotinonitrile
Figure imgf000152_0001
To a solution of 2-chloro-3-cyano-4,5,6-trimethylpyridine 1-oxide (634.0 mg, 3.22 mmol) in DCM (9.86 mL) was added dropwise 2,2,2-trifluoroacetic acid (2,2,2-trifluoro-l- oxoethyl) ester (1.34 mL, 9.67 mmol) in DCM (9.86 mL) at 0 °C and the mixture was stirred at 25 °C for 15 hrs. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (2x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (650 mg, 100%) as a pale yellow solid. 'H NMR (400 MHz, DMSO- e) 6 5.42 (t, J = 5.8 Hz, 1H), 4.60 (d, J = 5.4 Hz, 2H), 2.50 (s, 3H), 2.28 (s, 3H). MS-ESI (m/z) calc’d for C9H10CIN2O [M+H]+: 197.0. Found 197.0.
Figure imgf000152_0002
To a solution of 2-chloro-6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (100.0 mg, 0.51 mmol) in acetone (1.5 mL) was added dropwise a solution of potassium permanganate (88.41 mg, 0.56 mmol) in water (0.75 mL) at r.t. and the mixture was stirred for 2 hrs. The dark solid was removed by filtration and washed with 1 M K2CO3 solution. The filtrate was concentrated to remove the organic solvent and the aqueous phase was extracted with EtOAc. The pH was adjusted to 2 by addition of 6 M HC1 and the solution was extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (78 mg, 73%) as a beige solid. 'H NMR (400 MHz, DMSO- e) 82.55 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc’d for C9H8CIN2O2 [M+H]+: 211.0. Found 211.0.
Figure imgf000152_0003
To a solution of 6-chloro-5-cyano-3,4-dimethylpyridine-2-carboxylic acid (1500.0 mg, 7.12 mmol) in DMF (30 mL) was added potassium carbonate (2952.92 mg, 21.37 mmol) and lodomethane (0.89 mL, 14.24 mmol); then the mixture was stirred at r.t. overnight. Water (150 mL) was added and the mixture was extracted with EtOAc (150 mL). The organic phase was separated, washed with saturated aqueous NaHCOi. dried over NaiSOi. filtered, and concentrated under vacuum. The material obtained was purified by silica gel column chromatography using a 0-30% EtOAc/cyclohexane gradient eluent to afford the title compound (393 mg, 25%) as a white solid. JH NMR (400 MHz, CDCh) 82.43 (s, 3H), 2.60 (s, 3H), 3.91 - 4.06 (m, 3H). MS-ESI (m/z) calc’d for C10H10CIN2O2 [M+H]+: 225.0. Found 225.0.
Step
Figure imgf000153_0001
A mixture of methyl 6-chloro-5-cyano-3,4-dimethylpicolinate (393.0 mg, 1.75 mmol), 4,4,5,5-tetramethyl-2-(l-methylethenyl)-l,3,2-dioxaborolane (881.94 mg, 5.25 mmol), potassium carbonate (362.69 mg, 2.62 mmol) and palladium tetrakis triphenylphosphine (202.16 mg, 0.170 mmol) in 1,4-di oxane (8 mL) was degassed with N2 and then stirred in a sealed micro wave vial at 110 °C for 24 hrs. The mixture was allowed to cool to r.t. and then diluted with H2O and extracted with EtOAc (x3). The organic layer was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a 0-15% EtOAc/cyclohexane gradient eluent to afford the title compound (167 mg, 41%) as ayellow oil. 'H NMR (400 MHz, CDCh) 82.23 (s, 3H), 2.40 (s, 3H), 2.58 (s, 3H), 3.99 (d, J = 3.25 Hz, 3H), 5.56 - 5.61 (m, 2H). MS-ESI (m/z) calc’d for C13H15N2O2 [M+H]+: 231.3. Found 231.1.
Step 8: 5-Cyano-3,4-dimethyl-6-(prop-l-en-2-yl)picolinic acid
Figure imgf000153_0002
To a solution of methyl 5-cyano-3,4-dimethyl-6-(prop-l-en-2-yl)picolinate (167.0 mg, 0.730 mmol) in THF (5 mL), was added a solution of LiOHHLO (30.43 mg, 0.730 mmol) in water (3 mL) and the resulting mixture was stirred at r.t. for 2 hrs. I M HC1 was added drop wise to pH=l, followed by EtOAc. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the organic phases were passed through a phase separator to afford the title compound (144 mg, 92%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 3.92 (s, 3H), 2.56 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc’d for C12H12N2O2 [M+H]+: 216.40. Found 217.07. 'H NMR (400 MHz, CDCh) 82.25 (t, J = 1.21 Hz, 3H), 2.67 (s, 3H), 2.79 (d, J = 7.49 Hz, 4H), 5.69 (q, J = 1.57 Hz, 1H), 5.75 (d, J = 1.04 Hz, 1H). MS-ESI (m/z) calc’d for C12H13N2O2 [M+H]+: 217.2. Found 217.E
Step 9: 5-Cyano-3, 4-dimethyl-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)-6-(pr op-1- en-2-yl)picolinamide
Figure imgf000154_0001
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide using 5-cyano-3,4-dimethyl-6-(prop-l-en-2-yl)picolinic acid in place of 4-cyano-3-(prop-l-en-2-yl)picolinic acid (120 mg) to afford the title compound (23.8 mg, 12%) as ayellow solid. 'H NMR (400 MHz, CDCh) 8 2.32 (t, J = 1.20 Hz, 3H), 2.66 (s, 3H), 2.82 (s, 3H), 4.03 (s, 3H), 5.69 (d, J = 1.65 Hz, 1H), 5.76 (s, 1H), 7.12 (dd, J = 8.58, E76 Hz, 1H), 7.74 (d, J = 8.57 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 8.09 (d, J = E03 Hz, 1H), 8.44 (s, 1H), 10.23 (s, 1H). MS-ESI (m/z) calc’d for C23H22N7O [M+H]+: 412.5. Found 412.2.
Example 20: 5-Cyaiio-6-isopropyl-3,4-dimethyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//- indazol-6-yl)picolinamide
Figure imgf000154_0002
A solution of 4-cyano-5,6-dimethyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide (120.0 mg, 0.29 mmol) in methanol (240 mL) was hydrogenated using an H-Cube apparatus in the presence of 10% Pd/C. Reaction conditions: Flow 1 mL/min, full H2 method; P=latm, 30 °C; single cycle. The solvent was evaporated under reduced pressure and a residue was obtained. The material was purified by flash silica gel chromatography using a 0-70% EtOAc/cyclohexane gradient eluent to afford the title compound (58 mg, 48%) as a white solid. 'H NMR (400 MHz, CDCk) 6 1.42 (d, J = 6.80 Hz, 6H), 2.62 (s, 3H), 2.80 (s, 3H), 3.59 (p, J = 6.78 Hz, 1H), 4.03 (s, 3H), 7.09 (dd, J = 8.61, 1.78 Hz, 1H), 7.74 (d, J = 8.54 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 8.09 (d, J = 1.01 Hz, 1H), 8.48 (s, 1H), 10.41 (s, 1H). MS-ESI (m/z) calc’d for C23H24N7O [M+H]+: 414.2. Found 414.2.
Example 21: 5-Cyano-3,4-dimethyI-7V-(5-methyI-l-(l-methyI-lH-pyrazol-4-yI)-lH- indazol-6-yl)-6-(trifluoromethyl)picolinamide
Figure imgf000155_0001
Step 1: 4,5 ,6-Trimethylnicotinonitrile
Figure imgf000155_0002
To a suspension of 2-chloro-4,5,6-trimethylpyridine-3-carbonitrile (9.0 g, 49.83 mmol) in methanol (124.56 mL) was added 10% Pd/C (2.65 g, 2.49 mmol) and triethylamine (6.94 mL, 49.83 mmol) and the mixture was hydrogenated at 1 atm for 6 hrs. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness to obtain a yellow solid which was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (5 g, 69%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.23 (s, 3H). MS-ESI (m/z) calc’d for C9H11N2 [M+H]+: 147.1. Found 147.0.
Figure imgf000155_0003
To a solution of 4,5,6-trimethylnicotinonitrile (4.67 g, 28.79 mmol) in DCM (44.06 mL) was added dropwise trifluoroacetic anhydride (12.01 mL, 86.38 mmol) in DCM (44.06 mL) and the mixture was stirred at 25 °C for 15 hrs. The solvent was evaporated to dryness and the red oil was dissolved in MeOH (60 mL). Then K2CO3 (5 g) was added and the suspension was stirred for 1 hr. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (4.13 g, 88%) as a beige solid. 'H NMR (400 MHz, DMSO-tL) 6 8.70 (s, 1H), 5.22 (t, J= 5.6 Hz, 1H), 4.64 (d, J= 5.5 Hz, 2H), 2.46 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc’d for C9H11N2O [M+H]+: 163.1. Found 163.0.
Step 3: 5-Cyano-3, 4-dimethylpicolinic acid
Figure imgf000156_0001
To a solution of 6-(hydroxymethyl)-4,5-dimethylnicotinonitrile (4.13 g, 25.46 mmol) in acetone (71.26 mL) was added dropwise a solution of KMnCti (4.43 g, 28.01 mmol) in H2O (35.63 mL) at 25 °C and the mixture was stirred for 30 minutes. The dark solid was filtered, washed with H2O, and the filtrate was concentrated to remove the organic solvent. The aqueous solution was washed with Et20, then the pH was adjusted to ~1 by addition of cone. HC1 and the solution was extracted with EtOAc (5x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (3.02 g, 67%) as ayellow solid. 'H NMR (400 MHz, DMSO- e) 6 13.83 (s, 1H), 8.78 (s, 1H), 2.50 (s, 3H), 2.33 (s, 3H). MS-ESI (m/z) calc’d for C9H9N2O2 [M+H]+: 177.1. Found 177.0.
Figure imgf000156_0002
To a solution of 5-cyano-3, 4-dimethylpicolinic acid (500.0 mg, 2.16 mmol) in DMF (4 mL) was added potassium carbonate (894.36 mg, 6.47 mmol) and iodomethane (268.57 uL, 4.31 mmol), then the mixture was stirred at 80 °C for 1 hr. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with saturated aqueous NaHCO3 (1x), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by chromatography on a 25 g silica gel column, using as a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (375 mg, 91%) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) ^ 8.82 (s, 1 H) 3.92 (s, 3 H) 2.52 (s, 3 H) 2.33 (s, 3 H). MS-ESI (m/z) calc’d for C10H11N2O2 [M+H]+: 191.1. Found 191.1. Step 6: Methyl 5-cyano-3,4-dimethyl-6-(trifluoromethyl)picolinate 0.0 mg, 2.84 mmol) and zinc
Figure imgf000157_0001
trifluoromethanesulfinate (1881.82 mg, 5.68 mmol) in DMSO (8 mL) was cooled in ice H2O. The mixture was stirred vigorously while adding 2-hydropperoxy-2-methylpropane (0.82 mL, 5.9 mmol, 70% solution in H2O). The solution was then allowed to reach room temperature and warmed at 50 °C for 2 hrs. An additional 1.3 g of sulfinate and 0.82 mL of t-butyl hydroperoxide (70% solution in H2O) were added and the reaction was stirred at 50 °C for an additional 2 hrs. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x), the combined organic phases were washed with saturated aqueous NaHCO3 (1x) and H2O (1x), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by chromatography on a 25 g silica gel column using as 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (100 mg, 20%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1 H) 3.92 (s, 3 H) 2.52 (s, 3 H) 2.33 (s, 3 H). MS-ESI (m/z) calc’d for C11H10F3N2O2 [M+H]+: 259.1. Found 259.1. Step 7: 5-Cyano-3,4-dimethyl-6-(trifluoromethyl)picolinic acid To a solution of methyl 5-cyano-3,4-dimethy
Figure imgf000157_0002
l-6-(trifluoromethyl)picolinate (100.0 mg, 0.39 mmol) in MeOH (5 mL) was added a 1 N aqueous solution of sodium hydroxide (0.39 mL, 0.39 mmol) and the mixture was stirred at r.t. for 2 hrs. Volatiles were removed under reduced pressure to afford the title compound (105 mg) which was used without further purification. 'H NMR (400 MHz, DMSO-d6) δ ppm 2.50 (s., 3 H) 2.26 (s, 3 H). MS- ESI (m/z) calc’d for C10H8F3N2O2 [M+H]+: 245.0. Found 244.9.
Step 8: 5-Cyano-3, 4-dimethyl-N-(5 -methyl- 1-( I -methyl- IH-pyr azol-4-yl)-l H-indazol-6-yl)-6- (trifluoromethyl)picolinamide
Figure imgf000158_0001
Prepared as described for 4-cyano-N-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide, using 5-cyano-3,4-dimethyl-6-(trifluoromethyl)picolinic acid in place of 4-cyano-3-(prop-l-en-2-yl)picolinic acid and 5-methyl-l-(l-methyl-17/- pyrazol-4-yl)-17/-indazol-6-amine in place of l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- amine to afford the title compound (24.5 mg, 66%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (1 H, br. s) 8.27 (1 H, s) 8.20 (1 H, d, J=0.88 Hz) 8.05 (1 H, s) 7.85 (1 H, s) 7.74 (1 H, s) 3.95 (3 H, s) 2.68 (3 H, s) 2.58 (3 H, s) 2.40 (3 H, s). MS-ESI (m/z) calc’d for C22H19F3N7O [M+H]+: 454.4. Found 454.2.
Example 22: 5-Cyaiio-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6-yl)-2-(prop-l-en-
2-yl)benzamide (22a) and 5-Cyano-2-isopropyl-7V-( l-( l-methyl-l//-pyrazol-4-yl)-l//- indazol-6-yl)benzamide (22b)
Figure imgf000158_0002
Step 1: Methyl 2-bromo-5 -cyanobenzoate
Figure imgf000158_0003
To a solution of 2-bromo-5-cyanobenzoic acid (951.0 mg, 4.21 mmol) in DMF (14.02 mL) was added iodomethane (523.86 uL, 8.41 mmol) and potassium carbonate (1.16 g, 8.41 mmol) and the mixture was stirred at 25 °C for 2 hrs. The mixture was poured into H2O and stirred for 10 minutes. The solid formed was filtered and dried under vacuum to afford the title compound (917 mg, 91%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.94 (dd, J = 8.4, 2.1 Hz, 1H), 3.89 (s, 3H). MS-ESI (m/z) calc’d for C9H7BrNO2 [M+H]+: 240.0, 242.0. Found 239.9, 241.7. Step 2: Methyl 5-cyano-2-(prop-1-en-2-yl)benzoate (240.05 mg, 1 mmol), 4,4,5,5-
Figure imgf000159_0001
tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (0.28 mL, 1.5 mmol), Pd(dppf)Cl2 (109.76 mg, 0.15 mmol) and potassium carbonate (276.42 mg, 2 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was stirred under N2 at 100 °C for 3 hrs. The mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a black residue which purified by flash silica gel chromatography using a 0-30% EtOAc/cyclohexane gradient eluent to afford the title compound (177 mg, 88%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J = 1.8, 0.5 Hz, 1H), 8.00 (dd, J = 8.0, 1.8 Hz, 1H), 7.54 (dd, J = 8.0, 0.6 Hz, 1H), 5.20 (p, J = 1.5 Hz, 1H), 4.87 (dq, J = 1.8, 0.9 Hz, 1H), 3.82 (s, 3H), 2.04 (dd, J = 1.6, 0.9 Hz, 3H). MS- ESI (m/z) calc’d for C12H12NO2 [M+H]+: 202.1 Found 202.0. Step 3: Methyl 5-cyano-2-(prop-1-en-2-yl)benzoate and Methyl 5-cyano-2-isopropylbenzoate To a solution of m
Figure imgf000159_0002
ate (177.0 mg, 0.88 mmol) in methanol (9 mL) was added 10% Pd/C (9.36 mg, 0.01 mmol) and ammonium formate (111 mg, 1.76 mmol). The mixture was stirred at 65 °C for 2 hrs. The mixture was diluted with H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford a mixture of the title compounds (170 mg, 95%) as a yellow oil. MS-ESI (m/z) calc’d for C12H12NO2 [M+H]+: 202.1. Found 202.1. MS-ESI (m/z) calc’d for C12H14NO2 [M+H]+: 204.1. Found 204.1. Step 4: 5-Cyano-2-(prop-1-en-2-yl)benzoic acid and 5-Cyano-2-isopropylbenzoic acid
Figure imgf000160_0001
ano-2- isopropylbenzoate (170.0 mg, 0.84 mmol) in THF (3.5 mL) and H2O (3.5 mL) was added LiOH•H2O (70.54 mg, 1.68 mmol) and the mixture was stirred at 25 °C for 24 hrs. The mixture was diluted with water and the pH was adjusted to ∼3 by addition of 2 N HCl. The mixture was extracted with EtOAc (3x) and the combined organic layers were passed through a phase separator and evaporated to afford a mixture of the title compounds (159.05 mg, 100%) as a beige solid. MS-ESI (m/z) calc’d for C11H10NO2 [M+H]+: 188.1. Found 188.0. MS-ESI (m/z) calc’d for C11H12NO2 [M+H]+: 190.1. Found 190.0. Step 5: 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-(prop-1-en-2- yl)benzamide (22a) Prepared as describe
Figure imgf000160_0002
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide, using 5-cyano-2-(prop-1-en-2-yl)benzoic acid in place of 4-cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (42.5 mg, 53%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.25 – 8.16 (m, 3H), 8.03 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 – 7.73 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.39 – 7.32 (m, 1H), 5.19 (s, 1H), 5.05 (s, 1H), 3.95 (s, 3H), 2.07 (s, 3H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.1. Found 383.2. Step 6: 5-Cyano-2-isopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide (22b) Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000161_0001
yl)-3-(prop-1-en-2-yl)picolinamide, using 5-cyano-2-isopropylbenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (5 mg, 7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.28 (s, 1H), 8.23 – 8.20 (m, 2H), 7.96 – 7.91 (m, 2H), 7.82 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H), 3.28 – 3.24 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2. Example 23: 3-Cyano-2,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide
Figure imgf000161_0002
15 g, 5 mmol) in DMF (16.67 mL) was added iodomethane (622.54 uL, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) and the mixture was stirred at 25 °C for 2 hrs. The mixture was then poured into H2O and extracted with Et2O (3x). The combined organic layers were washed with H2O (3x), dried over Na2SO4, and evaporated to afford the title compound (1.19 g, 98%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.93 – 3.82 (m, 3H), 2.25 (s, 3H), 2.18 (s, 3H). MS-ESI (m/z) calc’d for C10H12BrO2 [M+H]+: 243.0, 245.0. Found 243.0, 245.0. Step 2: 3-Bromo-2,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide To a mixture of 1-(1- mine (42.65 mg, 0.20 mmol)
Figure imgf000162_0001
and methyl 3-bromo-2,6-dimethylbenzoate (48.62 mg, 0.20 mmol) in toluene (2 mL) was added 2 M trimethylaluminum (0.3 mL, 0.60 mmol) and the mixture was stirred at 100 °C for 5 hrs. The reaction was carefully quenched by addition of H2O and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (32 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.33 – 8.30 (m, 1H), 8.23 – 8.20 (m, 2H), 7.82 (t, J = 1.0 Hz, 1H), 7.81 – 7.77 (m, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.38 (dd, J = 8.7, 1.7 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 2.32 (s, 3H), 2.25 (s, 3H). MS-ESI (m/z) calc’d for C20H19BrN5O [M+H]+: 424.1, 426.1. Found 424.1, 426.1. Step 3: 3-Cyano-2,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide To a mixture of 3-br
Figure imgf000162_0002
-1H-pyrazol-4-yl)-1H-indazol- 6-yl)benzamide (32.0 mg, 0.08 mmol), potassium acetate (14.8 mg, 0.15 mmol) and XPhos Pd G3 (19.15 mg, 0.02 mmol) was added 0.1 M potassium ferrocyanide (0.75 mL, 0.08 mmol) and the mixture was stirred at 100 °C for 2 hrs. The solvent was evaporated and the residue was taken up in water and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator, evaporated, and purified by prep-HPLC using Method V to afford the title compound (7.8 mg, 28%) as a beige solid.1H NMR (400 MHz, DMSO- d6) δ 10.77 (s, 1H), 8.33 – 8.29 (m, 1H), 8.25 – 8.19 (m, 2H), 7.83 (d, J = 0.8 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.41 – 7.34 (m, 2H), 3.95 (s, 3H), 2.46 (s, 3H), 2.36 (s, 3H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.2. Found 371.2. Example 24: 3-Cyano-2-cyclopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Step 1: 3-Cyano-2-cyclopropyl
Figure imgf000163_0001
To a solution of methyl 3-cyan pylbenzoate (45.79 mg, 0.230 mmol)
Figure imgf000163_0002
in THF (1.138 mL) and water (1.138 mL) was added LiOH•H2O (9.55 mg, 0.230 mmol) and the mixture was stirred at 25 °C for 24 hrs. The mixture was then diluted with H2O and the pH was adjusted to ∼3 by addition of 2 N HCl. The mixture was extracted with EtOAc (3x) and the combined organic layers were passed through a phase separator and evaporated to afford the title compound (43 mg, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 2.28 – 2.17 (m, 1H), 1.11 – 0.97 (m, 2H), 0.65 (t, J = 5.7 Hz, 2H). MS-ESI (m/z) calc’d for C11H10NO2 [M+H]+: 188.1. Found 188.0. Step 2: 3-Cyano-2-cyclopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide
Figure imgf000163_0003
yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyano-2-cyclopropylbenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid (120 mg) which was purified by prep-HPLC using Method W to afford the title compound (55.5 mg, 73%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.28 (s, 1H), 8.25 – 8.20 (m, 2H), 7.92 (dd, J = 7.8, 1.4 Hz, 1H), 7.82 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 7.7, 1.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.40 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H), 2.32 – 2.22 (m, 1H), 1.01 – 0.92 (m, 2H), 0.71 – 0.64 (m, 2H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.2. Found 383.2. Example 25: 2-Chloro-4-cyano-6-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe pyrazol-4-yl)-1H-indazol-6-
Figure imgf000164_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 2-chloro-4-cyano-6-fluorobenzoic acid in place of 4-cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (60 mg, 76%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.24 (d, J = 1.0 Hz, 1H), 8.23 (d, J = 0.8 Hz, 1H), 8.21 (dt, J = 1.8, 0.8 Hz, 1H), 8.16 (t, J = 1.1 Hz, 1H), 8.13 (dd, J = 8.6, 1.3 Hz, 1H), 7.84 (dd, J = 8.7, 0.7 Hz, 1H), 7.82 (d, J = 0.9 Hz, 1H), 7.32 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C19H13ClFN6O [M+H]+: 395.1. Found 395.1. Example 26: 5-Cyano-3,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide g, 5 mmol)
Figure imgf000164_0002
and tributyl(ethenyl)stannane (1.46 mL, 5 mmol) in toluene (25 mL) was purged with N2 for 10 minutes. Tetrakis(triphenylphosphine) palladium(0) (0.29 g, 0.250 mmol) was added and the mixture was stirred at 100 °C under N2 for 3 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-10% EtOAc/cyclohexane gradient eluent to afford the title compound (1.06 g, 100%) as a clear oil.1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.95 (dd, J = 16.9, 10.6 Hz, 1H), 6.28 (dd, J = 16.9, 2.5 Hz, 1H), 5.49 (dd, J = 10.7, 2.5 Hz, 1H), 2.53 (s, 3H), 2.29 (d, J = 1.1 Hz, 3H). MS-ESI (m/z) calc’d for C8H11BrN [M+H]+: 212.0, 214.0. Found 212.0, 214.0. Step 2: 5-Bromo-3,6-dimethylpicolinic acid To a solution of 3-bromo-2,5
Figure imgf000165_0001
lpyridine (1.06 g, 5 mmol) in acetone (25 mL) was added a solution of potassium permanganate (1.74 g, 11 mmol) in H2O (25 mL) and the mixture was stirred at 25 °C for 2 days. The excess permanganate was quenched by addition of formic acid, then the solid was removed by filtration. The filtrate was evaporated and the residue was taken up in H2O and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (900 mg, 78%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.01 (s, 1H), 2.55 (s, 3H), 2.39 (s, 3H). MS-ESI (m/z) calc’d for C8H9BrNO2 [M+H]+: 230.0, 232.0. Found 230.0, 232.0. Step 3: Methyl 5-bromo-3,6-dimethylpicolinate To a solution of 5-bromo-3,6
Figure imgf000165_0002
ic acid (900.0 mg, 3.91 mmol) in DMF (6.52 mL) was added potassium carbonate (1.62 g, 11.74 mmol) and iodomethane (0.49 mL, 7.82 mmol) and then the mixture was stirred at 80 °C for 1 hr. The mixture was then poured into H2O (150 mL) and stirred for 10 minutes. The solid that formed was filtered and dried under vacuum to afford the title compound (833 mg, 87%) as a brown liquid.1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 3.85 (s, 3H), 2.56 (s, 3H), 2.40 (s, 3H). MS-ESI (m/z) calc’d for C9H11BrNO2 [M+H]+: 244.0, 246.0. Found 244.0, 246.0. Step 4: Methyl 3,6-dimethyl-5-vinylpicolinate A solution of methyl 5-bromo-3 ate (0.83 g, 3.41 mmol)
Figure imgf000165_0003
and tributyl(ethenyl)stannane (1.99 mL, 6.83 mmol) in 1,4-dioxane (34.13 mL) was purged with N2 for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.24 g, 0.340 mmol) was added and the mixture was stirred at 100 °C under N2 for 2 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-20% EtOAc/cyclohexane gradient eluent to afford the title compound (460 mg, 70%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 6.94 (dd, J = 17.5, 11.2 Hz, 1H), 5.92 (dd, J = 17.4, 1.2 Hz, 1H), 5.52 (dd, J = 11.0, 1.1 Hz, 1H), 3.84 (s, 3H), 2.49 (s, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc’d for C11H14 NO2 [M+H]+: 192.1. Found 192.1. Step 5: Methyl 5-formyl-3,6-dimethylpicolinate To a solution of methyl 3,6- colinate (460.0 mg, 2.41 mmol) in 1,4-
Figure imgf000166_0001
dioxane (12 mL) was added a solution of sodium periodate (1.03 g, 4.81 mmol) in water (12 mL) and the mixture was stirred at 25 °C for 5 minutes. Osmium tetroxide (766 uL, 0.12 mmol) was added and the reaction was then stirred for 1 hr. The mixture was partitioned between DCM and H2O and the layers were separated. The H2O layer was washed with DCM (2x) and the combined organic layers were passed through a phase separator and evaporated to afford the title compound (464 mg, 100%) as a dark solid.1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.15 (s, 1H), 3.89 (s, 3H), 2.76 (s, 3H), 2.44 (t, J = 0.7 Hz, 3H). MS-ESI (m/z) calc’d for C10H12NO3 [M+H]+: 194.1. Found 194.1. Step 6: Methyl 5-cyano-3,6-dimethylpicolinate To a solution of methyl 5-fo
Figure imgf000166_0002
picolinate (464.75 mg, 2.41 mmol) in DMSO (2.406 mL) was added hydroxylamine hydrochloride (183.88 mg, 2.65 mmol) and the mixture was stirred at 90 °C for 4 hrs. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with H2O (3x), passed through a phase separator, and evaporated to afford the title compound (380 mg, 83%) as a purple solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 3.89 (s, 3H), 2.65 (s, 3H), 2.41 (s, 3H). MS-ESI (m/z) calc’d for C10H11N2O2 [M+H]+: 191.2. Found 191.2. Step 7: 5-Cyano-3,6-dimethylpicolinic acid
Figure imgf000167_0001
To a solution of methyl 5-cyano-3,6-dimethylpicolinate (380.0 mg, 2 mmol) in THF (10 mL) was added a solution of sodium hydroxide (81.93 mg, 2 mmol) in H2O (5 mL) and the mixture was stirred at 25 °C for 2 hrs. The THF was evaporated and the solution was extracted with Et20. The combined aqueous layers were acidified by addition of 1 M HC1 and extracted with EtOAc (6x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (260 mg, 74%) as a grey-purple solid. 'H NMR (400 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.25 (s, 1H), 2.65 (s, 3H), 2.39 (s, 3H). MS- ESI (m/z) calc’d for C9H9N2O2 [M+H]+: 177.1. Found 177.1.
Step 8: 5-Cyano-3, 6-dimethyl-N-(l-(l -methyl- IH-pyr azol-4-yl)-l H-indazol-6- yl)picolinamide
Figure imgf000167_0002
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide using 5-cyano-3,6-dimethylpicolinic acid in place of 4- cyano-3-(prop-l-en-2-yl)picolinic acid to afford the title compound (61 mg, 82%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.85 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H), 2.75 (s, 3H), 2.51 (s, 3H). MS-ESI (m/z) calc’d for C20H18N7O [M+H]+: 372.1. Found 372.1.
Example 27 : 6-Cyano-2-methyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l //-indazol-6- yl)nicotinamide
Figure imgf000167_0003
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 6-cyano-2-methylnicotinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (58 mg, 81%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.27 (s, 1H), 8.23 (d, J = 1.0 Hz, 1H), 8.22 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.86 – 7.79 (m, 2H), 7.39 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 2.62 (s, 3H). MS-ESI (m/z) calc’d for C19H16N7O [M+H]+: 358.1. Found 358.1. Example 28: 2-Bromo-6-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)nicotinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000168_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 2-bromo-6-cyanonicotinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (70 mg, 83%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.26 – 8.23 (m, 1H), 8.22 (dd, J = 6.3, 0.9 Hz, 2H), 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.82 (dd, J = 8.6, 0.7 Hz, 1H), 7.81 (d, J = 0.8 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.37 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H) MS-ESI (m/z) calc’d for C18H13BrN7O [M+H]+: 421.0, 423.0. Found 421.0, 423.0. Example 29: 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)pyrazine-2- carboxamide Prepared as describe
Figure imgf000168_0002
pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyanopyrazine-2-carboxylic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (61 mg, 89%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.45 (d, J = 1.5 Hz, 1H), 9.40 (d, J = 1.5 Hz, 1H), 8.41 (dd, J = 1.7, 0.9 Hz, 1H), 8.24 (d, J = 1.0 Hz, 2H), 7.87 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.79 (dd, J = 8.8, 1.7 Hz, 1H), 3.97 (s, 3H). MS-ESI (m/z) calc’d for C17H13N8O [M+H]+: 345.1. Found 345.1. Example 30: 5-Cyano-3-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe
Figure imgf000169_0001
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyanopyrazine-2-carboxylic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (39 mg, 54%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.09 – 9.03 (m, 1H), 8.68 (dd, J = 10.2, 1.6 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.24 (s, 1H), 8.23 (d, J = 1.0 Hz, 1H), 7.86 – 7.85 (m, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.58 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C18H13FN7O [M+H]+: 362.1. Found 362.1. Example 31: 6-Cyano-4-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)nicotinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000169_0002
yl)-3-(prop-1-en-2-yl)picolinamide using 6-cyano-4-methylnicotinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (39 mg, 54%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.28 (s, 1H), 8.24 – 8.22 (m, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 2.48 (s, 3H). MS-ESI (m/z) calc’d for C19H16N7O [M+H]+: 358.1. Found 358.1. Example 32: 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)picolinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000170_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyanopicolinic acid in place of 4-cyano-3-(prop- 1-en-2-yl)picolinic acid to afford the title compound (55 mg, 80%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.22 (dd, J = 2.1, 0.9 Hz, 1H), 8.60 (dd, J = 8.2, 2.1 Hz, 1H), 8.42 (q, J = 1.0 Hz, 1H), 8.32 (dd, J = 8.2, 0.9 Hz, 1H), 8.25 (d, J = 0.8 Hz, 1H), 8.23 (d, J = 1.0 Hz, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.83 (dd, J = 8.8, 0.8 Hz, 1H), 7.80 (dd, J = 8.7, 1.6 Hz, 1H), 3.97 (s, 3H). MS-ESI (m/z) calc’d for C18H14N7O [M+H]+: 344.1. Found 344.1. Example 33: 4-Cyano-2-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe
Figure imgf000170_0002
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 4-cyano-2-methylbenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (55 mg, 80%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.29 (s, 1H), 8.24 – 8.19 (m, 2H), 7.85 (d, J = 1.5 Hz, 1H), 7.82 (s, 3H), 7.67 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.6, 1.7 Hz, 1H), 3.95 (s, 3H), 2.42 (s, 3H). MS-ESI (m/z) calc’d for C20H17N6O [M+H]+: 357.1. Found 357.1. Example 34: 4-Cyano-2-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000170_0003
yl)-3-(prop-1-en-2-yl)picolinamide using 4-cyano-2-methoxybenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (57 mg, 76%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.30 (s, 1H), 8.24 – 8.19 (m, 2H), 7.82 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.54 (dd, J = 7.8, 1.4 Hz, 1H), 7.37 (dd, J = 8.8, 1.6 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H). MS-ESI (m/z) calc’d for C20H17N6O2 [M+H]+: 373.1. Found 373.1. Example 35: 3-Chloro-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000171_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 3-chloro-5-cyanopicolinic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (62.5 mg, 84%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.12 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.24 (dt, J = 6.0, 1.0 Hz, 3H), 7.83 (dd, J = 4.8, 3.9 Hz, 2H), 7.43 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C18H13ClN7O [M+H]+: 378.1. Found 378.1. Example 36: 2-Chloro-4-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe
Figure imgf000171_0002
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 2-chloro-4-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (62.5 mg, 84%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.25 (dd, J = 1.8, 0.9 Hz, 1H), 8.23 (dd, J = 2.1, 1.2 Hz, 2H), 8.21 (d, J = 0.8 Hz, 1H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.88 – 7.78 (m, 3H), 7.37 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C19H14ClN6O [M+H]+: 377.1. Found 377.1. Example 37: 5-Cyano-3,4,6-trimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide
Figure imgf000172_0001
ylpyridine-3-carbonitrile (150.0 mg, 0.76 mmol), potassium carbonate (210.87 mg, 1.53 mmol) and trimethylboroxine (0.21 mL, 1.53 mmol) in 1,4-dioxane (2 mL) and H2O (1 mL) was degassed with N2 for 15 min. Then tetrakis(triphenylphosphine) palladium(0) (176.3 mg, 0.15 mmol) was added and the mixture was stirred at 90 °C for 6 hrs. The residue was taken up in H2O and extracted with EtOAc (2x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-98% MeCN/ H2O (0.1% formic acid) gradient eluent to afford the title compound (83 mg, 62%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 5.19 (t, J = 5.5 Hz, 1H), 4.60 (d, J = 5.5 Hz, 2H), 2.62 (s, 3H), 2.44 (s, 3H), 2.25 (s, 3H). MS-ESI (m/z) calc’d for C10H13N2O [M+H]+: 177.0. Found 177.0. Step 2: 5-Cyano-3,4,6-trimethylpicolinic acid To a solution of 6-(hydroxy
Figure imgf000172_0002
ethylnicotinonitrile (83.0 mg, 0.47 mmol) in acetone (1.5 mL) was added dropwise a solution of potassium permanganate (81.88 mg, 0.52 mmol) in H2O (0.75 mL) at r.t. and the mixture was stirred for 2 hrs. The dark solid was removed by filtration and the filtrate was washed with 1 M K2CO3 solution, concentrated to remove the organic solvent, and extracted with EtOAc. Then the pH of the aqueous layer was adjusted to 2 by addition of 6 M HCl and the solution was extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (90 mg, 100%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.63 (br s, 1H), 2.63 (s, 3H), 2.49 (s, 3H), 2.29 (s, 3H). MS-ESI (m/z) calc’d for C10H11N2O2 [M+H]+: 189.2. Found 189.2. Step 3: 5-Cyano-3,4,6-trimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000173_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyano-3,4,6-trimethylpicolinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (63 mg, 84%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.28 (dd, J = 1.8, 0.9 Hz, 1H), 8.23 (d, J = 0.8 Hz, 1H), 8.22 (d, J = 1.0 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.81 (dd, J = 8.6, 0.7 Hz, 1H), 7.48 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 2.71 (s, 3H), 2.53 (s, 3H), 2.37 (s, 3H). MS-ESI (m/z) calc’d for C21H20N7O [M+H]+: 386.2. Found 386.2. Example 38: 5-Cyano-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000173_0002
yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyano-6-methylpicolinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (36 mg, 50%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 8.29 – 8.20 (m, 2H), 8.12 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.75 (dd, J = 8.8, 1.7 Hz, 1H), 3.96 (s, 3H), 2.86 (s, 3H) MS-ESI (m/z) calc’d for C19H16N7O [M+H]+: 358.1. Found 358.1. Example 39: 4-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- (trifluoromethyl)benzamide Prepared as describe
Figure imgf000174_0001
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 4-cyano-2-(trifluoromethyl)benzoic acid in place of 4-cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (28 mg, 34%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.51 – 8.46 (m, 1H), 8.33 (dd, J = 7.9, 1.6 Hz, 1H), 8.23 (d, J = 1.0 Hz, 1H), 8.21 (d, J = 0.8 Hz, 1H), 8.19 (dt, J = 1.8, 0.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.82 (dd, J = 9.0, 0.8 Hz, 2H), 7.35 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C20H14F3N6O [M+H]+: 411.1. Found 411.1. Example 40: 6-Chloro-3-cyano-2-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide To a mixture of 1-(1
Figure imgf000174_0002
ine (42.65 mg, 0.200 mmol) and methyl 3-cyano-6-chloro-2-fluorobenzoate (42.72 mg, 0.20 mmol) in toluene (2 mL) was added 2 M trimethylaluminum (0.3 mL, 0.60 mmol) and the mixture was stirred at 100 °C for 3 hrs. The reaction was quenched by addition of Na2SO4•10 H2O, then diluted with EtOAc and filtered under vacuum. The filtrate was evaporated and purified by prep- HPLC (Method X) to afford the title compound (25 mg, 32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.27 – 8.23 (m, 2H), 8.21 – 8.18 (m, 1H), 8.13 (dd, J = 8.5, 7.1 Hz, 1H), 7.89 – 7.81 (m, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C19H13ClFN6O [M+H]+: 395.1. Found 395.1. Compound 41: 6-Cyano-3-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe -(1-(1-methyl-1H-pyrazol-4-
Figure imgf000175_0001
yl)-1H-indazol-6-yl)benzamide using methyl 6-cyano-3-methylpyridine-2-carboxylate in place of methyl 3-cyano-6-chloro-2-fluorobenzoate. The material was purified by prep- HPLC (Method Y) to afford the title compound (42 mg, 59%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 10.81 (s, 1H), 8.29 (dt, J = 1.8, 0.9 Hz, 1H), 8.23 (dd, J = 4.9, 0.9 Hz, 2H), 8.15 (d, J = 8.0 Hz, 1H), 8.10 (dd, J = 8.0, 0.8 Hz, 1H), 7.85 (d, J = 0.8 Hz, 1H), 7.82 (dd, J = 8.7, 0.7 Hz, 1H), 7.57 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H), 2.60 (s, 3H) MS- ESI (m/z) calc’d for C19H16N7O [M+H]+: 358.1. Found 358.1. Compound 42: 5-Cyano-2-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe
Figure imgf000175_0002
-(1-(1-methyl-1H-pyrazol-4- yl)-1H-indazol-6-yl)benzamide using methyl 5-cyano-2-fluorobenzoate in place of methyl 3- cyano-6-chloro-2-fluorobenzoate. The material was purified by prep-HPLC using Method Y to afford the title compound (33 mg, 45%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.27 (dd, J = 6.4, 2.2 Hz, 1H), 8.25 (s, 1H), 8.23 (d, J = 1.0 Hz, 1H), 8.22 (s, 1H), 8.12 (ddd, J = 8.7, 4.7, 2.2 Hz, 1H), 7.87 – 7.79 (m, 2H), 7.64 (dd, J = 9.7, 8.7 Hz, 1H), 7.41 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C19H14FN6O [M+H]+: 361.1. Found 361.1. Compound 43: 2-Chloro-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)nicotinamide
Figure imgf000175_0003
Prepared as described for 6-chloro-3-cyano-2-fluoro-N-(1-(1-methyl-1H-pyrazol-4- yl)-1H-indazol-6-yl)benzamide, using methyl 2-chloro-5-cyanopyridine-3-carboxylate in place of methyl 3-cyano-6-chloro-2-fluorobenzoate. The material was purified by prep- HPLC using Method Y to afford the title compound (50 mg, 66%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.06 (d, J = 2.3 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 1.0 Hz, 1H), 8.23 – 8.20 (m, 2H), 7.84 (dd, J = 8.7, 0.7 Hz, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.35 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C18H13ClN7O [M+H]+: 378.1. Found 378.1. Example 44: 2-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)isonicotinamide Prepared as describe
Figure imgf000176_0001
-(1-(1-methyl-1H-pyrazol-4- yl)-1H-indazol-6-yl)benzamide, using methyl 2-cyanoisonicotinate in place of methyl 3- cyano-6-chloro-2-fluorobenzoate. The material was purified via prep-HPLC (Method Z) to afford the title compound (26 mg, 37%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.99 (dd, J = 5.1, 0.9 Hz, 1H), 8.54 (dd, J = 1.8, 0.9 Hz, 1H), 8.27 (dt, J = 1.7, 0.8 Hz, 1H), 8.24 (d, J = 1.0 Hz, 1H), 8.23 (d, J = 0.8 Hz, 1H), 8.21 (dd, J = 5.0, 1.7 Hz, 1H), 7.85 (dd, J = 8.7, 0.7 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.54 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C18H14N7O [M+H]+: 344.1. Found 344.2. Example 45: 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)nicotinamide Prepared as describe -(1-(1-methyl-1H-pyrazol-4-
Figure imgf000176_0002
yl)-1H-indazol-6-yl)benzamide, using methyl 5-cyanonicotinate in place of methyl 3-cyano- 6-chloro-2-fluorobenzoate. The material was purified by prep-HPLC using Method AA to afford the title compound (46.3 mg, 67%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.36 (d, J = 2.2 Hz, 1H), 9.24 (d, J = 2.0 Hz, 1H), 8.84 (t, J = 2.1 Hz, 1H), 8.28 (s, 1H), 8.27 – 8.21 (m, 2H), 7.85 (d, J = 8.9 Hz, 2H), 7.54 (dd, J = 8.7, 1.7 Hz, 1H), 3.97 (s, 3H). MS-ESI (m/z) calc’d for C18H14N7O [M+H]+: 344.1. Found 344.2. Example 46: 5-Cyano-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)nicotinamide Prepared as describe -(1-(1-methyl-1H-pyrazol-4-
Figure imgf000177_0001
yl)-1H-indazol-6-yl)benzamide, using methyl 5-cyanonicotinate in place of methyl 3-cyano- 6-chloro-2-fluorobenzoate. The material was purified via prep-HPLC using Method X to afford the title compound (48.6 mg, 68%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 2.3 Hz, 1H), 8.27 (p, J = 0.8 Hz, 1H), 8.25 – 8.21 (m, 2H), 7.86 – 7.82 (m, 2H), 7.54 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H), 2.78 (s, 3H). MS-ESI (m/z) calc’d for C19H16N7O [M+H]+: 358.1. Found 358.2. Example 47: 2-Bromo-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000177_0002
yl)-3-(prop-1-en-2-yl)picolinamide using 2-bromo-5-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (48 mg, 57%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.27 – 8.13 (m, 4H), 7.99 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.7, 2.0 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H14BrN6O [M+H]+: 421.0, 423.0. Found 421.0, 423.0. Example 48: 3-Cyano-2,6-difluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000178_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyano-2,6-difluorobenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (57.7 mg, 76%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.29 – 8.18 (m, 4H), 7.88 – 7.80 (m, 2H), 7.63 – 7.52 (m, 1H), 7.33 (dd, J = 8.6, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C19H13F2N6O [M+H]+: 379.1. Found 379.1. Example 49: 2-Bromo-3-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe
Figure imgf000178_0002
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 2-bromo-3-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (52 mg, 62%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.25 (dt, J = 1.7, 0.8 Hz, 1H), 8.22 (dd, J = 5.7, 0.9 Hz, 2H), 8.07 (dd, J = 7.8, 1.6 Hz, 1H), 7.91 (dd, J = 7.7, 1.6 Hz, 1H), 7.85 – 7.80 (m, 2H), 7.72 (t, J = 7.7 Hz, 1H), 7.37 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H14BrN6O [M+H]+: 421. Found 421, 423. Example 50: 3-Cyano-2-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000178_0003
yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyano-2-fluorobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (57 mg, 79%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.27 – 8.18 (m, 3H), 8.13 (td, J = 6.9, 6.0, 1.8 Hz, 1H), 8.06 (td, J = 8.2, 7.6, 1.8 Hz, 1H), 7.83 (t, J = 4.3 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.40 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C19H14FN6O [M+H]+: 361.1. Found 361.1. Example 51: 3-Bromo-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000179_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 3-bromo-5-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (55 mg, 65%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.50 – 8.39 (m, 3H), 8.29 – 8.19 (m, 3H), 7.84 (t, J = 4.4 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H14BrN6O [M+H]+: 421.0, 423.0. Found 421.0, 423.0. Example 52: 4-Cyano-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide Prepared as describe
Figure imgf000179_0002
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 4-cyano-6-methylpicolinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (48.6 mg, 68%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 3.96 (s, 3H), 2.72 (s, 3H). MS-ESI (m/z) calc’d for C19H16N7O [M+H]+: 358.1. Found 358.1. Example 53: 5-Cyano-2-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000180_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 5-cyano-2-methylbenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (52 mg, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.28 (s, 1H), 8.25 – 8.18 (m, 2H), 8.00 (d, J = 1.8 Hz, 1H), 7.88 (dd, J = 7.9, 1.8 Hz, 1H), 7.84 – 7.78 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 2.47 (s, 3H). MS-ESI (m/z) calc’d for C20H17N6O [M+H]+: 357.1. Found 357.1. Example 54: 2-Chloro-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describ
Figure imgf000180_0002
-pyrazol-4-yl)-1H-indazol-6- yl)-3-(prop-1-en-2-yl)picolinamide using 2-chloro-5-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid to afford the title compound (43.8 mg, 58%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.28 – 8.18 (m, 4H), 8.02 (dd, J = 8.4, 2.1 Hz, 1H), 7.87 – 7.80 (m, 3H), 7.38 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H14ClN6O [M+H]+: 377.1. Found 377.1. Example 55: 3-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000180_0003
yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyanobenzoic acid in place of 4-cyano-3-(prop- 1-en-2-yl)picolinic acid. The material was purified via prep-HPLC using Method AB to afford the title compound (48.5 mg, 71%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.44 (t, J = 1.7 Hz, 1H), 8.31 – 8.26 (m, 2H), 8.23 (dd, J = 2.1, 0.9 Hz, 2H), 8.09 (dt, J = 7.7, 1.4 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.57 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H15N6O [M+H]+: 343.1. Found 343.1. Example 56: 3-Cyano-2-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000181_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyano-2-methylbenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid. The material was purified via prep-HPLC using Method Z to afford the title compound (49 mg, 69%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.30 (s, 1H), 8.21 (t, J = 1.1 Hz, 2H), 7.94 (dd, J = 7.7, 1.4 Hz, 1H), 7.86 – 7.77 (m, 3H), 7.54 (t, J = 7.7 Hz, 1H), 7.41 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 2.56 (s, 3H). MS-ESI (m/z) calc’d for C20H17N6O [M+H]+: 357.1. Found 357.2. Example 57: 3-Cyano-2-methoxy-N-[1-(1-methylpyrazol-4-yl)indazol-6-yl]benzamide
Figure imgf000181_0002
200.0 mg, 1.05 mmol) in THF (2.6 mL) was added 1 M NaOH (2.09 mL, 2.1 mmol) and the mixture was stirred at r.t. for 6 hrs. The organic solvent was evaporated, the mixture was acidified by addition of 1 M HCl and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (146 mg, 79%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H), 8.00 (ddd, J = 8.9, 7.8, 1.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C9H8NO3 [M+H]+: 178.0. Found 178.0. Step 2: 3-Cyano-2-methoxy-N-[1-(1-methylpyrazol-4-yl)indazol-6-yl]benzamide H-indazol-6-
Figure imgf000182_0001
yl)-3-(prop-1-en-2-yl)picolinamide using 3-cyano-2-methoxybenzoic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (40 mg, 54%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.29 – 8.26 (m, 1H), 8.24 – 8.20 (m, 2H), 7.96 (dd, J = 7.7, 1.7 Hz, 1H), 7.88 (dd, J = 7.7, 1.7 Hz, 1H), 7.84 – 7.78 (m, 2H), 7.43 – 7.38 (m, 2H), 3.99 (s, 3H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C20H17N6O2 [M+H]+: 373.1. Found 373.2. Example 58: 2-Chloro-3-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describe -pyrazol-4-yl)-1H-indazol-6-
Figure imgf000182_0002
yl)-3-(prop-1-en-2-yl)picolinamide using 2-chloro-3-cyanobenzoic acid in place of 4-cyano- 3-(prop-1-en-2-yl)picolinic acid. The material was purified by prep-HPLC using Method Y to afford the title compound (37 mg, 49%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.26 (p, J = 0.8 Hz, 1H), 8.24 – 8.20 (m, 2H), 8.13 (dd, J = 7.8, 1.6 Hz, 1H), 7.98 (dd, J = 7.7, 1.6 Hz, 1H), 7.85 – 7.80 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H14ClN6O [M+H]+: 377.1. Found 377.1. Example 59: 5-Cyano-3,4-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)- 6-(trifluoromethyl)picolinamide
Figure imgf000183_0001
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide using 5-cyano-3,4-dimethyl-6-(trifluoromethyl)picolinic acid in place of 4-cyano-3-(prop-l-en-2-yl)picolinic acid. The material was purified by prep- HPLC using Method AC to afford the title compound (21 mg, 47%) as a beige solid. 'H NMR (400 MHz, DMSO-d6) δ 10.97 (1 H, br. s.) 8.15 - 8.33 (3 H, m) 7.73 - 7.92 (2 H, m) 7.42 (1 H, dd, J=8.69, 1.65 Hz) 3.96 (3 H, s) 2.68 (3 H, s) 2.48 (3 H, s). MS-ESI (m/z) calc’d for C21H17F3N7O [M+H]+: 440.1. Found 440.1.
Example 60: 4-Cyano-3-methyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6- yl)picolinamide
Figure imgf000183_0002
Ethyl 3-chloro-4-cyanopyridine-2-carboxylate (250.0 mg, 1.19 mmol) and trimethylboroxine (223.5 mg, 1.78 mmol) were dissolved in 1,4-di oxane (5 mL) and potassium carbonate (492.15 mg, 3.56 mmol) was added. The mixture was degassed with N2 for 5 minutes; tetrakis(triphenylphosphine) palladium(O) (137.16 mg, 0.12 mmol) was added and the mixture was stirred at 100 °C under N2 for 6 hrs. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (120 mg, 53%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 8.65 - 8.78 (m, 1 H) 8.03 (d, J=4.84 Hz, 1 H) 4.39 (q, J=7.12 Hz, 2 H) 2.60 (s, 3 H) 1.34 (t, J=7.15 Hz, 3 H). MS-ESI (m/z) calc’d for C10H11N2O2 [M+H]+: 191.1. Found 191.1. Step 2: 4-Cyano-3-methylpicolinic acid To a solution of ethyl 4-cya
Figure imgf000184_0001
ate (120.0 mg, 0.63 mmol) in THF (3.8 mL) was added 2 M NaOH (0.32 mL, 0.63 mmol) and the mixture was stirred at 25 °C for 30 minutes. The solvent was evaporated and the residue was taken up in 1 M HCl and extracted with EtOAc (3x) The combined organic layers were passed through a phase separator and evaporated to afford the title compound (95 mg, 93%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 8.68 (dd, J = 4.9, 0.7 Hz, 1H), 7.97 (d, J = 4.9 Hz, 1H), 2.60 (s, 3H). MS-ESI (m/z) calc’d for C8H7N2O2 [M+H]+: 162.0. Found 162.9. Step 3: 4-Cyano-3-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)picolinamide 6-
Figure imgf000184_0002
yl)-3-(prop-1-en-2-yl)picolinamide using 4-cyano-3-methylpicolinic acid in place of 4- cyano-3-(prop-1-en-2-yl)picolinic acid to afford the title compound (60 mg, 84%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.78 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.26 – 8.20 (m, 2H), 8.06 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.59 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H), 2.73 (s, 3H). MS-ESI (m/z) calc’d for C19H16N7O [M+H]+: 358.1. Found 358.1. Example 61: 6-Chloro-1-((1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-2,3- dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2 Step 1: 1-
Figure imgf000184_0003
A mixture of 1H-indazol-6-
Figure imgf000185_0001
), 4-iodo-1-methylpyrazole (6.24 g, 30 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.42 g, 10 mmol), cuprous iodide (761.8 mg, 4 mmol) and potassium phosphate (4.24 g, 20 mmol) in dry DMSO (50 mL) was stirred at 25 °C under N2 atmosphere for 24 hrs. The mixture was diluted with aqueous citrate buffer (pH 3) and extracted with EtOAc (3x); solids were removed by filtration. The combined organic layers were washed with H2O (3x), dried over Na2SO4, evaporated and triturated with Et2O to afford the title compound (1.22 g, 28%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.20 (d, J = 0.8 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.61 (dd, J = 8.7, 0.6 Hz, 1H), 6.89 (dt, J = 1.8, 0.8 Hz, 1H), 6.75 (dd, J = 8.7, 2.0 Hz, 1H), 3.92 (s, 3H). MS-ESI (m/z) calc’d for C11H11N4O [M+H]+: 215.0. Found 215.0. Step 2: 5-Bromo-6-chloro-2,3-dihydro-1H-inden-1-ol To a solution of 5-bromo-6-c
Figure imgf000185_0002
roinden-1-one (330.0 mg, 1.34 mmol) in methanol (4.5 mL) was added sodium borohydride (51.31 mg, 1.36 mmol) at 25 °C and the resulting mixture was stirred for 1 hr. The reaction was concentrated under reduced pressure and then saturated aqueous NaHCO3 (50 mL) was added. The mixture was extracted with DCM (3x 50 mL) and then the organic phase was filtered through a phase separator and concentrated under reduced pressure to afford the title compound (304 mg, 91%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.48 (s, 1H), 5.41 (s, 1H), 5.01 (t, J = 6.8 Hz, 1H), 2.89 (ddd, J = 16.3, 8.7, 3.9 Hz, 1H), 2.79 – 2.63 (m, 1H), 2.43 – 2.27 (m, 1H), 1.88 – 1.70 (m, 1H). MS-ESI (m/z) calc’d for C9H9BrClO [M+H-H2O]+: 228.9, 230.9. Found 228.9, 230.9. Step 3: 6-((5-Bromo-6-chloro-2,3-dihydro-1H-inden-1-yl)oxy)-1-(1-methyl-1H-pyrazol-4-yl)- 1H-indazole To a cooled (0°C) so .39 mg, 1.71 mmol) in DCM
Figure imgf000186_0001
(11.73 mL) was added diisopropyl azodicarboxylate (0.22 mL, 1.14 mmol). After 10 min a suspension of 5-bromo-6-chloro-2,3-dihydro-1H-inden-1-ol (304.0 mg, 1.14 mmol) and 1- (1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-ol (244.68 mg, 1.14 mmol) in DCM (11.73 mL) was added and the mixture was stirred at 25 °C for 1 hr. Water was added and the mixture was extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was filtered through a basic alumina pad (the pad was washed 3x with 10 mL of EtOAc) and then the filtrate was concentrated under reduced pressure. The material was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford a yellow oil which was further purified by filtration through a basic alumina pad (the pad was washed 3x with 10 mL of EtOAc) and then the filtrate was concentrated under reduced pressure to afford the title compound (170 mg, 33%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.21 (s, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.10 – 5.97 (m, 1H), 3.93 (s, 3H), 3.12 – 2.99 (m, 1H), 2.99 – 2.84 (m, 1H), 2.71 – 2.59 (m, 1H), 2.18 – 2.03 (m, 1H). MS-ESI (m/z) calc’d for C20H17BrClN4O [M+H]+: 443.1, 445.1. Found 443.1, 445.1. Step 4: 6-Chloro-1-((1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H- indene-5-carbonitrile
Figure imgf000186_0002
Potassium hexacyanoferrate (II), 0.1 N standardized solution (1.56 mL, 0.16 mmol), 6-((5-bromo-6-chloro-2,3-dihydro-1H-inden-1-yl)oxy)-1-(1-methyl-1H-pyrazol-4- yl)-1H-indazole (138.0 mg, 0.31 mmol) and potassium acetate (30.52 mg, 0.31 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and H2O (0.7 mL). The mixture was degassed with N2 for 15 minutes. Then XPHOS (22.24 mg, 0.05 mmol) and XPHOS PD G3 (39.49 mg, 0.05 mmol) were added and the mixture was stirred at 100 °C for 1 hr. Additional XPHOS (22.24 mg, 0.05 mmol), potassium acetate (30.52 mg, 0.31 mmol), and XPHOS PD G3 (39.49 mg, 0.05 mmol) were then added and the mixture was stirred at 100 °C for an additional 45 min. The reaction mixture was partitioned between H2O (100 mL) and EtOAc (100 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (101 mg, 83%) as a racemic mixture. Step 5: 6-Chloro-1-((1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H- indene-5-carbonitrile, enantiomer 1 and 2 6
Figure imgf000187_0001
ihydro-1H- indene-5-carbonitrile was subjected to chiral separation using Method AD to afford 6-chloro- 1-[1-(1-methylpyrazol-4-yl)indazol-6-yl]oxy-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 (1 mg, 1%), as a white solid.1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.00 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.8, 2.1 Hz, 1H), 5.80 (t, J = 6.1 Hz, 1H), 4.01 (s, 3H), 3.15 (ddd, J = 16.6, 8.9, 4.6 Hz, 1H), 2.97 (dt, J = 16.1, 7.5 Hz, 1H), 2.76 – 2.63 (m, 1H), 2.35 – 2.22 (m, 1H). MS-ESI (m/z) calc’d for C21H17ClN5O [M+H]+: 390.1. Found 390.1. A later eluting fraction was also isolated to afford 6-chloro-1-[1-(1-methylpyrazol-4-yl)indazol-6-yl]oxy-2,3- dihydro-1H-indene-5-carbonitrile, enantiomer 2 (1 mg, 1%) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 1.0 Hz, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.00 (s, 1H), 6.93 – 6.89 (m, 1H), 5.80 (t, J = 6.1 Hz, 1H), 4.01 (s, 3H), 3.15 (ddd, J = 16.6, 8.8, 4.6 Hz, 1H), 2.97 (dt, J = 16.2, 7.6 Hz, 1H), 2.75 – 2.63 (m, 1H), 2.34 – 2.23 (m, 1H).. MS-ESI (m/z) calc’d for C21H17ClN5O [M+H]+: 390.1. Found 390.1. Example 62: 5-((5-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000188_0001
To a solution of 6-cyano-l -tetral one (3.42 g, 20 mmol) in MeOH (66.67 mL) was added sodium borohydride (1.51 g, 40 mmol) and the mixture was stirred at 25 °C for 30 minutes. The solvent was evaporated and the residue was taken up in H2O and stirred for 1 hr. The solid that formed was filtered, washed with H2O, and dried under vacuum to afford the title compound (3.4 g, 98%) as a light orange solid. JH NMR (400 MHz, DMSO- e) 6 7.59 (d, J = 1.1 Hz, 2H), 7.55 (t, J = 1.1 Hz, 1H), 5.40 (d, J = 5.5 Hz, 1H), 4.59 (q, J = 5.8, 5.2 Hz, 1H), 2.85 - 2.63 (m, 2H), 2.02 - 1.80 (m, 2H), 1.68 (tdd, J = 11.4, 6.5, 2.8 Hz, 2H). MS-ESI (m/z) calc’d for C11H12NO [M+H]+: 173.1. Found 174.1.
Step 2: N-(5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-2- nitrobenzenesulfonamide
Figure imgf000188_0002
To a solution of 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-amine (700.0 mg, 3.08 mmol) in DCM (30 mL) was added pyridine (316.72 mg, 4 mmol) and then 2- nitrobenzenesulfonyl chloride (887.38 mg, 4 mmol). The mixture was stirred at r.t. overnight and then at 45 °C for 2 hrs. The reaction mixture was partitioned between H2O and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-70% EtOAc/cyclohexane gradient eluent to afford the title compound (915 mg, 72%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 10.20 (1 H, s) 8.17 (1 H, d, J=0.88 Hz) 8.07 (1 H, s) 7.99 - 8.02 (1 H, m) 7.86 - 7.94 (1 H, m) 7.75 - 7.82 (2 H, m) 7.67 (1 H, d, J=0.66 Hz) 7.63 (1 H, s) 7.26 (1 H, s) 3.94 (3 H, s) 2.17 (3 H, s). MS-ESI (m/z) calc’d for C18H17N6O4S [M+H]+:413.1. Found 413.1.
Step 3: N-( 6-Cyano-l, 2, 3, 4-tetrahydronaphthalen-l-yl)-N-(5-methyl-l-( 1 -methyl- 1H-
Figure imgf000189_0001
To a solution of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (100.0 mg, 0.58 mmol), /V-[5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-yl]-2-nitrobenzenesulfonamide (238.1 mg, 0.58 mmol) and triphenylphosphine (302.86 mg, 1.15 mmol) in THF (8 mL), was added dropwise diisopropyl azodicarboxylate (0.14 mL, 0.69 mmol) and the mixture was stirred at r.t. overnight. An additional 1.2 equivalents of DI AD were added and the mixture was stirred at r.t. for 4 hrs. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford a yellow solid containing the title compound (770 mg, 28%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 8.31 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.21 (s, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.10 - 5.97 (m, 1H), 3.93 (s, 3H), 3.12 - 2.99 (m, 1H), 2.99 - 2.84 (m, 1H), 2.71 - 2.59 (m, 1H), 2.18 - 2.03 (m, 1H). MS-ESI (m/z) calc’d for C29H26N7O4S [M+H]+: 568.2. Found 568.2.
Step 4: 5-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000189_0002
To a solution of A-(6-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-[5-methyl-l-(l- methylpyrazol-4-yl)indazol-6-yl]-2-nitrobenzenesulfonamide (770.0 mg, 0.38 mmol) in DMF (8 mL) was added potassium carbonate (209.99 mg, 1.52 mmol) and benzenethiol (0.12 mL, 1.14 mmol) and the mixture was stirred at r.t. for 1 hr. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x) The combined organic phases were washed with brine (1x), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by SCX, using a 5 g cartridge, washed with MeOH and then eluted with a 2 M solution of NH3 in MeOH. The product containing fractions were combined and evaporated to dryness to afford the title compound (70 mg, 48%) as a yellow solid. Step 5: 5-((5-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000190_0001
6,7,8- tetrahydronaphthalene-2-carbonitrile (25 mg) was resolved by preparative chiral HPLC using Method AE to afford 5-((5-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (10 mg, 7%) as a white solid.1H NMR (400 MHz, DMSO-d6) ^ 8.09 (1 H, s) 7.89 (1 H, s) 7.73 (1 H, d, J=0.66 Hz) 7.65 (1 H, d, J=1.32 Hz) 7.53 - 7.59 (1 H, m) 7.47 - 7.51 (1 H, m) 7.41 (1 H, s) 6.63 (1 H, s) 5.51 (1 H, d, J=9.02 Hz) 4.92 - 5.02 (1 H, m) 3.89 (3 H, s) 2.85 (2 H, t, J=5.83 Hz) 2.21 (3 H, s) 1.78 - 2.10 (4 H, m MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.2. A later eluting fraction was also isolated to afford 5-((5-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol- 6-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (10 mg, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ^ ppm 8.10 (1 H, s) 7.90 (1 H, s) 7.74 (1 H, d, J=0.66 Hz) 7.66 (1 H, d, J=0.88 Hz) 7.54 - 7.60 (1 H, m) 7.46 - 7.52 (1 H, m) 7.46 - 7.52 (1 H, m) 7.42 (1 H, s) 6.64 (1 H, s) 5.51 (1 H, d, J=8.80 Hz) 4.93 - 5.02 (1 H, m) 3.90 (3 H, s) 2.86 (2 H, t, J=5.94 Hz) 2.22 (3 H, s) 1.81 - 2.10 (4 H, m). MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.2. Example 63: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2 Step 1: 6-B
Figure imgf000191_0001
ne To a solution of 6-bromo dine (0.99 g, 5 mmol) in DMF (12.5
Figure imgf000191_0002
mL) was added potassium carbonate (760.16 mg, 5.5 mmol) and 2- (chloromethoxy)ethyltrimethylsilane (0.97 mL, 5.5 mmol), then the mixture was stirred at 25 °C for 30 minutes. The mixture was diluted with H2O and extracted with Et2O (3x). The combined organic layers were passed through a phase separator and evaporated to obtain an oil which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (581 mg, 35%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 9.12 – 8.26 (m, 3H), 5.88 – 5.67 (m, 2H), 3.57 (dt, J = 43.1, 8.1 Hz, 2H), 0.91 – 0.70 (m, 2H), -0.09 (d, J = 20.8 Hz, 9H). MS-ESI (m/z) calc’d for C12H19BrN3OSi [M+H]+: 328.1, 330.0. Found 328.1, 330.1. Step 2: (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)boronic acid A mixture of 6-bromo- methyl)-1H-pyrazolo[4,3-
Figure imgf000191_0003
b]pyridine (417.0 mg, 1.27 mmol), bis(pinacolato)diboron (354.83 mg, 1.4 mmol), potassium acetate (373.99 mg, 3.81 mmol) and Pd(dppf)Cl2 (92.94 mg, 0.13 mmol) was heated at 100 °C under nitrogen for 4 hrs. The solvent was evaporated to afford material containing the title compound (1.239 g, about 30% pure), as a black solid, which was used for the next step without any further purification. MS-ESI (m/z) calc’d for C12H21BN3O3Si [M+H]+: 294.1. Found 294.1. Step 3: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-6-ol To a solution of (1-((2-(t hyl)-1H-pyrazolo[4,3-b]pyridin-6-
Figure imgf000192_0001
yl)boronic acid (372.36 mg, 1.27 mmol) in MeOH (21.13 mL) was added hydrogen peroxide urea (179.2 mg, 1.91 mmol) and the mixture was stirred at 25 °C for 30 minutes. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (240 mg, 71%) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 1.0 Hz, 1H), 7.35 (dd, J = 2.4, 1.0 Hz, 1H), 5.66 (s, 2H), 3.53 – 3.46 (m, 2H), 0.80 (dd, J = 8.4, 7.5 Hz, 2H), -0.10 (s, 9H). MS-ESI (m/z) calc’d for C12H20N3O2Si [M+H]+: 266.2. Found 266.1. Step 4: 5-((1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile To a solution of tr mol) in DCM (5 mL) was
Figure imgf000192_0002
added DIAD (0.21 mL, 1.09 mmol) dropwise at 0 °C and the mixture was stirred until the yellow color faded. A solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3- b]pyridin-6-ol (240.0 mg, 0.90 mmol) and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carbonitrile (172.14 mg, 0.90 mmol) in DCM (5 mL) was then added at 0 °C and the mixture was stirred at 25 °C for 6 hrs. The solvent was evaporated and the residue was passed through an SCX cartridge (5g), to obtain a brown oil which was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (125 mg, 86%) as a clear oil.1H NMR (400 MHz, DMSO-d6) δ 8.77 – 7.45 (m, 6H), 5.84 – 5.61 (m, 3H), 3.59 (dt, J = 31.3, 8.1 Hz, 2H), 3.03 – 2.71 (m, 2H), 2.24 – 1.69 (m, 4H), 0.84 (dt, J = 25.5, 8.0 Hz, 2H), -0.08 (d, J = 25.7 Hz, 9H). MS-ESI (m/z) calc’d for C23H29N4O2Si [M+H]+: 421.2. Found 421.1. Step 5: 5-((1H-Pyrazolo[4,3-b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile A solution of 5-((1-((2
Figure imgf000193_0001
l)-1H-pyrazolo[4,3-b]pyridin-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (125.0 mg, 0.300 mmol) in DCM (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 24 hrs. The solvent was evaporated to obtain a residue which was taken up in MeOH, then NH4OH was added and the solution was stirred at 25 °C for 1 hr. The solvent was evaporated and the residue was passed through an SCX (5g) cartridge to afford the title compound (85 mg, 98%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.27 (d, J = 2.5 Hz, 1H), 8.18 (s, 1H), 7.74 – 7.62 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 5.73 (t, J = 5.5 Hz, 1H), 2.97 – 2.86 (m, 1H), 2.80 (dt, J = 16.6, 7.2 Hz, 1H), 2.14 – 1.98 (m, 2H), 1.98 – 1.74 (m, 2H). MS-ESI (m/z) calc’d for C17H15N4O [M+H]+: 291.2. Found 291.1. Step 6: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile A mixture of 5-((1H -5,6,7,8-
Figure imgf000193_0002
tetrahydronaphthalene-2-carbonitrile (85.0 mg, 0.24 mmol), 4-iodo-1-methylpyrazole (74.9 mg, 0.36 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (17.07 mg, 0.12 mmol), copper (I) iodide (9.14 mg, 0.05 mmol) and tripotassium phosphate (152.69 mg, 0.72 mmol) in dry 1,4-dioxane (2 mL) was heated and stirred at 100 °C for 15 hrs. The mixture was diluted with DCM and passed through an alumina pad. The filtrate was evaporated to dryness to afford 5-[1-(1-methylpyrazol-4-yl)pyrazolo[4,3-b]pyridin-6-yl]oxy-5,6,7,8- tetrahydronaphthalene-2-carbonitrile (136 mg). Step 7: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2 )-5,6,7,8-
Figure imgf000194_0001
tetrahydronaphthalene-2-carbonitrile was resolved by preparative chiral HPLC using Method AF to afford 5-((1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (19 mg, 22%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 0.9 Hz, 1H), 8.36 (d, J = 2.6 Hz, 1H), 8.35 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 0.9 Hz, 1H), 7.81 (dd, J = 2.5, 1.0 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.65 (dd, J = 8.0, 1.7 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.89 (t, J = 4.8 Hz, 1H), 3.94 (s, 3H), 2.92 (dt, J = 17.2, 5.6 Hz, 1H), 2.80 (ddd, J = 17.1, 8.2, 6.2 Hz, 1H), 2.05 (q, J = 5.0, 4.0 Hz, 2H), 1.97 – 1.75 (m, 2H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.1. A later eluting fraction was also isolated to afford 5-((1-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (16 mg, 18%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 0.9 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.36 – 8.35 (m, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.83 – 7.80 (m, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 8.0, 1.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 5.89 (t, J = 4.9 Hz, 1H), 3.94 (s, 3H), 2.92 (dt, J = 17.3, 5.6 Hz, 1H), 2.80 (ddd, J = 17.1, 8.3, 6.0 Hz, 1H), 2.11 – 2.01 (m, 2H), 1.97 – 1.74 (m, 2H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.1. Example 64: 5-((1-(1-(Bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl)-5-methyl-1H- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000195_0001
mg, 1.34 mmol) and 1,1,3,3-tetramethoxypropane (220.76 mg, 1.34 mmol) were suspended in EtOH (5 mL). Then conc. HCl (0.36 mL, 4.3 mmol) was added in one portion and the suspension was stirred at 80 °C for 16 hrs. The reaction was cooled to r.t., quenched with H2O, and extracted with DCM (5x). The combined organic layers were washed with H2O (1x) passed through a phase separator and concentrated carefully (product is volatile) to afford the title compound (178 mg, 99%) as a dark yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.80 (1 H, m) 7.45 (1 H, d, J=1.32 Hz) 6.25 (1 H, t, J=1.98 Hz) 2.60 (1 H, s) 2.21 (6 H, s). MS- ESI (m/z) calc’d for C8H11N2 [M+H]+: 135.0. Found 135.0. Step 2: 1-(Bicyclo[1.1.1]pentan-1-yl)-4-iodo-1H-pyrazole
Figure imgf000195_0002
-pyrazole (175.0 mg, 1.3 mmol) and 1-iodopyrrolidine-2,5-dione (293.42 mg, 1.3 mmol) were dissolved in acetic acid (4 mL) and the reaction was stirred at 80 °C for 2 hrs. The reaction mixture was partitioned between H2O and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (1x), passed through a phase separator and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-15% EtOAc/cyclohexane gradient eluent to afford the title compound (230 mg, 68%) as a pink oil.1H NMR (400 MHz, DMSO-d6) ^ 7.97 (1 H, d, J=0.66 Hz) 7.54 (1 H, s) 2.60 (1 H, s) 2.20 (6 H, s). MS-ESI (m/z) calc’d for C8H10IN2 [M+H]+: 261.0. Found 261.0.
Figure imgf000196_0001
In a sealed vial, a mixture of 5-methyl-17/-indazol-6-ol (120.0 mg, 0.81 mmol), 1- (bicyclo[l.l.l]pentan-l-yl)-4-iodo-17/-pyrazole (231.7 mg, 0.89 mmol), (1R,2R)-N1,N2- dimethylcyclohexane-l,2-diamine (57.6 mg, 0.40 mmol), copper (I) iodide (30.85 mg, 0.160 mmol) and tripotassium phosphate (515.12 mg, 2.43 mmol) in dry 1,4-dioxane (2.2 mL) was stirred at 90 °C for 2 hrs. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4 and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (120 mg, 53%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 9.83 (1 H, br. s.) 8.22 (1 H, d, J=0.66 Hz) 8.00 (1 H, d, J=0.88 Hz) 7.83 (1 H, d, J=0.66 Hz) 7.49 (1 H, s) 6.96 (1 H, s) 2.67 (1 H, s) 2.30 (6 H, s) 2.22 (3 H, s). MS-ESI (m/z) calc’d for C16H17N4O [M+H]+: 281.1. Found 281.1.
Step 4: 5-( (1-(1 -(Bicyclo[l. 1. 1 ]pentan-l-yl)-lH-pyrazol-4-yl)-5-methyl-lH-indazol-6-
Figure imgf000196_0002
To a solution of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (30.9 mg, 0.18 mmol), l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol (50.0 mg, 0.18 mmol) and triphenylphosphine (93.57 mg, 0.36 mmol) in THF (4.5 mL), was added diisopropyl azodicarboxylate (0.04 mL, 0.21 mmol) dropwise and the mixture was allowed to stir at r.t. for 1 hr. The reaction mixture was partitioned between water and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4 and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (65 mg).
Step 5: 5-( (1-(1 -(Bicyclo[l.1.1 ]pentan-l-yl)-lH-pyrazol-4-yl)-5-methyl-lH-indazol-6-
Figure imgf000197_0001
5-((l-(l-(Bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile was purified by chiral prep HPLC using Method AG to afford 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (4 mg, 5%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.29 (1 H, s) 8.08 (1 H, s) 8.02 (1 H, s) 7.70 (1 H, s) 7.64 (1 H, d, J=8.14 Hz) 7.59 (1 H, s) 7.53 (1 H, d, J=8.14 Hz) 7.31 (1 H, s) 5.85 (1 H, t, J=4.95 Hz) 2.76 - 2.99 (2 H, m) 2.65 (1 H, s) 2.30 (6 H, s) 2.16 (3 H, s) 1.80 - 2.13 (4 H, m). MS-ESI (m/z) calc’d for C27H26N5O [M+H]+: 436.2. Found 436.2. A later eluting fraction was also isolated to afford 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (2.6 mg, 3%). 'H NMR (400 MHz, DMSO-d6) δ 8.29 (1 H, s) 8.09 (1 H, s) 8.03 (1 H, s) 7.71 (1 H, s) 7.65 (1 H, d, J=9.46 Hz) 7.60 (1 H, s) 7.54 (1 H, d, J=8.14 Hz) 7.32 (1 H, s) 5.86 (1 H, t, J=5.39 Hz) 2.89 - 3.02 (1 H, m) 2.77 - 2.88 (1 H, m) 2.66 (1 H, s) 2.31 (6 H, s) 2.17 (3 H, s) 1.79 - 2.13 (4 H, m). MS-ESI (m/z) calc’d for C27H26N5O [M+H]+: 436.2. Found 436.2.
Example 65 : 8-((l-(l-(Bicyclo [ 1.1.1] pentan- 1-yl)- 17/-py razol-4-y l)-5-methy 1-1 //- indazol-6-yl)oxy)-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000197_0002
Step 1: 8-Hydroxy-4-methyl-5, 6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000198_0001
To a solution of 4-methyl-8-oxo-6,7-dihydro-57/-quinoline-3-carbonitrile (300.0 mg, 1.61 mmol) in methanol (10 mL) was added sodium borohydride (121.89 mg, 3.22 mmol) and the mixture was stirred at r.t. for 1 hr. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x), the combined organic layers were washed with H2O (lx), passed through a phase separator and evaporated to dryness to afford the title compound (290 mg, 96%) as a beige solid. JH NMR (400 MHz, DMSO-d6) δ 8.74 (1 H, s) 5.34 (1 H, d, J=3.08 Hz) 4.58 (1 H, br. s.) 2.68 - 2.85 (1 H, m) 2.54 - 2.67 (1 H, m) 2.39 (3 H, s) 1.66 - 2.01 (4 H, m). MS-ESI (m/z) calc’d for C11H13N2O [M+H]+: 189.1. Found 189.1.
Step 2: 8-( (1-(1 -(Bicyclo[l.1.1 ]pentan-l-yl)-lH-pyrazol-4-yl)-5-methyl-lH-indazol-6-
Figure imgf000198_0002
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 8-hydroxy- 4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 5-hy droxy-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, to afford the title compound (75 mg).
Step 3: 8-( 1-(1 -(Bicyclo[l.1.1 ]pentan-l-yl)-lH-pyrazol-4-yl)-5-methyl-lH-indazol-6-
Figure imgf000198_0003
8-((l-(l-(Bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6- yl)oxy)-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile was subjected to chiral prep HPLC using Method AH to afford 8-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-1H-indazol-6-yl)oxy)-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (5.6 mg, 7%) as a white solid.1H NMR (400 MHz, DMSO-d6) ^ 8.79 (1 H, s) 8.31 (1 H, s) 8.07 (1 H, s) 8.02 (1 H, s) 7.57 (1 H, s) 7.56 (1 H, s) 5.74 - 5.80 (1 H, m) 2.88 - 3.00 (1 H, m) 2.64 - 2.78 (2 H, m) 2.48 (3 H, s) 2.24 - 2.36 (7 H, m) 2.15 (3 H, s) 1.88 - 2.07 (3 H, m). MS-ESI (m/z) calc’d for C27H27N6O [M+H]+: 451.2. Found 451.2. A later eluting fraction was also isolated to afford 8-((1-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol- 4-yl)-5-methyl-1H-indazol-6-yl)oxy)-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (4.7 mg, 6%).1H NMR (400 MHz, DMSO-d6) ^ 8.79 (1 H, s) 8.31 (1 H, d, J=0.66 Hz) 8.07 (1 H, d, J=0.66 Hz) 8.01 (1 H, d, J=0.44 Hz) 7.57 (1 H, s) 7.55 (1 H, d, J=0.66 Hz) 5.77 (1 H, t, J=2.97 Hz) 2.88 - 2.98 (1 H, m) 2.64 - 2.78 (2 H, m) 2.48 (3 H, s) 2.22 - 2.37 (7 H, m) 2.14 (3 H, s) 1.85 - 2.07 (3 H, m). MS-ESI (m/z) calc’d for C27H27N6O [M+H]+: 451.2. Found 451.2. Example 66: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2 4-iodo-1-
Figure imgf000199_0001
methylpyrazole (6.77 g, 32.56 mmol), tripotassium phosphate (4.15 g, 19.54 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (463.11 mg, 3.26 mmol) and cuprous iodide (0.25 g, 1.3 mmol) in dry DMF (30 mL) was heated and stirred at 120 °C for 5 hrs. After cooling the mixture was diluted with DCM and filtered through a Celite pad. The filtrate was evaporated to dryness to obtain a black residue that was purified by flash silica gel chromatography using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (747 mg, 49%) as a slight yellow solid.1H NMR (400 MHz, CDCl3) δ 4.01 – 4.05 (m, 3H), 7.23 (dd, J = 8.32, 0.93 Hz, 1H), 8.06 (dd, J = 8.31, 0.94 Hz, 1H), 8.11 – 8.16 (m, 2H), 8.21 (s, 1H). MS-ESI (m/z) calc’d for C10H9ClN5 [M+H]+: 234.0. Found Step 2: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile To a solution of 5-h
Figure imgf000200_0001
ene-2-carbonitrile (162.92 mg, 0.86 mmol) in DMF (6 mL) was added NaH (60% w/w, 36.29 mg, 0.91 mmol) at r.t.. The mixture was then heated to 90 °C and stirred for 30 minutes. Then 6-chloro-1-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine (200.0 mg, 0.86 mmol) was added portionwise and the reaction was stirred at 90 °C for an additional 2 hours. NaH (60% w/w, 68.48 mg, 1.71 mmol) was added and the reaction was warmed to 90 °C and stirred overnight. The solvent was then evaporated under reduced pressure; trifluoroacetic anhydride (5.0 mL, 35.97 mmol) was added and the mixture was heated to reflux for 1 hr. The TFA was removed under reduced pressure and the material obtained (653 mg) was subjected to prep- HPLC using Method AI to afford the title compound (50 mg). Step 3: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000200_0002
)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was purified by chiral prep HPLC using method AJ to afford 5-((1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (25 mg, 8%) as a white solid.1H NMR (400 MHz, CDCl3) δ 1.96 (dt, J = 11.37, 5.40 Hz, 1H), 2.10 (dt, J = 13.40, 4.58 Hz, 1H), 2.29 (dp, J = 14.12, 4.92 Hz, 2H), 2.81 – 3.04 (m, 2H), 4.00 (s, 3H), 6.49 (t, J = 5.33 Hz, 1H), 6.67 (d, J = 8.64 Hz, 1H), 7.45 (d, J = 8.44 Hz, 1H), 7.49 – 7.59 (m, 2H), 7.97 (d, J = 8.62 Hz, 1H), 8.02 (s, 2H), 8.23 (d, J = 0.74 Hz, 1H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.1. A later eluting fraction was also isolated to afford 5-((1-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (24 mg, 8%) as a white solid.1H NMR (400 MHz, CDCl3) δ 1.94 (dd, J = 11.45, 6.05 Hz, 1H), 2.02 – 2.14 (m, 1H), 2.26 (dq, J = 9.67, 5.05 Hz, 2H), 2.79 – 2.91 (m, 1H), 2.97 (dt, J = 17.27, 5.97 Hz, 1H), 3.98 (s, 3H), 6.47 (t, J = 5.31 Hz, 1H), 6.66 (d, J = 8.61 Hz, 1H), 7.44 (d, J = 8.07 Hz, 1H), 7.47 – 7.55 (m, 2H), 7.95 (d, J = 8.64 Hz, 1H), 8.00 (s, 2H), 8.21 (s, 1H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.1. Example 67: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000201_0001
4-iodo-1- methylpyrazole (2.03 g, 9.77 mmol), tripotassium phosphate (2.76 g, 13.02 mmol), DMEDA (0.21 mL, 1.95 mmol) and cuprous iodide (2.48 g, 13.02 mmol) in dry DMF (26.05 mL) was heated and stirred at 120 °C for 6 hrs. After cooling the mixture was diluted with DCM and filtered through Celite. The filtrate was evaporated to dryness to obtain a black residue that was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (390 mg, 26%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 3.93 (d, J = 2.6 Hz, 3H). MS-ESI (m/z) calc’d for C10H9ClN5 [M+H]+: 234.0. Found 234.0. Step 2: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile To a solution of 5-hy
Figure imgf000202_0001
ene-2-carbonitrile (103.93 mg, 0.60 mmol) in 1,4-dioxane (6 mL) was added NaH (60% w/w, 24.0 mg, 0.60 mmol) and the mixture was stirred at 25 °C for 5 minutes.6-Chloro-1-(1-methylpyrazol-4-yl)pyrazolo[4,3- c]pyridine (140.2 mg, 0.60 mmol) was added and the reaction was stirred at 75 °C for 24 hrs. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (284 mg) as a yellow solid. Step 3: 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile 5-((1-(
Figure imgf000202_0002
,7,8- tetrahydronaphthalene-2-carbonitrile was purified by chiral HPLC purification using Method AK to afford 5-((1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (18 mg, 8%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 1.0 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.0, 1.7 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 1.0 Hz, 1H), 6.40 (t, J = 5.3 Hz, 1H), 3.90 (s, 3H), 2.92 (dt, J = 17.2, 5.8 Hz, 1H), 2.80 (dt, J = 17.2, 7.0 Hz, 1H), 2.18 – 2.11 (m, 1H), 2.08 – 1.76 (m, 3H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.1. A later eluting fraction was also isolated to afford 5-((1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (12 mg, 5%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 1.0 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.0, 1.7 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 1.0 Hz, 1H), 6.40 (t, J = 5.3 Hz, 1H), 3.90 (s, 3H), 2.92 (dt, J = 17.2, 5.9 Hz, 1H), 2.80 (dt, J = 17.1, 6.7 Hz, 1H), 2.14 (ddt, J = 13.6, 8.6, 3.9 Hz, 1H), 2.07 – 1.77 (m, 3H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.1.
Example 68: 5-((l-(l-(Difluoromethyl)-lff-pyrazol-4-yl)-5-methyl-lff-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000203_0001
In a sealed vial, a mixture of 5-methyl-17/-indazol-6-ol (250.0 mg, 1.69 mmol), 1- (difluoromethyl)-4-iodopyrazole (494.02 mg, 2.02 mmol), (1R,2R)-JV1,JV2- dimethylcyclohexane-l,2-diamine (120.01 mg, 0.84 mmol), copper (I) iodide (64.27 mg, 0.340 mmol) and tripotassium phosphate (1073.16 mg, 5.06 mmol) in dry 1,4-dioxane (5.5 mL) was stirred at 90 °C for 4 hrs. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with brine (lx), dried over anhydrous Na2SC>4, and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (95 mg, 21%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 9.92 (1 H, br. s.) 8.69 (1 H, s) 8.21 (1 H, s) 8.07 (1 H, d, J=0.66 Hz) 7.72 - 8.05 (1 H, m) 7.52 (1 H, s) 7.00 (1 H, s) 2.22 (3 H, s). MS-ESI (m/z) calc’d for C12H11F2N4O [M+H]+: 265.1, Found 265.1.
Step 2: 5-( (1-(1 -(Difluoromethyl)- !H-pyrazol-4-yl)-5-methyl-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000204_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile using 1-(1- (difluoromethyl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol in place of 1-(1- (bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol, to afford the title compound (35 mg).
Step 3: 5-( (1-(1 -(Difluoromethyl)- lH-pyrazol-4-yl)-5-methyl-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000204_0002
5-((l-(l -(Difluoromethyl)- 17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile was purified by chiral prep HPLC using Method AL to afford 5-((l-(l-(difluoromethyl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (5 mg, 6%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, s) 8.39 (1 H, s) 8.16 (1 H, s) 7.72 - 8.06 (1 H, m) 7.70 (1
H, s) 7.60 - 7.66 (2 H, m) 7.53 (1 H, d, J=8.14 Hz) 7.44 (1 H, s) 5.94 (1 H, t, J=5.06 Hz) 2.89 - 3.02 (1 H, m) 2.75 - 2.87 (1 H, m) 2.15 (3 H, s) 1.99 - 2.12 (2 H, m) 1.77 - 1.95 (2 H, m). MS-ESI (m/z) calc’d for C23H20F2N5O [M+H]+: 420.1. Found 420.1. A later eluting fraction was also isolated to afford 5-((l-(l-(difluoromethyl)-lH-pyrazol-4-yl)-5-methyl-lH-indazol- 6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (5, 7%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, s) 8.39 (1 H, s) 8.16 (1 H, s) 7.72 - 8.05 (1 H, m) 7.70 (1 H, s) 7.61 - 7.67 (2 H, m) 7.54 (1 H, d, J=7.92 Hz) 7.44 (1 H, s) 5.94 (1 H, t, J=4.84 Hz) 2.88 - 3.00 (1 H, m) 2.76 - 2.86 (1 H, m) 2.15 (3 H, s) 2.00 - 2.12 (2 H, m) 1.78 -
I.96 (2 H, m). MS-ESI (m/z) calc’d for C23H20F2N5O [M+H]+: 420.1. Found 420.1.
Example 69: 7-Methyl-l-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-2,3- dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2 Step 1: 5
Figure imgf000205_0001
Figure imgf000205_0002
To a solution of 5-bromo-7-methyl-2,3-dihydro-1H-inden-1-one (110.0 mg, 0.49 mmol) in methanol (2.3 mL) was added sodium borohydride (18.66 mg, 0.49 mmol) at 25 °C and the resulting mixture was stirred for 1 hr. The reaction was concentrated under reduced pressure and then saturated aqueous NaHCO3 (50 mL) was added. The mixture was extracted with DCM (3x 50 mL) and then the organic phase was filtered through a phase separator and concentrated under reduced pressure to afford the title compound (108 mg, 97%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.23 (s, 1H), 7.16 (s, 1H), 5.11 – 5.03 (m, 1H), 4.99 (s, 1H), 2.99 (dt, J = 15.8, 7.7 Hz, 1H), 2.70 (ddd, J = 16.2, 8.8, 4.2 Hz, 1H), 2.32 (s, 3H), 2.23 (ddt, J = 13.6, 8.8, 7.1 Hz, 1H), 1.85 (dddd, J = 13.1, 8.3, 4.3, 3.0 Hz, 1H). MS-ESI (m/z) calc’d for C10H12BrO [M+H-H2O]+: 209.1, 211.0. Found 209.0, 211.0. Step 2: 1-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-5-methyl-1H-indazol-6-ol A mixture of 5-methyl-1H
Figure imgf000205_0003
g, 1.69 mmol), 1-(difluoromethyl)- 4-iodopyrazole (494.02 mg, 2.02 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (120.01 mg, 0.84 mmol), copper (I) iodide (64.27 mg, 0.340 mmol), and tripotassium phosphate (1073.16 mg, 5.06 mmol) in dry 1,4-dioxane (5.5 mL) was stirred at 90 °C for 4 hrs in a sealed vial. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with brine (1x), dried over anhydrous Na2SO4 and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (95 mg, 21%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 9.92 (1 H, br. s.) 8.69 (1 H, s) 8.21 (1 H, s) 8.07 (1 H, d, J=0.66 Hz) 7.72 - 8.05 (1 H, m) 7.52 (1 H, s) 7.00 (1 H, s) 2.22 (3 H, s). MS-ESI (m/z) calc’d for C12H11F2N4O [M+H]+: 265.1, Found 265.1.
Step 3: 7 -Methyl- 1-( (1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-2, 3-dihydro-lH- indene-5-carbonitrile
Figure imgf000206_0001
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17/-pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 5-bromo-7-methyl-2,3-dihydro-17/- inden-l-ol in place of 6-((5-bromo-6-chloro-2,3-dihydro-17/-inden-l-yl)oxy)-l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazole, to afford the title compound (60 mg).
Step 4: 7 -Methyl- 1-( (1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-2, 3-dihydro-lH- indene-5-carbonitrile, enantiomer 1 and 2
Figure imgf000206_0002
7-Methyl-l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile was purified by chiral prep HPLC using Method AM to afford 7- methyl- 1 -((1 -(1 -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-2,3-dihy dro- 17/-indene-5- carbonitrile, enantiomer 1 (2 mg, 4%) as a white solid. 1 H NMR (400 MHz, methanol-<A) 8 8.07 - 8.22 (2 H, m) 7.89 (1 H, d, J=0.66 Hz) 7.74 (1 H, d, J=8.58 Hz) 7.54 (1 H, s) 7.45 (1 H, s) 7.11 (1 H, d, J=1.76 Hz) 6.89 - 6.98 (1 H, m) 6.08 (1 H, dd, J=6.60, 2.42 Hz) 3.97 - 4.08 (3 H, m) 3.13 - 3.27 (1 H, m) 2.96 - 3.09 (1 H, m) 2.62 (1 H, ddt, J=14.22, 8.94, 7.12, 7.12 Hz) 2.35 - 2.45 (3 H, m) 2.30 (1 H, dddd, J=14.28, 8.56, 3.58, 2.64 Hz). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.1. Found 370.1. A later eluting fraction was also isolated to afford 7 -methyl- 1 -(( 1 -(1 -methyl- 17/-py razol -4-y I )- 1 //-indazol -6-y l)oxy)-2, 3 -dihydro- 1H- indene-5-carbonitrile, enantiomer 2 (1.8, 4%) as a white solid. 'H NMR (400 MHz, methanol-^) 8 8.03 - 8.20 (2 H, m) 7.89 (1 H, s) 7.74 (1 H, d, J=8.80 Hz) 7.54 (1 H, s) 7.45 (1 H, d, J=0.66 Hz) 7.11 (1 H, d, J=1.98 Hz) 6.93 (1 H, dd, J=8.80, 1.98 Hz) 6.08 (1 H, dd, J=6.82, 2.42 Hz) 3.97 - 4.06 (3 H, m) 3.12 - 3.27 (1 H, m) 2.96 - 3.08 (1 H, m) 2.54 - 2.70 (1 H, m) 2.39 (3 H, s) 2.30 (1 H, dddd, J=14.31, 8.53, 3.69, 2.53 Hz). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.1. Found 370.1.
Example 70: 4-MethyI-8-((5-methyI-l-(l-methyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-
5,6,7,8-tetrahydroquinoline-3-carbonitriIe, enantiomer 1 and 2
Figure imgf000207_0001
A mixture of 6-bromo-5-methyl-17/-indazole (1.0 g, 4.74 mmol), 4-iodo-l- methylpyrazole (1.48 g, 7.11 mmol), (lR,2R)-Al,A2-dimethylcyclohexane-l,2-diamine (336.97 mg, 2.37 mmol), copper (I) iodide (180.47 mg, 0.95 mmol) and tripotassium phosphate (3.01 g, 14.21 mmol) in dry 1,4-dioxane (15 mL) was stirred at 90 °C under a nitrogen atmosphere for 4 hrs in a sealed vial. The mixture was allowed to cool to r.t. and partitioned between H2O and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with H2O (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-60% EtOAc/cyclohexane gradient eluent to afford the title compound (1.23 g, 89%) as an off-white solid. JH NMR (400 MHz, DMSO- e) 6 8.37 (1 H, s) 8.24 (1 H, d, J=l.10 Hz) 7.98 (1 H, s) 7.90 (1 H, d, J=0.66 Hz) 7.83 (1 H, s) 3.94 (3 H, s) 2.47 (3 H, s). MS-ESI (m/z) calc’d for Ci2Hi2BrN4 [M+H]+: 291.0, 293.0. Found 291.0, 293.0.
Step 2: 5-Methyl-l-( 1 -methyl-lH-pyrazol-4-yl)-6-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)-lH-indazole To a solution of 6-bromo
Figure imgf000208_0001
H-pyrazol-3-yl)-1H-indazole (1.0 g, 3.43 mmol) in 1,4-dioxane (20 mL) was added potassium acetate (1.01 g, 10.3 mmol) and bis(pinacolato)diborane (1.74 g, 6.87 mmol). The mixture was degassed with N2 then Pd(dppf)Cl2•CH2Cl2 (0.28 g, 0.340 mmol) was added and the reaction was stirred at 100 °C for 16 hrs. The reaction mixture was partitioned between H2O and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (1x), passed through a phase separator and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-70% EtOAc/cyclohexane gradient eluent to afford the title compound (1.2 g, 100%) as a light brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.25 (1 H, s) 8.18 (1 H, d, J=0.88 Hz) 7.83 (1 H, d, J=0.88 Hz) 7.80 (1 H, s) 7.61 (1 H, d, J=0.88 Hz) 3.96 (3 H, s) 2.57 (3 H, s) 1.33 (12 H, s). MS-ESI (m/z) calc’d for C18H24BN4O2 [M+H]+: 339.1. Found 339.1. Step 3: 5-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-ol
Figure imgf000208_0002
l)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole (1.1 g, 3.25 mmol) in MeOH (25 mL) was added a 30% solution of hydrogen peroxide (1.66 mL, 16.26 mmol) and the mixture was stirred at 25 °C for 1.5 hrs. The solvent was evaporated and the residue was taken up in H2O and extracted with EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with H2O (1x), dried over anhydrous Na2SO4, and evaporated to dryness. The material was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent and then with a 0-10% MeOH/EtOAc gradient eluent to afford the title compound (535 mg, 72%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.80 (1 H, br. s.) 8.13 (1 H, s) 7.97 (1 H, s) 7.75 (1 H, s) 7.47 (1 H, s) 6.93 (1 H, s) 3.92 (3 H, s) 2.21 (3 H, s). MS-ESI (m/z) calc’d for C12H13N4O [M+H]+: 229.1. Found 229.1. Step 4: 4-Methyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
Figure imgf000209_0001
To a solution of rac-8-hydroxy-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile (57.73 mg, 0.31 mmol), 5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-ol (70.0 mg, 0.31 mmol) and triphenylphosphine (160.88 mg, 0.61 mmol) in THF (5 mL) was added diisopropyl azodicarboxylate (0.07 mL, 0.370 mmol) dropwise and the mixture was allowed to stir at r.t. for 1 hr. 8-Hydroxy-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile (0.3 equivalents) was then added followed by 0.5 eq. of DIAD. The reaction mixture was stirred at r.t. for an additional 30 minutes. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with brine (lx), dried over anhydrous Na2SC>4, evaporated, and purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent. The material was further purified by prep HPLC using Method AP to afford the title compound (58 mg)
Step 5: 4-Methyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000209_0002
4-Methyl-8-((5-methyl-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral prep. HPLC using Method AQ to afford 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (19.8 mg, 16%) as a white solid. XH NMR (400 MHz, DMSO-d6) δ 8.79 (1 H, s) 8.29 (1 H, s) 8.05 (1 H, s) 7.92 (1 H, s) 7.55 (1 H, s) 7.51 (1 H, s) 5.77 (1 H, t, J=3.19 Hz) 3.94 (3 H, s) 2.88 - 2.98 (1 H, m) 2.64 - 2.77 (1 H, m) 2.47 (3 H, s) 2.20 - 2.31 (1 H, m) 2.13 (3 H, s) 1.85 - 2.04 (3 H, m). MS-ESI (m/z) calc’d for C23H23N6O [M+H]+: 399.2. Found 399.2. A later eluting fraction was also isolated to afford 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (18.7 mg, 15%) as a white solid . 'H NMR (400 MHz, DMSO-d6) δ 8.79 (1 H, s) 8.29 (1 H, s) 8.05 (1 H, s) 7.92 (1 H, s) 7.55 (1 H, s) 7.51 (1 H, s) 5.77 (1 H, br. s.) 3.94 (3 H, s) 2.88 - 2.99 (1 H, m) 2.64 - 2.79 (1 H, m) 2.47 (3 H, s) 2.20 - 2.31 (1 H, m) 2.13 (3 H, s) 1.85 - 2.04 (3 H, m). MS-ESI (m/z) calc’d for C23H23N6O [M+H]+: 399.2. Found 399.2.
Example 71 : 7-Fluoro- l-((l-(l-methyl- 1 H-py razol-4-y 1)- lff-indazol-6-yl)oxy)-2,3- dihydro-lH-indene-5-carbonitriIe, enantiomer 1 and 2
Figure imgf000210_0001
To a solution of 5-bromo-7-fluoro-2,3-dihydro-17/-inden-l-one (320.0 mg, 1.4 mmol) in methanol (7 mL) was added sodium borohydride (53.33 mg, 1.41 mmol) at 25 °C and the resulting mixture was stirred for 1 hr. The reaction was concentrated under reduced pressure and then saturated aqueous NaHCOs (50 mL) was added. The mixture was extracted with DCM (3x 50 mL) and the organic phase was filtered through a phase separator and concentrated under reduced pressure to afford the title compound (322 mg, 99%) as a brown solid. 'H NMR (400 MHz, DMSO- e) 6 7.31 (d, J = 1.4 Hz, 1H), 7.27 (dd, J = 8.7, 1.6 Hz, 1H), 5.31 (s, 1H), 5.20 (dd, J = 6.8, 3.3 Hz, 1H), 3.04 (dt, J = 15.7, 7.6 Hz, 1H), 2.77 (ddd, J = 16.5, 8.7, 4.5 Hz, 1H), 2.27 (ddt, J = 13.5, 8.7, 6.9 Hz, 1H), 1.88 (dddd, J = 13.1, 8.0, 4.5, 3.2 Hz, 1H). MS-ESI (m/z) calc’d for C^BrFO [M+H-H20]+: 213.0, 215.0. Found 212.9, 214.9.
Step 2: 6-((5-Bromo-7 -fluor o-2, 3-dihydro-lH-inden-l-yl)oxy)-l-(l-methyl-lH-pyrazol-4-yl)- IH-indazole
Figure imgf000211_0001
Diisopropyl azodicarboxylate (0.13 mL, 0.64 mmol) was added to a cooled (0 °C) solution of triphenylphosphine (250.3 mg, 0.95 mmol) in DCM (6.097 mL). After 10 min a suspension of 5-bromo-7-fluoro-2, 3-dihydro- 1 //-inden- 1 -ol (150.0 mg, 0.64 mmol) and 1-(1- methylpyrazol-4-yl)indazol-6-ol (136.29 mg, 0.64 mmol) in DCM (6 mL) was added and the mixture was left stirring at 25 °C for 1 hr. Water was added and the mixture was extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by filtration through a basic alumina pad (the pad was washed 3 times with 10 mL of EtOAc) and then the filtrate was concentrated under reduced pressure. The material was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford a brown oil (72 mg). This material was further purified by flash silica gel chromatography using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (52 mg, 19%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.31 (s, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.40 (dd, J = 8.8, 1.6 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 6.88 (dd, J = 8.8, 2.1 Hz, 1H), 6.22 (dd, J = 6.5, 2.2 Hz, 1H), 3.93 (s, 3H), 3.20 - 3.09 (m, 1H), 2.97 (ddd, J = 17.0, 8.9, 3.4 Hz, 1H), 2.62 - 2.52 (m, 1H), 2.25 - 2.12 (m, 1H). MS-ESI (m/z) calc’d for C2oHi7BrFN40 [M+H]+: 427.1, 429.1. Found 427.1, 429.1.
Step 3: 7-Fluoro-l-( (1-(1 -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-2, 3-dihydro-lH- indene-5-carbonitrile
Figure imgf000211_0002
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17 -pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 6-((5-bromo-7-fluoro-2,3-dihydro-17 - inden-l-yl)oxy)-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazole in place of 6-((5-bromo-6- chl oro-2, 3-dihydro- 1 //-inden- 1 -yl)oxy)- 1 -(1 -methyl- I /-py razol-4-y I )- 1 //-indazole, to afford the title compound (15 mg). Step 4: 7-Fluoro-l-( (1-(1 -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-2, 3-dihydro-lH- indene-5-carbonitrile, enantiomer 1 and 2
Figure imgf000212_0001
7-Fluoro-l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile was subjected to chiral prep HPLC using Method AO to afford 7- fluoro- 1 -(( 1 -(1 -methyl- 17/-py razol -4-y 1)- 1 //-indazol -6-y I )oxy )-2.3 -dihydro- 17/-i ndene-5 - carbonitrile, enantiomer 1 (4.4 mg, 10%) as a white solid. ’H NVIR (400 MHz, methanol-t/v) 6 8.15 - 8.02 (m, 2H), 7.86 (d, J = 0.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.48 - 7.35 (m, 1H), 7.16 - 7.06 (m, 1H), 6.90 (dd, J = 8.8, 2.1 Hz, 1H), 6.18 (dd, J = 6.6, 2.5 Hz, 1H), 4.00 (s, 3H), 3.29 - 3.18 (m, 1H), 3.05 (ddd, J = 16.9, 8.9, 3.6 Hz, 1H), 2.61 (ddt, J = 13.9, 8.8, 7.0 Hz, 1H), 2.35 (ddt, J = 14.3, 8.3, 3.2 Hz, 1H). MS-ESI (m/z) calc’d for C21H17FN5O [M+H]+: 374.1. Found 374.1. A later eluting fraction was also isolated to afford 7-fluoro- !-((!-( 1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2, 3- dihydro-17/-indene-5-carbonitrile, enantiomer 2 (4.7, 10%) as a white solid. 'H NMR (400 MHz, methanol-^) 6 8.13 - 8.06 (m, 2H), 7.88 - 7.85 (m, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.40 (dd, J = 8.7, 1.2 Hz, 1H), 7.15 - 7.11 (m, 1H), 6.90 (dd, J = 8.8, 2.1 Hz, 1H), 6.18 (dd, J = 6.6, 2.5 Hz, 1H), 4.00 (s, 3H), 3.29 - 3.20 (m, 1H), 3.05 (ddd, J = 16.8, 8.9, 3.6 Hz, 1H), 2.61 (ddt, J = 14.0, 8.9, 7.0 Hz, 1H), 2.35 (dddd, J = 14.3, 8.4, 3.7, 2.6 Hz, 1H). MS-ESI (m/z) calc’d for C21H17FN5O [M+H]+: 374. E Found 374.1.
Example 72: 2-Methyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-
5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000212_0002
To a solution of 2-chloro-5,6,7,8-tetrahydroquinoline-3-carbonitrile (2.0 g, 10.38 mmol) in trifluoroacetic acid (50 mL) was added a 30% solution of hydrogen peroxide (3.18 mL, 31.15 mmol) and the mixture was stirred at 75 °C for 15 hrs. Water was added and the solution was neutralized by addition of solid K2CO3 and then extracted with DCM (3x). The combined organic layers were washed with water (lx), passed through a phase separator, and evaporated under reduced pressure to afford the title compound (1.98 g, 91%) as a light yellow solid. 'H NMR (400 MHz, DMSO- e) 6 7.77 (1 H, s) 2.78 (4 H, dt, J=16.40, 6.33 Hz) 1.77 - 1.87 (2 H, m) 1.62 - 1.71 (2 H, m). MS-ESI (m/z) calc’d for C10H10CIN2O [M+H]+: 209.0. Found 209.0.
Figure imgf000213_0001
To a solution of 2-chloro-3-cyano-5,6,7,8-tetrahydroquinoline 1-oxide (1.92 g, 9.2 mmol) in DCM (50 mL) was added trifluoroacetic anhydride (3.84 mL, 27.61 mmol) dropwise and the mixture was stirred at 25 °C for 20 hrs. The solvent was evaporated and the residue was taken up in MeOH. K2CO3 was then added till basic pH and the suspension was stirred at 25 °C for 1 hr. The solvent was evaporated keeping the temperature under 40 °C. The residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to dryness. The material obtained was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (1.43 g, 74%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.25 (1 H, s) 5.62 (1 H, d, J=5.28 Hz) 4.56 (1 H, q, J=4.84 Hz) 2.76 - 2.87 (1 H, m) 2.62 - 2.75 (1 H, m) 1.80 - 1.95 (3 H, m) 1.65 - 1.76 (1 H, m). MS-ESI (m/z) calc’d for C10H10CIN2O [M+H]+: 209.0. Found 209.0.
Step 3: 8-Hydroxy-2-methyl-5, 6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000213_0002
A solution of 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (500.0 mg, 2.4 mmol), potassium carbonate (662.43 mg, 4.79 mmol), and trimethylboroxine (0.67 mL, 4.79 mmol) in 1,4-dioxane (6 mL) and H2O (3 mL) was degassed with N2 for 15 min. Then tetrakis(triphenylphosphine) palladium(O) (553.85 mg, 0.480 mmol) was added and the mixture was irradiated in a microwave reactor at 100 °C for 45 minutes; the irradiation cycle was repeated an addition 2 times. The reaction mixture was partitioned between H2O and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (lx), passed through a phase separator and evaporated to dryness. The material obtained was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (350 mg, 78%) as a light yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 7.97 (1 H, s) 5.31 (1 H, d, J=4.62 Hz) 4.54 (1 H, q, J=4.33 Hz) 2.71 - 2.83 (1 H, m) 2.64 - 2.71 (1 H, m) 2.62 (3 H, s) 1.80 - 1.95 (3 H, m) 1.61 - 1.74 (1 H, m). MS-ESI (m/z) calc’d for C11H13N2O [M+H]+: 189.1. Found 189.0.
Step 4: 2-Methyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
Figure imgf000214_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 8-hydroxy-2-methyl- 5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 8-hydroxy -4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, to afford material (130 mg), which was subjected to prep HPLC using Method AR to afford the title compound (32 mg).
Step 5: 2-Methyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000214_0002
2-Methyl-8-((5-methyl-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral prep-HPLC using Method AK to afford 2-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (14 mg, 11%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.29 (1 H, s) 8.13 (1 H, s) 8.05 (1 H, s) 7.93 (1 H, s) 7.60 (1 H, s) 7.55 (1 H, s) 5.69 (1 H, t, J=2.75 Hz) 3.94 (3 H, s) 2.89 - 2.99 (1 H, m) 2.72 - 2.84 (1 H, m) 2.59 (3 H, s) 2.19 - 2.31 (1 H, m) 2.15 (3 H, s) 1.94 - 2.01 (2 H, m) 1.77 - 1.90 (1 H, m). MS- ESI (m/z) calc’d for C23H23N6O [M+H]+: 399.2. Found 399.2. A later eluting fraction was also isolated to afford 2-methyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (13, 11%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.29 (1 H, s) 8.13 (1 H, s) 8.06 (1 H, s) 7.93 (1 H, s) 7.60 (1 H, s) 7.55 (1 H, s) 5.69 (1 H, t, J=2.42 Hz) 3.94 (3 H, s) 2.88 - 3.01 (1 H, m) 2.72 - 2.84 (1 H, m) 2.59 (3 H, s) 2.21 - 2.31 (1 H, m) 2.15 (3 H, s) 1.93 - 2.03 (2 H, m) 1.76 - 1.89 (1 H, m). MS-ESI (m/z) calc’d for C23H23N6O [M+H]+: 399.2. Found 399.2.
Example 73 : 8-((l-(l-(Difluoromethyl)- lff-pyrazol-4-yI)- lff-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000215_0001
Step 1: 8-((l-(l-(Difluoromethyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
Figure imgf000215_0002
To a solution of 1-(1 -(difluoromethyl)- 17/-pyrazol-4-yl)-17/-indazol-6-amine (40 mg, 160.50 umol) and 8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (33.16 mg, 192.60 umol) in MeOH (1.5 mL) was added AcOH (96.38 ug, 1.61 umol) to adjust pH = 5, then the mixture was stirred at 50 °C for 2 hrs. NaBHsCN (50.43 mg, 802.51 umol) was then added at 20 °C and the resulting mixture was stirred at 20 °C for another 12 hrs. The mixture was purified by HPLC using Method BA to afford the title compound (12 mg, 17%) as a yellow solid. MS-ESI (m/z) calc’d for C21H18F2N7 [M+H]+: 406.2. Found 406.3. Step 2: 8-((l -(1 -(Difluoromethyl)- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8-
Figure imgf000216_0001
8-((l-(l -(Difluoromethyl)- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral separation using Method BB to afford 8-((l-(l-(difluoromethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (4 mg, 41%) as a pale yellow gum. 'H NMR (400 MHz, CDCh) 8 8.73 (d, J=1.83 Hz, 1 H), 8.19 (s, 1 H), 8.10 (s, 1 H), 7.99 (d, J=0.61 Hz, 1 H), 7.74 - 7.80 (m, 1 H), 7.57 (d, J=8.56 Hz, 1 H), 7.41-7.11 (m, 1 H), 6.80 (s, 1 H), 6.73 (dd, J=8.68, 1.83 Hz, 1 H), 5.07 (br s, 1 H), 4.64 (br s, 1 H), 2.92 - 2.98 (m, 2 H), 2.37 - 2.53 (m, 1 H), 1.91 - 2.10 (m, 3 H). MS-ESI (m/z) calc’d for C21H18F2N7 [M+H]+: 406.2. Found 406.2. A later eluting fraction was also isolated to afford 8-((l-(l-(difluoromethyl)- l7/-pyrazol-4-yl)-l7/-indazol-6-yl)ammo)-5.6.7.8-tetrahydroquinolme-3-carbonitrile. enantiomer 2 (2 mg, 27%) as a pale yellow gum. 'H NMR (400 MHz, CDCh) 8 8.74 (s, 1 H), 8.21 (s, 1 H), 8.08 (d, J=6.84 Hz, 2 H), 7.81 (s, 1 H), 7.63 (d, J=9.04 Hz, 1 H), 7.42 - 7.12 (m, 1 H), 6.90 (s, 1 H), 6.79 (d, J=7.06 Hz, 1 H), 5.26 (s, 1 H), 4.66 - 4.75 (m, 1 H), 2.95 (br s, 2 H), 2.40 (br s, 1 H), 1.92 - 2.12 (m, 3 H). MS-ESI (m/z) calc’d for C21H18F2N7 [M+H]+: 406.2. Found 406.2.
Example 74: 5-((l-(l-MethyI-lH-pyrazol-4-yI)-LH-indazol-6-yI)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000216_0002
Stepl : 5-((l-(l -Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000217_0001
To a solution of 6-bromo-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazole (50 mg, 180.43 umol) in THF (5 mL) were added 5-amino-5,6,7,8-tetiahydronaphthalene-2-carbonitrile (31.07 mg, 180.43 umol) , /-BuONa (34.68 mg, 360.86 umol), and tBuXPhos Pd Gs (14.33 mg, 18.04 umol) at 20 °C. The mixture was stirred at 70 °C for 5 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 1/3) to afford the title compound (12 mg, 18%) as a brown oil. MS-ESI (m/z) calc’d for C22H21N6 [M+H]+: 369.2. Found 369.3.
Step 2: 5-((l-(l -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000217_0002
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method BC to afford 5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (2 mg, 17%) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 8.15 (s, 1 H), 7.94 (s, 1 H), 7.79 (s, 1 H), 7.64 (s, 1 H), 7.58 (d, J=8.16 Hz, 1 H), 7.48 (dd, J=8.34, 3.33 Hz, 2 H), 6.67 - 6.74 (m, 2 H), 6.44 (d, J=9.03 Hz, 1 H), 4.84 - 4.91 (m, 1 H), 3.90 (s, 3 H), 2.79 - 2.86 (m, 2 H), 1.92 - 2.01 (m, 1 H), 1.78 - 1.91 (m, 3 H). MS-ESI (m/z) calc’d for C22H21N6 [M+H]+: 369.2. Found 369.1. A later eluting fraction was also isolated to afford 5-(( I -( I -methyl- 17/-pyrazol-4-yl)- l//-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (2 mg, 24%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1 H), 7.94 (s, 1 H), 7.79 (s, 1 H), 7.64 (s, 1 H), 7.58 (dd, J=8.03, 1.63 Hz, 1 H), 7.48 (dd, J=8.34, 3.20 Hz, 2 H), 6.67 - 6.73 (m, 2 H), 6.44 (d, J=8.91 Hz, 1 H), 4.82 - 4.90 (m, 1 H), 3.90 (s, 3 H), 2.79 - 2.86 (m, 2 H), 1.94 - 2.01 (m, 1 H), 1.78 - 1.90 (m, 3 H). MS-ESI (m/z) calc’d for C22H21N6 [M+H]+: 369.2. Found 369.2. Example 75: 5-((l-(2-Methyl-lff-imidazol-5-yl)-lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000218_0001
Step 1: 5-Iodo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole
Figure imgf000218_0002
To a solution of 5-iodo-2-methyl-17/-imidazole (2 g, 9.62 mmol) in DMF (30 mL) was added NaH (461.49 mg, 11.54 mmol) at 0 °C under an N2 atmosphere. The mixture was stirred at 20 °C for 1 hr. and then the mixture was cooled to 0 °C. 2- (Trimethylsilyl)ethoxymethyl chloride (1.92 g, 11.54 mmol) was added and the mixture was stirred at 20 °C for 6 hrs. The reaction mixture was diluted with saturated aqueous NH4CI and extracted with EtOAc (3x). The combined organic layers were washed with brine (2x), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (2.4 g, 73%) as a yellow oil. JH NMR (400 MHz, CDCh) 6 6.99 (s, 1H), 5.14 (s, 2H), 3.51 - 3.45 (m, 2H), 2.42 (d, J=0.6 Hz, 3H), 0.90 - 0.86 (m, 2H), -0.01 (s, 9H). MS-ESI (m/z) calc’d for CioH2oIN2OSi [M+H]+: 339.0. Found 339.2.
Step 2: 6-Bromo-l-(2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)-lH- indazole
Figure imgf000218_0003
To a solution of 6-bromo-17/-indazole (470.76 mg, 2.37 mmol), 5-iodo-2-methyl-l- ((2-(trimethylsilyl)ethoxy)methyl)-17/-imidazole (1.2 g, 3.55 mmol) in dioxane (15 mL) were added Cui (90.08 mg, 473.01 umol), K3PO4 (1.51 g, 7.10 mmol), and (1S,2S)-NI,N2- dimethylcyclohexane-l,2-diamine (168.20 mg, 1.18 mmol) at 20 °C. The mixture was stirred at 105 °C for 12 hrs under an N2 atmosphere and then filtered and concentrated under vacuum. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-11% EtOAc/petroleum ether gradient eluent to afford the title compound (800 mg, 83%) as a white solid. 'H NMR (400 MHz, CDCh) 8 8.52 (s, 1H), 8.12 (br s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.38 - 7.28 (m, 1H), 7.21 (br s, 1H), 5.29 (s, 2H), 3.68 - 3.54 (m, 1H), 3.67 - 3.52 (m, 1H), 2.61 - 2.51 (m, 3H), 1.03 - 0.88 (m, 2H), 0.03 (s, 9H). MS-ESI (m/z) calc’d for Ci7H24BrN4OSi [M+H]+: 407.1, 409.1. Found 407.3, 409.3.
Step 3: l-(2-Methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)-6-(4, 4,5,5-
Figure imgf000219_0001
To a solution of 6-bromo-l-(2-methyl-l-((2-(trimethylsilyl) ethoxy) methyl)-!//- imidazol-5-yl)-17/-indazole (800 mg, 1.96 mmol) in dioxane (10 mL) were added Pd(dppt)Ch (143.69 mg, 196.38 umol), AcOK (578.17 mg, 5.89 mmol), and bis(pinacolato)diboron (598.41 mg, 2.36 mmol) at 20 °C. The mixture was stirred at 100 °C for 2 hrs under an N2 atmosphere and then concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0-12% EtOAc/petroleum ether gradient eluent to afford the title compound (300 mg, 33%) as a yellow oil. MS-ESI (m/z) calc’d for C23H36BN4O3Si [M+H]+: 455.3. Found 455.4.
Figure imgf000219_0002
To a solution of l-(2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-17/-imidazol-5-yl)- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17/-indazole (300 mg, 660.15 umol) in THF (3 mL) and H2O (3 mL) was added sodium perborate tetrahydrate (304.71 mg, 1.98 mmol) and the mixture was stirred at 50 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford the title compound (190 mg, 83%) as a yellow oil. JH NMR (400 MHz, CDCh) 8 8.03 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.30 (s, 2H), 6.81 (br d, J=8.4 Hz, 1H), 5.28 (s, 2H), 3.68 - 3.58 (m, 2H), 2.54 (s, 3H), 1.01 - 0.93 (m, 2H), 0.04 (s, 9H). MS-ESI (m/z) calc’d for Cn^lShChSi [M+H]+: 345.2. Found 345.3.
Step 4: 5-((l-(2-Methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)-lH-indazol-6- yl)oxy)-5, 6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000220_0001
To a solution of l-(2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-17/-imidazol-5-yl)- 17/-indazol-6-ol(159.10 mg, 461.87 umol) and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carbonitrile (80 mg, 461.87 umol) in toluene (3 mL) were added 1,1- (azodicarbonyl)dipiperidine (233.07 mg, 923.73 umol) and tributylphosphane (186.89 mg, 923.73 umol) at 0 °C. The mixture was stirred at 50 °C for 3 hrs under an N2 atmosphere and then concentrated under reduced pressure to remove solvent. The residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 1/1, Rf = 0.47) to afford the title compound (110 mg, 47%) as ayellow solid. MS-ESI (m/z) calc’d for C28H34NsO2Si [M+H]+: 500.2. Found 500.4.
Step 5: 5-((l-(2-Methyl-lH-imidazol-5-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000220_0002
To a solution of 5-((l-(2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-17/-imidazol-5- yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (80 mg, 160.10 umol) in DCM (5 mL) was added TFA (2.31 g, 20.26 mmol) at 0 °C. The mixture was then stirred at 20 °C for 6 hrs. The reaction mixture was added to saturated aqueous NaHCOs at 0 °C to pH = 8 and extracted with CH2CI2 (4x). The combined organic phases were dried with anhydrous Na2SC>4, the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method BD to afford the title compounds (4 mg, 6%) as a white solid. MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.0.
Step 6: 5-((l-(2-Methyl-lH-imidazol-5-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000221_0001
5-((l-(2-Methyl-17f-imidazol-5-yl)-17f-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method BE to afford 5-((l-(2-methyl-17f-imidazol-5-yl)-17f-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (1.13 mg, 14%) as a colorless gum. JH NMR (400 MHz, DMSO- e) 6 11.99 (br s, 1H), 8.11 (s, 1H), 7.78 (s, 1H), 7.73 - 7.69 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 6.98 (dd, J=2.1, 8.9 Hz, 1H), 5.62 (t, J=4.9 Hz, 1H), 2.96 - 2.87 (m, 1H), 2.84 - 2.74 (m, 1H), 2.35 (s, 3H), 2.09 - 2.03 (m, 2H), 1.93 - 1.77 (m, 2H). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.2. A later eluting fraction was also isolated to afford 5-((l-(2-methyl-17f-imidazol-5-yl)- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (0.85 mg, 10%) as a colorless gum. 'H NMR (400 MHz, DMSO- e) 6 11.99 (br s, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.74 - 7.68 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.16 (d, J=1.8 Hz, 1H), 6.98 (dd, J=2.0, 8.8 Hz, 1H), 5.62 (t, J=4.8 Hz, 1H), 2.95 - 2.87 (m, 1H), 2.84 - 2.73 (m, 1H), 2.35 (s, 3H), 2.09 - 2.03 (m, 2H), 1.95 - 1.76 (m, 2H). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.2.
Example 76: 5-((l-(Thiazol-5-yl)-LH-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 1 and 2
Figure imgf000221_0002
Step 1: 5 -(6-Bromo-lH-indazol-l-yl) thiazole
Figure imgf000222_0001
5-Bromothiazole (457.86 mg, 2.79 mmol), 6-bromo-17/-indazole (500 mg, 2.54 mmol), CS2CO3 (1.65 g, 5.08 mmol), 3,4,7,8-tetramethyl-l,10-phenanthroline (59.97 mg, 253.77 umol) and (Bu4NCuI)2 (142.06 mg, 126.88 umol) were combined in a microwave tube in DMA (10 mL) at 20 °C under an N2 atmosphere. The tube was sealed and heated at 120 °C for 5 hrs in a microwave reactor. The mixture was diluted with EtOAc and filtered. The filtrate was washed with H2O and the aqueous phase was extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (70 mg, 9%) as a white solid. JH NMR (400 MHz, CDCh) 8 8.78 (s, 1 H), 8.22 (s, 1 H), 8.13 (s, 1 H), 7.91 (s, 1 H), 7.70 (d, J=8.56 Hz, 1 H), 7.44 (dd, J=8.50, 1.41 Hz, 1 H). MS-ESI (m/z) calc’d for CioH7BrN3S [M+H]+: 280.0, 282.0. Found 280.1, 282.1.
Figure imgf000222_0002
A mixture of 5-(6-bromo-17/-indazol-l-yl)thiazole (70 mg, 249.87 umol), bis(pinacolato)diboron (76.14 mg, 299.85 umol), Pd(dppf)Ch (18.28 mg, 24.99 umol), and AcOK (73.57 mg, 749.62 umol) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C and then the mixture was stirred at 120 °C for 2 hrs under an N2 atmosphere. The mixture was concentrated and purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 1/1, Rf = 0.72) to afford the title compound (64 mg, 78%) as a white solid. 'H NMR (400 MHz, CDCh) 8 8.63 (s, 1 H), 8.26 (s, 1 H), 8.19-8.22 (m, 1 H), 8.09 (s, 1 H), 7.55-7.59 (m, 1 H), 7.42 (d, J=8.50 Hz, 1 H), 1.30 (s, 12 H) MS-ESI (m/z) calc’d for C16H19BN3O2S [M+H]+: 328.1. Found 328.3.
Step 3: l-(Ihiazol-5-yl)-lH-indazol-6-ol
Figure imgf000223_0001
To a solution of 5-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17/-indazol-l- yl)titiazole (64 mg, 195.59 umol) in THF (1 mL) and H2O (1 mL) was added NaBOs FLO (90.28 mg, 586.78 umol) at 20 °C. The mixture was then stirred at 50 °C for 1 hr. The reaction mixture was filtered, and the filtrate was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated to afford the title compound (42 mg, 98%) as a yellow oil. JH NMR (400 MHz, DMSO- e) 6 10.11 (s, 1 H), 8.98 (d, J=0.63 Hz, 1 H), 8.26 (d, J=0.88 Hz, 1 H), 8.17 (d, J=0.63 Hz, 1 H), 7.70 (d, J=8.63 Hz, 1 H), 7.10 - 7.14 (m, 1 H), 6.85 (dd, J=8.69, 1.94 Hz, 1 H). MS-ESI (m/z) calc’d for CioHsNsOS [M+H]+: 218.0. Found 218.2.
Step 4: 5-((l-(Ihiazol-5-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2- carbonitrile
Figure imgf000223_0002
To a solution of l-(thiazol-5-yl)-17/-indazol-6-ol (30 mg, 138.09 umol) in THF (3 mL) were added 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (28.70 mg, 165.71 umol), PPhs (39.84 mg, 151.90 umol) and DIAD (33.51 mg, 165.71 umol) at 0 °C. The mixture was degassed and purged with N2 (3x), and then the mixture was stirred at 0 °C for 1 hr under an N2 atmosphere. The mixture was concentrated and purified by HPLC using Method BF to afford the title compound (27 mg, 52%) as white solid. MS-ESI (m/z) calc’d for C21H17N4OS [M+H]+: 373.1. Found 373.2.
Step 5: 5-((l-(Ihiazol-5-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 1 and 2
Figure imgf000223_0003
5-((l-(Thiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile was subjected to chiral separation using Method BG to afford 5-((l-(thiazol-5- yl)-17/-indazol
-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (1.88 mg, 20%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.98 (d, J=0.63 Hz, 1 H), 8.41 (d, J=0.63 Hz, 1 H), 8.34 (d, J=0.75 Hz, 1 H), 7.81 (d, J=8.75 Hz, 1 H), 7.70 (s, 1 H), 7.62 - 7.67 (m, 1 H), 7.55 (d, J=8.38 Hz, 2 H), 7.03 (dd, J=8.76, 2.00 Hz, 1 H), 5.90 (t, J=4.88 Hz, 1 H), 2.87 - 2.94 (m, 1 H), 2.77 - 2.84 (m, 1 H), 2.00 - 2.12 (m, 2 H), 1.78 - 1.93 (m, 2 H). MS-ESI (m/z) calc’d for C21H17N4OS [M+H]+: 373.1. Found 373.1. A later eluting fraction was also isolated to afford 5-((l-(thiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 2 (2 mg, 21%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.97 (s, 1 H), 8.40 (s, 1 H), 8.33 (s, 1 H), 7.81 (d, J=8.75 Hz, 1 H), 7.69 (s, 1 H), 7.64 (d, J=8.00 Hz, 1 H), 7.55 (d, J=8.38 Hz, 2 H), 7.03 (dd, J=8.76, 2.00 Hz, 1 H), 5.90 (t, J=4.82 Hz, 1 H), 2.86 - 2.95 (m, 1 H), 2.76 - 2.84 (m, 1 H), 1.98 - 2.11 (m, 2 H), 1.75 - 1.95 (m, 2 H). MS-ESI (m/z) calc’d for C21H17N4OS [M+H]+: 373.1. Found 373.1.
Example 77 : 4-Methyl-5-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000224_0001
Step 1: l-(4-Bromo-2-methylphenyl)cyclobutanol
Figure imgf000224_0002
To a solution of 4-bromo-l-iodo-2-methylbenzene (2 g, 6.74 mmol) in THF (20 mL) was added w-BuLi (2.5 M, 3.37 mL) at -78 °C under an N2 atmosphere. The mixture was stirred at -78 °C for 0.5 hr then cyclobutanone (472.10 mg, 6.74 mmol) was added at -78 °C under an N2 atmosphere and stirring was continued for an additional 1.5 hrs. The reaction mixture was quenched by addition of saturated aqueous NH4CI at 0 °C and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-17% EtOAc/petroleum ether gradient eluent to afford the title compound (970 mg, 59%) as a pale yellow oil. 'H NMR (400 MHz, CDCh) 8 7.26 - 7.34 (m, 2 H), 7.09 - 7.15 (m, 1 H), 2.59 - 2.69 (m, 1 H), 2.35 - 2.44 (m, 4 H), 2.31 - 2.33 (m, 1 H), 2.28 (s, 1 H), 2.14 - 2.25 (m, 1 H), 1.65 - 1.78 (m, 1 H).
Figure imgf000225_0001
To a solution of l-(4-bromo-2-methylphenyl)cyclobutanol (400 mg, 1.66 mmol) in MeCN (5 mL) and H2O (5 mL) was added ceric ammonium nitrate (2.27 g, 4.15 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 minute. The mixture was adjusted to pH = 8 with saturated aqueous NaHCOs. then the mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0- 8% EtOAc/petroleum ether gradient eluent to afford the title compound (91 mg, 22%) as a yellow gum. 'H NMR (400 MHz, MeOD-t/v) 8 7.37 (s, 1 H), 7.31 (s, 1 H), 2.96 (t, J=6.14 Hz, 2 H), 2.62 (t, J=6.58 Hz, 2 H), 2.57 (s, 3 H), 2.02 - 2.10 (m, 2 H). MS-ESI (m/z) calc’d for CnHnBrO [M+H]+: 239.0, 241.0. Found 239.2, 241.2.
Figure imgf000225_0002
To a solution of 6-bromo-8-methyl-3,4-dihydronaphthalen-l(277)-one (100 mg, 418.22 umol) in MeOH (2 mL) was added NaBH4 (18.99 mg, 501.87 umol). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O and the mixture was concentrated under reduced pressure to remove MeOH. Then the mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (70 mg, 69%) as a yellow oil. 1 H NMR (400 MHz, CDCh) 8 7.19 (s, 1 H), 7.13 (s, 1 H), 4.88 (dt, J=5.86, 3.10 Hz, 1 H), 2.77 - 2.85 (m, 1 H), 2.63 - 2.74 (m, 1 H), 2.43 (s, 3 H), 2.10 - 2.17 (m, 1 H), 1.85 - 1.99 (m, 1 H), 1.74 - 1.83 (m, 2 H). Step 4: N-( 6-Bromo-8-methyl-l , 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( 1-(1 -methyl- 1H-
Figure imgf000226_0001
To a solution of JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-nitrobenzene sulfonamide (130 mg, 326.31 umol) in toluene (5 mL) was added (cyanomethylene)tributylphosphorane (236.27 mg, 978.93 umol) and 6-bromo-8-methyl- 1,2,3,4-tetrahydronaphthalen-l-ol (94.42 mg, 391.57 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography using a 0-53% EtOAc/petroleum ether gradient eluent to afford the title compound (100 mg, 49%) as a brown gum. MS-ESI (m/z) calc’d for C28H26BrN6O4S [M+H]+: 621.1, 623.1. Found 621.0, 623.0.
Step 5: N-( 6-bromo-8-methyl-l, 2, 3, 4-tetrahydronaphthalen-l-yl)-l-( 1 -methyl- lH-pyrazol-4- yl)-lH-indazol-6-amine
Figure imgf000226_0002
To a solution of A-(6-bromo-8-methyl-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-(l-(l- methyl- l//-pyrazol-4-yl)- l //-indazol-6-yl)-2-nitrobenzenesulfonamide (100 mg, 160.90 umol) in DMF (2 mL) were added PhSH (290 mg, 2.63 mmol) and K2CO3 (111.19 mg, 804.50 umol) and the mixture was stirred at 20 °C for 3 hrs. The reaction mixture was then diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (100% EtOAc, Rf = 0.5) to afford the title compound (50 mg, 71%) as a brown gum. MS-ESI (m/z) calc’d for C22H23BrN5 [M+H]+: 436.1, 438.1. Found 436.0, 437.9.
Step 6: 4-Methyl-5-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000227_0001
To a solution of /V-(6-bromo-8-methyl-l,2,3,4-tetrahydronaphthalen-l-yl)-l-(l- methyl-17/-pyrazol-4-yl)-17/-indazol-6-amine (50 mg, 114.59 umol) in DMA (2 mL) were added Zn(CN)2 (26.91 mg, 229.18 umol), Zn (14.99 mg, 229.18 umol), and DPPF (12.71 mg, 22.92 umol), and Pd2(dba)3 (20.99 mg, 22.92 umol) at 20 °C. The mixture was stirred at 120 °C for 2 hrs under an N2 atmosphere in a microwave reactor. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by HPLC using Method BH to afford the title compound (7 mg, 15%) as a white solid. MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.3.
Step 7: 4-Methyl-5-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000227_0002
4-Methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method BI to afford 4-methyl-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (2 mg, 27%) as a yellow solid. 'H NMR (400 MHz, DMSO-rfc) 6 8.19 (s, 1 H), 7.93 (s, 1 H), 7.84 (s, 1 H), 7.44 - 7.52 (m, 3 H), 6.67 - 6.73 (m, 2 H), 6.31 (d, J=8.16 Hz, 1 H), 4.82 (br d, J=5.27 Hz, 1 H), 3.92 (s, 3 H), 2.84 - 2.93 (m, 1 H), 2.70 - 2.77 (m, 1 H), 2.25 (s, 3 H), 2.08 - 2.15 (m, 1 H), 1.57 - 1.86 (m, 3 H). MS- ESI (m/z) calc’d for C23H23Ne [M+H]+: 383.2. Found 383.2. A later eluting fraction was isolated and further purified by HPLC using Method BH to afford 4-methyl-5-((l-(l-methyl- l//-pyrazol-4-yl)-l//-indazol-6-yl) amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (1 mg, 11%) as a white solid. 'H NMR (400 MHz, MeOH-tL) 8 8.05 (s, 1 H), 7.92 (s, 1 H), 7.82 (s, 1 H), 7.50 (d, J=8.55 Hz, 1 H), 7.36 (d, J=5.04 Hz, 2 H), 6.68 (dd, J=9.21, 1.32 Hz, 1 H), 6.63 (s, 1 H), 4.79 (br s, 1 H), 3.99 (s, 3 H), 2.89 - 2.98 (m, 1 H), 2.72 - 2.84 (m, 1 H), 2.29 (s, 3 H), 2.25 - 2.28 (m, 1 H), 1.90 - 1.98 (m, 1 H), 1.77 - 1.86 (m, 1 H), 1.72 (br d, J=12.28 Hz, 1 H). MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.2.
Example 78: l-MethyI-5-((l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitriIe, enantiomer 1 and 2
Figure imgf000228_0001
To a solution of 6-amino-3,4-dihydronaphthalen-l(277)-one (2 g, 12.41 mmol) in DCM (124 mL) was added NBS (2.21 g, 12.41 mmol) at 0 °C and the mixture was stirred at 0 °C for 4 hrs. The pH of the mixture was adjusted to 8 with saturated aqueous NaHCOs. and then extracted with EtOAc (3x). The combined organic layers were dried with Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (2.5 g, 83%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 7.89 (d, J=8.50 Hz, 1H), 6.69 (d, J=8.50 Hz, 1H), 2.97 (t, J=6.19 Hz, 2H), 2.53-2.60 (m, 2H), 2.07-2.16 (m, 2H). MS-ESI (m/z) calc’d for CioHnBrNO [M+H]+: 240.0, 242.0. Found 240.2, 242.2.
Figure imgf000228_0002
Two identical reactions were carried out in parallel. To a solution of 6-amino-5- methyl-3,4-dihydronaphthalen-l(277)-one (1.25 g, 5.21 mmol) in dioxane (10 mL) and H2O (1 mL) were added Pd(dppt C12*CH2C12 (425.16 mg, 520.62 umol), K2CO3 (3.24 g, 23.43 mmol), and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (1.44 g, 5.73 mmol) at 20 °C. The mixture was stirred at 90 °C for 12 hrs under an N2 atmosphere. The two parallel reactions were then combined and the final mixture was concentrated under reduced pressure to give a residue that was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by flash silica gel chromatography using a 0-13% EtOAc/petroleum ether gradient eluent to afford the title compound (1 g, 54%) as a brown solid. JH NMR (400 MHz, CDCh) 8 7.87 (d, J=8.38 Hz, 1H), 6.61 (d, J=8.50 Hz, 1H), 2.87 (t, J=6.13 Hz, 2H), 2.53-2.58 (m, 2H), 2.06-2.14 (m, 5H). MS-ESI (m/z) calc’d for C11H14NO [M+H]+: 176.1. Found 176.3.
Figure imgf000229_0001
To a solution of 6-amino-5-methyl-3.4-dihydronaphthalen- 1 (27/)-one (300 mg, 1.71 mmol) in MeCN (12 mL) were added t-BuNCh (529.65 mg, 5.14 mmol) and CuBr (736.79 mg, 5.14 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hrs and then diluted with H2O and EtOAc. Then the mixture was filtered and the filtrate was extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-6% EtOAc/petroleum ether gradient eluent to afford the title compound (263.67 mg, 64%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 7.77 (d, J=8.38 Hz, 1H), 7.53 (d, J=8.50 Hz, 1H), 2.93 (t, J=6.13 Hz, 2H), 2.59-2.64 (m, 2H), 2.42 (s, 3H), 2.13-2.18 (m, 2H). MS-ESI (m/z) calc’d for CnHnBrO [M+H]+: 239.0, 241.0. Found 239.2, 241.2.
Figure imgf000229_0002
To a solution of 6-bromo-5-methyl-3.4-dihydronaphthalen- 1 (27/)-one (200 mg, 836.44 umol) in MeOH (5 mL) was added NaBH4 (37.97 mg, 1.00 mmol). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O and the mixture was concentrated under reduced pressure to remove MeOH and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford the title compound (150 mg, 74%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 7.39 (d, J=8.28 Hz, 1 H), 7.19 (d, J=8.41 Hz, 1 H), 5.15 (d, J=5.77 Hz, 1 H), 4.47 - 4.55 (m, 1 H), 2.57 - 2.70 (m, 2 H), 2.27 (s, 3 H), 1.88 - 1.98 (m, 1 H), 1.79 - 1.86 (m, 1 H), 1.60 - 1.70 (m, 2 H).
Step 5: N-( 6-Bromo-5-methyl-l , 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( 1-(1 -methyl- 1H-
Figure imgf000230_0001
Two identical reactions were carried out in parallel. To a solution of/V-(l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-nitrobenzenesulfonamide (75 mg, 188.26 umol) in toluene (3.5 mL) was added (tributylphosphoranylidene)acetonitrile (136.31 mg, 564.77 umol) and 6-bromo-5-methyl-l,2,3,4-tetrahydronaphthalen-l-ol (54.47 mg, 225.91 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The two parallel reactions were then combined and the final mixture was concentrated under reduced pressure to remove solvent. The material was purified by flash silica gel chromatography using a 0- 52% EtOAc/petroleum ether gradient eluent to afford the title compound (160 mg, 68%) as a brown oil. MS-ESI (m/z) calc’d for C28H26BrN6O4S [M+H]+: 621.1, 623.1. Found 620.9, 622.6.
Step 6: N-( 6-Bromo-5-methyl-l , 2, 3, 4-tetrahydronaphthalen-l-yl)-l-( I -methyl- lH-pyrazol-4- yl)-lH-indazol-6-amine
Figure imgf000230_0002
To a solution of JV-(6-bromo-5 -methyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)-JV-( 1 -( 1 - methyl- l//-pyrazol-4-yl)- l //-indazol-6-yl)-2-nitrobenzenesulfonamide (160 mg, 257.44 umol) in DMF (3 mL) were added PhSH (140 mg, 1.27 mmol) and K2CO3 (177.90 mg, 1.29 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative-TLC, (100 % EtOAc, Rf = 0.4) to afford the title compound (70 mg, 62%) as a brown solid. MS-ESI (m/z) calc’d for C22H23BrN5 [M+H]+: 436.1, 438.1. Found 436.2, 438.1.
Step 7: l-Methyl-5-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000231_0001
To a solution of A-(6-bromo-5-methyl-l,2,3,4-tetrahydronaphthalen-l-yl)-l-(l- methyl-17/-pyrazol-4-yl)-17/-indazol-6-amine (80 mg, 183.34 umol) in DMA (1 mL) was added zinc cyanide (43.06 mg, 366.68 umol), DPPF (20.33 mg, 36.67 umol), Pd2(dba)3 (33.58 mg, 36.67 umol), and Zn (23.98 mg, 366.68 umol) at 20 °C. The mixture was stirred at 120 °C for 2 hrs under an N2 atmosphere in a microwave reactor. The reaction was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, the mixture was filtered, and the filtrate was concentrated under vacuum. The material was purified by HPLC using Method BJ to afford the title compound (9 mg, 12%) as a white solid. MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.3.
Step 8: l-Methyl-5-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000231_0002
l-Methyl-5-((l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method BKto afford l-methyl-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (4 mg, 47%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.16 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.54 (d, J=8.13 Hz, 1H), 7.48 (d, J=8.63 Hz, 1H), 7.33 (d, J=8.13 Hz, 1H), 6.66-6.74 (m, 2H), 6.42 (d, J=8.88 Hz, 1H), 4.85 (br s, 1H), 3.90 (s, 3H), 2.64-2.74 (m, 2H), 2.42 (s, 3H), 1.81-1.97 (m, 4H). MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.2. A later eluting fraction was also isolated to afford l-methyl-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (4 mg, 47%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.16 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.54 (d, J=8.13 Hz, 1H), 7.48 (d, J=8.63 Hz, 1H), 7.33 (d, J=8.00 Hz, 1H), 6.65-6.73 (m, 2H), 6.42 (d, J=8.88 Hz, 1H), 4.85 (br s, 1H), 3.90 (s, 3H), 2.65-2.72 (m, 2H), 2.42 (s, 3H), 1.80-1.97 (m, 4H). MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.2.
Example 79: 3-Methyl-5-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000232_0001
A mixture of 5-hydroxy-3-methyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (70 mg, 373.86 umol), 7V-(1-(1 -methyl- IT/-pyrazol-4-y l)-17/-indazol-6-yl)-2- nitrobenzenesulfonamide (148.94 mg, 373.86 umol), (tributylphosphoranylidene)acetonitrile (180.46 mg, 747.71 umol) in toluene (5 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The material was purified by preparative TLC (SiCh, 100% EtOAc, Rf = 0.42) to afford the title compound (118 mg, 55%) as colorless gum. MS-ESI (m/z) calc’d for C29H26N7O4S [M+H]+: 568.2.
Found 568.3.
Step 2: Methyl-5-(( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000233_0001
To a solution of /V-(6-cyano-7-methyl-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-(l-(l- methyl- l//-pyrazol-4-yl)- l //-indazol-6-yl)-2-nitrobenzenesulfonamide (140 mg, 246.65 umol) in DMF (3 mL) was added K2CO3 (68.18 mg, 493.29 umol) and benzenethiol (54.35 mg, 493.29 umol) at 20 °C. The mixture was stirred at 50 °C for 2 hrs. The mixture was diluted with H2O and extracted with EtOAc (4x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiCh, 100% EtOAc, Rf = 0.48) to afford the title compound (56 mg, 59%) as a yellow solid. MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.3.
Step 3: 3-Methyl-5-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000233_0002
3-Methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile compound was subjected to chiral separation using Method BK to afford 3-methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (2 mg, 19%) as a pale yellow gum. 'H NMR (400 MHz, MeOH-t/v) 8 7.98 (s, 1 H), 7.91 (d, J=0.63 Hz, 1 H), 7.75 (s, 1 H), 7.50 (d, J=8.75 Hz, 1 H), 7.42 (s, 1 H), 7.39 (s, 1 H), 6.70 (dd, J=8.76, 1.88 Hz, 1 H), 6.57 (s, 1 H), 4.72 (t, J=5.57 Hz, 1 H), 3.96 (s, 3 H), 2.71 - 2.90 (m, 2 H), 2.40 (s, 3 H), 1.80 - 2.06 (m, 4 H) MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383. E A later eluting fraction was also isolated to afford 3-methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (2 mg, 16%) as a pale yellow gum. 'H NMR (400 MHz, MeOD-t/v) 8 7.99 (s, 1 H), 7.92 (s, 1 H), 7.76 (s, 1 H), 7.51 (d, J=8.76 Hz, 1 H), 7.43 (s, 1 H), 7.40 (s, 1 H), 6.71 (dd, J=8.76, 1.88 Hz, 1 H), 6.58 (s, 1 H), 4.73 (t, J=5.69 Hz, 1 H), 3.97 (s, 3 H), 2.74 - 2.87 (m, 2 H), 2.41 (s, 3 H), 1.83 - 2.06 (m, 4 H) MS-ESI (m/z) calc’d for C23H23N6 [M+H]+: 383.2. Found 383.1.
Example 80: 5-Chloro-4-cyano-2,3-dimethyl-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//- indazol-6-yI)benzamide
Figure imgf000234_0001
Step 1: 4-Formyl-3-hydroxy-2-methylbenzonitrile
Figure imgf000234_0002
To a solution of 3-hydroxy-2-methyl-benzonitrile (440 mg, 3.30 mmol) in THF (5 mL) were added EtsN (835.98 mg, 8.26 mmol) and MgCh (786.59 mg, 8.26 mmol) and paraformaldehyde (414.5 mg, 3.30 mmol) at 25 °C. The mixture was heated at 70 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with 1 M HC1 and extracted with EtOAc (3x). The combined organic layers were washed with brine (lx), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (130 mg, 24%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.72 (d, J=8.25 Hz, 1 H), 7.15 (d, J=8.13 Hz, 1 H), 2.33 (s, 3 H). MS-ESI (m/z) calc’d for C9H6NO2 [M-H]’: 160.1. Found 160.0.
Step 2: 4-Cyano-2-hydroxy-3-methylbenzoic acid
Figure imgf000235_0001
To a solution of 4-formyl-3-hydroxy-2-methylbenzonitrile (370 mg, 2.30 mmol) in t- BuOH (2.3 mL) and THF (1.2 mL) was added NaFbPCh (550.91 mg, 4.59 mmol) and NaCICh (830.56 mg, 9.18 mmol) and 2-methyl-2-butene (966.11 mg, 13.78 mmol) in FhO (0.6 mL) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were washed with brine (lx), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a residue to afford the title compound (366 mg, 90%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 7.72 (d, J=8.25 Hz, 1 H), 7.15 (d, J=8.13 Hz, 1 H), 2.33 (s, 3 H). MS-ESI (m/z) calc’d for C9H6NO3 [M-H]’: 176.0. Found 176.0.
Step 3: 4-Cyano-2-hydroxy-3-methylbenzoyl chloride
Figure imgf000235_0003
To a solution of 4-cyano-2-hydroxy-3-methylbenzoic acid (366 mg, 2.07 mmol) in DCM (3 mL) were added DMF (1.51 mg, 20.66 umol) and (COC1)2 (786.68 mg, 6.20 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 hrs. The solvent was evaporated to afford the title compound (400 mg) as yellow oil which was used without further purification.
Step 4: Methyl 4-cyano-2-hydroxy-3-methylbenzoate
Figure imgf000235_0002
4-Cyano-2-hydroxy-3-methylbenzoyl chloride (400 mg, 2.04 mmol) was added to MeOH (6 mL) dropwise at 20 °C, the mixture was stirred at 20 °C for 12 hrs. The solvent was evaporated and the residue was purified by silica gel chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (179 mg, 45%) as a yellow solid. 'H NMR (400 MHz, CDCh) 6 11.24 (d, J=0.88 Hz, 1 H), 7.77 (d, J=8.11 Hz, 1 H), 7.12 (d, J=8.33 Hz, 1 H), 4.00 (d, J=l.10 Hz, 3 H), 2.48 (s, 3 H). MS-ESI (m/z) calc’d for CioHsNOs [M-H]': 190.1. Found 190.0.
Step 5: Methyl 5-chloro-4-cyano-2-hydroxy-3-methylbenzoate
Figure imgf000236_0001
To a solution of methyl 4-cyano-2-hydroxy-3-methylbenzoate (179 mg, 936.28 umol) in DMF (3 mL) was added NCS (179.00 mg, 1.34 mmol) in DMF (3 mL) at 0 °C. The mixture was stirred at 30 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 5/1, Rf = 0.55) to afford title compound (92.7 mg, 43%) as a yellow oil. 'H NMR (400 MHz, CDCh) 6 11.13 (s, 1 H), 7.82 (s, 1 H), 4.01 (s, 3 H), 2.51 (s, 3 H). MS-ESI (m/z) calc’d for C10H7CINO3 [M-H]': 224.0. Found 224.0.
Step 6: Methyl 5-chloro-4-cyano-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate
Figure imgf000236_0002
To a solution of methyl 5-chloro-4-cyano-2-hydroxy-3-methylbenzoate (103 mg, 456.50 umol) in DCM (2 mL) was added pyridine (288.88 mg, 3.65 mmol) and Tf2O (515.19 mg, 1.83 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The solvent was evaporated and the residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 5/1, Rf = 0.43) to afford the title compound (41 mg, 25%) as ayellow oil. 'H NMR (400 MHz, CDCh) 8 7.96 (s, 1 H), 3.97 - 4.01 (m, 3 H), 2.65 (s, 3 H). Step 7: Methyl 5-chloro-4-cyano-2, 3-dimethylbenzoate
Figure imgf000237_0001
To a solution of methyl 5-chloro-4-cyano-3-methyl-2- (((trifluoromethyl)sulfonyl)oxy)benzoate (41 mg, 114.62 umol) and 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (86.34 mg, 343.87 umol) in dioxane (1 mL) were added Pd(dppf)C12*CH2C12 and K2CO3 (47.53 mg, 343.87 umol) at 20 °C. The mixture was stirred at 70 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 5/1, Rf = 0.37) to afford the title compound (13 mg, 50%) as a yellow oil. JH NMR (400 MHz, CDCh) 8 7.71 (s, 1 H), 3.93 (d, J=0.63 Hz, 3 H), 2.58 (s, 3 H), 2.45 (s, 3 H).
Step 8: 5-Chloro-4-cyano-2, 3-dimethylbenzoic acid
Figure imgf000237_0002
To a solution of methyl 5-chloro-4-cyano-2, 3-dimethylbenzoate (13 mg, 58.13 umol) in H2O (0.5 mL) and THF (0.5 mL) was added LiOH»H2O (12.20 mg, 290.63 umol) at 20 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove THF. 1 M HC1 was added dropwise until pH = 5-6 and the mixture was extracted with EtOAc (3x). The combined organic phases were dried over Na2SC>4 and evaporated to afford the title compound (10 mg, 80%) as a white solid. MS-ESI (m/z) calc’d for C10H7CINO2 [M-H]’: 208.0. Found 208.0.
Step 9: 5-Chloro-4-cyano-2, 3-dimethyl-N-( l-(l -methyl-lH-pyrazol-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000238_0001
To a solution of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (4.67 mg, 21.92 umol) in DCM (1 mL) were added TsP (41.85 mg, 65.77 umol), EtsN (11.09 mg, 109.61 umol), and 5-chloro-4-cyano-2,3-dimethylbenzoic acid (4.60 mg, 21.92 umol) in DCM (1 mL) at 20 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction was combined with another 10 mg scale reaction before work up. The combined reaction mixtures were evaporated to dryness. The residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 5/1, Rf = 0.55). The residue was purified by HPLC using Method BM to afford the title compound (1 mg, 5%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.79 (s, 1 H), 8.27 (s, 1 H), 8.20 - 8.24 (m, 2 H), 7.79 - 7.84 (m, 2 H), 7.74 (s, 1 H), 7.38 (dd, J=8.74, 1.65 Hz, 1 H), 3.95 (s, 3 H), 2.54 (s, 3 H), 2.29 (s, 3 H). MS-ESI (m/z) calc’d for C21H18CIN6O [M+H]+: 405.1. Found 405.1.
Example 81: 2-ChIoro-7-((l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-6,7- diliydro-5//-cyclopenta|b|pyridine-3-carbonitrile. enantiomer 1 and 2
Figure imgf000238_0002
Step 1: Sodium (2-oxocyclopentylidene)methanolate
Figure imgf000238_0003
Na (4.71 g, 205.07 mmol) was dissolved in MeOH (44 mL) at 25 °C and the mixture was stirred at 25 °C for 0.5 hr. A solution of cyclopentanone (15 g, 178.32 mmol) in methyl formate (10.71 g, 178.32 mmol) was then added to the mixture dropwise at 25 °C and stirring was continued at 25 °C for 0.5 hr. A yellow solid formed. The reaction mixture was filtered, the solid was washed with EtOAc (3x) and then dried under vacuum to afford the title compound (24 g, 100%) as a pale yellow solid.
Figure imgf000239_0001
A freshly prepared solution of acetic acid (4.2 mL) and piperidine (7.2 mL) in water (10 mL) was added to a solution of sodium (2-oxocyclopentylidene)methanolate (24.42 g, 182.09 mmol) and 2-cyanoacetamide (16.84 g, 200.30 mmol) in H2O (200 mL) at 20 °C. The mixture was stirred at 100 °C for 12 hrs. The reaction was cooled to room temperature, then AcOH (18 mL) was added to the mixture and the resulted mixture was cooled to 0 °C and filtered. The solid was collected by filtration and set aside. The filtrate was extracted with EtOAc (4x) and the organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was triturated with EtOAc and filtered. The solids were combined and dried under vacuum to give the title compound (12.59 g, 43%) as a gray solid. 'H NMR (400 MHz, DMSO-de) 6 7.90 - 8.06 (m, 1 H) 2.80 (br t, J=7.57 Hz, 2 H) 2.59 - 2.69 (m, 2 H) 2.03 (m, J=7.47 Hz, 2 H). MS-ESI (m/z) calc’d for C9H9N2O [M+H]+: 161.1, Found 161.2.
Figure imgf000239_0002
2-Hydroxy-6,7-dihydro-57/-cyclopenta[/i]pyridine-3-carbonitrile (6.49 g, 40.52 mmol) was added to POOL (30 mL) slowly at 20 °C, then the mixture was stirred at 100 °C for 12 hrs. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc and then poured into saturated aqueous NaHCOs at 20 °C. A black solid formed that was collected by filtration. The solid was dried under vacuum to afford the title compound (1.73 g, 23%) as a pale yellow solid. MS-ESI (m/z) calc’d for C9H8CIN2 [M+H]+: 179.0. Found 179.2.
Step 4: 2-Chloro-3-cyano-6, 7-dihydro-5H-cyclopenta[b]pyridine 1 -oxide
Figure imgf000240_0001
To a solution of 2-chloro-6.7-dihydro-5//-cyclopenta|6|pyridme-3-carbonitrile (3.48 g, 19.48 mmol) in DCM (50 mL) was added m-CPBA (5.93 g, 29.22 mmol) at 20 °C, then the mixture was stirred at 50 °C for 12 hrs. The reaction was cooled to room temperature and a 10% aqueous solution of Na2SOs was added at 0 °C. This mixture was stirred at 20 °C for 10 min and then extracted with EtOAc (3x). The organic layer was dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-50% EtOAc/petroleum ether gradient eluent to afford the title compound (1.31 g, 34%) as ayellow solid. MS-ESI (m/z) calc’d for C9H8CIN2O [M+H]+: 195.0. Found 195.2.
Figure imgf000240_0002
A solution of 2-chloro-3-cyano-6,7-dihydro-57/-cyclopenta[6]pyridine 1-oxide (1.31 g, 6.73 mmol) in AC2O (15 mL) was stirred at 100 °C for 12 hrs. The reaction was concentrated under vacuum to afford the title compound (840 mg, 54%) as a brown liquid. MS-ESI (m/z) calc’d for C11H10CIN2O2 [M+H]+: 237.0. Found 237.0.
Figure imgf000240_0003
A solution of 2-chloro-3-cyano-6,7-dihydro-57/-cyclopenta[/i]pyridin-7-yl acetate (1.6 g, 6.76 mmol) in 2 M NaOH (15 mL) was stirred at 20 °C for 1 hr. The reaction was then extracted with EtOAc (3x). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-28% EtOAc/petroleum ether gradient eluent to afford the title compound (331 mg, 25%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.10 (s, 1 H) 5.09 (t, J=6.94 Hz, 1 H) 2.98 - 3.10 (m, 1 H) 2.80 - 2.92 (m, 1 H) 2.50 - 2.63 (m, 1 H) 1.93 - 2.03 (m, 1 H). MS-ESI (m/z) calc’d for C9H8CIN2O [M+H]+: 195.0. Found 195.0.
Step 7: 2-Chloro-7-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-6, 7-dihydro-5H- cyclopenta [b ]pyridine-3-carboni trile
Figure imgf000241_0001
To a solution of 2-chloro-7-hydroxy-6.7-dihydro-57/-cyclopenta|6 ]pyridine-3- carbonitrile (90.85 mg, 466.80 umol) and l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-ol (100 mg, 466.80 umol) in toluene (1 mL) were added l,l-(azodicarbonyl)dipiperidine (235.56 mg, 933.61 umol) and t-BusP (188.89 mg, 933.61 umol) at 0 °C. The mixture was stirred at 90 °C for 12 hrs and then concentrated under reduced pressure to remove solvent. The mixture was purified by preparative-TLC (EtOAc/MeOH = 10/1, Rf = 0.41) to obtained 100 mg of a residue. The residue was diluted with MeOH, then filtered and the solid was dried under vacuum. The filtrate was further purified by HPLC using Method BN to give material that was combined with the solid to afford the title compound (23 mg, 12%) as a white solid. MS- ESI (m/z) calc’d for C20H16CIN6O [M+H]+: 391.1. Found 391.2.
Step 8: 2-Chloro-7-(( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-6, 7-dihydro-5H-
Figure imgf000241_0002
2-Chloro-7-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57/- cyclopenta|6 |pyridme-3-carbonitrile was subjected to chiral separation using Method BO to afford 2-chl oro-7 -(( 1 -( 1 -methyl- 17/-py razol-4-y 1)- I //-indazol -6-y l)oxy )-6,7-dihy dro-57/- cyclopenta|6|pyridme-3-carbonitrile. enantiomer 1 (3 mg, 30%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.51 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.38 (s, 1H), 6.94 (dd, J=1.7, 8.8 Hz, 1H), 6.06 (dd, J=4.6, 7.1 Hz, 1H), 3.94 (s, 3H), 3.17 - 3.07 (m, 1H), 3.02 - 2.93 (m, 1H), 2.79 - 2.69 (m, 1H), 2.26 - 2.14 (m, 1H). MS-ESI (m/z) calc’d for C20H16CIN6O [M+H]+: 391.1, Found 391.1. A later eluting fraction was also isolated to afford 2-chloro-7-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7- dihydro-5//-cyclopenta|6 |pyridine-3-carbonitrile. enantiomer 2 (3 mg, 28%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.51 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.39 (s, 1H), 6.94 (dd, J=1.9, 8.8 Hz, 1H), 6.06 (dd, J=4.6, 7.1 Hz, 1H), 3.94 (s, 3H), 3.19 - 3.05 (m, 1H), 3.05 - 2.91 (m, 1H), 2.79 - 2.70 (m, 1H), 2.27 - 2.13 (m, 1H). MS-ESI (m/z) calc’d for C20H16CIN6O [M+H]+: 391.1, Found 391.1.
Example 82: 5-((l-(l-Cyclopentyl-lH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000242_0001
Stepl: l-Cyclopentyl-4-iodo-lH-pyr azole
Figure imgf000242_0002
To a solution of 4-iodo-l/f-pyrazole (1 g, 5.16 mmol) in DMF (12.5 mL) were added K2CO3 (1.78 g, 12.89 mmol) and bromocyclopentane (998.78 mg, 6.70 mmol) at 20 °C and the mixture was stirred at 20 °C for 12 hrs. The mixture was then filtered and the filtrate was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (1 g, 74%) as a colorless oil. JH NMR (400 MHz, CDCh) 6 7.50 (s, 1H), 7.46 (s, 1H), 4.66 (m, J=7.04 Hz, 1H), 2.10-2.21 (m, 2H), 1.93-2.03 (m, 2H), 1.80-1.92 (m, 2H), 1.66-1.77 (m, 2H). MS-ESI (m/z) calc’d for C8H12IN2 [M+H]+: 263.0. Found 263.1.
Step 2: 5-( (1-(1 -Cyclopentyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000243_0001
To a solution of l-cyclopentyl-4-iodo-17/-pyrazole (11 mg, 41.97 umol) in dioxane (1 mL) were added (/?)-5-(( 17/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile (14.57 mg, 50.36 umol), Cui (1.60 mg, 8.39 umol), K3PO4 (26.73 mg, 125.91 umol), and Ni,N2-dimethylcyclohexane-l,2-diamine (2.98 mg, 20.99 umol) at 20 °C. The mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and the material was purified by HPLC using Method BP to afford the title compound (7 mg, 36%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 8.34 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=8.77 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J=7.89 Hz, 1H), 7.54 (d, J=8.11 Hz, 1H), 7.27 (s, 1H), 6.97 (dd, J=1.97, 8.77 Hz, 1H), 5.78 (t, J=4.82 Hz, 1H), 4.77 (quin, J=7.02 Hz, 1H), 2.85-2.97 (m, 1H), 2.72-2.84 (m, 1H), 2.07-2.17 (m, 2H), 1.94-2.06 (m, 4H), 1.74-1.93 (m, 4H), 1.60-1.72 (m, 2H). MS-ESI (m/z) calc’d for C26H26N5O [M+H]+: 424.2. Found 424.2.
Example 83 : 5-((l-(Benzo [ «7| oxazol-2-yl)- 1 H-ind azol-6-y l)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000243_0002
To a solution of 6-bromo-17/-indazole (40 g, 203.01 mmol) in DCM (800 mL) were added PTSA (3.50 g, 20.30 mmol) and 3,4-dihydro-27/-pyran (51.23 g, 609.04 mmol, 55.68 mL) at 20 °C and the mixture was stirred at 20 °C for 4 hrs. The reaction mixture was diluted with H2O and extracted with DCM (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (45 g, 78%) as a yellow solid. JH NMR (400 MHz, CDCh) 8 7.93 (d, J=0.75 Hz, 1 H), 7.74 (s, 1 H), 7.52 (d, J=8.50 Hz, 1 H), 7.19 - 7.26 (m, 1 H), 5.61 (dd, J=9.32, 2.69 Hz, 1 H), 3.94 - 4.03 (m, 1 H), 3.64 - 3.75 (m, 1 H), 2.06 - 2.15 (m, 1 H), 1.98 - 2.06 (m, 1 H), 1.67 - 1.75 (m, 2 H), 1.54 - 1.67 (m, 2 H).
Step 2: l-(Tetrahydro-27/-pyran-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17/- indazole
Figure imgf000244_0001
A mixture of 6-bromo-l-(tetrahydro-27/-pyran-2-yl)-17/-indazole (37 g, 131.60 mmol), bis(pinacolato)diboron (40.10 g, 157.92 mmol), Pd(dppf)C12 (9.63 g, 13.16 mmol), and AcOK (38.75 g, 394.81 mmol) in dioxane (350 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 120 °C for 2 hrs under an N2 atmosphere. The reaction was combined with another 8 g scale reaction before work up. The final mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-1% EtOAc/petroleum ether gradient eluent to afford the title compound (50 g, 95%) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 8.04 (d, J=2.25 Hz, 2 H), 7.72 (dd, J=8.00, 0.75 Hz, 1 H), 7.59 (d, J=8.13 Hz, 1 H), 5.80 (dd, J=9.76, 2.63 Hz, 1 H), 4.03 - 4.09 (m, 1 H), 3.79 (td, J=11.19, 2.63 Hz, 1 H), 2.57 - 2.70 (m, 1 H), 2.12 - 2.23 (m, 1 H), 2.00 - 2.05 (m, 1 H), 1.74 - 1.82 (m, 2 H), 1.63 - 1.69 (m, 1 H), 1.39 (s, 12 H). MS-ESI (m/z) calc’d for C18H26BN2O3 [M+H]+: 329.2. Found 329.3.
Step 3: l-(Tetrahydro-2H-pyran-2-yl)-lH-indazol-6-ol
Figure imgf000244_0002
To a solution of l-(tetrahydro-27/-pyran-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-17/-indazole (43 g, 131.01 mmol) in THF (200 mL) and H2O (200 mL) was added sodium perborate tetrahydrate (60.47 g, 393.04 mmol) at 20 °C. The mixture was then stirred at 50 °C for 1 hr. The mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (30 g, 89%) as a brown oil. 'H NMR (400 MHz, CDCh) 5 7.93 (s, 1 H), 7.55 (d, J=8.68 Hz, 1 H), 6.97 (s, 1 H), 6.76 (dd, J=8.62, 2.02 Hz, 1 H), 5.60 (dd, J=9.54, 2.57 Hz, 1 H), 3.99 - 4.07 (m, 1 H), 3.72 (td, J=10.94, 2.81 Hz, 1 H), 2.49 - 2.60 (m, 1 H), 2.10 - 2.18 (m, 1 H), 1.59 - 1.81 (m, 4 H). MS- ESI (m/z) calc’d for C12H15N2O2 [M+H]+: 219.1. Found 219.2.
Step 4: 5-((l-(Tetrahydro-2H-pyran-2-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000245_0001
A mixture of l-(tetrahydro-27/-pyran-2-yl)-17/-indazol-6-ol (1 g, 4.58 mmol), 5- hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (793.63 mg, 4.58 mmol), and (tributylphosphoranylidene)acetonitrile (2.21 g, 9.16 mmol) in toluene (20 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 100 °C for 2 hrs under an N2 atmosphere. The mixture was concentrated to give a residue that was purified by silica gel chromatography using a 0-11% EtOAc/petroleum ether gradient eluent to afford the title compound (1.16 g, 67%) as a yellow oil. MS-ESI (m/z) calc’d for C23H24N3O2 [M+H]+: 374.2. Found 374.3.
Figure imgf000245_0002
To a solution of 5-(( I -(tetrahydro-27/-pyran-2-yl)- l//-indazol-6-yl)oxy)-5.6,7,8- tetrahydro naphthalene-2-carbonitrile (900 mg, 2.41 mmol) in EtOH (20 mL) and H2O (20 mL) was added PTSA (1.25 g, 7.23 mmol) at 20 °C. The mixture was then stirred at 70 °C for 2 hrs. The mixture was concentrated to give a residue that was purified by reversed phase HPLC using Method EH to afford the title compound (296 mg, 42%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 7.98 (br s, 1 H), 7.61 (d, J=8.88 Hz, 1 H), 7.38 - 7.47 (m, 3 H), 6.99 (s, 1 H), 6.85 (br d, J=7.25 Hz, 1 H), 5.36 (t, J=5.07 Hz, 1 H), 2.83 - 2.92 (m, 1 H), 2.71 - 2.80 (m, 1 H), 2.03 - 2.15 (m, 2 H), 1.71 - 1.97 (m, 2 H). MS-ESI (m/z) calc’d for CisHieNsO [M+H]+: 290.1. Found 290.2.
Step 6: 5-((lH-Indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000246_0001
5-(( 17/-Indazol-6-yl)oxy )-5.6.7.8-tetrahydronaphthalene-2-carbonitrile was subj ected to chiral separation using Method BQ to afford 5-((17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (890 mg, 22%) as a brown solid. 1 H NMR (400 MHz, DMSO- e) 6 12.79 (br d, J=15.63 Hz, 1 H), 7.96 (s, 1 H), 7.69 (s, 1 H), 7.62 - 7.67 (m, 2 H), 7.54 (d, J=7.88 Hz, 1 H), 7.14 (s, 1 H), 6.83 (dd, J=8.75, 2.13 Hz, 1 H), 5.63 (t, J=4.88 Hz, 1 H), 2.86 - 2.94 (m, 1 H), 2.74 - 2.83 (m, 1 H), 2.00 - 2.07 (m, 2 H), 1.78 - 1.91 (m, 2 H). MS-ESI (m/z) calc’d for CisHieNsO [M+H]+: 290.1. Found 290.2. A later eluting fraction was also isolated to afford 5-(( IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene- 2-carbonitrile, enantiomer 2 (920 mg, 23%) as a brown solid. 1 H NMR (400 MHz, DMSO- e) 6 12.86 (br s, 1 H), 7.96 (d, J=0.75 Hz, 1 H), 7.69 (s, 1 H), 7.62 - 7.67 (m, 2 H), 7.54 (d, J=8.00 Hz, 1 H), 7.14 (s, 1 H), 6.83 (dd, J=8.76, 2.13 Hz, 1 H), 5.63 (t, J=5.13 Hz, 1 H), 2.73 - 2.97 (m, 2 H), 2.01 - 2.07 (m, 2 H), 1.80 - 1.91 (m, 2 H). MS-ESI (m/z) calc’d for C18H16N3O [M+H]+: 290.E Found 290.2.
Step 7: 5-((l-(Benzo[d]oxazol-2-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 2
Figure imgf000246_0002
A mixture of 5-(( 17/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (15.00 mg, 51.84 umol), 2-bromobenzo[d]oxazole (10.27 mg, 51.84 umol), Cui (1.97 mg, 10.37 umol), K3PO4 (33.01 mg, 155.53 umol), and (1S,2S)-N1,N2- dimethylcyclohexane-l,2-diamine (3.69 mg, 25.92 umol) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue. The residue was purified via HPLC using Method BR to afford the title compound (10.54 mg, 46%) as a white solid: 'H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 8.11 (s, 1 H), 7.91 (d, J=8.80 Hz, 1 H), 7.81 (br d, J=7.21 Hz, 1 H), 7.75 (br d, J=6.97 Hz, 1 H), 7.71 (s, 1 H), 7.63 - 7.67 (m, 1 H), 7.56 - 7.60 (m, 1 H), 7.36 - 7.44 (m, 2 H), 7.25 (dd, J=8.74, 1.77 Hz, 1 H), 5.77 (t, J=4.65 Hz, 1 H), 2.89 - 2.98 (m, 1 H), 2.75 - 2.86 (m, 1 H), 2.12 (q, J=5.34 Hz, 2 H), 1.78 - 1.97 (m, 2 H). MS- ESI (m/z) calc’d for C25H19N4O2 [M+H]+: 407.1. Found 407.1.
Example 84: 5-((l-(l-(2,2,2-TrifluoroethyI)-lH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000247_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo-l -(2,2,2-trifluoroethyl)- 1H- pyrazole in place of 2-bromobenzo|<7| oxazole. The material was purified by prep-HPLC using Method BS to afford the title compound (7 mg, 37%) as a yellow gum. JH NMR (400 MHz, DMSO-O 8 8.48 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.78 (d, J=8.77 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J=8.11 Hz, 1H), 7.55 (d, J=7.89 Hz, 1H), 7.30 (s, 1H), 7.00 (dd, J=1.75, 8.77 Hz, 1H), 5.79 (t, J=4.71 Hz, 1H), 5.21 (q, J=9.13 Hz, 2H), 2.85-2.95 (m, 1H), 2.74-2.84 (m, 1H), 2.00-2.10 (m, 2H), 1.84-1.95 (m, 1H), 1.74-1.84 (m, 1H). MS-ESI (m/z) calc’d for C23H19F3N5O [M+H]+: 438.2 Found 438.1.
Example 85: 5-((l-(l-(2-MethoxyethyI)-lH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000248_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-bromo-l-(2-methoxyethyl)-lH- pyrazole in place of 2-bromobenzo|<7| oxazole. The material was purified by prep-HPLC using Method BT to afford the title compound (8 mg, 27%) as a pink solid. JH NMR (400 MHz, MeOH-t/v) 6 8.13 (s, 1 H), 8.09 (s, 1 H), 7.88 (s, 1 H), 7.72 (d, J=8.82 Hz, 1 H), 7.55 (s, 1 H), 7.51 (s, 2 H), 7.14 (s, 1 H), 6.96 (dd, J=8.82, 0.95 Hz, 1 H), 5.62 (t, J=4.47 Hz, 1 H), 4.39 (t, J=5.13 Hz, 2 H), 3.80 (t, J=5.19 Hz, 2 H), 3.34 (s, 3 H), 2.75 - 2.99 (m, 2 H), 2.07 - 2.17 (m, 2 H), 1.81 - 2.05 (m, 2 H). MS-ESI (m/z) calc’d for C24H24N5O2 [M+H]+: 414.2. Found 414.2
Example 86 : 5-((l-(3-Methoxy- 1-methyl- lff-pyrazol-4-yl)- lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000248_0002
Prepared as described for l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-bromo-3-methoxy-l-methyl-lH- pyrazole in place of 2-bromobenzo|<7| oxazole. The material was purified by prep-HPLC using Method BU to afford the title compound (2 mg, 16%) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 8.12 (s, 1H), 8.02 (s, 1H), 7.67-7.72 (m, 2H), 7.64 (br d, J=8.00 Hz, 1H), 7.51 (d, J=8.00 Hz, 1H), 6.96 (s, 1H), 6.90 (dd, J=2.00, 8.76 Hz, 1H), 5.64 (t, J=4.75 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.85-2.93 (m, 1H), 2.73-2.81 (m, 1H), 1.98-2.04 (m, 2H), 1.75- 1.89 (m, 2H) MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2. Found 400.1.
Example 87 : cis-7-Methyl-8-((l-(l-methyl-LH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)- 5,6,7,8-tetrahydroquinoline-3-carbonitrile (“87-cis”), enantiomer 1 and 2 and trans-7-
Methyl-8-((l-(l-methyl-lff-pyrazol-4-yl)-lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile (“87-trans”), enantiomer 1 and 2.
Figure imgf000249_0001
A mixture of 3-methylcyclohexan-l-one (2.19 mL, 17.83 mmol) and ethyl formate (1.72 mL, 21.4 mmol) was cooled to 0 °C. Sodium ethoxide (21% wt. in EtOH) (6.66 mL, 17.83 mmol) was added and the reaction mixture was then stirred at room temperature for 2 hrs. Insoluble material was collected by filtration and washed with diethyl ether to afford a solid (2.47 g, 85%) which was added to a solution of 2-cyanoacetamide (1.19 g, 14.16 mmol) in H2O (10 mL). Piperidinium acetate (1.05 mL, 6.74 mmol) (prepared by adding 3.6 mL of piperidine to a cold solution of 2.1 mL acetic acid in 5.0 mL of H2O) was then added and the reaction mixture was refluxed for 18 hrs at which point acetic acid (1 mL) was slowly added to the solution. The mixture was then stirred at r.t. for 1 hr. The precipitated solids were then collected by filtration and washed with H2O (30 mL) to afford the title compound (1.33 g, 52%).1H NMR (400 MHz, DMSO- e) 6 12.27 (s, 1H), 7.89 (s, 1H), 2.72 - 2.56 (m, 1H), 2.48 - 2.35 (m, 2H), 2.19 (dd, J = 18.3, 10.1 Hz, 1H), 1.86 - 1.68 (m, 2H), 1.25 (dtd, J = 13.0, 11.0, 5.9 Hz, 1H), 0.98 (d, J = 6.5 Hz, 3H); MS-ESI (m/z) calc’d for C11H13N2O [M+H]+: 189.1. Found 189.0.
Step 2: 2-Chloro-7-methyl-5,6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000250_0001
A solution of 7-methyl-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (1.33 g, 7.05 mmol) in phosphorus(V) oxychloride (1.98 mL, 21.15 mmol) was refluxed for 6 hrs. Then the mixture was concentrated under reduced pressure. The residue was taken up in DCM and washed with saturated aqueous NaHCOs. The organic phase was concentrated under reduced pressure and the material was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (1.21 g, 83%), as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.20 (s, 1H), 3.00 - 2.90 (m, 1H), 2.89 - 2.80 (m, 1H), 2.80 - 2.69 (m, 1H), 2.54 - 2.43 (m, 1H), 2.00 - 1.80 (m, 2H), 1.35 (dtd, J = 13.0, 10.8, 5.7 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H). MS-ESI (m/z) calc’d for C11H12CIN2 [M+H]+: 207.1. Found 207.0.
Step 3: 7-Methyl-5,6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000250_0002
To a mixture of 2-chloro-7-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile (800.0 mg, 3.87 mmol) in acetic acid (0.387 mL), H2O (4 mL), and EtOH (4 mL) was added zinc (506.16 mg, 7.74 mmol) and the suspension was stirred at 95 °C for 7 hrs. The mixture was extracted with DCM (2x) and the combined organic layers were passed through a phase separator and evaporated to obtain a yellow solid which was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (498 mg, 75%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.71 (d, J = 2.1 Hz, 1H), 8.01 (s, 1H), 3.03 - 2.93 (m, 1H), 2.90 - 2.72 (m, 2H), 2.55 - 2.44 (m, 1H), 2.01 - 1.81 (m, 2H), 1.36 (dtd, J = 13.1, 10.7, 6.0 Hz, 1H), 1.05 (d, J = 6.5 Hz, 3H). MS-ESI (m/z) calc’d for C11H13N2 [M+H]+: 173.1. Found 173.0.
Step 4: 3-Cyano-7-methyl-5,6,7,8-tetrahydroquinoline 1 -oxide
Figure imgf000251_0001
To a solution of 7-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile (498.0 mg, 2.89 mmol) in trifluoroacetic acid (11.12 mL) was added a 30% solution of hydrogen peroxide (0.89 mL, 8.67 mmol) and the mixture was stirred at 75 °C for 2 hrs. An additional 3 eq of hydrogen peroxide (0.89 mL, 8.67 mmol) was then added portionwise and the reaction was stirred at 75 °C for an additional 6 hrs. The mixture was cooled to r.t.; H2O was added (100 mL) and the solution was neutralized by addition of solid K2CO3. The mixture was then extracted with DCM (3 x 100 mL) and the combined organic layers were washed with H2O (1 x 100 mL), passed through a phase separator, and evaporated to dryness to obtain material which was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (63 mg, 12% ) as white solid. MS-ESI (m/z) calc’d for C11H13N2O [M+H]+: 189.1. Found 189.0.
Figure imgf000251_0002
To a solution of 3-cyano-7-methyl-5,6,7,8-tetrahydroquinoline 1-oxide (108.0 mg, 0.570 mmol) in DCM (2.746 mL) was added trifluoroacetic anhydride (0.24 mL, 1.72 mmol) dropwise and the mixture was stirred at 25 °C for 2 hrs. The solvent was evaporated and the residue was taken up in MeOH. K2CO3 was then added and the suspension was stirred at 25 °C for 1 hr. The solvent was evaporated keeping the temperature under 40 °C. The residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a solid which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (55 mg, 51%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.88 - 8.78 (m, 1H), 8.10 - 8.04 (m, 1H), 5.50 - 5.17 (m, 1H), 4.50 - 3.98 (m, 1H), 2.92 - 2.70 (m, 2H), 1.96 - 1.64 (m, 2H), 1.62 - 1.43 (m, 1H), 1.12 - 0.97 (m, 3H). MS-ESI (m/z) calc’d for C11H13N2O [M+H]+: 189. Found 189. Step 6: 7-Methyl-8-( (1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile
Figure imgf000252_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile using 8-hydroxy- 7-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 5-hy droxy-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile and 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol to afford the title compound (28 mg).
Step 7: cis-7-Methyl-8-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2 and trans-7-Methyl-8-((l-(l-methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2.
Figure imgf000252_0002
7-Methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was separated by prep HPLC using Method AN to afford two fractions (fraction 1: 3.5 mg and fraction 2: 7.2 mg), which were in turn subjected to chiral preparative HPLC using Method AO to afford from fraction 1, cis-7-methyl-8-((l-(l- methyl- l7/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroqumolme-3-carbonitrile (“87-cis”), enantiomer 1 (1.1 mg, 1%) as a white solid. 1H NMR (400 MHz, MeOH-<A) 6 8.72 (dd, J = 1.9, 0.9 Hz, 1H), 8.11 - 8.09 (m, 2H), 8.04 - 8.01 (m, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.71 (dd, J = 8.8, 0.6 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.01 (dd, J = 8.8, 2.1 Hz, 1H), 5.30 (d, J = 5.9 Hz, 1H), 4.01 (s, 3H), 2.99 (q, J = 6.1 Hz, 2H), 2.46 (qd, J = 7.1, 3.5 Hz, 1H), 2.22 (dtd, J = 13.6, 6.7, 3.6 Hz, 1H), 1.77 (dq, J = 13.7, 6.8 Hz, 1H), 1.11 (d, J = 7.0 Hz, 3H). MS- ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2. A later eluting fraction was also isolated, cis-7-methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile (“87-cis”), enantiomer 2 (1.1 mg, 1%) as a white solid. 'H NMR (400 MHz, MeOH-t/v) 8 8.72 - 8.69 (m, 1H), 8.10 - 8.07 (m, 2H), 8.02 - 8.00 (m, 1H), 7.85 (d, J = 0.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 6.99 (dd, J = 8.8, 2.1 Hz, 1H), 5.28 (d, J = 5.9 Hz, 1H), 3.99 (s, 3H), 2.97 (q, J = 6.1 Hz, 2H), 2.44 (qd, J = 7.0, 3.4 Hz, 1H), 2.20 (dtd, J = 13.6, 6.7, 3.5 Hz, 1H), 1.75 (dq, J = 13.7, 6.7 Hz, 1H), 1.09 (d, J = 7.0 Hz, 3H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2. From fraction 2 the enantiomers were separated by prep-HPLC using Method AO to afford trans-7-methyl- 8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3- carbonitrile (“87-trans”), enantiomer 1 (2 mg, 2%) as a white solid. 'H NMR (400 MHz, MeOH-t/v) 8 8.70 (dt, J = 1.9, 0.9 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 8.06 (d, J = 0.9 Hz, 1H), 8.01 (dd, J = 2.1, 1.1 Hz, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.69 - 7.63 (m, 2H), 6.99 (dd, J = 8.7, 2.1 Hz, 1H), 5.49 (d, J = 3.1 Hz, 1H), 4.02 (s, 3H), 3.07 (ddd, J = 17.8, 6.3, 2.9 Hz, 1H), 2.94 (ddd, J = 17.6, 10.5, 6.6 Hz, 1H), 2.21 (ddt, J = 12.0, 6.5, 3.2 Hz, 1H), 2.09 (tdd, J = 12.0, 10.6, 6.3 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2. A later eluting fraction was also isolated, trans-7- methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline- 3-carbonitrile (“87-trans”), enantiomer 2 (2 mg, 2%) as a white solid. 'H NMR (400 MHz, MeOH-t/v) 8 8.69 (dd, J = 2.0, E0 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 8.06 (d, J = 0.9 Hz, 1H), 8.01 (dt, J = 2.1, EO Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.66 (s, 2H), 6.99 (dd, J = 8.7, 2.1 Hz, 1H), 5.49 (d, J = 3.2 Hz, 1H), 4.02 (s, 3H), 3.07 (ddd, J = 17.8, 6.3, 2.9 Hz, 1H), 2.94 (ddd, J = 17.6, 10.6, 6.7 Hz, 1H), 2.26 - 2.16 (m, 1H), 2.09 (tdd, J = 12.1, 10.5, 6.3 Hz, 1H), E84 (ddt, J = 12.7, 6.6, 3.1 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2.
Example 88 : 5-((l-(Oxazol-2-yl)- 1 //-indazol-6-y 1 )oxy )-5.6, 7, 8- tetrahydronap hthalene-2- carbonitrile, enantiomer 2
Figure imgf000254_0001
Prepared as described for 5-((l-(benzo[rf]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-iodooxazole in place of 2- bromobenzo|<7| oxazole. The material was purified by prep-HPLC using Method BV to afford the title compound (8 mg, 31%) as a white solid. 'H NMR (400 MHz, MeOH-t/4) 8 8.27 (s, 1 H), 7.99 (d, J=1.91 Hz, 1 H), 7.90 (d, J=0.83 Hz, 1 H), 7.79 (d, J=8.82 Hz, 1 H), 7.58 (s, 1 H), 7.52 - 7.55 (m, 2 H), 7.30 (s, 1 H), 7.09 (dd, J=8.76, 2.21 Hz, 1 H), 5.68 (t, J=5.07 Hz, 1 H), 2.79 - 3.06 (m, 2 H), 2.14 - 2.25 (m, 2 H), 2.02 - 2.10 (m, 1 H), 1.85 - 1.96 (m, 1 H). MS-ESI (m/z) calc’d for C21H17N4O2 [M+H]+: 357.1. Found 357.2
Example 89: 5-((l-(4-PhenyIoxazol-2-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000254_0002
Prepared as described for 5-((l-(benzo[rf]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-iodo-4-phenyloxazole in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method BW to afford the title compound (5 mg, 21 %) as a pale yellow solid. JH NMR (400 MHz, DMSO- tZe) 6 8.65 (s, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.84 - 7.92 (m, 3H), 7.73 (s, 1H), 7.59 - 7.69 (m, 2H), 7.48 (t, J=7.64 Hz, 2H), 7.34 - 7.40 (m, 1H), 7.20 (dd, J=2.02, 8.74 Hz, 1H), 5.78 (t, J=4.89 Hz, 1H), 2.78 - 2.99 (m, 2H), 2.09 - 2.24 (m, 2H), 1.83-1.96 (m, 2H) MS-ESI (m/z) calc’d for C27H21N4O2 [M+H]+: 433.2. Found 433.2
Example 90 : 5-((l-(4,5-Dimethyloxazol-2-yl)- lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000255_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-iodo-4,5-dimethyloxazole in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method BX and further purified using Method BY to afford the title compound (3 mg, 16%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.37 (s, 1H), 7.87 - 7.82 (m, 2H), 7.70 (s, 1H), 7.67 - 7.62 (m, 1H), 7.58 - 7.53 (m, 1H), 7.19 - 7.14 (m, 1H), 5.70 (t, J=4.8 Hz, 1H), 2.98 - 2.86 (m, 1H), 2.85 - 2.71 (m, 1H), 2.32 (s, 3H), 2.15 - 2.03 (m, 5H), 1.96 - 1.74 (m, 2H). MS- ESI (m/z) calc’d for C23H21N4O2 [M+H]+: 385.2. Found 385.1
Example 91: 5-((l-(5-Methyloxazol-2-yl)-LH-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000255_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-bromo-5-methyloxazole in place of 2-bromobenzo|<7|oxazole. The material was purified by prep-HPLC using Method BS to afford the title compound (7 mg, 28%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.39 (s, 1H), 7.82-7.89 (m, 2H), 7.70 (s, 1H), 7.64 (d, J=7.91 Hz, 1H), 7.55 (d, J=8.03 Hz, 1H), 7.13 (dd, J=2.01, 8.78 Hz, 1H), 7.02 (d, J=1.25 Hz, 1H), 5.69 (t, J=4.71 Hz, 1H), 2.87- 2.96 (m, 1H), 2.74-2.84 (m, 1H), 2.39 (d, J=1.00 Hz, 3H), 2.08 (q, J=5.52 Hz, 2H), 1.77-1.92 (m, 2H). MS-ESI (m/z) calc’d for C22H19N4O2 [M+H]+: 371.1. Found 371.2.
Example 92: 5-((l-(4-Methyloxazol-2-yl)-lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000256_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-bromo-4-methyloxazole in place of 2-bromobenzo|<7|oxazole. The material was purified by prep-HPLC using Method BZ to afford the title compound (10 mg, 50%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.41 (s, 1 H) 7.79 - 7.91 (m, 3 H) 7.70 (br s, 1 H) 7.64 (br d, J=8 Hz, 1 H) 7.56 (br d, J=8 Hz, 1 H) 7.18 (br d, J=8 Hz, 1 H) 5.71 (br s, 1 H) 2.74 - 2.97 (m, 2 H) 2.13 - 2.26 (m, 3 H) 2.09 (br d, J=5 Hz, 2 H) 1.75 - 1.96 (m, 2 H). MS-ESI (m/z) calc’d for C22H19N4O2 [M+H]+: 371.1. Found 371.2
Example 93: 5-((l-(2-Methylthiazol-5-yl)-Lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000256_0002
Prepared as described for (5-((l-(benzo[d]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 5-bromo-2-methylthiazole in place of 2-bromobenzo|<7|oxazole. The material was purified by prep-HPLC using Method CA to afford the title compound (5 mg, 22%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.30 (s, 1 H), 8.08 (s, 1 H), 7.79 (d, J=8.68 Hz, 1 H), 7.69 (s, 1 H), 7.64 (d, J=8.31 Hz, 1 H), 7.54 (d, J=7.95 Hz, 1 H), 7.45 (s, 1 H), 7.01 (dd, J=8.74, 1.41 Hz, 1 H), 5.86 (t, J=4.71 Hz, 1 H), 2.86 - 2.95 (m, 1 H), 2.74 - 2.84 (m, 1 H), 2.68 (s, 3 H), 1.98 - 2.10 (m, 2 H), 1.77 - 1.94 (m, 2 H). MS-ESI (m/z) calc’d for C22H19N4OS [M+H]+: 387.1. Found 387.1
Example 94: 5-((l-(Pyrimidin-5-yl)-LH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000257_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 5-iodopyrimidine in place of 2- bromobenzo|t/|oxazole. The material was purified by prep-HPLC using Method BZ to afford the title compound (8 mg, 44%) as a white solid. 'H NMR (DMSO- e) 6 9.33 (s, 2H), 9.21 (s, 1H), 8.42 (s, 1H), 7.83 (d, J=8.80 Hz, 1H), 7.69 (s, 1H), 7.62-7.67 (m, 2H), 7.55 (d, J=8.07 Hz, 1H), 7.03 (dd, J=1.89, 8.74 Hz, 1H), 5.87 (t, J=4.89 Hz, 1H), 2.75-2.95 (m, 2H), 2.01- 2.07 (m, 2H), 1.77-1.94 (m, 2H). MS-ESI (m/z) calc’d for C22H18N5O [M+H]+:368.1. Found 368.1.
Example 95: 5-((l-(2-Methylpyrimidin-5-yl)-LH-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000257_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 5-bromo-2-methylpyrimidine in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method CB to afford the title compound (7 mg 31%) as a brown solid. JH NMR (DMSO- e) 6 9.18 (s, 2 H), 8.38 (s, 1 H), 7.81 (d, J=8.99 Hz, 1 H), 7.69 (s, 1 H), 7.64 (br d, J=8.11 Hz, 1 H), 7.58 (s, 1 H), 7.54 (d, J=8.11 Hz, 1 H), 7.00 (br d, J=8.55 Hz, 1 H), 5.82 - 5.86 (m, 1 H), 2.77 - 2.94 (m, 2 H), 2.72 (s, 3 H), 2.03 (br d, J=5.26 Hz, 2 H), 1.77 - 1.91 (m, 2 H) MS-ESI (m/z) calc’d for C23H20N5O [M+H]+:382.2. Found 382.1.
Example 96: 5-((l-(3-Methylpyridin-4-yl)-lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000258_0001
Prepared as described for 5-((l-(benzo[</]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-bromo-3 -methylpyridine in place of 2-bromobenzo|</|oxazole. The material was purified by prep-HPLC using Method CB to afford the title compound (2 mg, 9%) as a yellow solid. 1 H NMR (400 MHz, DMSO- e) 6 8.77 (br s, 1 H), 8.66 (br s, 1 H), 8.37 (s, 1 H), 7.82 (d, J=8.75 Hz, 1 H), 7.68 (s, 2 H), 7.63 (d, J=8.13 Hz, 1 H), 7.51 (d, J=8.13 Hz, 1 H), 7.16 (s, 1 H), 7.03 (dd, J=8.94, 1.94 Hz, 1 H), 5.70 (t, J=4.88 Hz, 1 H), 2.84 - 2.90 (m, 1 H), 2.76 - 2.81 (m, 1 H), 2.30 (s, 3 H), 1.98 - 2.04 (m, 2 H), 1.75 - 1.89 (m, 2 H). MS-ESI (m/z) calc’d for C24H21N4O [M+H]+: 381.2. Found 381.0
Example 97: 5-((l-(l-MethyI-lH-imidazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000258_0002
Prepared as described for 5-((l-(benzo[</]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo- 1 -methyl- 1 //-imidazole in place of 2-bromobenzo|</| oxazole. The material was purified by prep-HPLC using Method CC to afford the title compound (2 mg, 11%) as an off-white solid. JH NMR (400 MHz, DMSO- e) 6 8.14 (s, 1 H), 7.83 (s, 1 H), 7.73 (d, J=8.76 Hz, 1 H), 7.69 (d, J=5.88 Hz, 2 H), 7.64 (d, J=8.13 Hz, 1 H), 7.54 (d, J=8.00 Hz, 1 H), 7.37 (d, J=1.50 Hz, 1 H), 6.97 (dd, J=8.75, 2.13 Hz, 1 H), 5.61 (t, J=4.88 Hz, 1 H), 3.74 (s, 3 H), 2.88 - 2.94 (m, 1 H), 2.77 - 2.83 (m, 1 H), 2.03 - 2.09 (m, 2 H), 1.79 - 1.92 (m, 2 H). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.1.
Example 98 : 5-((l-Pyrazin-2-yl)- 17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahyd ronaphthalene-2- carbonitrile, enantiomer 2
Figure imgf000259_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-iodopyrazine in place of 2- bromobenzo|t/|oxazole. The material was purified by prep-HPLC using Method CD to afford the title compound (11 mg, 54%) as a white solid. 1 H NMR (400 MHz, DMSO- e) 6 9.30 (d, J=1.38 Hz, 1 H), 8.60 (dd, J=2.63, 1.50 Hz, 1 H), 8.54 (d, J=2.63 Hz, 1 H), 8.46 (d, J=0.63 Hz, 1 H), 8.30 (d, J=1.88 Hz, 1 H), 7.87 (d, J=8.76 Hz, 1 H), 7.72 (s, 1 H), 7.62 - 7.68 (m, 1 H), 7.54 - 7.60 (m, 1 H), 7.18 (dd, J=8.76, 2.25 Hz, 1 H), 5.73 (t, J=4.75 Hz, 1 H), 2.89 - 2.98 (m, 1 H), 2.76 - 2.86 (m, 1 H), 2.07 - 2.14 (m, 2 H), 1.80 - 1.97 (m, 2 H). MS-ESI (m/z) calc’d for C22H18N5O [M+H]+: 368.1. Found 368.1.
Example 99 : 5-((l-(Pyridazin-3-yl)- 1 //-indazol-6-y 1 )oxy )-5.6, 7 ,8- tetrahydronap hthalene-
2-carbonitrile, enantiomer 2
Figure imgf000259_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 3-bromopyridazine in place of 2- bromobenzo|t/|oxazole. The material was purified by prep-HPLC using Method BZ to afford the title compound (7 mg, 35%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 9.15 (dd, J=4.65, 1.34 Hz, 1 H), 8.48 (s, 1 H), 8.43 (d, J=1.71 Hz, 1 H), 8.29 (dd, J=9.05, 1.34 Hz, 1 H), 7.85 - 7.92 (m, 2 H), 7.70 (s, 1 H), 7.61 - 7.66 (m, 1 H), 7.55 - 7.59 (m, 1 H), 7.17 (dd, J=8.74, 2.14 Hz, 1 H), 5.70 (t, J=4.83 Hz, 1 H), 2.75 - 2.97 (m, 2 H), 2.07 - 2.14 (m, 2 H), 1.77 - 1.98 (m, 2 H). MS-ESI (m/z) calc’d for C22H18N5O [M+H]+: 368.1. Found 368.1.
Example 100: 5-((l-(2-(Pyrrolidin-l-yl)pyrimidin-5-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000260_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 5-bromo-2-(pyrrolidin-l- yl)pyrimidine in place of 2-bromobenzo|t/| oxazole. The material was purified by prep-HPLC using Method CE to afford the title compound (14 mg, 55%) as a white solid. 'H NMR (400 MHz, DMSO-O 8 8.67 (s, 2H), 8.23 (s, 1H), 7.75 (d, J=8.68 Hz, 1H), 7.66 (s, 1H), 7.62 (d, J=8.07 Hz, 1H), 7.51 (d, J=8.07 Hz, 1H), 7.27 (s, 1H), 6.92 (dd, J=1.90, 8.74 Hz, 1H), 5.75 (t, J=4.83 Hz, 1H), 3.55 (br t, J=6.60 Hz, 4H), 2.83-2.93 (m, 1H), 2.71-2.81 (m, 1H), 1.99-2.04 (m, 2H), 1.94-1.98 (m, 4H), 1.83-1.91 (m, 1H), 1.74-1.82 (m, 1H). MS-ESI (m/z) calc’d for C26H25N6O [M+H]+: 437.2. Found 437.3.
Example 101: 5-((l-(l-MethyI-LH-l,2,3-triazol-4-yI)-LH-indazol-6-yI)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000260_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo-l-methyl-lH-l,2,3-triazole in place of 2-bromobenzo|<7| oxazole. The material was purified by prep-HPLC using Method BZ to afford the title compound (10 mg, 45%) as a yellow gum. JH NMR (400 MHz, DMSO- d ) 8 8.45 (s, 1H), 8.29 (s, 1H), 7.76-7.82 (m, 2H), 7.69 (s, 1H), 7.64 (d, J=8.11 Hz, 1H), 7.54 (d, J=8.11 Hz, 1H), 7.01-7.06 (m, 1H), 5.66 (t, J=4.82 Hz, 1H), 4.14 (s, 3H), 2.85-2.97 (m, 1H), 2.72-2.84 (m, 1H), 2.04-2.10 (m, 2H), 1.75-1.96 (m, 2H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.2. Found 371.2.
Example 102: 5-((l-(4-MethyIpyrimidin-2-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000261_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-bromo-4-methylpyrimidine in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method CF to afford the title compound (6 mg, 37%) as a white solid. 'H NMR (400 MHz, DMSO- d ) 8 8.75 (d, J=4.89 Hz, 1H), 8.32-8.43 (m, 2H), 7.82 (d, J=8.66 Hz, 1H), 7.71 (s, 1H), 7.63-
7.69 (m, 1H), 7.55-7.62 (m, 1H), 7.30 (d, J=5.14 Hz, 1H), 7.13 (dd, J=2.13, 8.66 Hz, 1H),
5.70 (t, J=4.71 Hz, 1H), 2.88-2.96 (m, 1H), 2.76-2.86 (m, 1H), 2.57 (s, 3H), 2.13 (br d, J=4.52 Hz, 2H), 1.81-1.94 (m, 2H). MS-ESI (m/z) calc’d for C23H20N5O [M+H]+: 382.2. Found 382.2.
Example 103: 5-((l-(2-Morpholinopyridin-4-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000261_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-(4-bromopyridin-2-yl)morpholine in place of 2-bromobenzo|<7| oxazole. The material was purified by prep-HPLC using Method CG to afford the title compound (5 mg, 27%) as a white solid. JH NMR (400 MHz, DMSO- d ) 8 8.33 (s, 1H), 8.26 (d, J=5.40 Hz, 1H), 7.82 (d, J=8.78 Hz, 1H), 7.69 (s, 1H), 7.64 (br d, J=8.16 Hz, 1H), 7.52-7.58 (m, 2H), 7.16 (br d, J=5.40 Hz, 1H), 7.13 (s, 1H), 7.05 (dd, J=1.63, 8.78 Hz, 1H), 5.78 (br t, J=4.77 Hz, 1H), 3.71 (br t, J=4.58 Hz, 4H), 3.52 (br d, J=4.64 Hz, 4H), 2.85-2.96 (m, 1H), 2.74-2.85 (m, 1H), 2.04-2.13 (m, 2H), 1.74-1.91 (m, 2H) MS-ESI (m/z) calc’d for C27H26N5O2 [M+H]+: 452.2. Found 452.1.
Example 104: 5-((l-(2-(Trifluoromethyl)pyrimidin-5-yl)- lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000262_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 5-bromo-2- (trifluoromethyl)pyrimidine in place of 2-bromobenzo|c/| oxazole. The material was purified by prep-HPLC using Method CH to afford the title compound (6 mg, 22%) as a white solid. 'H NMR (400 MHz, DMSO-cL) 8 9.60 (s, 2H), 8.51 (s, 1H), 7.81-7.88 (m, 2H), 7.70 (s, 1H), 7.65 (d, J=8.16 Hz, 1H), 7.55 (d, J=8.16 Hz, 1H), 7.06 (dd, J=1.54, 8.82 Hz, 1H), 5.92 (t, J=4.52 Hz, 1H), 2.87-2.95 (m, 1H), 2.75-2.84 (m, 1H), 2.02-2.08 (m, 2H), 1.78-1.94 (m, 2H) MS-ESI (m/z) calc’d for C23H17F3N5O [M+H]+: 436.1. Found 436.1.
Example 105: 5-((l-(l-Isopropyl-LH-pyrazol-4-yl)-Lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000262_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo- 1 -isopropyl- 1 //-pyrazole in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method BU to afford the title compound (10 mg, 49%) as a yellow gum. JH NMR (400 MHz, DMSO- d ) 8 8.34 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=8.55 Hz, 1H), 7.69 (s, 1H), 7.65 (d, J=7.89 Hz, 1H), 7.55 (d, J=8.11 Hz, 1H), 7.28 (s, 1H), 6.98 (dd, J=1.97, 8.77 Hz, 1H), 5.79 (t, J=4.71 Hz, 1H), 4.52-4.61 (m, 1H), 2.85-2.95 (m, 1H), 2.73-2.84 (m, 1H), 2.00-2.07 (m, 2H), 1.74-1.94 (m, 2H), 1.48 (d, J=6.80 Hz, 6H). MS-ESI (m/z) calc’d for C24H24N5O [M+H]+: 398.2. Found 398.1
Example 106: 5-((l-(l,3-DimethyI-LH-pyrazol-4-yI)-ZH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000263_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo-l ,3-dimethyl- l/f-pyrazole in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method CI to afford the title compound (7 mg, 33%) as a brown solid. 'H NMR (400 MHz, DMSO- e) 8 8.17 (s, 1H), 7.73 (d, J=8.77 Hz, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 7.62 (br d, J=7.89 Hz, 1H), 7.50 (d, J=8.11 Hz, 1H), 6.97 (s, 1H), 6.91 (br d, J=8.77 Hz, 1H), 5.66 (br t, J=4.49 Hz, 1H), 3.83 (s, 3H), 2.83-2.94 (m, 1H), 2.71-2.82 (m, 1H), 2.19 (s, 3H), 1.94-2.04 (m, 2H), 1.72- 1.91 (m, 2H). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.1
Example 107 : 5-((l-(l-BenzyI-lH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000263_0002
Prepared as described for (5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using l-benzyl-4-iodo- l/f-p razole in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method CJ to afford the title compound (3 mg, 12%) as a yellow solid. JH NMR (400 MHz, CDCh) 8 8.15 (s, 1H), 7.83-7.99 (m, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.46-7.53 (m, 3H), 7.32-7.43 (m, 5H), 6.83-7.08 (m, 2H), 5.36-5.52 (m, 3H), 2.71-3.13 (m, 2H), 1.85-2.21 (m, 4H). MS-ESI (m/z) calc’d for C28H24N5O [M+H]+: 446.2. Found 446.1.
Example 108: 5-((l-(l-PhenyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000264_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo-l -phenyl- l/f-pyrazole in place of 2-bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method CK to afford the title compound (2 mg, 9%) as a yellow solid. 'H NMR (400 MHz, DMSO- d ) 8 8.32 (s, 1H), 8.06-8.17 (m, 2H), 7.74 (dd, J=14.3, 8.3 Hz, 3H), 7.47-7.57 (m, 5H), 7.32- 7.42 (m, 1H), 7.12 (s, 1H), 6.98 (dd, J=8.8, 2.0 Hz, 1H), 5.47 (t, J=5.0 Hz, 1H), 2.90-3.00 (m, 1H), 2.78-2.88 (m, 1H), 2.05-2.22 (m, 3H), 1.82-1.92 (m, 1H). MS-ESI (m/z) calc’d for C27H22N5O [M+H]+: 432.2. Found 432.1.
Example 109: 5-((l-(l-(tert-Butyl)-LH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000264_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-bromo-l -(ter /-butyl)- l/f-pyrazole in place of 2 -bromobenzo [rf] oxazole. The material was purified by prep-HPLC using Method CF to afford the title compound (8 mg, 46%) as a pale yellow solid. JH NMR (400 MHz, DMSO- e) 6 8.32 (s, 1 H), 8.17 (s, 1 H), 7.96 (s, 1 H), 7.75 (d, J=8.77 Hz, 1 H), 7.69 (s, 1 H), 7.62 - 7.66 (m, 1 H), 7.55 (d, J=7.89 Hz, 1 H), 7.26 (s, 1 H), 6.98 (dd, J=8.88, 1.86 Hz, 1 H), 5.77 (t, J=4.71 Hz, 1 H), 2.85 - 2.94 (m, 1 H), 2.73 - 2.82 (m, 1 H), 2.01 - 2.08 (m, 2 H), 1.73 - 1.95 (m, 2 H), 1.59 (s, 9 H). MS-ESI (m/z) calc’d for C25H26N5O [M+H]+: 412.2. Found 412.1.
Example 110: 5-((l-(l,5-DimethyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000265_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile using 4-bromo-l,5-dimethyl-pyrazole in place of 2- bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method CL and further purified by prep-HPLC using Method CM to afford the title compound (2 mg, 9%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J=0.75 Hz, 1 H), 7.73 (d, J=8.63 Hz, 1 H), 7.71 (s, 1 H), 7.68 (s, 1 H), 7.60 - 7.65 (m, 1 H), 7.50 (d, J=8.00 Hz, 1 H), 6.97 (s, 1 H), 6.91 (dd, J=8.76, 2.13 Hz, 1 H), 5.66 (t, J=4.82 Hz, 1 H), 3.83 (s, 3 H), 2.84 - 2.93 (m, 1 H), 2.71 - 2.81 (m, 1 H), 2.19 (s, 3 H), 2.00 (q, J=5.42 Hz, 2 H), 1.72 - 1.91 (m, 2 H). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.1.
Example 111: 5-((l-(l-(Oxetan-3-yI)-LH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000265_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo- l-(oxetan-3- l)- l/f-pyrazole in place of 2 -bromobenzo [rf] oxazole. The material was purified by prep-HPLC using Method CO to afford the title compound (10 mg, 43%) as a white solid. JH NMR (400 MHz, DMSO- d6) 8 8.51 (s, 1 H), 8.20 (s, 1 H), 8.11 (s, 1 H), 7.77 (d, J=8.76 Hz, 1 H), 7.70 (s, 1 H), 7.62 - 7.67 (m, 1 H), 7.55 (d, J=8.00 Hz, 1 H), 7.34 (s, 1 H), 7.00 (dd, J=8.76, 2.00 Hz, 1 H), 5.80 (t, J=4.82 Hz, 1 H), 5.61 - 5.71 (m, 1 H), 4.94 - 5.02 (m, 4 H), 2.75 - 2.97 (m, 2 H), 2.01 - 2.09 (m, 2 H), 1.77 - 1.96 (m, 2 H). MS-ESI (m/z) calc’d for C24H22N5O2 [M+H]+: 412.2. Found 412.1
Example 112: 5-((l-(l-(Pyridin-2-yl)-lff-pyrazol-4-yl)-lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000266_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-(4-bromo- l/f-pyrazol-l - yl)pyridine in place of 2-bromobenzo|t/| oxazole. The material was purified by prep-HPLC using Method CP to afford the title compound (1 mg, 5%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 9.07 (s, 1 H), 8.53 (d, J=4.16 Hz, 1 H), 8.41 (s, 1 H), 8.27 (s, 1 H), 7.99 - 8.09 (m, 2 H), 7.79 (d, J=8.80 Hz, 1 H), 7.69 (s, 1 H), 7.62 - 7.67 (m, 1 H), 7.54 - 7.59 (m, 1 H), 7.45 (s, 1 H), 7.42 (ddd, J=6.72, 5.07, 1.53 Hz, 1 H), 7.00 (dd, J=8.74, 2.02 Hz, 1 H), 5.86 (t, J=4.95 Hz, 1 H), 2.86 - 2.95 (m, 1 H), 2.74 - 2.84 (m, 1 H), 2.00 - 2.10 (m, 2 H), 1.76 - 1.95 (m, 2 H). MS-ESI (m/z) calc’d for C26H21N6O [M+H]+: 433.2. Found 433.1.
Example 113 : 5-((l-(l-(T etrahyd ro-2/f-py ran-4-yl)- lff-pyrazol-4-yl)- lff-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000266_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-iodo- l-(tetrahydro-27/-pyran-4- yl)-17/-pyrazole in place of 2-bromobenzo[rf] oxazole. The material was purified by prep- HPLC using Method CQ to afford the title compound (4 mg, 16%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.38 (s, 1 H), 8.17 (d, J = 0.61 Hz, 1 H), 7.96 (s, 1 H), 7.75 (d, J = 8.80 Hz, 1 H), 7.69 (s, 1 H), 7.60 - 7.66 (m, 1 H), 7.54 (d, J = 7.95 Hz, 1 H), 7.29 (s, 1 H), 6.97 (dd, J = 8.80, 1.96 Hz, 1 H), 5.78 (t, J = 4.83 Hz, 1 H), 4.42 - 4.53 (m, 1 H), 3.98 (dt, J = 11.43, 3.09 Hz, 2 H), 3.48 (td, J = 5.72, 2.14 Hz, 2 H), 2.85 - 2.95 (m, 1 H), 2.73 - 2.84 (m, 1 H), 1.99 - 2.06 (m, 6 H), 1.76 - 1.92 (m, 2 H) MS-ESI (m/z) calc’d for C26H26N5O2 [M+H]+: 440.2. Found 440.1. Example 114: 5-((l-(l-EthyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000267_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile using 4-bromo- 1 -ethyl- 1 //-pyrazole in place of 2- bromobenzo[rf] oxazole. The material was purified by prep-HPLC using Method BZ and further purified using Method CR to afford the title compound (2 mg, 10%) as a brown solid. 'H NMR (400MHz, DMSO- e) 6 8.34 (s, 1H), 8.17 (d, J=0.7 Hz, 1H), 7.93 (d, J=0.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.62 (m, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.28 (s, 1H), 6.97 (dd, J=2.0, 8.7 Hz, 1H), 5.79 (t, J=4.9 Hz, 1H), 4.21 (q, J=7.3 Hz, 2H), 2.96 - 2.71 (m, 2H), 2.08 - 1.98 (m, 2H), 1.95 - 1.71 (m, 2H), 1.44 (t, J=7.3 Hz, 3H). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.1.
Example 115: 5-((l-(5-Methylthiazol-2-yl)-Lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000267_0002
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-bromo-5-methylthiazole in place of 2-bromobenzo|<7|oxazole. The material was purified by prep-HPLC using Method CS to afford the title compound (8 mg, 40%) as a white solid. 1 H NMR (400 MHz, DMSO- e) 6 8.35 (s, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.60 (m, 1H), 7.57 - 7.52 (m, 1H), 7.38 (d, J=1.2 Hz, 1H), 7.12 (dd, J=2.1, 8.8 Hz, 1H), 5.67 (t, J=4.8 Hz, 1H), 2.99 - 2.86 (m, 1H), 2.84 - 2.71 (m, 1H), 2.43 (d, J=l.1 Hz, 3H), 2.13 - 2.03 (m, 2H), 1.97 - 1.73 (m, 2H). MS-ESI (m/z) calc’d for C22H19N4OS [M+H]+: 387.1. Found 387.2.
Example 116: 5-((l-(l-Methyl-LH-pyrazol-3-yl)-LH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000268_0001
Prepared as described for 5-((l-(l-methyl-77/-pyrazol-3-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 3 -iodo- 1 -methyl- 1H- pyrazole in place of 2-bromobenzo|t/| oxazole. The material was purified by prep-HPLC using Method BZ to afford the title compound (4 mg, 19%) as a brown solid. 'H NMR (400 MHz, DMSO- e) 6 8.21 (s, 1H), 7.86 (s, 1H), 7.75 - 7.83 (m, 2H), 7.71 (s, 1H), 7.62 - 7.68 (m, 1H), 7.54 - 7.58 (m, 1H), 7.06 (dd, J=1.77, 8.74 Hz, 1H), 6.49 (d, J=2.20 Hz, 1H), 5.66 (br t, J=4.71 Hz, 1H), 3.91 (s, 3H), 2.75 - 2.96 (m, 2H), 2.08 (q, J=5.22 Hz, 2H), 1.78 - 1.94 (m, 2H). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.2.
Example 117: 5-((l-(2-MethyIoxazol-5-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000268_0002
Prepared as described for 5-((l-(benzo[<7]oxazol-2-yl)-177-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 5-bromo-2-methyloxazole in place of 2-bromobenzo|<7|oxazole. The material was purified by prep-HPLC using Method CT to afford the title compound (1 mg, 4%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 8.35 (s, 1 H), 7.79 (d, J=8.77 Hz, 1 H), 7.69 (s, 1 H), 7.62 - 7.66 (m, 1 H), 7.52 (d, J=8.33 Hz, 1 H), 7.36 (s, 1 H), 7.29 (s, 1 H), 7.03 (dd, J=8.88, 2.08 Hz, 1 H), 5.74 - 5.78 (m, 1 H), 2.85 - 2.89 (m, 1 H), 2.77 - 2.83 (m, 1 H), 1.99 - 2.04 (m, 2 H), 1.79 - 1.88 (m, 2 H). MS-ESI (m/z) calc’d for C22H19N4O2 [M+H]+: 371.1. Found 371.1.
Example 118: 3-Cyano-2-isopropyl-/V-(l-(l-(2-methoxyethyl)-l//-pyrazol-4-yl)-l//- indazol-6-yI)benzamide
Figure imgf000269_0001
3-Cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (30 mg, 98.57 umol), 4-bromo- 1- (2-methoxyethyl)-IT/-pyrazole (30.32 mg, 147.86 umol), Cui (7.51 mg, 39.43 umol), K3PO4 (125.54 mg, 591.43 umol) and/Vi,/ 2-dimethylcyclohexane-l,2-diamine (14.02 mg, 98.57 umol) in a sealed microwave reaction byl were heated at 120 °C for 5 hrs in a microwave reactor under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method CU to afford the title compound (3 mg, 6%) as a brown solid. 1 H NMR (400 MHz, DMSO- e) 6 10.81 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=2.5 Hz, 2H), 7.94 (d, J=7.6 Hz, 1H), 7.86 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.38 (dd, J=1.3, 8.8 Hz, 1H), 4.37 (t, J=5.2 Hz, 2H), 3.76 (br t, J=5.2 Hz, 2H), 3.39 - 3.34 (m, 1H), 3.27 (s, 3H), 1.42 (d, J=7.0 Hz, 6H). MS-ESI (m/z) calc’d for C24H25N6O2 [M+H]+: 429.2. Found 429.1.
Example 119: 3-Cyano-A (l-(4,5-dimethyloxazol-2-yl)- lff-indazol-6-yl)-2- isopropylbenzamide
Figure imgf000269_0002
To a solution of 6-nitro-17/-indazole (10 g, 61.30 mmol) and 3,4-dihydro-27/-pyran (10.31 g, 122.60 mmol) in THF (240 mL) was added methanesulfonic acid (883.68 mg, 9.19 mmol) at 20 °C. The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0-6% EtOAc/petroleum ether gradient eluent to afford the title compound (15 g, 98%) as ayellow solid. JH NMR (400 MHz, DMSO- e) 6 8.72 (s, 1H), 8.35 (s, 1H), 8.09 - 7.85 (m, 2H), 6.10 (br d, J=8.0 Hz, 1H), 3.95 - 3.73 (m, 2H), 2.09 - 1.92 (m, 2H), 1.59 (br s, 2H).
Step 2: l-(Tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine
Figure imgf000270_0001
A mixture of 6-nitro- 1 -(tetrahydro-2//-pyran-2-yl)- 1 //-indazole (15 g, 60.67 mmol) andlO% Pd/C (3.2 g) in MeOH (400 mL) was degassed and purged with H2 (3x) and then the mixture was stirred at 20 °C for 5 hrs under an H2 atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-33% EtOAc/petroleum ether gradient eluent to afford the title compound (12.8 g, 97%) as a red oil. JH NMR (400 MHz, DMSO- e) 6 7.74 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 6.60 (s, 1H), 6.52 (dd, J=1.7, 8.6 Hz, 1H), 5.53 (dd, J=2.5, 9.6 Hz, 1H), 5.35 (s, 2H), 3.92 - 3.80 (m, 1H), 3.71 - 3.58 (m, 1H), 2.43 - 2.28 (m, 1H), 2.07 - 2.00 (m, 1H), 1.94 - 1.84 (m, 1H), 1.81 - 1.64 (m, 1H), 1.61 - 1.46 (m, 2H).
Step 3: Methyl 3-cyanobenzoate
Figure imgf000270_0002
To a solution of 3-cyanobenzoic acid (22 g, 149.53 mmol) in MeOH (200 mL) was added H2SO4 (7.48 g, 74.76 mmol) at 20 °C. The mixture was then stirred at 90 °C for 12 hrs and concentrated under vacuum to give a residue. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (21.85 g, 90%) as a white solid which was used without further purification.
Step 4: Methyl 3-cyano-2-iodobenzoate
Figure imgf000270_0003
To a solution of methyl 3-cyanobenzoate (16 g, 99.28 mmol) in THF (280 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (1 M, 198.56 mL) at 0 °C under an N2 atmosphere. The mixture was stirred at 20 °C for 2 hrs then a solution of I2 (25.20 g, 99.28 mmol) in THF (280 mL) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 3 hrs under an N2 atmosphere, then quenched with H2O (300 mL) at 0 °C and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel column chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (10.8 g, 37%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 7.89 (dd, J=1.5, 7.8 Hz, 1H), 7.70 (dd, J=1.5, 7.6 Hz, 1H), 7.58 - 7.49 (m, 1H), 3.98 (s, 3H).
Figure imgf000271_0001
A mixture of methyl 3-cyano-2-iodobenzoate (10.8 g, 37.62 mmol), 2-isopropenyl- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (9.48 g, 56.44 mmol), Pd(dppl)C12 (1.38 g, 1.88 mmol), and CS2CO3 (36.78 g, 112.87 mmol) in dioxane (300 mL) and H2O (120 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 95 °C for 2 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (5x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated. The material was purified by silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (5.64 g, 74 %) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 8.04 (dd, J=7.9, 0.9 Hz, 1H), 7.80 (dd, J=7.8, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 5.36 (t, J=1.4 Hz, 1H), 4.93 (s, 1H), 3.86-3.90 (m, 3H), 2.18 (s, 3H).
Step 6: 3-Cyano-2-(prop-l-en-2-yl)benzoic acid
Figure imgf000271_0002
To a solution of methyl 3-cyano-2-(prop-l-en-2-yl)benzoate (6 g, 29.82 mmol) in THF (75 mL) and H2O (75 mL) was added LiOHHHO (2.50 g, 59.64 mmol) and the mixture was stirred at 20 °C for 12 hrs. THF was removed under vacuum and the aqueous layer was extracted with EtOAc (3x). The organic layer was discarded and the aqueous layer pH was adjusted to 1 with 1 M HC1. This mixture was extracted with EtOAc (5x). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (5 g, 89%) as a yellow solid. MS-ESI (m/z) calc’d for C11H10NO2 [M+H]+: 188.1. Found 188.2.
Step 7: 3-Cyano-2-(prop-l-en-2-yl)-N-( 1 -( tetrahydro-2H-pyran-2-yl)-lH-indazol-6- yl)benzamide
Figure imgf000272_0001
To a solution of 3-cyano-2-(prop-l-en-2-yl)benzoic acid (4 g, 21.37 mmol) and 1- (tetrahydro-27f-pyran-2-yl)-17f-indazol-6-amine (6.96 g, 32.05 mmol) in DCM (120 mL) was added a 50 wt % solution of T3P in EtOAc (27.20 g, 42.74 mmol) at 20 °C. The mixture was stirred at 40 °C for 0.5 hr. Then EtsN (5.41 g, 53.42 mmol) was added in the mixture at 40 °C. The mixture was stirred at 40 °C for 2 hrs. The mixture was concentrated under vacuum. The residue was diluted with H2O and extracted with DCM (3x). The combined organic phase was dried with anhydrous Na2SO4, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0- 31% EtOAc/petroleum ether gradient eluent to afford the title compound (8 g, 96%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 8.39 (s, 1H), 8.30 (s, 1H), 8.08 (d, J=7.7 Hz, 1H), 8.01 (s, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 5.75 (dd, J=9.8, 2.1 Hz, 1H), 5.71 (s, 1H), 5.42 (s, 1H), 4.04-4.11 (m, 1H), 3.72-3.86 (m, 1H), 2.55-2.69 (m, 1H), 2.19 (s, 3H), 2.12-2.17 (m, 1H), 2.10 (br s, 1H), 1.71- 1.86 (m, 2H), 1.67 (br s, 1H). MS-ESI (m/z) calc’d for C23H23N4O2 [M+H]+: 387.2. Found 387.3.
Figure imgf000272_0002
A mixture of 3-cyano-2-(prop-l-en-2-yl)-N-(l-(tetrahydro-27f-pyran-2-yl)-17f- indazol -6-yl) benzamide (8 g, 20.70 mmol) and Pd(OH)2 (8.00 g, 11.39 mmol) in EtOAc (150 mL) was degassed and purged with H2 (3x), and then the mixture was stirred at 20 °C for 2 hrs under H2 atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0- 20% EtOAc/petroleum ether gradient eluent to afford the title compound (4.1 g, 50%) as a red oil. 'H NMR (400 MHz, MeOH-tL) 8 8.36 (s, 1H), 8.01 (s, 1H), 7.83 (dd, J=7.8, 1.3 Hz, 1H), 7.69-7.74 (m, 2H), 7.46-7.52 (m, 1H), 7.24 (dd, J=8.7, 1.7 Hz, 1H), 5.78 (dd, J=9.9, 2.5 Hz, 1H), 4.04 (br d, J=11.5 Hz, 1H), 3.83 (td, J=11.2, 2.9 Hz, 1H), 3.41-3.52 (m, 1H), 2.50- 2.59 (m, 1H), 1.92-2.27 (m, 3H), 1.74-1.90 (m, 2H), 1.53 (d, J=7.3 Hz, 6H). MS-ESI (m/z) calc’d for C23H25N4O2 [M+H]+: 389.2. Found 389.3.
Figure imgf000273_0001
To a solution of 3-cyano-2-isopropyl-/V-(l-(tetrahydro-27/-pyran-2-yl)-17/-indazol-6- yl) benzamide (4.1 g, 10.55 mmol) in DCM (96 mL) was added TFA (32 mL) and the mixture was stirred at 20 °C for 12 hrs. The reaction was made basic with saturated aqueous NaHCOs to adjust to pH=8 and extracted with DCM (5x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (2.96 g, 92%) as a yellow oil. JH NMR (400 MHz, CDCh) 8 8.40 (s, 1H), 8.06 (s, 1H), 7.81 - 7.69 (m, 3H), 7.65 (dd, J=1.3, 7.7 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.00 (dd, J=1.7, 8.6 Hz, 1H), 3.56 - 3.48 (m, 1H), 1.53 (d, J=7.1 Hz, 6H). MS-ESI (m/z) calc’d for C18H17N4O [M+H]+: 305.1. Found 305.2.
Step 10: 2-Iodo-4, 5 -dimethyloxazole
Figure imgf000273_0002
To a solution of 4,5-dimethyloxazole (100 mg, 1.03 mmol) in THF (4 mL) was added LiHMDS (1 M, 1.24 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 hr. The I2 (392.02 mg, 1.54 mmol) in THF (2 mL) was added in the mixture at -78 °C under N2 atmosphere. The mixture was stirred at 20 °C for 1.5 hrs. The reaction mixture was quenched with H2O at 0 °C, then the mixture was extracted with EtOAc (3x). The combined organic phase was dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative-TLC (SiCh, petroleum ether/EtOAc = 10/1, Rf = 0.88) to afford the title compound (84 mg, 36%) as a white solid. 'H NMR (400 MHz, CDCh) 8 2.29 (d, J=0.9 Hz, 3H), 2.09 (d, J=0.9 Hz, 3H). MS-ESI (m/z) calc’d for C5H7INO [M+H]+: 224.0. Found 224.1.
Step 11: 3-Cyano-N-( 1 -( 4, 5-dimethyloxazol-2-yl)-lH-indazol-6-yl)-2-isopropylbenzamide
Figure imgf000274_0001
3-Cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (30 mg, 98.57 umol), 2-iodo- 4,5-dimethyloxazole (28.58 mg, 128.14 umol), 3,4,7,8-tetramethyl-l,10-phenanthroline (2.33 mg, 9.86 umol), CS2CO3 (64.23 mg, 197.14 umol), and bis(tetrabutylammonium)copper(I) iodide (5.52 mg, 4.93 umol) were combined in a micro wave tube in DMA (2 mL) at 20 °C. The sealed tube was heated at 130 °C for 5 hrs in a microwave reactor under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The material was purified by HPLC using Method CV and further purified by HPLC using Method CW to afford the title compound (1.87 mg, 4%) as a white solid. JH NMR (400 MHz, CDCh) 8 8.58 (s, 1H), 8.24 (br s, 1H), 7.84 - 7.70 (m, 4H), 7.67 (br d, J=7.5 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 3.54 (td, J=7.0, 14.1 Hz, 1H), 2.38 (br s, 3H), 2.18 (br s, 3H), 1.54 (d, J=7.0 Hz, 6H). MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2. Found 400.1.
Example 120: 3-Cyano-7V-(l-(l-cyclopentyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)-2- isopropylbenzamide
Figure imgf000274_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using l-cyclopentyl-4-iodo-17/-pyrazole in place of 2-iodo-4,5- dimethyloxazole. The material was purified by prep-HPLC using Method CX to afford the title compound (4 mg, 8%) as a brown solid. 'H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.20-8.31 (m, 3H), 7.94 (dd, J=1.22, 7.70 Hz, 1H), 7.84 (s, 1H), 7.80 (d, J=8.68 Hz, 1H), 7.74 (dd, J=1.34, 7.70 Hz, 1H), 7.53 (t, J=7.70 Hz, 1H), 7.41 (dd, J=1.65, 8.74 Hz, 1H), 4.80 (quin, J=7.03 Hz, 1H), 2.08-2.20 (m, 2H), 1.95-2.05 (m, 2H), 1.78-1.87 (m, 2H), 1.62-1.73 (m, 2H), 1.40-1.45 (m, 6H). MS-ESI (m/z) calc’d for C26H27N6O [M+H]+: 439.2. Found 439.1.
Example 121: 3-Cyano-2-isopropyl-7V-(l-(oxazol-2-yI)-LH-indazol-6-yI)benzamide
Figure imgf000275_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 2-iodooxazole in place of 2-iodo-4,5-dimethyloxazole. The material was purified by prep-HPLC using Method CY to afford the title compound (3 mg, 6%) as a red solid. 'H NMR (400 MHz, CDCh) 8 8.77 (s, 1H), 8.29 (s, 1H), 7.77-7.87 (m, 3H), 7.70 (br d, J=7.5 Hz, 2H), 7.44 (t, J=7.8 Hz, 1H), 7.31 (s, 1H), 3.55-3.62 (m, 1H), 1.58 (d, J=7.0 Hz, 6H). MS-ESI (m/z) calc’d for C21H18N5O2 [M+H]+: 372.1. Found 372.1.
Example 122: 3-Cyano-2-isopropyl-7V-(l-(4-phenyIoxazol-2-yI)-LH-indazol-6- yl)benzamide
Figure imgf000275_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide using 2-iodo-4-phenyloxazole in place of 2-iodo-4,5-dimethyloxazole. The material was purified by prep-HPLC using Method CZ to afford the title compound (3 mg, 6 %) as a brown solid. 'H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.17 (s, 1H), 8.69 (s, 1H), 8.52 (s, 1H), 7.92 - 7.98 (m, 4H), 7.83 (d, J=7.70 Hz, 1H), 7.72 (dd, J=1.53, 8.62 Hz, 1H), 7.57 (t, J=7.70 Hz, 1H), 7.49 (t, J=7.58 Hz, 2H), 7.36 - 7.41 (m, 1H), 1.46 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C27H22N5O2 [M+H]+: 448.2. Found 448.1. Example 123: /V-(l-(Benzo[r/|oxazol-2-yl)-l//-indazol-6-yl)-3-cyano-2- isopropylbenzamide
Figure imgf000276_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 2-bromobenzo[r/]oxazole in place of 2-iodo-4,5- dimethyloxazole. The material was purified by prep-HPLC using Method CO to afford the title compound (2 mg, 4%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.90 (s, 1 H), 9.39 (s, 1 H), 8.50 (dd, J=6.19, 3.06 Hz, 1 H), 8.35 (d, J=8.88 Hz, 1 H), 7.95 (dd, J=7.75, 1.25 Hz, 1 H), 7.90 (d, J=2.00 Hz, 1 H), 7.78 (dd, J=7.63, 1.25 Hz, 1 H), 7.62 - 7.68 (m, 2 H), 7.55 (t, J=7.63 Hz, 1 H), 7.39 - 7.44 (m, 2 H), 3.37 (br d, J=7.13 Hz, 1 H), 1.43 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C25H20N5O2 [M+H]+: 422.2. Found 422.1.
Example 124: 3-Cyano-2-isopropyl-/V-(l-(2-methylthiazol-5-yl)-l//-indazol-6- yl)benzamide
Figure imgf000276_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 5-bromo-2-methylthiazole in place of 2-iodo-4,5- dimethyloxazole. The material was purified by prep-HPLC using Method CO and further purified by prep-HPLC using Method DA to afford the title compound (1 mg, 2%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.91 (s, 1 H), 8.48 (s, 1 H), 8.36 (s, 1 H), 7.95 (d, J=7.50 Hz, 1 H), 7.83 - 7.91 (m, 2 H), 7.77 (d, J=7.75 Hz, 1 H), 7.54 (t, J=7.82 Hz, 1 H), 7.46 (d, J=8.75 Hz, 1 H), 2.71 (s, 3 H), 1.42 (d, J=7.25 Hz, 6 H). MS-ESI (m/z) calc’d for C22H20N5OS [M+H]+: 402.1. Found 402.0.
Example 125: 3-Cyano-2-isopropyl-/V-(l-(4-methylthiazol-5-yl)-l//-indazol-6- yl)benzamide
Figure imgf000277_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 5-bromo-4-methylthiazole in place of 2-iodo-4,5- dimethyloxazole. The material was purified by prep-HPLC using Method DB to afford the title compound (1 mg, 3%) as a brown solid. 'H NMR (400 MHz, DMSO- e) 6 10.70 (s, 1 H), 9.04 (s, 1 H), 8.79 (s, 1 H), 8.27 (s, 1 H), 7.94 (dd, J=7.70, 1.34 Hz, 1 H), 7.73 - 7.80 (m, 2 H), 7.54 (t, J=7.70 Hz, 1 H), 7.28 (dd, J=9.05, 1.59 Hz, 1 H), 2.53 (s, 3 H), 1.44 (d, J=7.09 Hz, 6 H). MS-ESI (m/z) calc’d for C22H20N5OS [M+H]+: 402.1. Found 402.0.
Example 126: 3-Cyano-2-isopropyl-7V-(l-(pyrimidin-5-yI)-LH-indazol-6-yI)benzamide
Figure imgf000277_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 5 -iodopyrimidine in place of 2-iodo-4, 5 -dimethyloxazole. The material was purified by prep-HPLC using Method DC to afford the title compound (4.92 mg, 12%) as ayellow solid. 'H NMR (DMSO- e) 6 10.91 (s, 1 H), 9.29 (s, 2 H), 9.24 (s, 1 H), 8.58 (s, 1 H), 8.48 (s, 1 H), 7.89 - 7.97 (m, 2 H), 7.76 (d, J=6.65 Hz, 1 H), 7.52 - 7.58 (m, 2 H), 1.42 (d, J=7.03 Hz, 6 H) MS-ESI (m/z) calc’d for C22H19N6O [M+H]+:383.2. Found 383.1.
Example 127 : 3-Cyano-2-isopropyl-/V-(l -(2-methylpyrimidin-5-yl)-l//-indazol-6- yl)benzamide
Figure imgf000277_0003
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 5-bromo-2-methylpyrimidine in place of 2-iodo-4,5-dimethyl oxazole. The material was purified by prep-HPLC using Method DD to afford the title compound (4 mg, 9%) as a yellow solid. 'H NMR (DMSO-d6) δ 10.90 (s, 1 H), 9.14 (s, 2 H), 8.55 (s, 1 H), 8.44 (d, J=0.88 Hz, 1 H), 7.95 (dd, J=7.78, 1.21 Hz, 1 H), 7.89 (d, J=8.55 Hz, 1 H), 7.76 (dd, J=7.67, 1.32 Hz, 1 H), 7.54 (t, J=7.67 Hz, 1 H), 7.47 (dd, J=8.77, 1.53 Hz, 1 H), 3.35 - 3.39 (m, 1 H), 2.74 (s, 3 H), 1.42 (d, J=7.02 Hz, 6 H). MS-ESI (m/z) calc’d for C23H21N6O [M+H]+: 397.2. Found 397.1.
Example 128: 3-Cyano-2-isopropyl-7V-(l-(3-methyIpyridin-4-yI)-LH-indazol-6- yl)benzamide
Figure imgf000278_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 4-bromo-3-methylpyridine hydrochloride in place of 2-iodo- 4,5-dimethyloxazole. The material was purified by prep-HPLC using Method DE to afford the title compound (1 mg, 1%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1 H), 8.79 (br s, 1 H), 8.70 (br s, 1 H), 8.42 (s, 1 H), 8.18 (s, 1 H), 7.92 - 7.95 (m, 1 H), 7.88 (d, J=8.88 Hz, 1 H), 7.73 (dd, J=7.63, 1.38 Hz, 1 H), 7.63 (br d, J=5.00 Hz, 1 H), 7.50 - 7.54 (m, 1 H), 7.44 (dd, J=8.63, 1.50 Hz, 1 H), 3.22 - 3.35 (m, 1 H), 2.29 (s, 3 H), 1.40 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C24H22N5O [M+H]+: 396.2. Found 396.1.
Example 129: 3-Cyano-2-isopropyl- \-( l-(pyridaziii-3-yl)-l//-indazol-6-yl)benzamide
Figure imgf000278_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)-
2- isopropylbenzamide using 3 -bromopy ridazine in place of 2-iodo-4, 5 -dimethyloxazole. The material was purified by prep-HPLC using Method CQ to afford the title compound (5 mg, 12%) as a red solid. 'H NMR (400 MHz, CDCh) 8 9.08 (br d, J=3.88 Hz, 1 H), 8.92 (s, 1 H), 8.42 (d, J=9.13 Hz, 1 H), 8.21 - 8.32 (m, 2 H), 7.90 (br s, 1 H), 7.86 (d, J=8.76 Hz, 1 H), 7.78 (d, J=7.75 Hz, 1 H), 7.74 (br dd, J=9.19, 4.57 Hz, 1 H), 7.70 (d, J=7.63 Hz, 1 H), 7.41 (t, J=7.69 Hz, 1 H), 3.58 (dt, J=14.26, 7.13 Hz, 1 H), 1.55 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.2. Found 383.1.
Example 130: 3-Cyano-2-isopropyl-/V-(l-(2-(pyrrolidiii-l-yl)pyrimidin-5-yl)-l//-indazol-
6-yl)benzamide
Figure imgf000279_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 5-bromo-2-(pyrrolidin-l-yl)pyrimidine in place of 2-iodo-4,5- dimethyloxazole. The material was purified by prep-HPLC using Method DF to afford the title compound (3 mg, 5%) as a brown solid. 'H NMR (400 MHz, DMSO- e) 6 10.82 (s, 1H), 8.66 (s, 2H), 8.29 (s, 2H), 7.90-7.97 (m, 1H), 7.83 (d, J=8.56 Hz, 1H), 7.73 (dd, J=1.10, 7.58 Hz, 1H), 7.52 (t, J=7.70 Hz, 1H), 7.35 (dd, J=1.28, 8.74 Hz, 1H), 3.55-3.58 (m, 4H), 3.33 (td, J=7.06, 14.24 Hz, 1H), 1.90-2.06 (m, 4H), 1.37-1.45 (m, 6H). MS-ESI (m/z) calc’d for C26H26N7O [M+H]+: 452.2. Found 452.1.
Example 131: 3-Cyano-2-isopropyl-7V-(l-(pyrazolo[l,5-a]pyridin-3-yl)-LH-indazol-6- yl)benzamide
Figure imgf000279_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2- isopropylbenzamide using 3-iodopyrazolo[l,5-a]pyridine in place of 2-iodo-4,5-dimethyl oxazole. The material was purified by prep-HPLC using Method DB to afford the title compound (4 mg, 9%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.81 (s, 1H), 8.82 (d, J=7.09 Hz, 1H), 8.45 (s, 1H), 8.34 (d, J=0.73 Hz, 1H), 8.18 (s, 1H), 7.84-7.94 (m, 2H), 7.70-7.75 (m, 1H), 7.59 (d, J=8.92 Hz, 1H), 7.48-7.54 (m, 1H), 7.33-7.44 (m, 2H), 7.06 (dt, , , ), ( , , 4.21 Hz, 1H), 1.39 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C25H21N6O [M+H]+:421.2. Found 421.1. Example 132: 3-Cyano-2-isopropyl-N-(1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as describ xazol-2-yl)-1H-indazol-6-yl)-
Figure imgf000280_0001
2- isopropylbenzamide using 4-iodo-1-isopropyl-1H-pyrazole in place of 2-iodo-4,5-dimethyl oxazole. The material was purified by prep-HPLC using Method DG to afford the title compound (5 mg, 12%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.27 (s, 2H), 8.22 (s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.84 (s, 1H), 7.71-7.82 (m, 2H), 7.53 (t, J=7.7 Hz, 1H), 7.42 (br d, J=8.5 Hz, 1H), 4.52-4.67 (m, 1H), 1.49 (d, J=6.6 Hz, 6H), 1.42 (d, J=7.1 Hz, 6H). MS-ESI (m/z) calc’d for C24H25N6O [M+H]+: 413.2. Found: 413.1. Example 133: 3-Cyano-N-(1-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- isopropylbenzamide Prepared as described
Figure imgf000280_0002
oxazol-2-yl)-1H-indazol-6-yl)- 2- isopropylbenzamide using 4-iodo-1,3-dimethyl-1H-pyrazole in place of 2-iodo-4,5- dimethyl oxazole. The material was purified by prep-HPLC using Method DH to afford the title compound (4 mg, 9%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.92 (d, J=7.09 Hz, 1H), 7.66-7.82 (m, 3H), 7.48-7.56 (m, 1H), 7.31 (dd, J=1.34, 8.68 Hz, 1H), 3.86 (s, 3H), 3.32 (td, J=7.06, 14.24 Hz, 1H), 2.19 (s, 3H), 1.40 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C23H23N6O [M+H]+:399.2. Found 399.1. Example 134: 3-Cyano-2-isopropyl-N-(1-(1-phenyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide
Figure imgf000281_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide using 4-iodo-l -phenyl- 17/-pyrazole in place of 2-iodo-4,5-dimethyl oxazole. The material was purified by prep-HPLC using Method DI to afford the title compound (2 mg, 4%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 8.46 (s, 1H), 8.38 (s, 1H), 8.18 (s, 2H), 7.74-7.84 (m, 4H), 7.62-7.69 (m, 2H), 7.52 (t, J=7.9 Hz, 2H), 7.33-7.45 (m, 2H), 7.09 (d, J=8.6 Hz, 1H), 3.53 (dt, J=14.3, 7.1 Hz, 1H), 1.54 (d, J=7.2 Hz, 6H). MS-ESI (m/z) calc’d for C27H23N6O [M+H]+: 447.2. Found 447.1.
Example 135: A (l-(l-(ter/-Butyl)-l/f-pyrazol-4-yl)-LH-indazol-6-yl)-3-cyano-2- isopropylbenzamide
Figure imgf000281_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide using 4-bromo-l-(ter/-butyl)-17/-pyrazole in place of 2-iodo-4,5- dimethyl oxazole. The material was purified by prep-HPLC using Method DJ to afford the title compound (4 mg, 7%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.81 (s, 1 H), 8.31 (s, 1 H), 8.27 (s, 1 H), 8.22 (s, 1 H), 7.94 (dd, J=7.67, 1.32 Hz, 1 H), 7.86 (s, 1 H), 7.80 (d, J=8.55 Hz, 1 H), 7.75 (dd, J=7.67, 1.32 Hz, 1 H), 7.53 (t, J=7.78 Hz, 1 H), 7.42 (dd, J=8.55, 1.53 Hz, 1 H), 3.31 - 3.39 (m, 1 H), 1.60 (s, 9 H), 1.42 (d, J=7.02 Hz, 6 H). MS-ESI (m/z) calc’d for C25H27N6O [M+H]+: 427.2. Found 427.1.
Example 136: 3-Cyano-2-isopropyl-7V-(l-(l-(oxetan-3-yI)-LH-pyrazol-4-yI)-LH-indazol- 6-yl)benzamide
Figure imgf000282_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide using 4-iodo-l-(oxetan-3-yl)-17/-pyrazole in place of 2-iodo-4,5- dimethyl oxazole. The material was purified by prep-HPLC using Method DK to afford the title compound (7 mg, 16%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.82 (s, 1 H), 8.42 (s, 1 H), 8.30 (s, 1 H), 8.24 (s, 1 H), 8.02 (s, 1 H), 7.94 (dd, J=7.75, 1.13 Hz, 1 H), 7.81 (d, J=8.63 Hz, 1 H), 7.74 (dd, J=7.69, 1.19 Hz, 1 H), 7.53 (t, J=7.69 Hz, 1 H), 7.41 (dd, J=8.69, 1.56 Hz, 1 H), 5.70 (quin, J=6.94 Hz, 1 H), 4.98 (d, J=6.75 Hz, 4 H), 3.33 - 3.39 (m, 1 H), 1.42 (d, J=7.00 Hz, 6 H). MS-ESI (m/z) calc’d for C24H23N6O2 [M+H]+: 427.2. Found 427.1.
Example 137 : 3-Cyano-2-isopropyl-/V-(l -(1-methyl-l //-pyrazol-3-yl)-l//-indazol-6- yl)benzamide
Figure imgf000282_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide using 3-iodo-l-methyl-17/-pyrazole in place of 2-iodo-4,5-dimethyl oxazole. The material was purified by prep-HPLC using Method DL and further purified by prep-HPLC using Method DM to afford the title compound (2 mg, 5%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.85 (s, 1H), 8.83 (s, 1H), 8.26 (s, 1H), 7.94 (d, J=7.94 Hz, 1H), 7.75 - 7.86 (m, 3H), 7.50 - 7.57 (m, 2H), 6.50 (d, J=2.21 Hz, 1H), 3.92 (s, 3H), 1.43 (d, J=7.28 Hz, 6H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2.
Example 138: 3-Cyano-2-isopropyl-/V-(l-(2-methoxy-6-methylpyridin-4-yl)-l//-indazol- 6-yl)benzamide
Figure imgf000283_0001
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide using 4-bromo-2-methoxy-6-methylpyridine in place of 2-iodo-4,5- dimethyl oxazole. The material was purified by prep-HPLC using Method DN to afford the title compound (3 mg, 6%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 8.85 (br s, 1H), 8.58 (br s, 1H), 8.25 (s, 1H), 7.64-7.83 (m, 3H), 7.34-7.51 (m, 3H), 4.14 (br s, 3H), 3.37-3.54 (m, 1H), 2.64 (br s, 3H), 1.48-1.55 (m, 6H). MS-ESI (m/z) calc’d for C25H24N5O2 [M+H]+: 426.2. Found 426.2.
Example 139: 3-Cyano-2-isopropyl-/V-(l-(3-morpholinophenyl)-///-indazol-6- yl)benzamide
Figure imgf000283_0002
Prepared as described for 3-cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide using 4-(3-iodophenyl)morpholine in place of 2-iodo-4,5- dimethyloxazole. The material was purified by prep-HPLC using Method DO to afford the title compound (12 mg, 24%) as a red solid. JH NMR (400 MHz, CDCh) 8 8.41 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.77 (dd, J=17.1, 8.3 Hz, 2H), 7.61-7.69 (m, 2H), 7.52-7.60 (m, 2H), 7.46 (br d, J=9.0 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.11 (br d, J=6.4 Hz, 1H), 3.92-4.09 (m, 4H), 3.37-3.57 (m, 5H), 1.51 (d, J=7.2 Hz, 6H) MS-ESI (m/z) calc’d for C28H28N5O2 [M+H]+: 466.2. Found 466.1.
Example 140: 3-Cyano-2-isopropyl-/V-(l-(5-methylthiazol-2-yl)-l//-indazol-6- yl)benzamide To a solution of 3-cy opylbenzamide (15 mg, 49.29
Figure imgf000284_0001
umol), 2-bromo-5-methylthiazole (8.78 mg, 49.29 umol) in dioxane (1 mL) was added CuI (1.88 mg, 9.86 umol) and K3PO4 (31.39 mg, 147.86 umol), N1,N2-dimethylcyclohexane-1,2- diamine (3.51 mg, 24.64 umol) at 20 °C. The mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere and then concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC using Method DP to afford the title compound (14 mg, 72%) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.11 (s, 1H), 8.41 (s, 1H), 7.95 (d, J=6.72 Hz, 1H), 7.87 (d, J=8.56 Hz, 1H), 7.78 (d, J=7.70 Hz, 1H), 7.51- 7.61 (m, 2H), 7.42 (d, J=1.10 Hz, 1H), 3.33-3.38 (m, 1H), 2.45 (s, 3H), 1.44 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C22H20N5OS [M+H]+: 402.1. Found 402.1. Example 141: 3-Cyano-2-isopropyl-N-(1-(pyrazin-2-yl)-1H-indazol-6-yl)benzamide Prepared as described
Figure imgf000284_0002
5-methylthiazol-2-yl)-1H- indazol-6-yl) benzamide using 2-iodopyrazine in place of 2-bromo-5-methylthiazole. The residue was purified by prep-HPLC using Method BJ to afford the title compound (2 mg, 15%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1 H), 9.32 (s, 1 H), 9.25 (s, 1 H), 8.61 (br d, J=1.38 Hz, 1 H), 8.55 (br d, J=2.50 Hz, 1 H), 8.50 (s, 1 H), 7.94 (dd, J=7.75, 1.00 Hz, 1 H), 7.90 (d, J=8.76 Hz, 1 H), 7.78 (dd, J=7.63, 1.13 Hz, 1 H), 7.65 (dd, J=8.63, 1.63 Hz, 1 H), 7.54 (t, J=7.69 Hz, 1 H), 3.39 (br s, 1 H), 1.44 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.3. Found 383.1. Example 142: 3-Cyano-2-isopropyl-N-(1-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-6- yl)benzamide Prepared as described 5-methylthiazol-2-yl)-1H-
Figure imgf000285_0001
indazol-6-yl) benzamide using 4-bromo-1-methyl-1H-1,2,3-triazole in place of 2-bromo-5- methylthiazole. The residue was purified by prep-HPLC using Method DQ to afford the title compound (8 mg, 24%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.88 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 7.93 (d, J=7.21 Hz, 1H), 7.84 (d, J=8.68 Hz, 1H), 7.77 (d, J=7.58 Hz, 1H), 7.43-7.58 (m, 2H), 4.16 (s, 3H), 1.43 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C21H20N7O [M+H]+: 386.2. Found: 386.1. Example 143: 3-Cyano-2-isopropyl-N-(1-(1-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-1H- indazol-6-yl)benzamide Prepared as descri
Figure imgf000285_0002
ethylthiazol-2-yl)-1H- indazol-6-yl) benzamide using 2-(4-bromo-1H-pyrazol-1-yl)pyrimidine in place of 2-bromo- 5-methylthiazole. The residue was purified by prep-HPLC using Method DR to afford the title compound (2 mg, 5%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1 H), 9.03 (s, 1 H), 8.94 (d, J=4.77 Hz, 2 H), 8.40 (s, 1 H), 8.35 (d, J=7.09 Hz, 2 H), 7.95 (d, J=7.70 Hz, 1 H), 7.87 (d, J=8.68 Hz, 1 H), 7.76 - 7.80 (m, 1 H), 7.52 - 7.60 (m, 3 H), 1.43 (d, J=7.09 Hz, 6 H). MS-ESI (m/z) calc’d for C25H21N8O [M+H]+: 449.2. Found 449.1. Example 144: 3-Cyano-2-isopropyl-N-(1-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1H-indazol- 6-yl)benzamide
Figure imgf000286_0001
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(5-methylthiazol-2-yl)-17/- indazol-6-yl) benzamide using 2-(4-bromo-17/-pyrazol-l-yl)pyridine in place of 2-bromo-5- methylthiazole. The residue was purified by prep-HPLC using Method DS to afford the title compound (10 mg, 22%) as a brown solid. 'H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1 H), 9.01 (s, 1 H), 8.53 (br d, J=4.82 Hz, 1 H), 8.39 (s, 1 H), 8.33 (d, J=5.26 Hz, 2 H), 8.02 - 8.10 (m, 2 H), 7.92 - 7.98 (m, 1 H), 7.87 (d, J=8.77 Hz, 1 H), 7.78 (dd, J=7.67, 0.88 Hz, 1 H), 7.51 - 7.60 (m, 2 H), 7.43 (t, J=5.15 Hz, 1 H), 3.36 (dt, J=14.20, 7.04 Hz, 1 H), 1.43 (d, J=7.23 Hz, 6 H). MS-ESI (m/z) calc’d for C26H22N7O [M+H]+:448.2. Found 448.1.
Example 145: 3-Cyano-7V-(l-(l-ethyl-LH-pyrazol-4-yl)-LH-indazol-6-yl)-2- isopropylbenzamide
Figure imgf000286_0002
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(5-methylthiazol-2-yl)-17/- indazol-6-yl)benzamide using 4-bromo-l -ethyl- 17/-pyrazole in place of 2-bromo-5- methylthiazole. The residue was purified by prep-HPLC using Method DT to afford the title compound (5 mg, 23%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.80 (s, 1H), 8.25-8.30 (m, 2H), 8.22 (s, 1H), 7.94 (d, J=7.70 Hz, 1H), 7.78-7.85 (m, 2H), 7.75 (d, J=7.70 Hz, 1H), 7.51-7.56 (m, 1H), 7.40 (dd, J=1.47, 8.68 Hz, 1H), 4.24 (q, J=7.21 Hz, 2H), 3.36 (br d, J=7.21 Hz, 1H), 1.41-1.48 (m, 9H). MS-ESI (m/z) calc’d for C23H23N6O [M+H]+: 399.2. Found 399.1.
Example 146: 3-Cyano-N-(l-(l-(difluoromethyl)-LH-pyrazol-4-yl)-LH-indazol-6-yl)-2- isopropylbenzamide Prepared as describ
Figure imgf000287_0001
methylthiazol-2-yl)-1H- indazol-6-yl) benzamide using 1-(difluoromethyl)-4-iodo-1H-pyrazole in place of 2-bromo-5- methylthiazole. The residue was purified by prep-HPLC using Method DU to afford the title compound (6 mg, 19%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1 H), 8.78 (s, 1 H), 8.31 (s, 2 H), 8.28 (s, 1 H), 7.79 - 8.09 (m, 3 H), 7.73 - 7.77 (m, 1 H), 7.54 (t, J=7.75 Hz, 1 H), 7.48 (dd, J=8.69, 1.31 Hz, 1 H), 3.34 (br s, 1 H), 1.42 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C22H19F2N6O [M+H]+: 421.2. Found 421.1 Example 147: 3-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-(prop-1-en- 2-yl)benzamide To a solution of 1-(1- dazol-6-amine (113.91 mg,
Figure imgf000287_0002
534.20 umol), 3-cyano-2-(prop-1-en-2-yl)benzoic acid (100 mg, 534.20 umol) in DMF (5 mL) were added Et3N (162.17 mg, 1.60 mmol), EDC (122.89 mg, 641.05 umol), and HOBT (86.62 mg, 641.05 umol ). The mixture was stirred at 20 °C for 12 hrs. The mixture was filtered and the filtrate was concentrated under vacuum. The material was purified by HPLC using Method DV to afford the title compound (78 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.21 (d, J=1.1 Hz, 3H), 7.95-8.04 (m, 1H), 7.84-7.92 (m, 1H), 7.74-7.83 (m, 2H), 7.63 (t, J=7.8 Hz, 1H), 7.34 (dd, J=8.8, 1.3 Hz, 1H), 5.34 (s, 1H), 5.03 (s, 1H), 3.95 (s, 3H), 2.02-2.14 (s, 3H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.2. Found: 383.1. Example 148: 3-Cyano-2-fluoro-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol- 6-yl)benzamide
Figure imgf000288_0001
Step 1: 3-Bromo-2-fluoro-6-methylbenzoic acid
Figure imgf000288_0002
To a solution of l-bromo-2-fluoro-4-methylbenzene (2 g, 10.58 mmol) in THF (10 mL) was added LDA (2 M, 5.29 mL) at -78 °C and the mixture was stirred at -78 °C for 1 hr. CO2 (4.66 g, 105.81 mmol) (dry ice, more than 10 eq) was then added to the mixture and the mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of saturated aqueous NH4CI (30 mL) at 20 °C and extracted with EtOAc (3x). HC1 (1 M) was added to the aqueous phase to adjust to pH = 2 and a white solid formed. The resulting mixture was filtered and the solid was washed with H2O and dried to afford the title compound (400 mg, 16%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.50 (m, 1 H), 7.06 (d, J=7.89 Hz, 1 H), 2.35 (s, 3 H).
Step 2: 3-Bromo-2-fluoro-6-methyl-N-( 1-(1 -methyl- IH-pyr azol-4-yl)-l H-indazol-6- yl)benzamide
Figure imgf000288_0003
To a solution of 3-bromo-2-fluoro-6-methylbenzoic acid (262.28 mg, 1.13 mmol) in DCM (4 mL) were added a 50 wt % solution of T3P in EtOAc (1.55 g, 2.44 mmol) and 1-(1- methylpyrazol-4-yl)indazol-6-amine (200 mg, 937.92 umol) at 20 °C and the mixture was stirred for 12 hrs. The mixture was concentrated to give a residue that was purified by silica gel chromatography using a 0-54% EtOAc/petroleum ether gradient eluent to afford the title compound (390 mg, 97%) as a white solid. 'H NMR (400 MHz, CDCh) 8 8.63 (br d, J=14.92 Hz, 1 H), 8.40 (s, 1 H), 8.11 (s, 1 H), 8.00 (t, J=7.89 Hz, 1 H), 7.92 (s, 1 H), 7.83 (s, 1 H), 7.74 (d, J=8.56 Hz, 1 H), 7.23 (d, J=8.19 Hz, 1 H), 7.12 (dd, J=8.56, 1.47 Hz, 1 H), 4.03 (s, 3 H), 2.52 (s, 3 H). MS-ESI (m/z) calc’d for CisHieBrFNsO [M+H]+: 428.0, 430.0. Found 428.1, 430.1.
Step 3: 3-Cyano-2-fluoro-6-methyl-N-( 1-(1 -methyl- lH-pyrazol-4-yl)-l H-indazol-6- yl)benzamide
Figure imgf000289_0001
A mixture of 3-bromo-2-fluoro-6-methyl-A-(l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl) benzamide (70 mg, 163.45 umol), Zn(CN)2 (38.39 mg, 326.91 umol), Zn (21.38 mg, 326.91 umol), DPPF (9.06 mg, 16.35 umol) and Pd2(dba)s (14.97 mg, 16.35 umol) in DMA (1 mL) was degassed and purged with N2 (3x) at 20 °C, and the mixture was stirred at 120 °C for 4 hrs under N2 atmosphere in microwave. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method DW to afford the title compound (13 mg, 21%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.76 (s, 1 H), 8.16 - 8.29 (m, 3 H), 7.94 (t, J=7.75 Hz, 1 H), 7.77 - 7.87 (m, 2 H), 7.47 (d, J=8.13 Hz, 1 H), 7.40 (dd, J=8.76, 1.38 Hz, 1 H), 3.95 (s, 3 H), 2.58 (s, 3 H). MS-ESI (m/z) calc’d for C20H16FN6O [M+H]+: 375.1. Found 375.1.
Example 149: 3-Cyano-2-methoxy-6-methyI-7V-(l-(l-methyI-LH-pyrazol-4-yI)-LH- indazol-6-yl)benzamide
Figure imgf000289_0002
To a solution of 3-cyano-2-fluoro-6-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl) benzamide (90 mg, 240.40 umol) in MeOH (1 mL) was added a solution of NaOMe (103.90 mg, 1.92 mmol) in MeOH (1 mL) at 20 °C. The mixture was then stirred at 80 °C for 12 hrs and concentrated to give a residue. The residue was purified by HPLC using Method DX and further purified by HPLC using Method CA to afford the title compound (2 mg, 2%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.65 (s, 1 H), 8.28 (s, 1 H), 8.22 (s, 2 H), 7.83 (s, 1 H), 7.79 (dd, J=13.45, 8.32 Hz, 2 H), 7.41 (dd, J=8.76, 1.50 Hz, 1 H), 7.31 (d, J=8.00 Hz, 1 H), 3.95 (s, 6 H), 2.52 (br s, 3 H). MS-ESI (m/z) calc’d for C21H19N6O2 [M+H]+: 387.2. Found 387.1.
Example 150: 3-Cyano-A-(l-(l-methyl-l/7-pyrazol-4-yl)-l/7-indazol-6-yl)-2-
(trifluoromethoxy)benzamide
Figure imgf000290_0001
To a solution of 2-(trifluoromethoxy)benzonitrile (1 g, 5.34 mmol) in THF (6 mL) was added LDA (2 M, 2.94 mL). The mixture was stirred at -65 °C for 2 hrs, then dry ice (CO2 solid, more than 10 eq.) was added to the mixture. The mixture was stirred at 20 °C for 2 hrs and then quenched with cool H2O. The reaction mixture was diluted with 2 M NaOH to pH = 12 and extracted with EtOAc (3x). Then the aqueous layer was acidified with 6 M HC1 to pH = 1. The aqueous layers were extracted with EtOAc (3x). Combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (260 mg, 16%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8.33 (dd, J=1.59, 7.95 Hz, 1H), 7.97 (dd, J=1.65, 7.76 Hz, 1H), 7.62 (t, J=7.89 Hz, 1H). MS-ESI (m/z) calc’d for C9H3F3NO3 [M-H]’: 230.0. Found 230.1.
Step 2: 3-Cyano-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)-2-
(trifluoromethoxy)benzamide
Figure imgf000290_0002
To a solution of 3-cyano-2-(trifluoromethoxy)benzoic acid (100 mg, 432.66 umol) and l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-amine (138.39 mg, 648.99 umol) in DCM (6 mL) was added a 50 wt % solution of T3P in EtOAc (1.07 g, 1.69 mmol) at 20 °C. The mixture was then stirred at 30 °C for 0.5 hr. Then EtsN (109.45 mg, 1.08 mmol) was added to the mixture at 30 °C and stirring was continued for an additional 1 hr. The reaction mixture was concentrated to dryness and the residue was purified by HPLC using Method DY to afford the title compound (36 mg, 18%) as a white solid. 'H NMR (400 MHz, DMSO- e) 8 10.92 (s, 1H), 8.23-8.27 (m, 2H), 8.21 (s, 1H), 8.19 (s, 1H), 8.13 (dd, J=1.41, 7.76 Hz, 1H), 7.79-7.85 (m, 3H), 7.37 (d, J=8.56 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C2OHI4F3N602 [M+H]+: 427.1. Found 427.2.
Example 151: 3-Cyano-2-ethyI-6-fluoro-7V-(l-(l-methyI-lH-pyrazol-4-yI)-lH-indazol-6- yl)benzamide
Figure imgf000291_0001
Step 1: Methyl 3-cyano-2-ethyl-6-fluorobenzoate
Figure imgf000291_0002
A mixture of methyl 3-bromo-2-ethyl-6-fluorobenzoate (200 mg, 766.03 umol), Zn(CN)2 (179.90 mg, 1.53 mmol), Zn (4.51 mg, 68.94 umol), DPPF (12.74 mg, 22.98 umol) and Pd2(dba)s (42.09 mg, 45.96 umol) in DMA (4 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 120 °C for 5 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-4% EtOAc/petroleum ether gradient eluent to afford the title compound (150 mg, 94%) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 7.63 (dd, J=8.63, 5.25 Hz, 1 H), 7.02 (t, J=8.63 Hz, 1 H), 3.90 (s, 3 H), 2.84 (q, J=7.50 Hz, 2 H), 1.20 - 1.25 (m, 3 H). Step 2: 3-Cyano-2-ethyl-6-fluoro-N-( 1-(1 -methyl- IH-pyr azol-4-yl)-l H-indazol-6- yl)benzamide
Figure imgf000292_0001
A mixture of methyl 3-cyano-2-ethyl-6-fluorobenzoate (60 mg, 289.57 umol), 1-(1- methyl-17/-pyrazol-4-yl)-17/-indazol-6-amine (61.75 mg, 289.57 umol) and bis(trimethylaluminum)-l,4-diazabicyclo[2.2.2]octane adduct (222.69 mg, 868.72 umol) in THF (2 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 130 °C for 15 mins under an N2 atmosphere in microwave reactor. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method DZ and further purified by HPLC using Method CA to afford the title compound (5 mg, 4%) as a white solid. JH NMR (400 MHz, DMSO-<A) 6 11.03 (s, 1 H), 8.21 - 8.26 (m, 3 H), 8.05 (dd, J=8.76, 5.50 Hz, 1 H), 7.80 - 7.85 (m, 2 H), 7.49 (t, J=8.63 Hz, 1 H), 7.32 - 7.38 (m, 1 H), 3.95 (s, 3 H), 2.83 (q, J=7.75 Hz, 2 H), 1.23 (t, J=7.50 Hz, 3 H) MS-ESI (m/z) calc’d for C21H18FN6O [M+H]+: 389.1. Found 389.1.
Example 152: 5-((l-(3-MorpholinophenyI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000292_0002
A mixture of 4-(3-bromophenyl)morpholine (1 g, 4.13 mmol), 6-methoxy- l //- indazole (407.97 mg, 2.75 mmol), Cui (209.77 mg, 1.10 mmol), K3PO4 (3.51 g, 16.52 mmol), and (l<S',2<S)-JVi,A2-dimethylcyclohexane-l,2-diamine (391.67 mg, 2.75 mmol) in dioxane (30 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-14% EtOAc/petroleum ether gradient eluent to afford the title compound (150 mg, 17%) as a yellow oil. JH NMR (400 MHz, CDCh) 8 8.08 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.43 (t, J=8. 1 Hz, 1H), 7.25 (br s, 1H), 7.20 (br d, J=7.8 Hz, 1H), 7.12 (s, 1H), 6.91 (ddd, J=16.7, 8.6, 1.9 Hz, 2H), 3.82-3.95 (m, 7H), 3.18-3.37 (m, 4H). MS-ESI (m/z) calc’d for C18H20N3O2 [M+H]+: 310.2. Found 310.3.
Step 2: l-(3-Morpholinophenyl)-lH-indazol-6-ol
Figure imgf000293_0001
To a solution of 4-(3-(6-methoxy-l //-indazol- l-yl)phenyl)morpholine (150 mg, 484.87 umol) in DCM (15 mL) was added BBn (485.88 mg, 1.94 mmol) at -78 °C. After 10 minutes, the reaction mixture was warmed to 20 °C and stirred for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative-TLC (SiO2, EtOAc/petroleum ether = 2/1, Rf = 0.58) to afford the title compound (70 mg, 49%) as a white solid. 'H NMR (400 MHz, CDCh) 8 8.09 (d, J=0.6 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.38 (t, J=8. 1 Hz, 1H), 7.21 (t, J=2. 1 Hz, 1H), 7.11-7.18 (m, 2H), 6.89 (dd, J=8.3, 2.1 Hz, 1H), 6.80 (dd, J=8.6, 2.0 Hz, 1H), 5.54 (br s, 1H), 3.84-3.90 (m, 4H), 3.18-3.26 (m, 4H). MS-ESI (m/z) calc’d for C17H18N3O2 [M+H]+: 296.1. Found 296.3.
Step 3: 5-((l-(3-Morpholinophenyl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2- carbonitrile
Figure imgf000294_0001
To a solution of l -(3-morpholinophen l)-/7/-mdazol-6-ol (60 mg, 203.16 umol) and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (35.19 mg, 203.16 umol) in toluene (4 mL) was added 2-(tributyl-Z5-phosphanylidene)acetonitrile (98.07 mg, 406.32 umol) at 20 °C. The mixture was stirred at 70 °C for 2 hrs under an N2 atmosphere and then concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method CR to afford the title compound (39 mg, 42%) as a yellow gum. MS-ESI (m/z) calc’d for C28H27N4O2 [M+H]+: 451.2. Found 451.3.
Step 4: 5-((l-(3-Morpholinophenyl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 1 and 2
Figure imgf000294_0002
5-((l -(3-Morpholinophenyl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2- carbonitrile was subjected to chiral separation using Method EA to afford 5-((l-(3- morpholmophenyl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (3 mg, 28%) as a white solid. JH NMR (400 MHz, CDCh) 8 8.12 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.38-7.53 (m, 5H), 7.29 (br s, 1H), 7.20 (br d, J=6.7 Hz, 1H), 6.96 (dd, J=8.6, 2.0 Hz, 2H), 5.45 (br s, 1H), 3.91 (br s, 4H), 3.22-3.31 (m, 4H), 2.91-2.98 (m, 1H), 2.79-2.86 (m, 1H), 2.03-2.17 (m, 3H), 1.86 (br s, 1H). MS-ESI (m/z) calc’d for C28H27N4O2 [M+H]+: 451.2. Found 451.1. A later eluting fraction was also isolated to afford 5-((l-(3- morpholinophenyl)- l//-mdazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (4 mg, 44%) as a white solid. 'H NMR (400 MHz, CDCh) 8 8.13 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.43-7.55 (m, 5H), 7.34 (br s, 2H), 7.01 (br d, J=7.2 Hz, 1H), 6.97 (dd, J=8.7, 1.8 Hz, 1H), 5.52 (br s, 1H), 3.97 (br s, 4H), 3.32 (br s, 4H), 2.90-2.98 (m, 1H), 2.79- 2.87 (m, 1H), 2.04-2.18 (m, 3H), 1.88 (br s, 1H). MS-ESI (m/z) calc’d for C28H27N4O2 [M+H]+: 451.2. Found 451.1.
Example 153: 3-Cyano-A-(l-(l-methyl-l/7-pyrazol-4-yl)-l/7-indazol-6-yl)-2-
(trifluoromethyl)benzamide
Figure imgf000295_0001
Step 1 : 3-Bromo-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)-2-
(trifluoromethyl)benzamide
Figure imgf000295_0002
To a solution of 3-bromo-2-(trifluoromethyl)benzoic acid (100 mg, 371.73 umol) and 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (95.12 mg, 446.07 umol) in DMF (4 mL) were added HATU (183.74 mg, 483.24 umol) and DIEA (144.13 mg, 1.12 mmol). The mixture was stirred at 20 °C for 12 hrs and then concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (petroleum ether/EtOAc = 1/1, Rf = 0.42) to afford the title compound (48 mg, 26%) as a yellow solid. MS-ESI (m/z) calc’d for CwHuBrFsNsO [M+H]+: 464.0, 466.0. Found 464.2, 466.0.
Step 2: 3-Cyano-N-( 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)-2-
(trifluoromethyl)benzamide
Figure imgf000295_0003
A mixture of 3-bromo-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- (trifhioromethyl)benzamide (65 mg, 140.01 umol), Zn (18.31 mg, 280.03 umol), Zn(CN)2 (32.88 mg, 280.03 umol), DPPF (7.76 mg, 14.00 umol), and Pd2(dba)3 (12.82 mg, 14.00 umol) in DMA (1 mL) was degassed and purged with N2 (3x), and then the mixture was stirred at 150 °C for 3 hrs under an N2 atmosphere in a microwave reactor. The mixture was filtered and the filtrate was evaporated to give a residue. The residue was purified by HPLC using Method DM to afford the title compound (15.48 mg, 26%) as a white solid. JH NMR (DMSO-tL) 6 10.97 (s, 1 H), 8.31 (d, J=7.24 Hz, 1 H), 8.22 - 8.24 (m, 2 H), 8.19 (s, 1 H), 8.01 - 8.09 (m, 2 H), 7.80 - 7.84 (m, 2 H), 7.32 (dd, J=8.77, 1.53 Hz, 1 H), 3.95 (s, 3 H) MS- ESI (m/z) calc’d for C20H14F3N6O [M+H]+: 411.1. Found 411.0.
Example 154: 5-((l-(l-MethyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)amino)-5, 6,7,8- tetrahydronaphthalene-l-carbonitrile, enantiomer 1 and 2
Figure imgf000296_0001
Step 1: 5-Oxo-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile
Figure imgf000296_0002
A mixture of 5-bromo-3.4-dihydronaphthalen- l(27/)-one (400 mg, 1.78 mmol), Zn(CN)2 (417.38 mg, 3.55 mmol), and Pd(PPh3)4 (61.61 mg, 53.31 umol) in DMF (4 mL) was degassed and purged with N2 (3x) at 25 °C. The mixture was stirred at 120 °C for 12 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-12% EtOAc/petroleum ether gradient eluent to afford the title compound (300 mg, 98%) as a white solid. MS-ESI (m/z) calc’d for C11H10NO [M+H]+: 172.1 Found 172.2.
Step 2: 5-Hydroxy-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile
Figure imgf000297_0001
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-l-carbonitrile (170 mg, 993.02 umol) in MeOH (5 mL) was added NaBT (56.35 mg, 1.49 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hr. and then concentrated to give a residue. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (170 mg, 98%) as a colorless oil. JH NMR (400 MHz, CDCh) 8 7.74 (d, J=7.70 Hz, 1 H), 7.59 (dd, J=7.58, 0.86 Hz, 1 H), 7.34 (t, J=7.70 Hz, 1 H), 4.83 (t, J=4.77 Hz, 1 H), 2.88 - 3.15 (m, 2 H), 2.07 - 2.15 (m, 2 H), 1.85 - 1.97 (m, 2 H). MS-ESI (m/z) calc’d for C11H12NO [M+H]+: 174.1 Found 174.3.
Step 3: N-(5-Cyano-l, 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( 1-(1 -methyl- IH-pyr azol-4-yl)-lH-
Figure imgf000297_0002
A mixture of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile (43.69 mg, 252.26 umol), -( l -( I -methyl- 1 H-pyrazol-4-yl)- l//-indazol-6-yl)-2 -nitrobenzenesulfonamide (67 mg, 168.17 umol), and (tributylphosphoranylidene)acetonitrile (81.18 mg, 336.35 umol) in toluene (4 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue that was purified by silica gel chromatography using a 0-14% EtOAc/petroleum ether gradient eluent to afford the title compound (60.8 mg, 65%) as a brown oil. MS-ESI (m/z) calc’d for C28H24N7O4S [M+H]+: 554.2 Found 554.0.
Step 4: 5-((l-(l -Methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8- tetrahydronaphthalene-1 -carbonitrile
Figure imgf000298_0001
To a solution of -(5-c ano- 1 ,2.3.4-tetrahydronaphthalen- 1 -yl)- -( I -( I -methyl- 17/- pyrazol-4-yl)-177-indazol-6-yl)-2-nitrobenzenesulfonamide (70 mg, 126.45 umol) in DMF (3.5 mL) were added PhSH (70 mg, 635.34 umol) and K2CO3 (87.38 mg, 632.24 umol) at 20 °C. The mixture was stirred at 20 °C for 2 hrs and then diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method DQ to afford the title compound (40 mg, 65%) as a white solid. MS-ESI (m/z) calc’d for C22H2iN6 [M+H]+: 369.2 Found 369.3.
Step 5: 5-((l-(l -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7,8- tetrahydronaphthalene-l-carbonitrile, enantiomer 1 and 2
Figure imgf000298_0002
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-l-carbonitrile separation using Method EE to afford 5-((l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile, enantiomer 1 (3.04 mg, 33%) as ayellow solid. ’H NVIR (400 MHz, DMSO- e) 6 8.16 (s, 1 H), 7.94 (s, 1 H), 7.80 (s, 1 H), 7.71 (d, J=7.46 Hz, 1 H), 7.63 (br d, J=7.82 Hz, 1 H), 7.48 (d, J=8.44 Hz, 1 H), 7.35 (t, J=7.70 Hz, 1 H), 6.67 - 6.73 (m, 2 H), 6.42 (br d, J=8.93 Hz, 1 H), 4.87 (br s, 1 H), 3.91 (s, 3 H), 2.82 - 3.00 (m, 2 H), 1.84 - 1.96 (m, 4 H). MS-ESI (m/z) calc’d for C22H21N6 [M+H]+: 369.2. Found 369.1. A later eluting fraction was also isolated to afford 5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-l-carbonitrile, enantiomer 2 (2.54 mg, 28%) as ayellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.16 (s, 1 H), 7.94 (s, 1 H), 7.80 (s, 1 H), 7.71 (br d, J=7.46 Hz, 1 H), 7.64 (br d, J=7.82 Hz, 1 H), 7.48 (d, J=8.44 Hz, 1 H), 7.36 (t, J=7.70 Hz, 1 H), 6.67 - 6.73 (m, 2 H), 6.43 (br d, J=8.93 Hz, 1 H), 4.87 (br s, 1 H), 3.87 - 3.94 (m, 3 H), 2.85 - 2.99 22H21N6 [M+H]+: 369.2. Found 369.1. Example 155: 4-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide To a solution of 4-cya 7 umol) in DCM (3 mL) were
Figure imgf000299_0001
added 1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-amine (144.93 mg, 679.67 umol) and a 50 wt % solution of T3P in EtOAc (1.12 g, 1.77 mmol) at 20 °C and the mixture was stirred at 35 °C for 0.5 hr. Then Et3N (227.65 mg, 2.25 mmol) was added and the mixture was stirred at 35 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method EF to afford the title compound (51.75 mg, 22%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.31 (s, 1H), 8.19-8.26 (m, 2H), 8.11-8.17 (m, 2H), 8.02-8.08 (m, 2H), 7.79-7.87 (m, 2H), 7.57 (dd, J=1.65, 8.74 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H15N6O [M+H]+: 343.1. Found 343.0. Example 156: 4-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-(prop-1-en- 2-yl)benzamide
Figure imgf000299_0002
00 mg, 1.53 mmol), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (257.73 mg, 1.53 mmol) in dioxane (20 mL) and H2O (5 mL) were added Cs2CO3 (1.50 g, 4.60 mmol) and Pd(dppf)Cl2 (56.11 mg, 76.69 umol) at 20 °C. The mixture was stirred at 100 °C for 5 hrs under an N2 atmosphere. The residue was purified by silica gel chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (77 mg, 25%) as a colorless oil. MS-ESI (m/z) calc’d for C12H12NO2 [M+H]+: 202.1. Found 202.3.
Step 2: 4-Cyano-2-(prop-l-en-2-yl)benzoic acid
Figure imgf000300_0001
To a solution of methyl 4-cyano-2-(prop-l-en-2-yl)benzoate (50 mg, 248.48 umol) in THF (4 mL) and H2O (2 mL) was added LiOFEFEO (83.42 mg, 1.99 mmol) at 20 °C. The mixture was stirred at 20 °C for 3 hrs. The reaction was combined with another 10 mg scale reaction before work up. The final mixture was adjusted to pH = 3 with 1 M HC1 and extracted with EtOAc (4x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford the title compound (48 mg, 86%) as a gray solid. MS-ESI (m/z) calc’d for C11H10NO2 [M+H]+: 188.1. Found 188.2.
Step 3: 4-Cyano-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)-2-(pr op- l-en-2- yl)benzamide
Figure imgf000300_0002
To a solution of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (56.96 mg, 267.10 umol) in DCM (3 mL) was added 4-cyano-2-(prop-l-en-2-yl)benzoic acid (50 mg, 267.10 umol) and a 50 wt % solution of T3P in EtOAc (424.93 mg, 667.76 umol) at 20 °C. The mixture was then stirred at 30 °C for 0.5 hr. EtsN (81.08 mg, 801.31 umol) was then added and the mixture was stirred at 30 °C for an additional 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method A to afford the title compound (11 mg, 10%) as a white solid. 'H NMR (400 MHz, DMSO-O 8 10.70 (s, 1H), 8.17-8.24 (m, 3H), 7.86-7.94 (m, 2H), 7.75-7.82 (m, 2H), 7.70 (d, J=7.89 Hz, 1H), 7.33 (dd, J=1.53, 8.77 Hz, 1H), 5.17 (s, 1H), 5.06 (s, 1H), 3.95 (s, 3H), 2.08 (s, 3H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.2. Found 383.1. Example 157 : 5-((l-(l-(Pyrimidin-2-yl)-Lff-pyrazol-4-yl)-Lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000301_0001
Prepared as described for 5-((l-(benzo[r/]oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-(4-bromo- l7/-pyrazol-l - yl)pyrimidine in place of 2-bromobenzo|t/| oxazole. The material was purified by prep-HPLC using Method CN to afford the title compound (1 mg, 4%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 9.11 (s, 1 H), 8.94 (br d, J=4.40 Hz, 2 H), 8.48 (s, 1 H), 8.29 (s, 1 H), 7.80 (d, J=8.80 Hz, 1 H), 7.70 (s, 1 H), 7.63 - 7.68 (m, 1 H), 7.53 - 7.59 (m, 2 H), 7.47 (s, 1 H), 7.02 (dd, J=8.93, 1.71 Hz, 1 H), 5.88 (t, J=4.46 Hz, 1 H), 2.75 - 2.97 (m, 2 H), 2.03 - 2.11 (m, 2 H), 1.77 - 1.95 (m, 2 H). MS-ESI (m/z) calc’d for C25H20N7O [M+H]+: 434.2. Found 434.1
Example 158: 8,8-Difluoro-5-((l-(l-methyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)amino)-
5,6,7,8-tetrahydronaphthalene-2-carbonitriIe, enantiomer 1 and 2
Figure imgf000301_0002
To a solution of 6-bromo-l,2,3,4-tetrahydronaphthalen-l-amine (1.4 g, 6.19 mmol) in CH2CI2 (15 mL) were added EtsN (2.04 g, 20.12 mmol, 2.80 mL) and TFAA (2.96 g, 14.12 mmol, 1.96 mL) at 0°C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was diluted with 1 M HC1 to adjust pH = 4. The aqueous layers were extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (1.3 g, 65%) as a white solid. MS-ESI (m/z) calc’d for CnHioBrFsNO [M-H]’: 320.0, 322.0. Found 319.9, 321.9.
Figure imgf000302_0001
To a solution of -(6-bromo- 1 ,2.3.4-tetrahydronaphthalen- 1 -yl)-2.2.2- trifluoroacetamide (1.3 g, 4.04 mmol) in acetone (20 mL) and H2O (20 mL) were added MgSCE (1.31 g, 10.90 mmol) and KMnCE (2.55 g, 16.14 mmol) slowly at 25 °C. The mixture was stirred at 25 °C for 12 hrs. Then EtOH (40 mL) was added and the mixture was stirred at 25 °C for an additional 1 hr. The reaction was filtered and the filtrate was added to a saturated aqueous solution of Na2SOs and stirred at 20 °C for 1 hr, then concentrated under vacuum. The residue was triturated with H2O and filtered; the solid was washed with H2O (2x) and dried under vacuum to afford the title compound (1 g, 73%) as a pink solid. JH NMR (400 MHz, CDCh) 8 8.11 (d, J=2.13 Hz, 1 H), 7.66 (dd, J=8.32, 2.19 Hz, 1 H), 7.17 (d, J=8.25 Hz, 1 H), 6.53 (br d, J=6.88 Hz, 1 H), 6.47 - 6.58 (m, 1 H), 5.31 (td, J=8.72, 4.44 Hz, 1 H), 2.64 - 2.82 (m, 3 H), 2.41 (ddt, J=13.35, 6.97, 4.60, 4.60 Hz, 1 H).
Step 3: N-(7'-Bromo-3 4 '-dihydro-2 'H-spiro[[l, 3 ] dithiolane-2, 1 '-naphthalen ]-4'-yl)-2, 2, 2- trifluoroacetamide
Figure imgf000302_0002
A mixture of A-(6-bromo-4-oxo-l,2,3,4-tetrahydronaphthalen-l-yl)-2,2,2- trifluoroacetamide (1 g, 2.98 mmol), ethane- 1,2-dithiol (420.40 mg, 4.46 mmol), and BF3*Et2O (633.42 mg, 4.46 mmol, 550.80 uL) in CH2CI2 (10 mL) was degassed and purged with N2 (3x) at 25 °C. The mixture was then stirred at 25 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue that was purified by silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to afford the title compound (850 mg, 69%) as a white solid. 'H NMR (400 MHz, CDCh) 8 8.03 (d, J=2.13 Hz, 1 H), 7.28 (dd, J=8.32, 2.06 Hz, 1 H), 6.93 (d, J=8.38 Hz, 1 H), 6.41 (br d, J=8.00 Hz, 1 H), 5.03 - 5.11 (m, 1 H), 3.52 - 3.60 (m, 2 H), 3.36 - 3.45 (m, 2 H), 2.31 - 2.37 (m, 2 H), 2.21 - 2.30 (m, 1 H), 1.95 - 2.06 (m, 1 H). MS-ESI (m/z) calc’d for Ci4Hi2BrF3NOS2 [M-H]': 410.0, 412.0. Found 409.8, 411.9.
Figure imgf000303_0001
A solution of NIS (927.68 mg, 4.12 mmol) in CH2CI2 (6 mL) was cooled to -70 °C in a dry ice-acetone bath. Pyridine hydrofluoride (1.17 g, 8.25 mmol) was then added dropwise maintaining -70 °C. A solution of A-(7'-bromo-3',4'-dihydro-27/-spiro [[l,3]dithiolane-2,l'- naphthalen]-4'-yl)-2, 2, 2-trifluoroacetamide (850 mg, 2.06 mmol) in CH2CI2 (6 mL) was next added dropwise and the mixture was stirred at -70 °C for 0.5 hr. The mixture was concentrated to give a residue that was purified by silica gel chromatography using a 0-3% EtOAc/petroleum ether gradient eluent to afford the title compound (300 mg, 40%) as a red solid. 'H NMR (400 MHz, CDCh) 8 7.81 (s, 1 H), 7.55 (d, J=8.38 Hz, 1 H), 7.10 (d, J=8.63 Hz, 1 H), 6.32 (br s, 1 H), 5.18 (br d, J=5.00 Hz, 1 H), 2.17 - 2.44 (m, 3 H), 1.98 - 2.07 (m, 1 H). MS-ESI (m/z) calc’d for CnHsBrFsNO [M-H]': 356.0, 358.0. Found 355.8, 357.9.
Figure imgf000303_0002
To a solution of /V-(6-bromo-4, 4-difluoro-l, 2,3, 4-tetrahydronaphthalen-l-yl)-2, 2,2- trifluoroacetamide (270 mg, 753.98 umol) in EtOH (4.5 mL) was added a solution of NaOH (8 M, 630.00 uL) at 20 °C. The mixture was stirred at 20 °C for 12 hrs and then concentrated to give a residue. The residue was purified by preparative-TLC (SiCh, DCM/MeOH = 10/1, Rf = 0.25) to afford the title compound (120 mg, 60%) as a white solid. 'H NMR (400 MHz, CDCh) 8 7.81 (s, 1 H), 7.57 (br d, J=7.58 Hz, 1 H), 7.44 (d, J=8.44 Hz, 1 H), 3.94 - 4.02 (m, 1 H), 2.45 - 2.60 (m, 1 H), 2.17 - 2.31 (m, 2 H), 1.79 - 1.92 (m, 1 H). MS-ESI (m/z) calc’d for CioHnBrF2N [M+H]+: 262.0, 264.0 Found 262.1, 264.1.
Step 6: 5-Amino-8,8-difluoro-5, 6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000304_0001
A mixture of 6-bromo-4,4-difluoro-l,2,3,4-tetrahydronaphthalen-l-amine (120 mg, 457.85 umol), Zn(CN)2 (161.29 mg, 1.37 mmol), Zn (89.82 mg, 1.37 mmol), DPPF (25.38 mg, 45.79 umol), and Pd2(dba)s (41.93 mg, 45.79 umol) in DMA (5 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 110 °C for 2 hrs under an N2 atmosphere in a microwave reactor. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative-TLC (SiO2, DCM/MeOH = 10/1, Rf = 0.55) to afford the title compound (45 mg, 47%) as a red oil. 'H NMR (400 MHz, CDCh) 8 8.00 (s, 1 H), 7.72 - 7.81 (m, 2 H), 4.08 (br s, 1 H), 2.55 - 2.65 (m, 1 H), 2.26 - 2.33 (m, 2 H), 1.93 (br d, J=8.80 Hz, 1 H).
Step 7: 8, 8-Difluoro-5-( (1-(1 -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000304_0002
A mixture of 5-amino-8,8-difluoro-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (15 mg, 72.04 umol), 6-bromo-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazole (19.96 mg, 72.04 umol), tBuXPhos Pd G3 (5.72 mg, 7.20 umol), and tBuONa (13.85 mg, 144.09 umol) in THF (1.5 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 50 °C for 1 hr under an N2 atmosphere. The reaction was combined together with another 20 mg scale reaction before work up. The final mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method BH to afford the title compound (9 mg, 13 %) as a white solid. MS-ESI (m/z) calc’d for C22H19F2N6 [M+H]+: 405.2 Found 405.0.
Step 8: 8, 8-Difluoro-5-( (1-(1 -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000305_0001
8,8-Difluoro-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method BL to afford 8,8-difluoro-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (4 mg, 41%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.09 - 8.14 (m, 2 H), 7.88 - 7.94 (m, 2 H), 7.78 (d, J=0.63 Hz, 1 H), 7.61 (d, J=8.13 Hz, 1 H), 7.49 (d, J=8.63 Hz, 1 H), 6.65 - 6.71 (m, 2 H), 6.61 (d, J=9.38 Hz, 1 H), 5.07 (br d, J=3.88 Hz, 1 H), 3.86 (s, 3 H), 2.49 (d, J=1.88 Hz, 1 H), 2.34 - 2.44 (m, 1 H), 2.16 (br s, 1 H), 1.92 - 2.03 (m, 1 H). MS-ESI (m/z) calc’d for C22H19F2N6 [M+H]+: 405.2 Found 405.1. A later eluting fraction was also isolated to afford 8,8-difluoro-5-((l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (4 mg, 43%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.08 - 8.13 (m, 2 H), 7.88 - 7.94 (m, 2 H), 7.77 (s, 1 H), 7.61 (d, J=8.25 Hz, 1 H), 7.48 (d, J=8.63 Hz, 1 H), 6.64 - 6.69 (m, 2 H), 6.60 (d, J=9.26 Hz, 1 H), 5.01 - 5.14 (m, 1 H), 3.86 (s, 3 H), 2.48 (br s, 1 H), 2.33 - 2.44 (m, 1 H), 2.15 (br s, 1 H), 1.97 (q, J=9.80 Hz, 1 H). MS-ESI (m/z) calc’d for C22H19F2N6 [M+H]+: 405.2 Found 405.1.
Example 159 : 2-Methyl-8-((l-(l-methyl- 17/-py razol-4-y 1)- LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000306_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 1 -(1 -methyl- 17/-pyrazol- 4-yl)-17/-indazol-6-ol in place of 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol to afford a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent (130 mg). The material was further purified by prep- HPLC using Method AS to afford the title compound (36 mg).
Step 2: 2-Methyl-8-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000306_0002
2-Methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral prep-HPLC using Method AT to afford 2-methyl-8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (10 mg, 8%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 8.32 (1 H, s) 8.15 (2 H, d, J=10.78 Hz) 7.92 (1 H, s) 7.73 (1 H, d, J=8.80 Hz) 7.41 (1 H, s) 6.95 (1 H, d, J=8.80 Hz) 5.67 (1 H, br. s.) 3.94 (3 H, s) 2.86 - 3.01 (1 H, m) 2.71 - 2.83 (1 H, m) 2.61 (3 H, s) 2.19 - 2.32 (1 H, m) 1.87 - 2.05 (2 H, m) 1.73 - 1.84 (1 H, m). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2. A later eluting fraction was also isolated to afford 2-methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol- 6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (12 mg, 10%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.31 (1 H, s) 8.14 (2 H, d, J=12.10 Hz) 7.91 (1 H, s) 7.72 (1 H, d, J=8.80 Hz) 7.40 (1 H, s) 6.94 (1 H, dd, J=8.80, 1.98 Hz) 5.59 - 5.73 (1 H, m) 3.93 (3 H, s) 2.86 - 2.99 (1 H, m) 2.70 - 2.82 (1 H, m) 2.60 (3 H, s) 2.19 - 2.32 (1 H, m) 1.85 - 2.05 (2 H, m) 1.72 - 1.83 (1 H, m) MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2.
Example 160: 4-MethyI-8-((l-(l-methyI-lH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitriIe, enantiomer 1 and 2
Figure imgf000307_0001
Step 1: 4-Methyl-8-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile
Figure imgf000307_0002
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetiahydroquinoline-3-carbonitrile using l-(l-methylpyrazol-4- yl)indazol-6-ol in place of 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol. The residue obtained was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent followed by a second purification by prep-HPLC using Method AS to afford the title compound (50.9 mg).
Step 2: 4-Methyl-8-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000307_0003
4-Methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile was subjected to chiral prep-HPLC using Method AU to afford 4-methyl-8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (22.5 mg, 18%) as a white solid. 'H NVIR (400 MHz, DMSO-d6) δ 8.78 (1 H, s) 8.30 (1 H, s) 8.15 (1 H, s) 7.90 (1 H, s) 7.72 (1 H, d, J=8.80 Hz) 7.35 (1 H, s) 6.94 (1 H, dd, J=8.69, 2.09 Hz) 5.72 (1 H, t, J=2.86 Hz) 3.93 (3 H, s) 2.80 - 2.97 (1 H, m) 2.63 - 2.76 (1 H, m) 2.46 (3 H, s) 2.17 - 2.29 (1 H, m) 1.82 - 2.02 (3 H, m). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2. A later eluting fraction was also isolated to afford 4-methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol- 6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (22.7 mg, 18%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.79 (1 H, s) 8.31 (1 H, s) 8.16 (1 H, d, J=0.88 Hz) 7.91 (1 H, d, J=0.66 Hz) 7.72 (1 H, d, J=8.80 Hz) 7.35 (1 H, s) 6.95 (1 H, dd, J=8.69, 2.09 Hz) 5.73 (1 H, t, J=2.97 Hz) 3.94 (3 H, s) 2.85 - 3.02 (1 H, m) 2.60 - 2.79 (1 H, m) 2.47 (3 H, s) 2.20 - 2.30 (1 H, m) 1.81 - 2.07 (3 H, m). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2.
Example 161: l-Methoxy-5-((l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000308_0001
To a solution of 5-hydroxy-l-tetralone (2.0 g, 12.33 mmol) in dry DCM (100 mL) under a nitrogen atmosphere was added A-ethylethanamine (0.15 mL, 1.48 mmol). Then a solution of 1 -bromopyrrolidine-2,5 -di one (2.19 g, 12.33 mmol) in DCM (100 mL) was slowly added over 2 hrs at r.t. After that time, the reaction was stirred at r.t. for 1 hr. The solvent was evaporated under reduced pressure and the mateiral was purified by flash silica gel chromatography using a 0-25% EtOAc/cyclohexane gradient eluent to afford the title compound (2.21 g, 74%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 9.51 (br. s., 1 H) 7.51 (d, J=8.36 Hz, 1 H) 7.33 (d, J=8.58 Hz, 1 H) 2.88 (t, J=6.05 Hz, 2 H) 2.53 - 2.61 (m, 2 H) 2.03 (quin, J=6.38 Hz, 2 H). MS-ESI (m/z) calc’d for CioHioBrCh [M+H]+: 241.0, 243.0. Found 241.0, 243.0.
Figure imgf000309_0001
To a solution of 6-bromo-5-hydroxy-3,4-dihydronaphthalen-l(2H)-one (300.0 mg, 1.24 mmol) in anhydrous DMF (2.1 mL) were added cesium carbonate (608.18 mg, 1.87 mmol) and iodomethane (0.08 mL, 1.24 mmol). The mixture was stirred for 2 hrs at 25 °C. Saturated aqueous NH4CI (30 mL) was added to quench the reaction, followed by addition of H2O (100 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic phases were washed with brine (1 x 100 mL), dried over anhydrous Na2SC>4 and evaporated under reduced pressure. The material was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (297 mg, 94%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.64 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 2.98 (t, J = 6.1 Hz, 2H), 2.64 - 2.56 (m, 2H), 2.13 - 1.97 (m, 2H). MS-ESI (m/z) calc’d for CnHnBrCh [M+H]+: 255.0, 257.0. Found 255.0, 257.0.
Step 3: l-Methoxy-5-oxo-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000309_0002
Potassium hexacyanoferrate (II), 0.1 N standardized solution (5.72 mL, 0.57 mmol), 6-bromo-5-methoxy-3.4-dihydronaphthalen-l (27/)-one (295.0 mg, 1.14 mmol) and potassium acetate (112.35 mg, 1.14 mmol) were dissolved in a mixture of 1,4-dioxane (14.01 mL)/H20 (2.1 mL). The mixture was degassed with N2 for 15 minutes. Then XPhos (81.86 mg, 0.170 mmol) and XPhos Pd G3 (145.35 mg, 0.170 mmol) were added and the mixture was stirred at 100 °C for 3 hrs. XPhos (81.86 mg, 0.170 mmol), potassium acetate (112.35 mg, 1.14 mmol) and XPhos Pd G3 (145.35 mg, 0.170 mmol) were again added and the mixture was stirred at 100 °C for an additional 2 hrs. The reaction mixture was partitioned between H2O (200 mL) and EtOAc (200 mL), the phases were separated. The aqueous layer was extracted with EtOAc (3x 200 mL) and the combined organic phases washed with brine (200 mL), dried over anhydrous Na2SC>4, filtered and evaporated to dryness. The material was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (55 mg, 24%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 7.81 - 7.68 (m, 2H), 3.97 (s, 3H), 2.94 (t, J = 6.1 Hz, 2H), 2.65 (dd, J = 7.3, 5.8 Hz, 2H), 2.06 (p, J = 6.3 Hz, 2H). MS-ESI (m/z) calc’d for C12H12NO2 [M+H]+: 202.1. Found 202.0.
Step 4: 5-Hydroxy-l-methoxy-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000310_0001
To a solution of l-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (55.0 mg, 0.25 mmol) in methanol (1.2 mL), sodium borohydride (9.51 mg, 0.25 mmol) was added at 25 °C and the resulting mixture was stirred for 1 hr. The reaction was concentrated under reduced pressure and saturated aqueous NaHCCh (50 mL) was added. The mixture was extracted with DCM (50 mL) and the organic phase was filtered through a phase separator and concentrated under reduced pressure to afford the title compound (50 mg, 98%) as a yellow oil. 'H NMR (400 MHz, DMSO- e) 6 7.57 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0, 1H), 5.41 (d, J = 6.0 Hz, 1H), 4.57 (q, J = 5.9 Hz, 1H), 3.89 (s, 3H), 2.75 - 2.57 (m, 2H), 1.99 - 1.78 (m, 2H), 1.75 - 1.56 (m, 2H). MS-ESI (m/z) calc’d for C12H14NO2 [M+H]+: 204.2. Found 204.0.
Step 5: l-Methoxy-5-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-
Figure imgf000310_0002
Prepared as described for 4-methyl-8-[5-methyl-l-(l-methylpyrazol-4-yl)indazol-6- yl]oxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile using l-(l-methylpyrazol-4-yl)indazol-6-ol in place of 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol and 5-hydroxy-l -methoxy - 5,6,7,8-tetrahydronaphthalene-2-carbonitrile in place of 8-hydroxy-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford l-methoxy-5- [l-(l-methylpyrazol-4-yl)indazol-6-yl]oxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40.6 mg). The material was subjected to chiral preparative HPLC using Method EK to afford 1 -methoxy-5-[l -(l-methylpyrazol-4-yl)indazol-6-yl]oxy-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (14.2 mg, 16%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.30 (s, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.91 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.28 - 7.26 (m, 1H), 6.96 (dd, J = 8.8, 2.0 Hz, 1H), 5.77 (t, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.86 (dt, J = 17.6, 5.6 Hz, 1H), 2.75 - 2.61 (m, 1H), 2.06 - 1.96 (m, 2H), 1.95 - 1.75 (m, 2H). MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2. Found 400.2. A later eluting fraction was also isolated to afford l-methoxy-5-[l-(l-methylpyrazol-4-yl)indazol-6-yl]oxy-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (15.1, 17%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.30 (s, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.28 - 7.26 (m, 1H), 6.96 (dd, J = 8.8, 2.0 Hz, 1H), 5.77 (t, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.86 (dt, J = 17.6, 5.6 Hz, 1H), 2.75 - 2.61 (m, 1H), 2.06 - 1.95 (m, 2H), 1.94 - 1.74 (m, 2H). MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2. Found 400.2.
Example 162 : 5-((5-Methoxy- l-(l-methyl- lff-pyrazol-4-yl)- lff-indazol-6-yl)oxy)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000311_0001
A mixture of 5-methoxy-17/-indazol-6-ol (300.0 mg, 1.83 mmol), 4-iodo-l- methylpyrazole (456.14 mg, 2.19 mmol), (l^^^j-ZV^/V^-dimethylcyclohexane-l^-diamine (129.97 mg, 0.910 mmol), copper(I) iodide (69.61 mg, 0.370 mmol) and tripotassium phosphate (1162.28 mg, 5.48 mmol) in dry 1,4-dioxane (6.5 mL) was stirred at 25 °C overnight. The mixture was warmed to 90 °C and stirred for 6 hrs. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic phases washed with brine (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (160 mg, 36%) as a beige solid. JH NMR (400 MHz, DMSO-d6) δ 9.44 (1 H, br. s.) 8.19 (1 H, s) 7.98 (1 H, d, J=0.88 Hz) 7.78 (1 H, s) 7.20 (1 H, s) 6.99 (1 H, d, J=0.66 Hz) 3.91 (3 H, s) 3.83 (3 H, s). MS-ESI (m/z) calc’d for C12H13N4O2 [M+H]+: 245.1. Found 245.1.
Step 2: 5-((5-Methoxy-l -(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-
Figure imgf000312_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 5-methoxy-l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of 5 -methyl- l-(l-methylpyrazol-4-yl)indazol-6-ol and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in place of 8-hydroxy-4-methyl- 5,6,7,8-tetrahydroquinoline-3-carbonitrile. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford 5-((5- methoxy-1 -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile (370 mg). The material which was subjected to chiral preparative HPLC using Method EL to afford 5-((5-methoxy- l-( l-methyl- l//-pyrazol-4-yl)- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (17.8 mg, 14%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.29 (1 H, s) 8.08 (1 H, s) 7.91 (1 H, s) 7.70 (1 H, s) 7.63 - 7.68 (1 H, m) 7.56 - 7.62 (1 H, m) 7.35 (1 H, s) 7.32 (1 H, s) 5.71 (1 H, t, J=4.40 Hz) 3.93 (3 H, s) 3.80 (3 H, s) 2.85 - 2.97 (1 H, m) 2.74 - 2.84 (1 H, m) 1.87 - 2.12 (3 H, m) 1.73 - 1.84 (1 H, m). MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2.
Found 400.2. A later eluting fraction was also isolated to afford 5-((5-methoxy-l-(l-methyl- IT/-pyrazol-4-yl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (19.5 mg, 15%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.29 (1 H, s) 8.08 (1 H, s) 7.91 (1 H, s) 7.70 (1 H, s) 7.63 - 7.68 (1 H, m) 7.57 - 7.62 (1 H, m) 7.35 (1 H, s) 7.32 (1 H, s) 5.71 (1 H, t, J=4.62 Hz) 3.93 (3 H, s) 3.80 (3 H, s) 2.86 - 3.00 (1 H, m) 2.73 - 2.85 (1 H, m) 1.87 - 2.11 (3 H, m) 1.71 - 1.85 (1 H, m). MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2. Found 400.2.
Example 163: 5-((5-ChIoro-l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000313_0001
In a sealed vial, a mixture of 6-bromo-5-chloro-17/-indazole (1.0 g, 4.32 mmol), 4- iodo-l-methylpyrazole (1.35 g, 6.48 mmol), (17?,27?)-JVl,JV2-dimethylcyclohexane-l,2- diamine (307.24 mg, 2.16 mmol), copper(I) iodide (164.55 mg, 0.86 mmol) and tripotassium phosphate (2.75 g, 12.96 mmol) in dry 1,4-dioxane (15 mL) was stirred at 90 °C under a nitrogen atmosphere for 4 hrs. The mixture was cooled to r.t. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic phases washed with H2O (lx), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford title compound (740 mg, 55%) as a brown solid. JH NMR (400 MHz, DMSO-d6) δ 8.40 (1 H, s) 8.31 (1 H, s) 8.19 (1 H, s) 8.15 (1 H, s) 7.92 (1 H, s) 3.94 (3 H, s). MS-ESI (m/z) calc’d for CnH9BrClN4 [M+H]+: 311.0, 313.0. Found 311.0, 313.0. Step 2: 5-Chloro-l-( 1 -methyl- lH-pyrazol-4-yl)-6-( 4, 4, 5, 5 -tetramethyl- 1 , 3, 2-dioxaborolan-2- yl)-lH-indazole
Figure imgf000314_0001
To a solution of 6-bromo-5-chloro-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazole (740.0 mg, 2.38 mmol) in 1,4-dioxane (15 mL) was added potassium acetate (699.27 mg, 7.13 mmol) and bis(pinacolato)diborane (1.21 g, 4.75 mmol). The mixture was degassed with N2 then PdC12(dppf »CH2C12 (194.43 mg, 0.240 mmol) was added and the reaction was stirred at 100 °C for 16 hrs. The reaction mixture was partitioned between water and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic phases washed with water (lx) dried over anhydrous NA2SO4 and evaporated to dryness to afford the title compound (1.2 g) which was used without further purification. MS-ESI (m/z) calc’d for C17H21BCIN4O2 [M+H]+: 359.1, 360.1. Found 359.0, 361.0.
Figure imgf000314_0002
To a solution of 5-chloro-l-(l-methyl-17/-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-17/-indazole (0.85 g, 2.38 mmol) in MeOH (15 mL) was added hydrogen peroxide (1.21 mL, 11.88 mmol) and the mixture was stirred at 25 °C for 1.5 hrs. The solvent was evaporated, the residue was taken up in H2O and extracted with EtOAc. The phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic phases washed with H2O (lx), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent and then with a gradient of MeOH in EtOAc from 0 to 5% to afford the title compound (190 mg, 32%) as a brown solid. 'H NMR (400 MHz, DMSO-d6) δ 10.53 (1 H, br. s.) 8.19 (1 H, s) 8.07 (1 H, s) 7.85 (1 H, s) 7.78 (1 H, s) 7.07 (1 H, s) 3.93 (3 H, s). MS-ESI (m/z) calc’d for C11H10CIN4O [M+H]+: 249.0. Found 249.0.
Step 4: 5-((5-Chloro-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000315_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 5-chloro-l-(l-methyl-17/- pyrazol-4-yl)-17/-indazol-6-ol in place of 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in place of 8-hydroxy-4-methyl- 5,6,7,8-tetrahydroquinoline-3-carbonitrile, to afford a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent. The material was submitted to preparative HPLC using Method EM, to afford 5-((5-chloro-l-(l-methyl- l//-pyrazol-4-yl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile (20 mg). The material was submitted to chiral preparative HPLC using Method EN, to afford 5- ((5-chloro-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (9.1 mg, 6%) as a white solid. XH NMR (400 MHz, DMSO-d6) δ 8.33 (1 H, s) 8.17 (1 H, s) 7.94 - 7.98 (2 H, m) 7.71 (1 H, s) 7.64 - 7.68 (1 H, m) 7.54 - 7.59 (1 H, m) 7.52 (1 H, s) 5.91 (1 H, t, J=4.73 Hz) 3.94 (3 H, s) 2.89 - 3.00 (1 H, m) 2.75 - 2.86 (1 H, m) 2.01 - 2.10 (2 H, m) 1.88 - 1.99 (1 H, m) 1.75 - 1.87 (1 H, m). MS-ESI (m/z) calc’d for C22H19CIN5O2 [M+H]+: 404.1. Found 404.1. A later eluting fraction was also isolated to afford 5-((5-chloro-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (9.3 mg, 6%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.33 (1 H, s) 8.18 (1 H, s) 7.94 - 7.98 (2 H, m) 7.71 (1 H, s) 7.66 (1 H, d, J=8.58 Hz) 7.57 (1 H, d, J=7.92 Hz) 7.53 (1 H, s) 5.92 (1 H, t, J=5.28 Hz) 3.95 (3 H, s) 2.89 - 3.02 (1 H, m) 2.76 - 2.87 (1 H, m) 2.01 - 2.12 (2 H, m) 1.90 - 2.00 (1 H, m) 1.78 - 1.87 (1 H, m). MS-ESI (m/z) calc’d for C22H19CIN5O2 [M+H]+: 404.1. Found 404.1.
Example 164: 5-((5-MethyI-l-(l-methyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000316_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 5-hy droxy-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile in place of 8-hydroxy-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, to afford a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent. The material was purified by preparative HPLC using Method EO, to afford 5-((5-methyl-l-(l-methyl-17/- pyrazol-4-yl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile (69 mg). This material was submitted to chiral preparative HPLC using Method EP to afford 5-((5- meth l- l-( l-methyl-IT/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene- 2-carbonitrile, enantiomer 1 (19.9 mg, 13%) as a white solid. 'H NMR (400 MHz, DMSO- de) 8 8.29 (1 H, s) 8.07 (1 H, s) 7.93 (1 H, s) 7.70 (1 H, s) 7.61 - 7.65 (1 H, m) 7.58 (1 H, s) 7.52 (1 H, d, J=8.14 Hz) 7.32 (1 H, s) 5.85 (1 H, t, J=5.06 Hz) 3.93 (3 H, s) 2.88 - 2.99 (1 H, m) 2.75 - 2.86 (1 H, m) 2.15 (3 H, s) 1.96 - 2.12 (2 H, m) 1.79 - 1.95 (2 H, m). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.2. A later eluting fraction was also isolated to afford 5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (20.3 mg, 13%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.29 (1 H, s) 8.07 (1 H, s) 7.93 (1 H, s) 7.70 (1 H, s) 7.64 (1 H, dd, J=7.70, 1.32 Hz) 7.58 (1 H, s) 7.52 (1 H, d, J=8.14 Hz) 7.32 (1 H, s) 5.85 (1 H, t, J=4.73 Hz) 3.93 (3 H, s) 2.88 - 2.98 (1 H, m) 2.75 - 2.86 (1 H, m) 2.15 (3 H, s) 1.97 - 2.13 (2 H, m) 1.78 - 1.96 (2 H, m). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.2.
Example 165: cis-6-Methyl-5-((l-(l-methyl-LH-pyrazol-4-yl)-LH-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile (Example 165A) enantiomer 1 and 2 and trans-6-Methyl-5-((l-(l-methyl-Lff-pyrazol-4-yl)-lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile (Example 165B), enantiomer 1 and 2
Figure imgf000317_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 1-(1- methyl-17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/- pyrazol-4-yl)-5 -methyl- 17/-indazol-6-ol to afford 6-methyl-5-((l-(l-methyl-17/-pyrazol-4- yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (71 mg). The diastereomers were separated by chiral preparative HPLC using Method ES to afford four fractions. The first eluting fraction, /ra/7.s-6-methyl-5-(( l-(l -methyl- l//-pyrazol-4-yl)-l//- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (165B), enantiomer 1, was obtained (22.4 mg, 12%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.31 (s, 1H),
8.16 (s, 1H), 7.91 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 6.99 (dd, J = 8.8, 2.0 Hz, 1H), 5.81 (d, J = 4.0 Hz, 1H), 3.93 (s, 3H), 3.04 - 2.89 (m, 1H), 2.89 - 2.76 (m, 1H), 2.35 - 2.24 (m, 1H), 1.96 - 1.77 (m, 2H), 1.00 (d, J = 6.8 Hz, 3H). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.2. The second eluting fraction, tra«s-6-methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (165B), enantiomer 2, was obtained (6,7 mg, 4%) as a white solid. 1 H NMR (400 MHz, DMSO- e) 6 8.27 (s, 1H),
8.17 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.60 (dd, J = 8.0, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 6.99 (dd, J = 8.8, 2.1 Hz, 1H), 5.50 (d, J = 7.1 Hz, 1H), 3.92 (s, 3H), 2.97 - 2.78 (m, 2H), 2.27 - 2.12 (m, 1H), 2.05 - 1.91 (m, 1H), 1.77 - 1.61 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.2. The third eluting fraction, c/s-6-methyl-5-((l-(l-methyl-17/-pyrazol-4- yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile (165A), enantiomer 1, was obtained (22.5 mg, 12%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.27 (s, 1H),
8.17 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.60 (dd, J = 8.0, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 6.99 (dd, J = 8.8, 2.1 Hz, 1H), 5.50 (d, J = 7.1 Hz, 1H), 3.92 (s, 3H), 2.97 - 2.78 (m, 2H), 2.27 - 2.12 (m, 1H), 2.05 - 1.91 (m, 1H), 1.77 - 1.61 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.2. The fourth eluting fraction, cA-6-methyl-5-((l-(l-methyl-17f-pyrazol-4- yl)-17f-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (165A), enantiomer 2, was obtained (6.3 mg, 3%), as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 6.99 (dd, J = 8.7, 2.0 Hz, 1H), 5.50 (d, J = 7.0 Hz, 1H), 3.92 (s, 3H), 2.94 - 2.83 (m, 2H), 2.27 - 2.13 (m, 1H), 2.07 - 1.91 (m, 1H), 1.79 - 1.61 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H). MS-ESI (m/z) calc’d for C23H22N5O [M+H]+: 384.2. Found 384.2.
Example 166: l-((5-MethyI-l-(l-methyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-2,3- dihydro-lH-indene-5-carbonitriIe, enantiomer 1 and 2
Figure imgf000318_0001
Step 1: 1 -Hydroxy-2, 3-dihydro-lH-indene-5-carbonitrile
Figure imgf000318_0002
A flask was charged with the 2,3-dihydro-l-oxo-lH-indene-5-carbonitrile (500.0 mg, 3.18 mmol) and MeOH (10 mL). Sodium borohydride (240.69 mg, 6.36 mmol) was then added to the stirred mixture and the resulting clear, colorless solution was stirred for 30 min at r.t. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried overNa2SO4, filtered, and concentrated under vacuum to afford the title compound (498 mg, 98%) as a white solid. JH NMR (400 MHz, CDCh) 8 1.82 - 1.94 (m, 1 H) 1.94 - 2.14 (m, 1 H) 2.48 - 2.68 (m, 1 H) 2.90 (s, 1 H) 3.01 - 3.19 (m, 1 H) 5.12- 5.50 (m, 1 H) 7.44 - 7.67 (m, 3 H). MS-ESI (m/z) calc’d for C10H10NO [M+H]+: 161.1. Found 161.1.
Step 2: l-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-2,3-dihydro-lH- indene-5-carbonitrile, enantiomer 1 and 2
Figure imgf000319_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 1 -hydroxy -2, 3-dihydro- IT/-indene-5 -carbonitrile in place of 8-hydroxy-4-methyl-5,6,7,8-tetrahydroquinoline-3- carbonitrile The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent. The material was purified by preparative HPLC using Method ET to afford l-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3- dihydro- l7/-indene-5-carbonitrile (27.2 mg). The enantiomers were separated by chiral preparative HPLC using Method EU to afford the first eluting fraction l-((5-methyl-l-(l- methyl- l7/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-2.3-dihydro-l7/-mdene-5-carbonitrile. enantiomer 1 (8.7 mg, 6%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.30 (1 H, s) 8.08 (1 H, s) 7.93 (1 H, s) 7.84 (1 H, s) 7.72 (1 H, d, J=7.26 Hz) 7.55 - 7.63 (2 H, m) 7.27 (1 H, s) 6.17 (1 H, t, J=5.94 Hz) 3.94 (3 H, s) 3.07 - 3.20 (1 H, m) 2.92 - 3.05 (1 H, m) 2.69 - 2.84 (1 H, m) 2.16 (3 H, s) 2.03 - 2.14 (1 H, m). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.2. A later eluting fraction was also isolated to afford l-((5- methy 1- 1 -( 1 -methyl- 17/-py razol -4-y 1 )- 17/-i ndazol -6-y I )oxy )-2.3-dihy dro- 17/-i ndene-5 - carbonitrile, enantiomer 2 (8.4 mg, 6%) as a white solid. 'H NMR (400 MHz, DMSO- e) 8 8.30 (1 H, s) 8.08 (1 H, s) 7.94 (1 H, s) 7.85 (1 H, s) 7.72 (1 H, d, J=7.92 Hz) 7.53 - 7.64 (2 H, m) 7.27 (1 H, s) 6.18 (1 H, t, J=5.94 Hz) 3.95 (3 H, s) 3.08 - 3.20 (1 H, m) 2.93 - 3.05 (1 H, m) 2.69 - 2.84 (1 H, m) 2.17 (3 H, s) 2.04 - 2.14 (1 H, m). MS-ESI (m/z) calc’d for C22H20N5O [M+H]+: 370.2. Found 370.2.
Example 167: 3-FIuoro-5-((l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000319_0002
Step 1: 6-Bromo-7-fluoro-l,2,3,4-tetrahydronaphthalen-l-ol
Figure imgf000320_0001
To a solution of 6-bromo-7-fluoro-3,4-dihydronaphthalen- l(277)-one (200.0 mg, 0.82 mmol) in methanol (8.3 mL) was added sodium borohydride (31.13 mg, 0.82 mmol) at 25 °C. The resulting mixture was stirred for 1 hr. The reaction was concentrated under reduced pressure and then saturated aqueous NaHCOs (100 mL) and DCM (100 mL) were added. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (198.5 mg, 98%) as a colorless oil. 'H NMR (400 MHz, MeOD) 6 7.33 (d, J = 7.0 Hz, 1H), 7.23 (d, J = 9.8 Hz, 1H), 4.63 (t, J = 5.8 Hz, 1H), 2.84 - 2.61 (m, 2H), 2.10 - 1.86 (m, 2H), 1.84 - 1.65 (m, 2H). MS-ESI (m/z) calc’d for CioHioBrF [M+H-0H]+: 227.0, 229.0. Found 227.0, 229.0.
Step 2: 6-( ( 6-Br omo-7 -fluor o- 1 , 2, 3, 4-tetrahydronaphthalen-l -yl)oxy)-l -( 1 -methyl- 1H- pyrazol-4-yl)-lH-indazole
Figure imgf000320_0002
To a solution of triphenylphosphine (144.47 mg, 0.550 mmol) in DCM (4.08 mL) was added diisopropyl azodicarboxylate (0.07 mL, 0.370 mmol). After 10 min, a suspension of 6-bromo-7-fluoro-l,2,3,4-tetrahydronaphthalen-l-ol (100.0 mg, 0.370 mmol) and 1-(1- methylpyrazol-4-yl)indazol-6-ol (78.66 mg, 0.370 mmol) in DCM (4.08 mL) was added and the mixture was stirred at 25 °C for 30 minutes. Water was added and the mixture was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (60 mg, 37%) as a colorless oil. MS-ESI (m/z) calc’d for C2iHi9BrFN4O [M+H]+: 441.1, 443.1. Found 441.1, 443.1.
Step 3: 3-Fluor o-5-((l-(l -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000321_0001
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17/-pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 6-((6-bromo-7-fluoro-l, 2,3,4- tetrahydronaphthalen- l-yl)oxy)- 1-( l-methyl- l//-pyrazol-4-yl)- l//-indazole in place of 6-((5-bromo-6-chloro-2,3-dihydro-17/-inden-l-yl)oxy)-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazole to afford 3-fluoro-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile (10 mg), which was subjected to chiral preparative HPLC using Method EV to afford a first eluting fraction, 3-fl uoro-5-(( 1 -( 1 -methy l- 17¥- pyrazol-4- l)-IT/-indazol-6- l)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (2.1 mg, 4%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.10 (d, J = 2.9 Hz, 2H), 7.86 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.34 (d, J = 10.0 Hz, 1H), 7.16 (s, 1H), 6.98 (dd, J = 8.8, 2.1 Hz, 1H), 5.62 (t, J = 5.5 Hz, 1H), 3.99 (s, 3H), 2.90 (dt, J = 12.4, 6.1 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.16 (ddt, J = 13.5, 8.7, 4.3 Hz, 1H), 2.10 - 1.94 (m, 2H), 1.94 - 1.80 (m, 1H). MS-ESI (m/z) calc’d for C22H19FN5O [M+H]+: 388.2. Found 388.2. A later eluting fraction was also isolated to afford 3-fluoro-5-((l-(l-methyl-17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (1.9, 3%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.10 (d, J = 3.1 Hz, 2H), 7.86 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.34 (d, J = 10.0 Hz, 1H), 7.16 (s, 1H), 6.98 (dd, J = 8.8, 2.0 Hz, 1H), 5.62 (t, J = 5.5 Hz, 1H), 3.99 (s, 3H), 2.96 - 2.86 (m, 1H), 2.85 - 2.75 (m, 1H), 2.21 - 2.11 (m, 1H), 2.11 - 1.94 (m, 2H), 1.93 - 1.82 (m, 1H). MS-ESI (m/z) calc’d for C22H19FN5O [M+H]+: 388.2. Found 388.2.
Example 168: 3-Methoxy-5-((l-(l-methyI-tH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000321_0002
Figure imgf000322_0001
To a solution of 3-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (55.0 mg, 0.27 mmol) in methanol (1.24 mL) was added sodium borohydride (10.34 mg, 0.27 mmol) at 25 °C. The resulting mixture was stirred for 1 hr. The reaction was concentrated under reduced pressure and saturated aqueous NaHCOs (50 mL) was added. The mixture was extracted with DCM (3 x 50 mL) and the organic layers were filtered through a phase separator and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (53 mg, 95%) as a white solid. JH NMR (400 MHz, MeOD) 6 7.33 (d, J = 1.1 Hz, 1H), 7.22 (s, 1H), 4.69 (t, J = 6.1 Hz, 1H), 3.92 (s, 3H), 2.83 - 2.59 (m, 2H), 2.11 - 2.00 (m, 1H), 2.00 - 1.90 (m, 1H), 1.84 - 1.67 (m, 2H). MS-ESI (m/z) calc’d for C12H14NO2 [M+H]+: 204.2. Found 204.0.
Step 2: 3-Methoxy-5-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-
Figure imgf000322_0002
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 5 -hydroxy -3 -methoxy - 5,6,7,8-tetrahydronaphthalene-2-carbonitrile in place of 8-hydroxy-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile and 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol. The material was subjected to chiral preparative HPLC using Method EX to afford 3-methoxy-5-((l -(l -methyl- IT/-pyrazol-4-yl)- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (11.5 mg, 11%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.31 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.19 (s, 1H), 6.99 (dd, J = 8.7, 2.0 Hz, 1H), 5.73 (t, J = 4.9 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 2.81 (dt, J = 17.1, 5.6 Hz, 1H), 2.75 - 2.61 (m, 1H), 2.08 - 1.94 (m, 2H), 1.93 - 1.82 (m, 1H), 1.81 - 1.70 (m, 1H). MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2. Found 400.2. A later eluting fraction was also isolated to afford 3-methoxy-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (10.6, 10%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.31 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.19 (s, 1H), 6.99 (dd, J = 8.6, 2.0 Hz, 1H), 5.73 (t, J = 4.7 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 2.81 (dt, J = 16.8, 5.6 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.07 - 1.94 (m, 2H), 1.92 - 1.82 (m, 1H), 1.81 - 1.71 (m, 1H). MS-ESI (m/z) calc’d for C23H22N5O2 [M+H]+: 400.2. Found 400.2.
Example 169: 5-((4-Fluoro- l-(l-methyl- 1 H-py razol-4-yl)- lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000323_0001
A mixture of 4-fluoro-17/-indazol-6-ol (150.0 mg, 0.99 mmol), 4-iodo-l- methylpyrazole (225.6 mg, 1.08 mmol), ( I /?.2/?)-Ati .N2-di meth l c clohexane- 1.2-diamine (70.12 mg, 0.49 mmol), copper(I) iodide (37.56 mg, 0.20 mmol) and tripotassium phosphate (627.1 mg, 2.96 mmol) in dry DMSO (3.3 mL) was stirred at 25 °C for 30 minutes. The mixture was diluted with a H2O buffer (citric acid/NaOH/HCl; pH=3) and extracted with EtOAc (3x). The combined organic layers were evaporated to obtain a solid residue which was washed with H2O and then the solid was triturated with DCM (2 x 2 mL) and MeOH (2 x 2 mL) to afford the title compound (67 mg, 29%) as a beige solid. 1 H NMR (400 MHz, DMSO- e) 6 10.20 (s, 1H), 8.23 (s, 1H), 8.18 (d, J = 0.9 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 6.73 (dd, J = 1.6, 1.0 Hz, 1H), 6.54 (dd, J = 11.7, 1.6 Hz, 1H), 3.92 (s, 3H). MS-ESI (m/z) calc’d for C11H10FN4O [M+H]+: 233.1. Found 233.1. Step 2: 5-((4-Fluoro-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000324_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 5-hy droxy-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile in place of 8-hy droxy-4-methyl-5, 6,7,8- tetrahy droquinoline-3-carbonitrile and 4-fluoro- 1 -(1 -methyl- 17/-py razol-4- l )- 17/-indazol-6- ol in place of 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol. The material was subjected to chiral preparative HPLC using Method EY to afford 5-((4-fluoro- l-(l -methyl- IT/-pyrazol-4- yl)- IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (11.5 mg, 11%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.33 (s, 1H), 8.29 (s, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 6.88 (d, J = 11.6 Hz, 1H), 5.81 (t, J = 4.9 Hz, 1H), 3.93 (s, 3H), 2.89 (dt, J = 11.3, 5.8 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.09 - 1.97 (m, 2H), 1.94 - 1.73 (m, 2H). MS-ESI (m/z) calc’d for C22H19FN5O [M+H]+: 388.1. Found 388.1. A later eluting fraction was also isolated to afford 5-((4-fluoro-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (10.6, 10%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.33 (s, 1H), 8.29 (s, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 6.88 (d, J = 11.2 Hz, 1H), 5.81 (t, J = 4.9 Hz, 1H), 3.93 (s, 3H), 2.89 (dt, J = 11.3, 5.6 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.10 - 1.98 (m, 2H), I.94 > 1.74 (m, 2H). MS-ESI (m/z) calc’d for C22H19FN5O [M+H]+: 388.1. Found 388.1.
Example 170: 8-((l-(l-MethyI-tH-pyrazol-4-yI)-tH-indazol-6-yI)oxy)-5,6,7,8- tetrahydroisoquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000324_0002
Step 1: 8-Oxo-5,6, 7,8-tetrahydroisoquinoline-3-carbonitrile
Figure imgf000325_0001
In a sealed microwave reaction vial, 3-chloro-6,7-dihydro-57/-isoquinolin-8-one (230.0 mg, 1.27 mmol), 0.1 N potassium hexacyanoferrate(II) (12.66 mL, 1.27 mmol) and potassium acetate (124.28 mg, 1.27 mmol) were dissolved in a mixture of 1,4-dioxane (11 mL)/ H2O (2 mL). The mixture was degassed with N2 for 15 minutes. Then XPhos (18.49 mg, 0.04 mmol) and XPhos PD G3 (85.75 mg, 0.10 mmol) were added and the mixture was stirred at 100 °C for 7 hrs. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic phases washed with water (lx), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (68 mg, 31%) as a light yellow solid. 'H NMR (400 MHz, DMSO-de) 8 9.00 (1 H, s) 8.14 (1 H, d, J=0.88 Hz) 3.01 (2 H, t, J=6.16 Hz) 2.63 - 2.75 (2 H, m) 2.09 (2 H, quin, J=6.38 Hz). MS-ESI (m/z) calc’d for C10H9N2O [M+H]+: 173.1. Found 173.1.
Figure imgf000325_0002
To a solution of 8-oxo-5,6,7,8-tetrahydroisoquinoline-3-carbonitrile (68.0 mg, 0.39 mmol) in methanol (3 mL) was added sodium borohydride (29.88 mg, 0.790 mmol) and the mixture was stirred at r.t. for 1 hr. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x), the combined organic layers were washed with H2O (lx), passed through a phase separator and evaporated to dryness. The residue was purified by flash silica gel chromatography using a 0-70% EtOAc/cyclohexane gradient eluent to afford the title compound (53 mg, 84%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.68 (1 H, s) 7.78 (1 H, s) 5.57 (1 H, d, J=5.72 Hz) 4.60 - 4.85 (1 H, m) 2.63 - 2.91 (2 H, m) 1.80 - 2.06 (2 H, m) 1.63 - 1.78 (2 H, m). MS-ESI (m/z) calc’d for C10H11N2O [M+H]+: 175.1. Found 175.0. Step 3: 8-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-
Figure imgf000326_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 8-hy droxy-5, 6,7,8- tetrahydroisoquinoline-3-carbonitrile in place of 8-hy droxy-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile and l-(l-methylpyrazol-4-yl)indazol-6-ol in place of 5- methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol. The material was subjected to chiral preparative HPLC using Method EZ to afford 8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol- 6-yl)oxy)-5,6,7,8-tetrahydroisoquinoline-3-carbonitrile, enantiomer 1 (9.9 mg, 8%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.71 (1 H, s) 8.32 (1 H, s) 8.19 (1 H, d, J=0.88 Hz) 7.88 - 7.98 (2 H, m) 7.77 (1 H, d, J=8.80 Hz) 7.33 (1 H, s) 6.99 (1 H, dd, J=8.80, 1.98 Hz) 5.87 (1 H, t, J=4.40 Hz) 3.94 (3 H, s) 2.89 - 3.03 (1 H, m) 2.73 - 2.88 (1 H, m) 1.97 - 2.16 (2 H, m) 1.75 - 1.96 (2 H, m). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.12. Found 371.1. A later eluting fraction was also isolated to afford 8-((l-(l-methyl-17/-pyrazol- 4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroisoquinoline-3-carbonitrile, enantiomer 2 (9.5 mg, 8%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.71 (1 H, s) 8.31 (1 H, s) 8.19 (1 H, d, J=0.88 Hz) 7.89 - 7.98 (2 H, m) 7.77 (1 H, d, J=8.80 Hz) 7.33 (1 H, s) 6.99 (1 H, dd, J=8.80, 1.98 Hz) 5.87 (1 H, t, J=4.40 Hz) 3.94 (3 H, s) 2.88 - 3.00 (1 H, m) 2.75 - 2.88 (1 H, m) 1.97 - 2.14 (2 H, m) 1.75 - 1.95 (2 H, m). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 37EE Found 37EE
Example 171: l-((l-(l-MethyI-FH-pyrazol-4-yI)-tH-indazol-6-yI)oxy)-2,3-dihydro-tH- indene-5-carbonitrile, enantiomer 1 and 2
Figure imgf000326_0002
Step 1: 1 -Hydroxy-2, 3-dihydro-lH-indene-5-carbonitrile
Figure imgf000327_0001
To a solution of 2,3-dihydro-l-oxo-17/-indene-5-carbonitrile (150.0 mg, 0.950 mmol) in MeOH (10 mL) was added sodium borohydride (36.1 mg, 0.950 mmol) at 25 °C. The resulting mixture was stirred for 1 hr. The reaction was concentrated under reduced pressure and saturated aqueous NaHCOs (10 mL) and DCM (10 mL) were added. The organic layer was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (142 mg, 93%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 7.69 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 5.50 (d, J = 5.9 Hz, 1H), 5.09 (q, J = 6.7 Hz, 1H), 2.95 (ddd, J = 16.2, 8.7, 3.5 Hz, 1H), 2.76 (dt, J = 16.3, 8.2 Hz, 1H), 2.44 - 2.32 (m, 1H), 1.80 (dtd, J = 12.7, 8.6, 7.1 Hz, 1H). MS-ESI (m/z) calc’d for C10H10NO [M+H]+: 160.0. Found 160.1.
Step 2: 1 -((!-( 1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-2, 3-dihydro-lH-indene-5- carbonitrile, enantiomer 1 and 2
Figure imgf000327_0002
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 1 -hydroxy -2, 3-dihydro- l//-indene-5 -carbonitrile in place of 8-hydroxy-4-methyl-5,6,7,8-tetrahydroquinoline-3- carbonitrile and l-(l-methylpyrazol-4-yl)indazol-6-ol in place of 5 -methyl- 1-(1- methylpyrazol-4-yl)indazol-6-ol. The material was subjected to chiral preparative HPLC using Method FA to afford l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3- dihydro- l7/-indene-5-carbonitrile. enantiomer 1 (14 mg, 13%) as a white solid. XH NMR (400 MHz, DMSO- e) 6 8.31 (d, J = 0.9 Hz, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.84 (s, 1H), 7.79 - 7.73 (m, 1H), 7.73 - 7.68 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.8, 2.1 Hz, 1H), 6.16 (dd, J = 6.8, 4.7 Hz, 1H), 3.94 (s, 3H), 3.17 - 3.06 (m, 1H), 3.05 - 2.91 (m, 1H), 2.75 - 2.59 (m, 1H), 2.19 - 2.05 (m, 1H). MS-ESI (m/z) calc’d for C21H18N5O [M+H]+: 356.1. Found 356.1. A later eluting fraction was also isolated to afford l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3- dihydro- l7/-indene-5-carbonitrile. enantiomer 2 (14 mg, 13%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.31 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 6.94 (dd, J = 8.8, 2.0 Hz, 1H), 6.16 (dd, J = 6.7, 4.8 Hz, 1H), 3.93 (s, 3H), 3.18 - 3.05 (m, 1H), 3.03 - 2.90 (m, 1H), 2.75 - 2.60 (m, 1H), 2.18 - 2.02 (m, 1H). MS-ESI (m/z) calc’d for C21H18N5O [M+H]+: 356.1. Found 356.1.
Example 172: 5-((l-(l-MethyI-lH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydroquinoline-2-carbonitrile, enantiomer 1 and 2
Figure imgf000328_0001
To a solution of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (250.0 mg, 1.45 mmol) in methanol (10 mL) was added sodium borohydride (109.86 mg, 2.9 mmol) and the mixture was stirred at 25 °C for 1 hr. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were washed with H2O (lx), passed through a phase separator and evaporated to dryness to afford the title compound (220 mg, 87%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 7.99 (1 H, d, J=7.92 Hz) 7.84 (1 H, d, J=7.92 Hz) 5.60 (1 H, d, J=5.94 Hz) 4.61 - 4.73 (1 H, m) 2.79 - 2.91 (2 H, m) 1.89 - 2.04 (2 H, m) 1.74 - 1.86 (1 H, m) 1.60 - 1.73 (1 H, m). MS-ESI (m/z) calc’d for CioHnN20 [M+H]+: 175.0. Found 175.1.
Step 2: 5-( (1-(1 -Methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahydroquinoline- 2-carbonitrile, enantiomer 1 and 2
Figure imgf000329_0001
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 5-hy droxy-5, 6,7,8- tetrahydroquinoline-2-carbonitrile in place of 8-hydroxy-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile and l-(l-methylpyrazol-4-yl)indazol-6-ol in place of 5- methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol. The material was subjected to chiral preparative HPLC using Method FB to afford 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol- 6-yl)oxy)-5,6,7,8-tetrahydroquinoline-2-carbonitrile, enantiomer 1 (7.6 mg, 7%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.30 (1 H, s) 8.18 (1 H, d, J=0.66 Hz) 8.00 (1 H, d, J=8.14 Hz) 7.91 (1 H, s) 7.87 (1 H, d, J=7.92 Hz) 7.76 (1 H, d, J=8.58 Hz) 7.31 (1 H, s) 6.98 (1 H, dd, J=8.80, 1.98 Hz) 5.86 (1 H, t, J=4.95 Hz) 3.93 (3 H, s) 2.85 - 3.06 (2 H, m) 1.96 - 2.18 (3 H, m) 1.85 - 1.95 (1 H, m). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.1. A later eluting fraction was also isolated to afford 5-((l-(l-methyl-17/-pyrazol- 4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroquinoline-2-carbonitrile. enantiomer 2 (8 mg, 8%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.30 (1 H, s) 8.18 (1 H, d, J=0.66 Hz) 8.00 (1 H, d, J=7.92 Hz) 7.91 (1 H, s) 7.87 (1 H, d, J=7.92 Hz) 7.76 (1 H, d, J=8.80 Hz) 7.30 (1 H, s) 6.98 (1 H, dd, J=8.69, 2.09 Hz) 5.86 (1 H, t, J=4.95 Hz) 3.93 (3 H, s) 2.84 - 3.10 (2 H, m) 1.94 - 2.18 (3 H, m) 1.92 (1 H, d, J=7.92 Hz) MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 37EE Found 37EE
Example 173: 4-Methyl-8-((5-methyl-l-(l-methyl-lff-pyrazol-4-yl)-lff-indazol-6- yl)amino)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000329_0002
To a solution of 4-methyl-8-oxo-6,7-dihydro-57/-quinoline-3-carbonitrile (300 mg, 1.61 mmol) in MeOH (10 mL) was added sodium borohydride (121.89 mg, 3.22 mmol) and the mixture was stirred at r.t. for 1 hr. The solvent was then evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were washed with H2O, passed through a phase separator and evaporated to dryness to afford the title compound (290 mg, 96%) as a beige solid. JH NMR (400 MHz, DMSO-d6) δ 8.74 (1 H, s) 5.34 (1 H, d, J=3.08 Hz) 4.58 (1 H, br. s.) 2.68 - 2.85 (1 H, m) 2.54 - 2.67 (1 H, m) 2.39 (3 H, s) 1.66 - 2.01 (4 H, m). MS-ESI (m/z) calc’d for C11H13N2O [M+H]+: 189.1. Found 189.1
Step 2: N-(3-Cyano-4-methyl-5 ,6, 7,8-tetrahydroquinolin-8-yl)-N-(5-methyl-l-(l-methyl-lH-
Figure imgf000330_0001
To a solution of 8-hydroxy-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile (70.0 mg, 0.370 mmol), N-(5 -methyl- 1-(1 -methyl- l//-pyrazol-4-y l)-17/-indazol-6-yl)-2- nitrobenzenesulfonamide (151.84 mg, 0.37 mmol) and triphenylphosphine (193.13 mg, 0.74 mmol) in THF (5.5 mL), was added diisopropyl azodicarboxylate (0.09 mL, 0.44 mmol), dropwise, and the mixture was stirred at r.t. overnight. The reaction mixture was partitioned between H2O and EtOAc. The phases were separated, the aqueous layer was extracted with EtOAc (3x), and the combined organic phases washed with brine (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient to afford the title compound (480 mg). MS-ESI (m/z) calc’d for C29H27N8O4S [M+H]+: 583.2. Found 583.2.
Step 3: 4-Methyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-
Figure imgf000330_0002
Prepared as described for 5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using/V-(3-cyano-4-methyl-5,6,7,8- tetrahydroquinolin-8-yl)-N-(5-methyl- l -( l-methyl-IT/-pyrazol-4-yl)- l7/-indazol-6-yl)-2- nitrobenzenesulfonamide in place of A-(6-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-JV-(5- methyl- l-( l-methyl-l7/-pyrazol-4-yl)- l7/-indazol-6-yl)-2-nitrobenzenesulfonamide. The material was subject to chiral preparative HPLC using Method FC to afford 4-methyl-8-((5- methyl- l-( l-methyl-l7/-pyrazol-4-yl)- l7/-indazol-6-yl)ammo)-5.6.7.8-tetrahydroqumoline- 3-carbonitrile, enantiomer 1 (3.5 mg, 4%) as a light yellow solid. JH NMR (400 MHz, DMSO-d6) δ 8.75 (1 H, s) 8.18 (1 H, s) 7.90 (1 H, s) 7.80 (1 H, s) 7.41 (1 H, s) 6.75 (1 H, s) 5.52 (1 H, d, J=6.38 Hz) 4.82 - 4.94 (1 H, m) 3.91 (3 H, s) 2.78 (2 H, br. s.) 2.45 (3 H, s) 2.17 (3 H, s) 2.08 - 2.16 (1 H, m) 1.88 - 2.05 (3 H, m). MS-ESI (m/z) calc’d for C23H24N7 [M+H]+: 398.2. Found 398.2. A later eluting fraction was also isolated to afford 4-methyl-8- ((5-methyl-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (4.6 mg, 6%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (1 H, s) 8.19 (1 H, s) 7.91 (1 H, s) 7.81 (1 H, s) 7.42 (1 H, s) 6.76 (1 H, s) 5.52 (1 H, d, J=6.16 Hz) 4.83 - 4.93 (1 H, m) 3.92 (3 H, s) 2.80 (2 H, br. s.) 2.46 (3 H, s) 2.18 (3 H, s) 2.10 - 2.16 (1 H, m) 1.88 - 2.06 (3 H, m). MS-ESI (m/z) calc’d for C23H24N7 [M+H]+: 398.2. Found 398.2.
Example 174: 8-((5-MethyI-l-(l-methyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-4- (trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000331_0001
A solution of 8-oxo-6,7-dihydro-57/-quinoline-3-carbonitrile (130.0 mg, 0.76 mmol) and zinc trifluoromethanesulfinate (750.92 mg, 2.27 mmol) in DCM (6 mL) and H2O (3 mL) was cooled in ice water. The mixture was stirred vigorously while adding tert-butyl hydroperoxide (0.42 mL, 3.02 mmol, 70% solution in H2O). The solution was warmed to r.t. and stirred overnight. An additional eqivalent of zinc trifluoromethanesulfinate and 1.3 equivalent of tert-butyl hydroperoxide (70% solution in H2O) were added at r.t. and the mixture was stirred for 2 hrs. The reaction mixture was partitioned between H2O and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The residue was purified by silica gel chromatography on a 10 g silica gel column, using a 0-60% EtOAc/cyclohexane gradient eluent to afford the title compound (55 mg, 30%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 9.30 (1 H, s) 3.18 (2 H, t, J=5.39 Hz) 2.79 - 2.85 (2 H, m) 2.16 (2 H, quin, J=6.33 Hz). MS-ESI (m/z) calc’d for C11H8F3N2O [M+H]+: 241.1. Found 241.1.
Step 2: 8-Hydroxy-4-(trifluoromethyl)-5,6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000332_0001
To a solution of sodium borohydride (12.65 mg, 0.33 mmol) in MeOH (2 mL) was added 8-oxo-4-(trifluoromethyl)-6,7-dihydro-57/-quinoline-3-carbonitrile (55.0 mg, 0.17 mmol) and the mixture was stirred at r.t. for 1 hr. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The material was purified by preparative HPLC using Method FD to afford the title compound (20 mg, 49%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) δ 9.13 (1 H, s) 5.68 (1 H, d, J=4.84 Hz) 4.68 (1 H, q, J=4.77 Hz) 2.93 - 3.10 (1 H, m) 2.78 - 2.92 (1 H, m) 1.84 - 2.06 (3 H, m) 1.69 - 1.81 (1 H, m). MS-ESI (m/z) calc’d for C11H10F3N2O [M+H]+: 243.1. Found 243.1.
Step 3: 8-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-
Figure imgf000332_0002
Prepared as described for 4-methyl-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile using 8-hydroxy-4- (trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 8-hydroxy-4-methyl- 5,6,7,8-tetrahydroquinoline-3-carbonitrile. The material was subjected to preparative HPLC using Method FE and then chiral preparative HPLC using Method FF to afford 8-((5-methyl- 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4-(trifluoromethyl)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (5.0 mg, 13%) as a white solid. Tf NMR (400 MHz, DMSO-d6) δ 9.17 (1 H, s) 8.29 (1 H, s) 8.07 (1 H, s) 7.93 (1 H, s) 7.57 (1 H, s) 7.48 (1 H, s) 5.90 (1 H, t, J=4.07 Hz) 3.95 (3 H, s) 3.09 - 3.23 (1 H, m) 2.91 - 3.05 (1 H, m) 2.23 - 2.32 (1 H, m) 2.15 (3 H, s) 2.08 - 2.14 (1 H, m) 1.85 - 2.08 (2 H, m). MS-ESI (m/z) calc’d for C23H20F3N6O [M+H]+: 453.2. Found 453.2. A later eluting fraction was also isolated to afford 8-((5-meth l- l-(l -methyl- IT/-pyrazol-4- l)- IT/-indazol-6- l)oxy)-4- (trifhioromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (5 mg 13%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 9.17 (1 H, s) 8.29 (1 H, s) 8.07 (1 H, d, J=0.66 Hz) 7.93 (1 H, d, J=0.66 Hz) 7.57 (1 H, s) 7.48 (1 H, s) 5.90 (1 H, t, J=4.40 Hz) 3.95 (3 H, s) 3.12 - 3.22 (1 H, m) 2.92 - 3.08 (1 H, m) 2.23 - 2.32 (1 H, m) 2.15 (3 H, s) 1.87 - 2.13 (3 H, m). MS-ESI (m/z) calc’d for C23H20F3N6O [M+H]+: 453.2. Found 453.2.
Example 175: l-Methoxy-5-((5-methyI-l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000333_0001
To a solution of 5-hydroxy-l-tetralone (2.0 g, 12.33 mmol) in dry DCM (100 mL) under a nitrogen atmosphere was added A-ethylethanamine (0.15 mL, 1.48 mmol). A solution of 1 -bromopyrrolidine-2,5 -di one (2.19 g, 12.33 mmol) in DCM (100 mL) was slowly added over 2 hrs at r.t. The reaction was stirred at r.t. for 1 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography on a 100 g silica gel column, using a 0-25% EtOAc/cyclohexane gradient eluent to afford the title compound (2.21 g, 74%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 9.51 (br. s., 1 H) 7.51 (d, J=8.36 Hz, 1 H) 7.33 (d, J=8.58 Hz, 1 H) 2.88 (t, J=6.05 Hz, 2 H) 2.53 - 2.61 (m, 2 H) 2.03 (quin, J=6.38 Hz, 2 H). MS-ESI (m/z) calc’d for CioHioBrCh [M+H]+: 241.0, 243.0. Found 241.0, 243.0.
Figure imgf000334_0001
To a solution of 6-bromo-5-hydroxy-3,4-dihydronaphthalen- 1 (27/)-one (300.0 mg, 1.24 mmol) in anhydrous DMF (2.1 mL) were added cesium carbonate (608.18 mg, 1.87 mmol) and iodomethane (0.08 mL, 1.24 mmol). The mixture was stirred for 2 hrs at 25 °C. Saturated aqueous NH4CI (30 mL) was then added followed by addition of H2O (100 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic phases were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography using a 0- 100% EtOAc/cyclohexane gradient eluent to afford the title compound (317 mg, 100%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.63 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 2.97 (t, J = 6.1 Hz, 2H), 2.59 (dd, J = 7.4, 5.7 Hz, 2H), 2.09 - 1.99 (m, 2H). MS-ESI (m/z) calc’d for CiiHi2BrO2 [M+H]+: 255.0, 257.0. Found 255.0, 257.0.
Figure imgf000334_0002
To a solution of 6-bromo-5-methoxy-3.4-dihydronaphthalen-l (27/)-one (317.1 mg, 1.24 mmol) in methanol (7.98 mL), sodium borohydride (47.02 mg, 1.24 mmol) was added and the resulting mixture stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure and then taken up in saturated aqueous NaHCOs (10 mL) and DCM (10 mL). The organic phase was filtered through a phase separator and evaporated to dryness. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (277 mg, 87%) as a white solid. MS-ESI (m/z) calc’d for CnHi4BrO2 [M+H]+: 257.0, 259.0. Found 239.0, 241.0 [M- H2O]+.
Step 4: 6-( ( 6-Bromo-5-methoxy-l , 2, 3, 4-tetrahydronaphthalen-l-yl)oxy)-5-methyl-l-( 1 - methyl-lH-pyrazol-4-yl)-lH-indazole
Figure imgf000335_0001
(Tributylphosphoranylidene)acetonitrile (0.15 mL, 0.56 mmol) was added to a solution of 6-bromo-5-methoxy-l,2,3,4-tetrahydronaphthalen-l-ol (143.0 mg, 0.56 mmol) and 5 -methyl- l-(l-methylpyrazol-4-yl)indazol-6-ol (126.94 mg, 0.56 mmol) in dry toluene (5.9 mL). The resulting mixture was stirred at 100 °C for 1 hr. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent. The material was further purified by flash silica gel chromatography (ISOLERA; NH-cartridge, 11 g) using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (75 mg, 29%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.29 (s, 1H), 8.06 (d, J = 0.9 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.29 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.76 (t, J = 4.8 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H), 2.92 (dt, J = 17.5, 5.5 Hz, 1H), 2.73 (dt, J = 17.5, 7.0 Hz, 1H), 2.14 (s, 3H), 2.08 - 1.96 (m, 2H), 1.94 - 1.76 (m, 2H). MS-ESI (m/z) calc’d for C23H24BrN4O2 [M+H]+: 467.1, 469.1. Found 467.1, 469.1.
Step 5: l-Methoxy-5-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000335_0002
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17 -pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 6-((6-bromo-5-methoxy-l,2,3,4- tetrahydronaphthalen- l -yl)oxy)-5-methyl-l -(l -methyl- l//-pyrazol -4-yl)- 1 //-indazole in place of 6-((5-bromo-6-chloro-2,3-dihydro-17/-inden-l-yl)oxy)-l-(l-methyl-17/-pyrazol-4- y I)- 1 //-indazole. The material was subjected to chiral preparative HPLC using Method FG to afford l-methoxy-5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (1.7 mg, 3%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.10 (d, J = 0.8 Hz, 1H), 8.01 (d, J = 0.9 Hz, 1H), 7.85 (d, J = 0.8 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 5.67 (t, J = 5.0 Hz, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 2.95 (dt, J = 17.7, 5.7 Hz, 1H), 2.79 -
2.66 (m, 1H), 2.21 (s, 3H), 2.16 - 2.09 (m, 2H), 2.06 - 1.96 (m, 1H), 1.95 - 1.84 (m, 1H). MS-ESI (m/z) calc’d for C24H24N5O2 [M+H]+: 414.2. Found 414.2. A later eluting fraction was also isolated to afford l-methoxy-5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (1.3, 2%) as a white solid. 1 H NMR (400 MHz, MeOD) 6 8.10 (s, 1H), 8.00 (d, J = 0.9 Hz, 1H), 7.85 (d, J = 0.8 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H),
5.67 (t, J = 5.0 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 2.95 (dt, J = 17.7, 5.7 Hz, 1H), 2.74 (ddd, J = 17.7, 8.1, 5.9 Hz, 1H), 2.21 (d, J = 1.0 Hz, 3H), 2.16 - 2.08 (m, 2H), 2.06 - 1.96 (m, 1H), 1.96 - 1.84 (m, 1H). MS-ESI (m/z) calc’d for C24H24N5O2 [M+H]+: 414.2. Found 414.2.
Example 176: 5-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-LH-indazol-6-yl)oxy)-6,7-
Figure imgf000336_0001
To a suspension of glycinamide hydrochloride (563.4 mg, 5.1 mmol) and cyclopentane-1, 2-dione (500.0 mg, 5.1 mmol) in EtOH (25 mL) was added 10 M sodium hydroxide (1.27 mL, 12.74 mmol) at 25 °C. The mixture was then gradually warmed to 80 °C and stirred for 3 hrs. Then the reaction was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a 0-10% MeOH/DCM gradient eluent to afford the title compound (146 mg, 21%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 7.74 (s, 1H), 2.85 - 2.69 (m, 4H), 2.08 (p, J = 7.7 Hz, 2H). MS-ESI (m/z) calc’d for C7H9N2O [M+H]+: 137.0. Found 137.0.
Step 2: 2-Chloro-6, 7-dihydro-5H-cyclopenta[b ]pyrazine
Figure imgf000336_0002
In a microwave reaction vial, a suspension of l.5.6.7-tetrahydro-27/- cyclopenta|6|pyrazm-2-one (145.0 mg, 1.01 mmol) and tetraethylammonium chloride (167.65 mg, 1.01 mmol) in phosphorus oxychloride (1.46 mL, 15.65 mmol) was heated at 100 °C for 1 hr. The solvent was evaporated, the residue was taken up in saturated aqueous NaHCOs and extracted with DCM (3x), the combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-25% EtOAc/cyclohexane gradient eluent to afford the title compound (70 mg, 45%) as a colorless oil. JH NMR (400 MHz, DMSO- e) 6 8.44 (t, J = 1.1 Hz, 1H), 3.04 - 2.89 (m, 4H), 2.27 - 2.08 (m, 2H). MS-ESI (m/z) calc’d for C7H8CIN2 [M+H]+: 155.0. Found 155.0.
Step 3: 3-Chloro-6, 7-dihydro-5H-cyclopenta[b]pyrazine 1 -oxide
O’ c
To a solution of 2-chloro-6,7-dihydro-57/-cyclopenta[6]pyrazine (1.05 g, 6.79 mmol) in DCE (33.96 mL) was added MCPBA (1.41 g, 8.15 mmol) and the mixture was stirred at 65 °C for 1.5 hrs. After cooling the mixture was diluted with DCM and washed with saturated aqueous NaHCOs. The organic phase was passed through a phase separator and evaporated to afford the title compound (1.15 g, 99%) as a yellow solid. 'H NMR (500 MHz, DMSO- e) 6 1.83 - 2.00 (m, 1 H), 2.42 - 2.53 (m, 1 H), 2.78 - 2.91 (m, 1 H), 2.95 - 3.08 (m, 1 H), 5.01 (dt, J=7.5, 5.8 Hz, 1 H), 5.69 (d, J=6.0 Hz, 1 H), 8.57 (s, 1 H). MS-ESI (m/z) calc’d for C7H8CIN2O [M+H]+: 171.0. Found 171.0.
Step 4: 2-Chloro-6, 7-dihydro-5H-cyclopenta[b ]pyrazin-5-ol
Figure imgf000337_0001
To a solution of 3-chloro-6.7-dihydro-57/-cyclopenta|/)|pyrazme 1-oxide (1.15 g, 6.74 mmol) in DCM (33.73 mL) was added dropwise trifluoroacetic anhydride (2.81 mL, 20.22 mmol) and the mixture was stirred at 40 °C for 3 days. The solvent was evaporated, the residue was taken up in MeOH, K2CO3 was added, and the suspension was stirred at 25 °C for 1 hr. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x), the combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford a residue (500 mg) which was further purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (435 mg, 38%) as a clear oil. MS-ESI (m/z) calc’d for C7H7CIN2 [M-H20]+: 155.0, Found 154.9 [M-H20]+. 'H NMR (500 MHz, DMSO- e) 6 1.83 - 2.00 (m, 1 H), 2.42 - 2.53 (m, 1 H), 2.78 - 2.91 (m, 1 H), 2.95 - 3.08 (m, 1 H), 5.01 (dt, J=7.5, 5.8 Hz, 1 H), 5.69 (d, J=6.0 Hz, 1 H), 8.57 (s, 1 H).
Step 5: 6-((2-Chloro-6, 7-dihydro-5H-cyclopenta[b]pyrazin-5-yl)oxy)-5-methyl-l-(l-methyl- !H-pyrazol-4-yl)-lH-indazole
Figure imgf000338_0001
2-(Tributylphosphoranylidene)acetonitrile (0.05 mL, 0.21 mmol) was added to a solution of 2-chloro-6.7-dihydro-57/-cyclopenta|/)|pyrazm-5-ol (40.0 mg, 0.21 mmol) and 5- methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol (47.63 mg, 0.21 mmol) in dry toluene (2.9 mL). The resulting mixture was stirred at 100 °C for 1 hr. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (30 mg, 38%) as a white solid. MS-ESI (m/z) calc’d for C isHisCINeO [M+H]+: 381.1. Found 381.1.
Step 6: 5-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-6, 7-dihydro-5H- cyclopenta[b]pyrazine-2-carbonitrile, enantiomer 1 and 2
Figure imgf000338_0002
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17/-pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 6-((2-chloro-6,7-dihydro-577- cyclopenta|/>|pyrazm-5-yl)oxy)-5-methyl-l -(l -methyl- l//-pyrazol-4-yl)-l//-mdazole in place of 6-((5-bromo-6-chloro-2,3-dihydro-17/-inden-l-yl)oxy)-l-(l-methyl-17/-pyrazol-4- y I)- 1 //-indazole. The material was subjected to chiral preparative HPLC using Method FH to afford 5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57 - cyclopenta|/> |pyrazine-2-carbonitrile. enantiomer 1 (2 mg, 4%) as a white solid. JH NMR (400 MHz, MeOD) 6 8.89 (t, J = 0.9 Hz, 1H), 8.11 (s, 1H), 8.01 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 6.02 (dd, J = 7.3, 4.5 Hz, 1H), 4.00 (s, 3H), 3.39 - 3.33 (m, 1H), 3.15 (dddd, J = 17.8, 8.6, 5.7, 1.0 Hz, 1H), 2.85 (dddd, J = 14.6, 8.9, 7.4, 5.8 Hz, 1H), 2.45 (dddd, J = 13.7, 9.0, 5.7, 4.5 Hz, 1H), 2.25 (d, J = 1.1 Hz, 3H).. MS-ESI (m/z) calc’d for C20H18N7O [M+H]+: 372.1. Found 372.1. A later eluting fraction was also isolated to afford 5 -((5-methy 1- 1 -( 1 -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-y l)oxy )-6,7-dihy dro-57/- cyclopenta[/?]pyrazine-2-carbonitrile, enantiomer 2 (2.3, 4%) as a white solid. 1 H NMR (400 MHz, MeOD) 6 8.91 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 6.04 (dd, J = 7.3, 4.5 Hz, 1H), 4.02 (s, 3H), 3.43 - 3.36 (m, 1H), 3.17 (ddd, J = 17.9, 9.0, 5.7 Hz, 1H), 2.87 (dddd, J = 14.2, 8.9, 7.3, 5.7 Hz, 1H), 2.47 (ddt, J = 14.0, 9.6, 5.2 Hz, 1H), 2.27 (s, 3H). MS-ESI (m/z) calc’d for C20H18N7O [M+H]+: 372.1. Found 372.1.
Example 177: l-Fluoro-5-((5-methyl-l-(l-methyl-lff-pyrazol-4-yl)-lff-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitriIe, enantiomer 1 and 2
Figure imgf000339_0001
To a solution of 6-chloro-5-fluoro-3,4-dihydro-27/-naphthalen-l-one (250.0 mg, 1.26 mmol) in methanol (6.29 mL), sodium borohydride (47.62 mg, 1.26 mmol) was added and the resulting mixture stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure and then taken up in saturated aqueous NaHCOs (10 mL) and DCM (10 mL). The organic phase was filtered through a phase separator to afford the title compound (251 mg, 99%) as a colorless oil. 'H NMR (400 MHz, DMSO- e) 6 7.39 - 7.31 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.31 (d, J = 5.8 Hz, 1H), 4.55 (q, J = 5.6, 4.9 Hz, 1H), 2.75 - 2.56 (m, 2H), 1.97 - 1.80 (m, 2H), 1.75 - 1.58 (m, 2H).
Step 2: 6-( ( 6-Chloro-5 -fluoro- 1 , 2, 3, 4-tetrahydronaphthalen-l-yl)oxy)-5-methyl-l-( 1 -methyl-
!H-pyrazol-4-yl)-lH-indazole
Figure imgf000340_0001
2-(Tributylphosphoranylidene(acetonitrile (0.16 mL, 0.60 mmol) was added to a solution of 6-chloro-5-fluoro-l,2,3,4-tetrahydronaphthalen-l-ol (120.0 mg, 0.60 mmol) and 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol (136.51 mg, 0.60 mmol) in dry toluene (6.72 mL). The resulting mixture was stirred at 100 °C for 1 hr. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4 and purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford a residue which was further purified by flash silica gel chromatography (ISOLERA; NH-cartridge, 28 g) using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (57 mg, 23%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.30 (s, 1H), 8.07 (d, J = 0.9 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.58 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.22 (d, J = 8.3 Hz, 1H), 5.82 (t, J = 4.5 Hz, 1H), 3.94 (s, 3H), 2.89 (dt, J = 17.4, 5.3 Hz, 1H), 2.77 - 2.63 (m, 1H), 2.14 (s, 3H), 2.10 - 1.96 (m, 2H), 1.95 - 1.79 (m, 2H). MS-ESI (m/z) calc’d for C22H21CIFN4O [M+H]+: 411.1. Found 411.1.
Step 3: 1 -Fluor o-5-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-
Figure imgf000340_0002
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17 -pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 6-((6-chloro-5-fluoro-l,2,3,4- tetrahydronaphthalen- l -yl)oxy)-5-methyl-l -(l -methyl- l//-pyrazol -4-yl)- 1 //-indazole in place of 6-((5-bromo-6-chloro-2,3-dihydro-17 -inden-l-yl)oxy)-l-(l-methyl-17 -pyrazol-4- yl)- 1 //-indazole. The material was subjected to chiral preparative HPLC using Method FJ to afford l-fluoro-5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (5.0 mg, 10%) as a white solid. 'H NVIR (400 MHz, DMSO- e) 6 8.29 (s, 1H), 8.08 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.79 - 7.69 (m, 1H), 7.59 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 5.89 (t, J = 5.0 Hz, 1H), 3.93 (s, 3H), 2.89 (dt, J = 17.6, 5.9 Hz, 1H), 2.80 - 2.69 (m, 1H), 2.15 (s, 3H), 2.09 - 1.97 (m, 2H), 1.96 - 1.82 (m, 2H). MS-ESI (m/z) calc’d for C23H21FN5O [M+H]+: 402.2. Found 402.2. A later eluting fraction was also isolated to afford l-fluoro-5-((5-methyl-l-(l-methyl- l//-pyrazol-4-yl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (4.1, 8%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.29 (s, 1H), 8.08 (s, 1H), 7.94 (s, 1H), 7.79 - 7.67 (m, 1H), 7.59 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 5.89 (t, J = 5.1 Hz, 1H), 3.93 (s, 3H), 2.89 (dt, J = 17.7, 5.9 Hz, 1H), 2.79 - 2.69 (m, 1H), 2.15 (s, 3H), 2.11 - 1.97 (m, 2H), 1.96 - 1.83 (m, 2H). MS-ESI (m/z) calc’d for C23H21FN5O [M+H]+: 402.2. Found 402.2.
Example 178: 5-((l-(Pyridazin-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000341_0001
Step 1: l-(Pyridazin-4-yl)-lH-indazol-6-ol
Figure imgf000341_0002
A mixture of 17/-indazol-6-ol (300.0 mg, 2.24 mmol), 4-bromopyridazine (426.66 mg, 2.68 mmol), (17?,27?)-Al,A2-dimethylcyclohexane-l,2-diamine (159.06 mg, 1.12 mmol), copper(I) iodide (85.19 mg, 0.45 mmol) and tripotassium phosphate (1422.39 mg, 6.71 mmol) in dry 1,4-di oxane (10 mL) was stirred at 90 °C overnight. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography on a 25 g silica gel column, using a 0-100% EtOAc/cyclohexane gradient eluent and then 95/5% EtOAc/MeOH isocratically to afford the title compound (40 mg, 8%) as a beige solid. 'H NMR (400 MHz, DMSO-d6) δ 10.18 (1 H, br. s.) 9.78 (1 H, dd, J=2.97, 0.99 Hz) 9.28 (1 H, dd, J=5.94, 0.88 Hz) 8.41 (1 H, d, J=0.66 Hz) 8.05 (1 H, dd, J=5.83, 2.97 Hz) 7.74 (1 H, d, J=8.58 Hz) 7.41 (1 H, s) 6.91 (1 H, dd, J=8.69, 1.87 Hz). MS-ESI (m/z) calc’d for C11H9N4O [M+H]+: 213.1. Found 213.1.
Step 2: 5-((l-(Pyridazin-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 1 and 2
Figure imgf000342_0001
2-(Tributylphosphoranylidene)acetonitrile (0.05 mL, 0.19 mmol) was added to a solution of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (32.65 mg, 0.19 mmol) and l-pyridazin-4-yl)-17/-indazol-6-ol (40.0 mg, 0.19 mmol) in dry toluene (3 mL). The resulting mixture was stirred at 100 °C for 48 hrs, adding a total of 10 eq of 2- (tributylphosphoranylidene)acetonitrile over the 48 hrs. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and evaporated. The residue was purified by preparative HPLC using Method FK. The material was then purified by chiral preparative HPLC using Method FL to afford 5-((l- (pyridazin-4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (4.1 mg, 6%) as a light yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 9.84 - 9.93 (1 H, m) 9.24 - 9.34 (1 H, m) 8.50 (1 H, s) 8.19 (1 H, dd, J=5.94, 2.86 Hz) 7.87 (1 H, d, J=8.80 Hz) 7.81 (1 H, s) 7.70 (1 H, s) 7.63 - 7.68 (1 H, m) 7.54 - 7.61 (1 H, m) 7.12 (1 H, dd, J=8.80, 1.76 Hz) 5.92 (1 H, t, J=5.06 Hz) 2.87 - 2.99 (1 H, m) 2.76 - 2.86 (1 H, m) 2.02 - 2.11 (2 H, m) 1.75 - 1.97 (2 H, m). MS-ESI (m/z) calc’d for C22H18N5O [M+H]+: 368.2. Found 368.2. A later eluting fraction was also isolated to afford 5-((l -(pyridazin-4- l)- 17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (3.8 mg, 5%) as a light yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 9.81 - 9.99 (1 H, m) 9.29 (1 H, dd, J=5.94, 0.88 Hz) 8.50 (1 H, s) 8.19 (1 H, dd, J=6.05, 2.97 Hz) 7.87 (1 H, d, J=8.80 Hz) 7.81 (1 H, s) 7.70 (1 H, s) 7.62 - 7.69 (1 H, m) 7.54 - 7.61 (1 H, m) 7.12 (1 H, dd, J=8.91, 1.87 Hz) 5.92 (1 H, t, J=4.84 Hz) 2.87 - 2.98 (1 H, m) 2.74 - 2.87 (1 H, m) 2.01 - 2.11 (2 H, m) 1.73 - 1.97 (2 H, m). MS-ESI (m/z) calc’d for C22H18N5O [M+H]+: 368.2. Found 368.2. Example 179: 4-(DifluoromethyI)-8-((l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000343_0001
A solution of 8-oxo-6,7-dihydro-57/-quinoline-3-carbonitrile (100.0 mg, 0.58 mmol) and zinc difluoromethanesulfinate (514.94 mg, 1.74 mmol) in DCM (4.4 mL) and H2O (2.2 mL) was cooled in ice H2O. The mixture was stirred vigorously while adding a 70% aqueous solution of tert-butyl hydroperoxide (0.32 mL, 2.32 mmol). Then the solution was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between water and DCM and the phases were separated. The aqueous layer was extracted with DCM (2x) and the combined organic phases were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (65 mg, 50%) as ayellow solid. 'H NMR (400 MHz, DMSO-d6) δ 9.19 (1 H, s) 7.31 - 7.74 (1 H, m) 3.15 (2 H, t, J=6.05 Hz) 2.75 - 2.82 (2 H, m) 2.13 (2 H, quin, J=6.44 Hz). MS-ESI (m/z) calc’d for C11H9F2N2O [M+H]+: 223.0. Found 223.0.
Figure imgf000343_0002
To a solution of sodium borohydride (22.13 mg, 0.59 mmol) in MeOH (3 mL) was added 4-(difluoromethyl)-8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (65.0 mg, 0.29 mmol) and the mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-60% EtOAc/cyclohexane gradient eluent to afford the title compound (35 mg, 53%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (1 H, s) 7.24 - 7.60 (1 H, m) 5.57 (1 H, d, J=4.62 Hz) 4.65 (1 H, q, J=4.55 Hz) 2.94 - 3.05 (1 H, m) 2.74 - 2.90 (1 H, m) E81 - 2.01 (3 H, m) E69 - E80 (1 H, m). MS-ESI (m/z) calc’d for C11H11F2N2O [M+H]+: 225.1. Found 225.1.
Step 3: 4-(Difluoromethyl)-8-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy) -5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000344_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 4- (difluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 5- hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. The material was subjected to chiral preparative HPLC using Method FM to afford 4-(difluoromethyl)-8-((l-(l-methyl-17T- pyrazol-4-yl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroqumoline-3-carbonitrile. enantiomer 1 (6.7 mg, 10%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 9.06 (1 H, s) 8.31 (1 H, s) 8.17 (1 H, d, J=0.88 Hz) 7.91 (1 H, d, J=0.66 Hz) 7.74 (1 H, d, J=8.80 Hz) 7.30 - 7.63 (2 H, m) 6.96 (1 H, dd, J=8.80, 2.20 Hz) 5.81 (1 H, t, J=3.96 Hz) 3.94 (3 H, s) 3.10 - 3.20 (1 H, m) 2.86 - 3.00 (1 H, m) 2.20 - 2.31 (1 H, m) 1.84 - 2.13 (3 H, m). MS-ESI (m/z) calc’d for C22H19F2N6O [M+H]+: 421.2. Found 421.2. A later eluting fraction was also isolated to afford 4-(difluoromethyl)-8-((l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (6.6 mg, 10%). 'H NMR (400 MHz, DMSO-d6) δ 9.06 (1 H, s) 8.31 (1 H, s) 8.17 (1 H, d, J=0.88 Hz) 7.91 (1 H, d, J=0.66 Hz) 7.74 (1 H, d, J=8.80 Hz) 7.31 - 7.61 (2 H, m) 6.96 (1 H, dd, J=8.80, 1.98 Hz) 5.81 (1 H, t, J=3.96 Hz) 3.94 (3 H, s) 3.09 - 3.20 (1 H, m) 2.87 - 2.99 (1 H, m) 2.21 - 2.31 (1 H, m) 1.83 - 2.14 (3 H, m). MS-ESI (m/z) calc’d for C22H19F2N6O [M+H]+: 42E2. Found 42E2.
Example 180: 5-((l-(l-MethyI-LH-pyrazol-4-yI)-LH-indazol-6-yI-3-</)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000345_0001
To a solution of 4-bromo-2-fluorobenzoic acid (2.19 g, 10 mmol) in THF (40 mL) was added CDI (3.24 g, 20 mmol) and the mixture was stirred at 25 °C for 24 hrs. The solution was then cooled to 0 °C and sodium borodeuteride (1.05 g, 25 mmol) and H2O (10 mL) were added, then the mixture was stirred at 25 °C for 30 minutes. Water was added and the mixture was extracted with DCM (3x), the combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (1.87 g, 90%) as a clear oil. 'H NMR (400 MHz, DMSO- e) 6 7.50 - 7.38 (m, 3H), 5.28 (s, 1H).
Step 2: 4-Bromo-2-fluorophenyl)-deuteriomethanone
Figure imgf000345_0002
To a solution of (4-bromo-2-fluorophenyl)methan-d2-ol (1.87 g, 9.03 mmol) in DCM (45.16 mL) was added manganese oxide (6.28 g, 72.26 mmol) and the mixture was stirred at 25 °C for 24 hrs. The black suspension was filtered through a Celite pad and the filtrate was dried to afford the title compound (1.6 g, 87%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.82 (dd, J = 10.2, 1.8 Hz, 1H), 7.79 (dd, J = 8.4, 7.6 Hz, 1H), 7.64 (ddd, J = 8.3, 1.8, 0.6 Hz, 1H).
Step 3: 6-Bromo-lH-indazole-3-d
Figure imgf000345_0003
A suspension of (4-bromo-2-fluorophenyl)-deutenomethanone (1.6 g, 7.84 mmol) in hydrazine hydrate (20.0 mL, 643.99 mmol) was heated at 105 °C for 4 hrs. After cooling, the slurry was poured into H2O and the solid that formed was collected by filtration, washed with H2O and dried to obtain the title compound (1.22 g, 78%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 13.17 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.5, 1.7 Hz, 1H). MS-ESI (m/z) calc’d for C7H5DBrN2 [M+H]+: 198.0, 200.0. Found 197.9, 199.9.
Figure imgf000346_0001
A mixture of 6-bromo-lA-indazole-3-d (1.22 g, 6.16 mmol), 4-iodo-l- methylpyrazole (1.23 mL, 9.24 mmol), potassium phosphate (3.92 g, 18.48 mmol), A,A- Dimethyl-(lR,2R)-cyclohexanediamine (0.44 g, 3.08 mmol) and potassium phosphate (3.92 g, 18.48 mmol) were stirred at 90 °C for 2 hrs. After cooling, the mixture was diluted with H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (1 g, 58%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.38 (d, J = 0.8 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.82 (dd, J = 8.5, 0.6 Hz, 1H), 7.38 (dd, J = 8.5, 1.6 Hz, 1H), 3.94 (s, 3H). MS-ESI (m/z) calc’d for CiiH9DBrN4 [M+H]+: 278.0. 280.0. Found 278.0, 280.0.
Step 5: 1-(1 -Methyl-lH-pyrazol-4-yl)-6-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH- indazole-3-d
Figure imgf000346_0002
To a solution of 6-bromo-3-deuterio-l-(l-methylpyrazol-4-yl)indazole (1.0 g, 3.6 mmol) in 1,4-dioxane (35.95 mL) was added potassium acetate (1.06 g, 10.79 mmol) and bis(pinacolato)diborane (1.83 g, 7.19 mmol). The mixture was degassed with N2 then PdCh(dppl)»CH2C12 (0.29 g, 0.36 mmol) was added and the reaction was stirred at 100 °C for 2 hrs. The solvent was evaporated and the residue was purified by flash silica gel chromatography using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (1.68 g, 66% UV area) as an orange oil which was used without further purification. 'H NMR (400 MHz, DMSO- e) 6 8.31 (d, J = 0.9 Hz, 1H), 7.87 - 7.82 (m, 3H), 7.49 (dd, J = 8.0, 0.9 Hz, 1H), 3.96 (s, 3H), 1.32 (s, 12H). MS-ESI (m/z) calc’d for C17H21DBN4O2 [M+H]+: 326.2. Found 326.4.
Step 6: 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-3-d-6-ol
Figure imgf000347_0001
To a solution of l-(l-methyl-17/-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-17/-indazole-3-d (1.68 g, 3.41 mmol) in methanol (51.66 mL) was added hydrogen peroxide (1.74 mL, 17.05 mmol) and the mixture was stirred at 25 °C for 3 hrs. The solvent was evaporated and the residue was taken up in H2O and stirred for 10 minutes. The solid formed was collected by filtration and dried under vacuum to obtain the title compound (591 mg, 81%) as a pink solid. 'H NMR (400 MHz, DMSO- e) 6 9.79 (s, 1H), 8.21 (d, J = 0.8 Hz, 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.7, 2.0 Hz, 1H), 3.92 (s, 3H). MS-ESI (m/z) calc’d for C11H10DN4O [M+H]+: 216.1. Found 216.1.
Step 7: 5-( (1-(1 -Methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl-3-d)oxy)-5, 6, 7, 8-
Figure imgf000347_0002
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile using 1-(1- methyl-17/-pyrazol-4-yl)-17/-indazol-3-d-6-ol in place of 1-(1 -methyl- 17/-pyrazol-4-yl)- 1H- indazol-6-ol. The material was subjected to chiral preparative HPLC using Method FN to afford 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl-3-d)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (35 mg, 19%) as a white solid. 'H NVIR (400 MHz, DMSO- e) 6 8.30 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.0, 1.7 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.8, 2.1 Hz, 1H), 5.78 (t, J = 5.0 Hz, 1H), 3.93 (s, 3H), 2.91 (dt, J = 17.2, 5.7 Hz, 1H), 2.85 - 2.73 (m, 1H), 2.13 - 1.98 (m, 2H), 1.97 - 1.73 (m, 2H). MS-ESI (m/z) calc’d for C22H19DN5O [M+H]+: 371.1. Found 371.1. A later eluting fraction was also isolated to afford 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl-3- d)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (39 mg, 21%). 'H NMR (400 MHz, DMSO- e) 6 8.30 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.64 (dd, J = 8.0, 1.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.8, 2.1 Hz, 1H), 5.78 (t, J = 5.0 Hz, 1H), 3.93 (s, 3H), 2.91 (dt, J = 17.2, 5.7 Hz, 1H), 2.85 - 2.73 (m, 1H), 2.12 - 1.99 (m, 2H), 1.97 - 1.73 (m, 2H). MS-ESI (m/z) calc’d for C22H19DN5O [M+H]+: 371.1. Found 371.1.
Example 181: 2-(Difliioromethyl)-8-((l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000348_0001
To a solution of 2-chloro-5,6,7,8-tetrahydroquinoline-3-carbonitrile (2.0 g, 10.38 mmol) in trifluoroacetic acid (50 mL) was added hydrogen peroxide (3.18 mL, 31.15 mmol) and the mixture was stirred at 75 °C for 15 hrs. Water was added and the solution was neutralized by addition of solid K2CO3 and then extracted with DCM (3x). The combined organic layers were washed with H2O (lx), passed through a phase separator and evaporated under reduced pressure to afford the title compound (1.98 g, 91%) as a light-yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 7.77 (1 H, s) 2.78 (4 H, dt, J=16.40, 6.33 Hz) 1.77 - 1.87 (2 H, m) 1.62 - 1.71 (2 H, m). MS-ESI (m/z) calc’d for C10H10CIN2O [M+H]+: 209.0. Found 209.0.
Figure imgf000349_0001
To a solution of 2-chloro-3-cyano-5,6,7,8-tetrahydroquinoline 1-oxide (1.92 g, 9.2 mmol) in DCM (50 mL) was added dropwise trifluoroacetic anhydride (3.84 mL, 27.61 mmol) and the mixture was stirred at 25 °C for 20 hrs. The solvent was evaporated and the residue was taken up in MeOH, then K2CO3 was added till basic pH and the suspension was stirred at 25 °C for 1 hr. The solvent was evaporated keeping the temperature under 40 °C, the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-60% EtOAc/cyclohexane gradient eluent to afford the title compound (1.43 g, 75%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.25 (1 H, s) 5.62 (1 H, d, J=5.28 Hz) 4.56 (1 H, q, J=4.84 Hz) 2.76 - 2.87 (1 H, m) 2.62 - 2.75 (1 H, m) 1.80 - 1.95 (3 H, m) 1.65 - 1.76 (1 H, m). MS-ESI (m/z) calc’d for C10H10CIN2O [M+H]+: 209.0. Found 209.0.
Step 3: 2-Chloro-8-((tetrahydro-2H-pyran-2-yl)oxy)-5,6, 7,8-tetrahydroquinoline-3- carbonitrile
Figure imgf000349_0002
To a suspension of 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (580.0 mg, 2.67 mmol) in DCM (13.8 mL), 3,4-dihydro-27/-pyran (0.49 mL, 5.34 mmol) and pyridinium p-toluenesulfonate (13.41 mg, 0.050 mmol) were sequentially added and the reaction was stirred at r.t. for 18 hrs. The solvent was removed and the residue was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (800 mg, 100%) as a colorless oil. 'H NMR (400 MHz, DMSO- e) 8 8.28 (d, J = 4.5 Hz, 2H), 5.11 (dd, J = 4.3, 2.7 Hz, 1H), 4.91 (s, 1H), 4.74 - 4.65 (m, 2H), 4.15 - 4.02 (m, 2H), 3.83 (ddd, J = 11.2, 7.9, 3.4 Hz, 1H), 3.58 - 3.38 (m, 2H), 2.85 (ddt, J = 13.4, 9.6, 5.0 Hz, 2H), 2.70 (dt, J = 16.5, 7.7 Hz, 2H), 2.15 - 2.00 (m, 2H), 1.97 - 1.81 (m, 1H), 1.80 - 1.70 (m, 3H), 1.64 (dddd, J = 11.9, 9.2, 5.6, 2.1 Hz, 3H), 1.55 - 1.41 (m, 11H). MS-ESI (m/z) calc’d for C15H18CIN2O2 [M+H]+: 293.1. Found 293.1.
Step 4: 8-((Tetrahydro-2H-pyran-2-yl)oxy)-2-vinyl-5,6, 7,8-tetrahydroquinoline-3- carbonitrile
Figure imgf000350_0001
A microwave reaction vial was charged with 2-chloro-8-((tetrahydro-27/-pyran-2- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (850.0 mg, 2.9 mmol), triphenylphosphine (22.85 mg, 0.09 mmol), tributyl(ethenyl)stannane (1.02 mL, 3.48 mmol) and toluene (10.15 mL) under N2. The reaction mixture was degassed with N2 for 10 min, then tetrakis(triphenylphosphine)palladium(0) (33.55 mg, 0.03 mmol) was added and the mixture was heated at 90 °C overnight. Additional tetrakis(triphenylphosphine)palladium(0) (33.55 mg, 0.03 mmol), tributyl(ethenyl)stannane (1.02 mL, 3.48 mmol) were added and the reaction was stirred for 5 hrs at 90 °C. The solvent was removed and the residue was purified by flash silica gel chromatography using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (674 mg, 82%) as a pale yellow oil. JH NMR (400 MHz, DMSO- d6) 8 8.07 (d, J = 7.0 Hz, 2H), 7.05 (ddd, J = 17.0, 10.6, 6.5 Hz, 2H), 6.48 (ddd, J = 19.1, 16.8, 2.0 Hz, 2H), 5.72 (dt, J = 10.5, 2.0 Hz, 2H), 5.26 (d, J = 4.3 Hz, 1H), 4.97 (d, J = 2.9 Hz, 1H), 4.78 - 4.68 (m, 2H), 4.28 - 4.16 (m, 1H), 3.92 - 3.81 (m, 1H), 3.47 (ddt, J = 31.1, 10.2, 4.7 Hz, 3H), 2.84 (ddd, J = 16.1, 10.5, 4.9 Hz, 2H), 2.71 (dq, J = 17.5, 5.8, 3.9 Hz, 2H), 1.83 - 1.38 (m, 13H). MS-ESI (m/z) calc’d for C17H21N2O2 [M+H]+: 285.1. Found 285.1.
Step 5: 2-Formyl-8-((tetrahydro-2H-pyran-2-yl)oxy)-5,6, 7,8-tetrahydroquinoline-3- carbonitrile
Figure imgf000351_0001
A solution of 8-((tetrahydro-27/-pyran-2-yl)oxy)-2-vinyl-5,6,7,8-tetrahydroquinoline- 3-carbonitrile (500.0 mg, 1.76 mmol) in DCM (30 mL) was cooled to -78 °C. A stream of ozone-enriched oxygen was introduced until a yellow color persisted. After 20 min a stream of dry nitrogen was bubbled through the reaction mixture and a solution of triphenylphosphine (553.45 mg, 2.11 mmol) in DCM (5 mL) was added dropwise. The resulting solution was stirred for 5 min and warmed to r.t. Volatiles were removed under reduced pressure to afford the title compound as a yellow oil and as a mixture of the two diasteroisomers (499 mg). This residue was used without further purification. MS-ESI (m/z) calc’d for C16H19N2O3 [M+H]+: 287.2. Found 287.2.
Step 6: 2-(Difluoromethyl)-8-((tetrahydro-2H-pyran-2-yl)oxy)-5,6, 7,8-tetrahydroquinoline- 3-carbonitrile
Figure imgf000351_0002
To a solution of 2-formyl-8-((tetrahydro-2H-pyran-2-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile (1.8 mmol theoretical, used as prepared from previous reaction) in DCM (2.5 mL) was added DAST (0.11 mL, 0.85 mmol) dropwise at 0 °C. The resulting mixture was warmed to r.t. and stirred for 18 hrs. The reaction solution was quenched with saturated aqueous NaHCOs. The reaction mixture was then partitioned between H2O and DCM and the phases were separated. The aqueous layer was extracted with DCM (2x) and the combined organic phases were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The residue was purified by silica gel chromatography on a 25 g silica gel column using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (130 mg, 24%) as a colorless oil. JH NMR (400 MHz, DMSO-d6) δ 8.34 - 8.35 (1 H, m) 6.84 - 7.26 (1 H, m) 4.91 - 5.22 (1 H, m) 4.77 (1 H, t, J=4.18 Hz) 3.80 - 4.15 (1 H, m) 3.42 - 3.58 (1 H, m) 2.88 - 3.00 (1 H, m) 2.74 - 2.86 (1 H, m) 2.03 - 2.22 (1 H, m) 1.57 - 2.02 (5 H, m) 1.42 - 1.56 (4 H, m). MS-ESI (m/z) calc’d for C16H19F2N2O [M+H]+: 309.1. Found 309.1.
Figure imgf000352_0001
To a solution of 2-(difluoromethyl)-8-(oxan-2-yloxy)-5,6,7,8-tetrahydroquinoline-3- carbonitrile (130.0 mg, 0.42 mmol) in DCM (6 mL), was added trifluoroacetic acid (1.5 mL) and the reaction mixture was stirred at r.t. for 1 hr. The reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography on an 11 g NH silica gel column, using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (80 mg, 85%) as a white solid. JH NMR (400 MHz, DMSO-rie) 8 8.31 (1 H, s) 6.89 - 7.28 (1 H, m) 5.52 (1 H, d, J=5.28 Hz) 4.57 - 4.69 (1 H, m) 2.84 - 2.96 (1 H, m) 2.71 - 2.82 (1 H, m) 1.84 - 1.99 (3 H, m) 1.67 - 1.78 (1 H, m). MS-ESI (m/z) calc’d for C11H11F2N2O [M+H]+: 225.1. Found 225.1.
Step 8: 2-(Difluoromethyl)-8-( (1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)oxy) -5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000352_0002
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile using 2- (difluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 5- hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. The material was subjected to chiral preparative HPLC using Method FO to afford 2-(difluoromethyl)-8-(( l-( l-methyl- l//- pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (8.4 mg, 13%) as a white solid. 'H NMR (400 MHz, DMSO-de) 8 8.46 (1 H, s) 8.30 (1 H, s) 8.16 (1 H, d, J=0.88 Hz) 7.90 (1 H, s) 7.73 (1 H, d, J=8.58 Hz) 7.35 (1 H, s) 6.90 - 7.27 (2 H, m) 5.77 (1 H, t, J=3.74 Hz) 3.92 (3 H, s) 2.96 - 3.09 (1 H, m) 2.79 - 2.95 (1 H, m) 2.21 - 2.31 (1 H, m) 1.77 - 2.11 (3 H, m). MS-ESI (m/z) calc’d for C22H19F2N6O [M+H]+: 421.2. Found 421.2. A later eluting fraction was also isolated to afford 2-(difluoromethyl)-8-((l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (9.0 mg, 14%). 'H NMR (400 MHz, DMSO-d6) δ 8.46 (1 H, s) 8.30 (1 H, s) 8.16 (1 H, d, J=0.88 Hz) 7.90 (1 H, d, J=0.66 Hz) 7.73 (1 H, d, J=8.80 Hz) 7.35 (1 H, s) 6.91 - 7.25 (2 H, m) 5.77 (1 H, t, J=3.63 Hz) 3.92 (3 H, s) 2.97 - 3.13 (1 H, m) 2.78 - 2.95 (1 H, m) 2.22 - 2.31 (1 H, m) 1.74 - 2.10 (3 H, m). MS-ESI (m/z) calc’d for C22H19F2N6O [M+H]+: 421.2. Found 421.2.
Example 182: 2-(DifluoromethyI)-8-((5-methyI-l-(l-methyI-lH-pyrazol-4-yI)-LH- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000353_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 2- (difluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 5- hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. The material was subjected to chiral preparative HPLC using Method FP to afford 2-(difluoromethyl)-8-((5-methyl-l-(l-methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (6.1 mg, 9%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 8.46 (1 H, s) 8.28 (1 H, s) 8.07 (1 H, s) 7.92 (1 H, s) 7.56 (1 H, s) 7.49 (1 H, s) 6.90 - 7.23 (1 H, m) 5.80 (1 H, t, J=3.63 Hz) 3.93 (3 H, s) 3.01 - 3.12 (1 H, m) 2.80 - 2.98 (1 H, m) 2.24 - 2.36 (1 H, m) 2.14 (3 H, s) 1.78 - 2.09 (3 H, m). MS-ESI (m/z) calc’d for C23H21F2N6O [M+H]+: 435.2. Found 435.2. A later eluting fraction was also isolated to afford 2-(difluoromethyl)-8-((5- methyl- l-( l-methyl-l7/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroquinolme-3- carbonitrile, enantiomer 2 (7.2 mg, 11%). 'H NMR (400 MHz, DMSO-d6) δ 8.46 (1 H, s) 8.28 (1 H, s) 8.06 (1 H, s) 7.92 (1 H, s) 7.56 (1 H, s) 7.49 (1 H, s) 6.77 - 7.26 (1 H, m) 5.80 (1 H, t, J=4.07 Hz) 3.93 (3 H, s) 3.01 - 3.12 (1 H, m) 2.84 - 2.98 (1 H, m) 2.24 - 2.32 (1 H, m) 2.14 (3 H, s) 1.78 - 2.10 (3 H, m). MS-ESI (m/z) calc’d for C23H21F2N6O [M+H]+: 435.2. Found 435.2. Example 183: 6-((6-Cyano-l,2,3,4-tetrahydronaphthalen-l-yI)oxy)-l-(l-methyI-LH- pyrazol-4-yI)-LH-indazole-5-carbonitriIe, enantiomer 1 and 2
Figure imgf000354_0001
Step 1: 5-((5-Chloro-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000354_0002
2-Tributylphosphoranylideneacetonitrile (82.5 mg, 0.34 mmol) was added to a solution of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (59.21 mg, 0.34 mmol) and 5-chloro-l-(l-methylpyrazol-4-yl)indazol-6-ol (85.0 mg, 0.34 mmol) in dry toluene (8.5 mL). The resulting mixture was stirred at 100 °C for 1 hr. Water (100 mL) was added and the mixture was extracted with EtOAc (3x 100 mL), the combined organic layers were dried over Na2SC>4, filtered and evaporated. The residue obtained was purified by flash silica gel chromatography (ISOLERA; 28 g NH cartridge) using a 0-80% EtOAc/cyclohexane gradient eluent. The material was further purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (32.5 mg, 24%) as a beige solid. 'H NMR (400 MHz, CDCh) 6 8.02 (d, J = 1.0 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.07 (s, 1H), 5.45 - 5.39 (m, 1H), 4.01 (s, 3H), 3.02 - 2.91 (m, 1H), 2.84 (dd, J = 15.4, 8.7 Hz, 1H), 2.27 - 2.06 (m, 3H), 1.94 - 1.79 (m, 1H). MS-ESI (m/z) calc’d for C22H19CIN2O [M+H]+: 404.0. Found 404.2.
Step 2: 6-( ( 6-Cyano-l, 2, 3, 4-tetrahydronaphthalen-l-yl)oxy)-l-( 1 -methyl- lH-pyrazol-4-yl)- lH-indazole-5-carbonitrile, enantiomer 1 and 2
Figure imgf000354_0003
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17/-pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 5-((5-chloro-l-(l-methyl-17/-pyrazol-4- yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in place of 6-((5- bromo-6-chl oro-2, 3 -dihydro- 17/-i nden- 1 -y l)oxy )- 1 -( 1 -methyl- 17/-py razol-4-y 1)- 1H- indazole. The material was subjected to chiral preparative HPLC using Method FQ to afford 6-((6-cy ano- 1 ,2,3 ,4-tetrahy dronaphthalen- 1 -y l)oxy )- 1 -( 1 -methyl- 1/f-py razol-4-y 1)- 1H- indazole-5 -carbonitrile, enantiomer 1 (2.2 mg, 7%) as a white solid. JH NMR (400 MHz, MeOD) 6 8.26 - 8.22 (m, 2H), 8.17 (s, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.57 - 7.50 (m, 2H), 7.38 (s, 1H), 5.83 (t, J = 4.7 Hz, 1H), 4.01 (s, 3H), 3.00 (dt, J = 17.3, 5.4 Hz, 1H), 2.93 - 2.80 (m, 1H), 2.25 - 2.03 (m, 3H), 1.98 - 1.84 (m, 1H). MS-ESI (m/z) calc’d for C23H19N6O [M+H]+: 395.2. Found 395.2. A later eluting fraction was also isolated to afford 6-((6-cy ano- 1 , 2, 3, 4-tetrahy dronaphthalen- 1 -yl)oxy)- 1 -(1 -methyl- 17/-pyrazol-4-yl)- 17/-indazole-5 -carbonitrile, enantiomer 2 (2.2, 7%) as a white solid. 1 H NMR (400 MHz, MeOD) 6 8.27 - 8.21 (m, 2H), 8.17 (s, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.57 - 7.49 (m, 2H), 7.38 (s, 1H), 5.83 (t, J = 4.7 Hz, 1H), 4.01 (s, 3H), 3.00 (dt, J = 17.2, 5.5 Hz, 1H), 2.91 - 2.80 (m, 1H), 2.26 - 2.04 (m, 3H), 1.97 - 1.86 (m, 1H). MS-ESI (m/z) calc’d for C23H19N6O [M+H]+: 395.2. Found 395.2.
Example 184: 8-((5-MethyI-l-(l-methyI-lH-pyrazol-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitriIe, enantiomer 1 and 2
Figure imgf000355_0001
To a solution of 8-oxo-5,6,7,8-tetrahydroquinolone-3-carbonitrile (250.0 mg, 1.45 mmol) in MeOH (10 mL) was added sodium borohydride (109.86 mg, 2.9 mmol) and the mixture was stirred at r.t. for 1 hr. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x), the combined organic layers were washed with H2O (lx), passed through a phase separator and evaporated to dryness to afford the title compound (205 mg, 81%) as a brownish solid. 'H NMR (400 MHz, DMSO-d6) δ 8.72 - 8.94 (1 H, m) 8.06 (1 H, s) 5.40 (1 H, d, J=3.96 Hz) 4.59 (1 H, br. s.) 2.63 - 2.92 (2 H, m) E81 - 2.06 (3 H, m) E59 - E80 (1 H, m). MS-ESI (m/z) calc’d for C10H11N2O [M+H]+: 175.1. Found 175.1.
Step 2: 8-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000356_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl- IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile using 8-hydroxy- 5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 5-hy droxy-5, 6,7,8- tetrahy dronaphthalene-2-carbonitrile and 5 -methyl- 1 -( 1 -methyl- 17/-py razol -4-y I )- 1H- indazol-6-ol in place of l-[l-(3-bicyclo[l.l.l]pentanyl)pyrazol-4-yl]-5-methylindazol-6-ol. The material was subjected to chiral preparative HPLC using Method FR to afford 8-((5- methyl- l-( l-methyl-l7/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroc|umolme-3- carbonitrile, enantiomer 1 (17.2 mg, 19%) as a white solid. JH NMR (400 MHz, DMSO- e) 8 8.87 (1 H, d, J=1.98 Hz) 8.29 (1 H, s) 8.22 (1 H, d, J=1.98 Hz) 8.06 (1 H, d, J=0.66 Hz) 7.93 (1 H, d, J=0.66 Hz) 7.55 (1 H, s) 7.51 (1 H, s) 5.79 (1 H, t, J=3.74 Hz) 3.95 (3 H, s) 2.95 - 3.05 (1 H, m) 2.80 - 2.93 (1 H, m) 2.24 - 2.31 (1 H, m) 2.13 (3 H, s) 1.92 - 2.11 (2 H, m) 1.82 - 1.91 (1 H, m). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 385.2. Found 385.2.
A later eluting fraction was also isolated to afford 8-((5-methyl- l-( l-methyl- IT/- pyrazol-4-yl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroc|umoline-3-carbonitrile. enantiomer 2 (17.4 mg, 20%). 'H NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, d, J=2.20 Hz) 8.29 (1 H, s) 8.22 (1 H, d, J=1.98 Hz) 8.06 (1 H, d, J=0.66 Hz) 7.93 (1 H, d, J=0.66 Hz) 7.55 (1 H, s) 7.51 (1 H, s) 5.79 (1 H, t, J=3.74 Hz) 3.95 (3 H, s) 2.94 - 3.07 (1 H, m) 2.80 - 2.92 (1 H, m) 2.23 - 2.32 (1 H, m) 2.13 (3 H, s) 1.92 - 2.11 (2 H, m) 1.82 - 1.92 (1 H, m). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 385.2. Found 385.2.
Example 185: 8-((5-IVIethyl-l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6-yl)amino)-
5,6,7,8-tetrahydroquinoline-3-carbonitriIe, enantiomer 1 and 2
Figure imgf000357_0001
Prepared as described for 5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using/V-(3-cyano-5,6,7,8- tetrahydroquinolin-8-yl)-N-(5-methyl- l -( l-methyl-IT/-pyrazol-4-yl)- l7/-indazol-6-yl)-2- nitrobenzenesulfonamide in place of /V-(6-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-(5- methyl- l-( l-methyl-l7/-pyrazol-4-yl)- l7/-indazol-6-yl)-2-nitrobenzenesulfonamide. The material was subjected to chiral preparative HPLC using Method FS to afford 8-((5-methyl- l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8-tetrahydroquinoline-3- carbonitrile, enantiomer 1 (4.9 mg, 8%) as a light yellow solid. JH NMR (400 MHz, DMSO- de) 8 8.82 (1 H, d, J=1.98 Hz) 8.18 (1 H, s) 8.15 (1 H, d, J=1.98 Hz) 7.91 (1 H, d, J=0.66 Hz) 7.82 (1 H, d, J=0.66 Hz) 7.42 (1 H, s) 6.77 (1 H, s) 5.54 (1 H, d, J=6.60 Hz) 4.86 - 4.95 (1 H, m) 3.92 (3 H, s) 2.86 - 2.93 (2 H, m) 2.15 - 2.25 (4 H, m) 1.87 - 2.03 (3 H, m). MS-ESI (m/z) calc’d for C22H22N7 [M+H]+: 384.2. Found 384.2. A later eluting fraction was also isolated to afford 8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (4.8 mg, 8%) as a light yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 8.82 (1 H, d, J=2.20 Hz) 8.18 (1 H, s) 8.15 (1 H, d, J=1.98 Hz) 7.91 (1 H, d, J=0.66 Hz) 7.82 (1 H, d, J=0.66 Hz) 7.42 (1 H, s) 6.77 (1 H, s) 5.54 (1 H, d, J=6.60 Hz) 4.86 - 4.99 (1 H, m) 3.92 (3 H, s) 2.85 - 2.93 (2 H, m) 2.16 - 2.25 (4 H, m) 1.86 - 2.02 (3 H, m). MS-ESI (m/z) calc’d for C22H22N7 [M+H]+: 384.2. Found 384.2.
Example 186: 8-((5-Fluoro- l-(l-methyl- 1 H-py razol-4-yl)- lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000357_0002
Step 1: 6-Bromo-5 -fluoro- 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazole
Figure imgf000358_0001
A mixture of 6-bromo-5-fluoro-17/-indazole (300.0 mg, 1.4 mmol), 4-iodo-l- methylpyrazole (290.21 mg, 1.4 mmol), (17?,27?)-Al,A2-dimethylcyclohexane-l,2-diamine (99.23 mg, 0.700 mmol), copper(I) iodide (53.14 mg, 0.28 mmol) and tripotassium phosphate (887.36 mg, 4.19 mmol) in dry DMSO (4.6 mL) was heated and stirred at 100 °C for 5 hrs. The mixture was diluted with a H2O buffer (pH 3) and extracted with EtOAc (3x). The combined organic layers were washed with H2O (3x), dried over Na2SO4, and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (177 mg, 43%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.39 (s, 1H), 8.30 (d, J = 1.0 Hz, 1H), 8.08 (dd, J = 5.5, 1.0 Hz, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H). MS- ESI (m/z) calc’d for CnH9BrFN4 [M+H]+: 295.0, 297.0. Found 295.0, 297.0.
Step 2: 5-Fluoro-l-( 1 -methyl- lH-pyrazol-4-yl)-6-( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2- yl)-lH-indazole
Figure imgf000358_0002
To a solution of 6-bromo-5 -fluoro- 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazole (170.0 mg, 0.58 mmol) in methoxy cyclopentane (2 mL) were added potassium acetate (169.6 mg, 1.73 mmol) and bis(pinacolato)diborane (0.29 g, 1.15 mmol). The mixture was degassed with N2 then PdC12(dppl »CH2C12 (47.16 mg, 0.06 mmol) was added and the reaction was stirred at 100 °C for 16 hrs. The reaction mixture was partitioned between H2O and EtOAc, the phases were separated, the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with H2O (lx), dried over anhydrous Na2SO4, and evaporated to dryness to afford the title compound (0.5 g) which was used without further purification. MS-ESI (m/z) calc’d for C17H21BFN4O2 [M+H]+: 343.2. Found 343.2.
Step 3: 5 -Fluoro- 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-ol
Figure imgf000359_0001
To a solution of 5-fluoro-l-(l-methyl-17/-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-17/-indazole (197.1 mg, 0.58 mmol) in MeOH (4 mL) was added hydrogen peroxide (0.29 mL, 2.88 mmol) and the mixture was stirred at 25 °C for 1.5 hrs. The solvent was evaporated, the residue was taken up in H2O and extracted with EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were washed with water (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography on a 25 g silica gel column, using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (60 mg, 45%) as an off-white solid. JH NMR (400 MHz, DMSO-d6) δ 10.33 (1 H, br. s.) 8.21 (1 H, s) 8.07 (1 H, d, J=0.88 Hz) 7.79 (1 H, d, J=0.66 Hz) 7.57 (1 H, d, J=10.56 Hz) 7.06 (1 H, d, J=7.26 Hz) 3.92 (3 H, s). MS-ESI (m/z) calc’d for C11H10FN4O [M+H]+: 233.1. Found 233.1.
Step 4: 8-((5-Fluoro-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000359_0002
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile using 5-fluoro-l- (1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)- l//-pyrazol-4-yl)-5-methyl- l//-indazol-6-ol. The material was subjected to chiral preparative HPLC using Method FT to afford 8-((5-fluoro-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (8.5 mg, 17%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.32 (1 H, s) 8.17 (1 H, d, J=0.66 Hz) 7.95 (1 H, s) 7.63 - 7.80 (3 H, m) 7.46 - 7.60 (2 H, m) 5.83 (1 H, t, J=4.62 Hz) 3.94 (3 H, s) 2.87 - 2.99 (1 H, m) 2.74 - 2.85 (1 H, m) 2.01 - 2.11 (2 H, m) 1.74 - 1.96 (2 H, m). MS-ESI (m/z) calc’d for C21H18FN6O [M+H]+: 388.2. Found 388.3. A later eluting fraction was also isolated to afford 8-((5 -fluoro- 1 -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (8.8mg, 18%). 'H NMR (400 MHz, DMSO-d6) δ 8.32 (1 H, s) 8.17 (1 H, d, J=0.66 Hz) 7.95 (1 H, s) 7.63 - 7.80 (3 H, m) 7.46 - 7.60 (2 H, m) 5.83 (1 H, t, J=4.62 Hz) 3.94 (3 H, s) 2.87 - 2.99 (1 H, m) 2.74 - 2.85 (1 H, m) 2.01 - 2.11 (2 H, m) E74 - E96 (2 H, m). MS-ESI (m/z) calc’d for C21H18FN6O [M+H]+: 388.2. Found 388.3.
Example 187: 8-((5-Fluoro- l-(l-methyl- 1 H-py razol-4-yl)- lH-indazol-6-yl)oxy)-4- methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000360_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 5-fluoro-l- (1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)- 17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol and 8-hy droxy-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile in place of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carbonitrile. The material was subjected to chiral preparative HPLC using Method FU to afford 8-((5-fluoro-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (11.4 mg, 22%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 8.78 (1 H, s) 8.32 (1 H, s) 8.15 (1 H, d, J=0.88 Hz) 7.93 (1 H, d, J=0.66 Hz) 7.60 - 7.67 (2 H, m) 5.81 (1 H, t, J=3.19 Hz) 3.94 (3 H, s) 2.87 - 2.97 (1 H, m) 2.69 - 2.76 (1 H, m) 2.46 (3 H, s) 2.20 - 2.31 (1 H, m) 1.85 - 2.05 (3 H, m). MS-ESI (m/z) calc’d for C22H20FN6O [M+H]+: 403.2. Found 403.2. A later eluting fraction was also isolated to afford 8-((5 -fluoro- l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4-methyl- 5, 6, 7, 8 -tetrahydroquinoline-3 -carbonitrile, enantiomer 2 (8.9 mg, 17%). 'H NMR (400 MHz, DMSO-d6) δ 8.78 (1 H, s) 8.32 (1 H, s) 8.15 (1 H, d, J=0.88 Hz) 7.93 (1 H, d, J=0.66 Hz) 7.60 - 7.68 (2 H, m) 5.81 (1 H, t, J=3.19 Hz) 3.94 (3 H, s) 2.85 - 2.97 (1 H, m) 2.68 - 2.77 (1 H, m) 2.46 (3 H, s) 2.22 - 2.30 (1 H, m) 1.84 - 2.04 (3 H, m). MS-ESI (m/z) calc’d for C22H20FN6O [M+H]+: 403.2. Found 403.2. Example 188: 2-ChIoro-8-((5-methyI-l-(l-methyI-tH-pyrazol-4-yI)-tH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000361_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 5-methyl-l- (1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)- 17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol and 2-chloro-8-hydroxy-5,6,7,8- tetrahydroquinoline-3-carbonitrile in place of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carbonitrile. The material was subjected to chiral preparative HPLC using Method FV to afford 2-chloro-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (20.0 mg, 16%) as a white solid. ’H NVIR (400 MHz, DMSO- e) 6 8.41 (s, 1H), 8.29 (s, 1H), 8.07 (d, J = 0.9 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 5.74 (t, J = 3.9 Hz, 1H), 3.94 (s, 3H), 3.02 - 2.93 (m, 1H), 2.87 - 2.75 (m, 1H), 2.28 - 2.19 (m, 1H), 2.16 (s, 3H), 2.08 - 1.91 (m, 2H), 1.87 (s, 1H). MS-ESI (m/z) calc’d for C22H20CIN6O [M+H]+: 419.1. Found 419.3. A later eluting fraction was also isolated to afford 2-chloro-8-((5-meth l- 1 -( I -methyl- IT/-pyrazol-4- l)- 17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (20.0 mg, 16%). 'H NMR (400 MHz, DMSO- e) 6 8.41 (s, 1H), 8.29 (s, 1H), 8.07 (d, J = 0.9 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.57 (d, J = 1.1 Hz, 1H), 7.51 (s, 1H), 5.74 (t, J = 3.9 Hz, 1H), 3.94 (s, 3H), 3.03 - 2.91 (m, 1H), 2.90 - 2.74 (m, 1H), 2.29 - 2.19 (m, 1H), 2.16 (s, 3H), 2.09 - 1.91 (m, 2H), 1.91 - 1.82 (m, 1H). MS-ESI (m/z) calc’d for C22H20CIN6O [M+H]+: 419.1. Found 419.3.
Example 189: 4-(Difluoromethyl)-8-((5-methyl-l-(l-methyl-lff-pyrazol-4-yl)-l/7- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000361_0002
Step 1: 4-(Difluoromethyl)-8-oxo-5,6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000362_0001
A solution of 8-oxo-6,7-dihydro-57/-quinoline-3-carbonitrile (100.0 mg, 0.580 mmol) and zinc difluoromethanesulfinate (514.94 mg, 1.74 mmol) in DCM (4.4 mL) and H2O (2.2 mL) was cooled in ice water. The mixture was stirred vigorously while adding 2- hydroperoxy-2-methylpropane (0.32 mL, 2.32 mmol) 70% solution in H2O. Then the solution was warmed to room temperature and stirred at r.t. overnight. The reaction mixture was partitioned between water and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (lx), passed through a phase separator and evaporated to dryness. The material was purified by silica gel chromatography on a 10 g silica gel column, using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (65 mg, 50%) was obtained as a yellow solid. JH NMR (400 MHz, DMSO-d6) δ 9.19 (1 H, s) 7.31 - 7.74 (1 H, m) 3.15 (2 H, t, J=6.05 Hz) 2.75 - 2.82 (2 H, m) 2.13 (2 H, quin, J=6.44 Hz). MS-ESI (m/z) calc’d for C11H9F2N2O [M+H]+: 223.1. Found 223.1.
Figure imgf000362_0002
To a solution of sodium borohydride (40.86 mg, 1.08 mmol) in MeOH (5.5 mL) was added 4-(difluoromethyl)-8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (120.0 mg, 0.540 mmol) and the mixture was stirred at r.t. for 1 hr. The solvent was evaporated, the residue was taken up in H2O and extracted with DCM (3x), the combined organic layers were washed with H2O (lx), passed through a phase separator and evaporated to dryness. The residue was purified by silica gel chromatography on a 10 g silica gel column, using as eluent a gradient of EtOAc in cyclohexane from 0 to 60% to afford the title compound (60 mg, 49%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) δ 9.02 (1 H, s) 7.23 - 7.67 (1 H, m) 5.57 (1 H, d, J=4.84 Hz) 4.65 (1 H, q, J=4.55 Hz) 2.94 - 3.06 (1 H, m) 2.75 - 2.91 (1 H, m) 1.81 - 2.03 (3 H, m) 1.68 - 1.80 (1 H, m). MS-ESI (m/z) calc’d for C11H11F2N2O [M+H]+: 225.1. Found 225.1. Step 3: 4-(Difluoromethyl)-8-( (5-methyl-l-( 1 -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-
Figure imgf000363_0001
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 5-methyl-l- (1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)- 17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol and 4-(difluoromethyl)-8-hydroxy-5, 6,7,8- tetrahydroquinoline-3-carbonitrile in place of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carbonitrile. The material was subjected to chiral preparative HPLC using Method FW to afford 4-(difluoromethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)- 5, 6, 7, 8 -tetrahydroquinoline-3 -carbonitrile, enantiomer 1 (15.1 mg, 17%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 9.07 (1 H, s) 8.29 (1 H, s) 8.07 (1 H, d, J=0.66 Hz) 7.93 (1 H, d, J=0.66 Hz) 7.31 - 7.61 (3 H, m) 5.86 (1 H, t, J=3.85 Hz) 3.95 (3 H, s) 3.11 - 3.22 (1 H, m) 2.88 - 3.01 (1 H, m) 2.23 - 2.32 (1 H, m) 2.14 (3 H, s) 1.88 - 2.13 (3 H, m). MS-ESI (m/z) calc’d for C23H21F2N6O [M+H]+: 435.2. Found 435.2. A later eluting fraction was also isolated to afford 4-(difluoromethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (15.2 mg, 17%). 'H NMR (400 MHz, DMSO-d6) δ 9.07 (1 H, s) 8.29 (1 H, s) 8.07 (1 H, d, J=0.66 Hz) 7.93 (1 H, s) 7.32 - 7.65 (3 H, m) 5.86 (1 H, t, J=3.85 Hz) 3.95 (3 H, s) 3.11 - 3.23 (1 H, m) 2.87 - 3.02 (1 H, m) 2.22 - 2.32 (1 H, m) 2.14 (3 H, s) 1.87 - 2.13 (3 H, m). MS-ESI (m/z) calc’d for C23H21F2N6O [M+H]+: 435.2. Found 435.2.
Example 190: 4-Methyl-7-((5-methyl-l-(l-methyl-lff-pyrazol-4-yl)-lff-indazol-6- yl)oxy )-6.7-dihydro-5//-cyclopenta|b|pyridine-3-carbonitrile. enantiomer 1 and 2
Figure imgf000363_0002
Step 1: 1 -Methyl- 3-oxo- 3, 5, 6, 7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile and 4-
Methyl-2-oxo-2, 5, 6, 7-tetrahydro-lH-cyclopenta[b ]pyridine-3-carbonitrile
Figure imgf000364_0001
To a solution of 2-acetyl-l -cyclopentanone (2.52 g, 20 mmol) and 2-cyanoacetamide (1.68 g, 20 mmol) was added piperidine (1.98 mL, 20 mmol) and the mixture was stirred at 75 °C for 22 hrs. After cooling the solid was filtered to obtain the title compounds (1.62 g, 46%) as a white solid. MS-ESI (m/z) calc’d for C10H11N2O [M+H]+: 175.1. Found 175.0.
Step 2: 3-Chloro-l -methyl-3,5 ,6, 7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile and
Figure imgf000364_0002
A suspension of l-methyl-3-oxo-3,5,6,7-tetrahydro-27/-cyclopenta[c]pyridine-4- carbonitrile; 4-methyl-2-oxo-2.5.6.7-tetrahydro- l7/-cyclopenta|b|pyridme-3-carbonitrile (1.62 g, 9.3 mmol) in POCh (10.0 mL, 106.96 mmol) was heated at 100 °C for 17 hrs. The excess POCh was removed by evaporation and the oil was taken up in H2O and stirred for 30 minutes. The solid formed was filtered and dried under vacuum to obtain the title compounds (1.79 g, 100%) as an off-white solid. MS-ESI (m/z) calc’d for C10H10CIN2 [M+H]+: 193.0. Found 193.0.
Figure imgf000364_0003
To a mixed solution of 3-chloro- l-methyl-3.5.6.7-tetrahydro-27/- cyclopenta[c]pyridine-4-carbonitrile and 2-chloro-4-methyl-2.5.6.7-tetrahydro- IT/- cyclopenta[/i]pyridine-3-carbonitrile (1.79 g, 9.3 mmol) in MeOH (46.5 mL) was added 10% Pd/C (0.99 g, 0.93 mmol), then ammonium formate (1.76 g, 27.9 mmol) was added and the mixture was stirred at 60 °C for 1 hr. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness. The residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain an oil which was further purified by flash silica gel chromatography (ISOLERA; NH-cartridge, 28 g) using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (380 mg, 26%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.65 (s, 1H), 2.99 (dd, J = 8.2, 7.4 Hz, 2H), 2.95 - 2.88 (m, 2H), 2.39 (s, 3H), 2.08 (p, J = 7.7 Hz, 2H). MS-ESI (m/z) calc’d for C10H11N2 [M+H]+: 159.0. Found 159.0.
Figure imgf000365_0001
To a solution of 4-methyl-6.7-dihydro-57/-cyclopenta|6|pyridme-3-carbonitrile (360.0 mg, 2.28 mmol) in DCM (24.02 mL) was added MCPBA (561.0 mg, 2.28 mmol) and the mixture was stirred at 25 °C for 24 hrs. The mixture was diluted with DCM and quenched by addition of saturated aqueous Na2S20s. The organic layer washed with K2CO3 solution, passed through a phase separator and evaporated to obtain the title compound (375 mg, 95%) as a beige solid. 'H NMR (400 MHz, DMSO- e) 6 8.65 (s, 1H), 3.05 - 2.99 (m, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.33 (s, 3H), 2.11 (p, J = 7.8 Hz, 2H). MS-ESI (m/z) calc’d for C10H11N2O [M+H]+: 175.1. Found 175.0.
Figure imgf000365_0002
To a solution of 3-cyano-4-methyl-6.7-dihydro-57/-cyclopenta|/)|pyridine 1-oxide (375.0 mg, 2.15 mmol) in DCM (10.76 mL) was added trifluoroacetic anhydride (0.9 mL, 6.46 mmol) and the mixture was stirred at 25 °C for 24 hrs. A solution of K2CO3 was added and stirring was continued for 6 hours. The organic layer was passed through a phase separator and evaporated to afford the title compound (375 mg, 100%) as a dark solid. 'H NMR (400 MHz, DMSO- e) 6 8.76 (s, 1H), 5.59 (d, J = 5.7 Hz, 1H), 4.99 (dt, J = 7.5, 5.8 Hz, 1H), 2.95 (ddd, J = 16.6, 8.9, 4.6 Hz, 1H), 2.74 (ddd, J = 16.1, 8.4, 6.9 Hz, 1H), 2.41 (s, 3H), 2.46 - 2.33 (m, 1H), 1.84 (dddd, J = 12.9, 8.9, 6.7, 5.9 Hz, 1H). MS-ESI (m/z) calc’d for CioHnN20 [M+H]+: 175.1. Found 175.0. Step 6: 4-Methyl-7-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-6, 7-
Figure imgf000366_0001
Prepared as described for 5-[l-[l-(3-bicyclo[l.l.l]pentanyl)pyrazol-4-yl]-5- methylindazol-6-yl]oxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 5-methyl-l-(l- methyl-17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/- pyrazol-4-yl)-5 -methyl- 17/-indazol-6-ol and 7-hydroxy-4-methyl-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile in place of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carbonitrile. The material was subjected to chiral preparative HPLC using Method FX to afford 4-methy l-7-((5 -methyl- 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6, 7- dihydro-5//-cyclopenta|6 |pyridine-3-carbonitrile. enantiomer 1 (7 mg, 9%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.84 (s, 1H), 8.28 (s, 1H), 8.06 (d, J = 0.9 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.49 (s, 1H), 6.07 (dd, J = 7.2, 4.3 Hz, 1H), 3.94 (s, 3H), 3.15 - 3.07 (m, 1H), 3.03 - 2.91 (m, 1H), 2.79 - 2.68 (m, 1H), 2.49 (s, 3H), 2.21 (tt, J = 9.0, 4.6 Hz, 1H), 2.16 (s, 3H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2437.2. A later eluting fraction was also isolated to afford 4-methyl-7-((5- methyl- l-( l-methyl-l7/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-6.7-dihydro-57/- cyclopenta|6 |pyridine-3-carbonitrile. enantiomer 2 (3.4 mg, 4%). 'H NMR (400 MHz, CDCh) 8 8.72 (s, 1H), 7.96 (d, J = 0.9 Hz, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 5.76 (dd, J = 7.1, 3.8 Hz, 1H), 4.01 (s, 3H), 3.25 - 3.13 (m, 1H), 2.95 (ddd, J = 16.7, 8.7, 4.5 Hz, 1H), 2.72 - 2.59 (m, 1H), 2.54 (s, 3H), 2.50 - 2.38 (m, 1H), 2.25 (s, 3H). MS- ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.2. Found 385.2.
Example 191: 8-((l-(l-MethyI-tH-pyrazol-4-yI)-tH-indazol-6-yI)oxy)-5,6,7,8- tetrahydrocinnoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000366_0002
Figure imgf000367_0001
To a solution of ethyl 2-(2-oxocyclohexyl)acetate (5.0 g, 27.14 mmol) in EtOH (100 mL) was added hydrazine monohydrate (1.58 mL, 32.57 mmol) and the mixture was stirred at 78 °C for 1 hr. The solvent was evaporated to afford the title compound (4.13 g, 100%) as ayellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.36 (s, 1H), 2.58 - 2.33 (m, 3H), 2.19 - 2.02 (m, 2H), 2.00 - 1.90 (m, 1H), 1.90 - 1.78 (m, 1H), 1.77 - 1.67 (m, 1H), 1.43 - 1.27 (m, 2H), 1.20 (tdd, J = 12.8, 11.2, 3.6 Hz, 1H). MS-ESI (m/z) calc’d for C8HI3N2O [M+H]+: 152.9. Found 153.0.
Figure imgf000367_0002
To a solution of 4,4a,5,6,7,8-hexahydrocinnolin-3(277)-one (4.13 g, 27.14 mmol) in MeCN (90.47 mL) was added copper(II) chloride (7.41 g, 54.28 mmol) and the mixture was stirred at 84 °C for 1 hr. After cooling the solid was filtered and washed with MeCN to afford the title compound (3.6 g, 88%) as a beige solid. 'H NMR (400 MHz, DMSO- e) 6 12.71 (s, 1H), 6.61 (s, 1H), 2.65 (td, J = 6.6, 1.7 Hz, 2H), 2.61 (t, J = 6.6 Hz, 2H), 1.78 - 1.69 (m, 2H), 1.68 - 1.59 (m, 2H). MS-ESI (m/z) calc’d for C8HnN2O [M+H]+: 150.9. Found 151.0.
Figure imgf000367_0003
A suspension of 5,6,7,8-tetrahydrocinnolin-3(277)-one (1.5 g, 10 mmol) in POCh (40 mL) was stirred at 100 °C for 30 minutes. The excess POCh was removed by evaporation and the residue was taken up in DCM and washed with KbCOsiaq). The organic layer was passed through a phase separator and evaporated to afford the title compound (1.686 g, 100%) as a red solid. 'H NMR (400 MHz, DMSO- e) 6 7.63 (s, IH), 2.99 (t, J = 6.4 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 1.89 - 1.81 (m, 2H), 1.77 - 1.68 (m, 2H). MS-ESI (m/z) calc’d for C8HIOC1N2 [M+H]+: 168.9. Found 168.9 170.9.
Step 4: 3-Chloro-5,6,7,8-tetrahydrocinnoline l-oxide
Figure imgf000368_0001
To a solution of 3-chloro-5,6,7,8-tetrahydrocinnoline (1.69 g, 10 mmol) in DCM (50 mL) was added MCPBA (2.24 g, 10 mmol) and the mixture was stirred at 25 °C for 15 hrs. The solvent was evaporated and the residue was taken up in EtOAc and washed with K2CO3 (aq) (3x). The organic layer was dried over Na2SO4 and evaporated to afford the title compound (1.35 g, 73%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 7.35 (t, J = 0.9 Hz, 1H), 2.77 (t, J = 6.2 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H), 1.86 - 1.77 (m, 2H), 1.72 - 1.62 (m, 2H). MS-ESI (m/z) calc’d for C8HIOC1N20 [M+H]+: 185.0. Found 185.0.
Step 5: 3-Chloro-5,6, 7,8-tetrahydrocinnolin-8-ol
Figure imgf000368_0002
To a solution of 3-chloro-5,6,7,8-tetrahydrocinnoline l-oxide (1.35 g, 7.31 mmol) in DCM (36.56 mL) was added trifluoroacetic anhydride (3.05 mL, 21.94 mmol) and the mixture was stirred at 25 °C for 4 hrs. The solvent was evaporated, the residue was taken up MeOH, then solid K2CO3 was added and the suspension was stirred for 15 minutes. After this time the mixture was diluted with DCM and the organic layer was washed with H2O, passed through a phase separator and evaporated to afford the title compound (1.23 g, 91%) as a yellow oil. 1 H NMR (400 MHz, DMSO- e) 6 7.70 - 7.67 (m, 1H), 5.62 (d, J = 4.6 Hz, 1H), 4.84 (q, J = 4.3 Hz, 1H), 2.87 (dt, J = 18.8, 4.8 Hz, 1H), 2.79 - 2.67 (m, 1H), 2.00 - 1.80 (m, 3H), 1.70 (ddd, J = 12.4, 7.2, 5.2 Hz, 1H). MS-ESI (m/z) calc’d for C8HIOC1N20 [M+H]+: 185.0. Found 185.0.
Step 6: 3-Chloro-8-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydrocinnoline
Figure imgf000369_0001
To a solution of l,T-(azodicarbonyl)dipiperidine (378.47 mg, 1.5 mmol) in toluene (4 mL) was added tributylphosphine (0.37 mL, 1.5 mmol) and the mixture was stirred until the solution became colorless. 3-Chloro-5,6,7,8-tetrahydrocinnolin-8-ol (0.18 g, 1 mmol) and l-(l-methylpyrazol-4-yl)indazol-6-ol (214.22 mg, 1 mmol) were then added and the mixture was stirred at 25 °C for 3 hrs. The solvent was evaporated, the residue was taken up cyclohexane, the solid formed was filtered and washed with cyclohexane. The filtrate was evaporated to dryness to obtain a black oil which was purified by silica gel chromatography on a 25 g silica gel column, using a 0-10% MeOH/DCM gradient eluent to afford the title compound (160 mg, 42%) as a yellow oil. JH NMR (400 MHz, DMSO- e) 6 8.31 (d, J = 0.8 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.45 - 7.42 (m, 1H), 6.96 (dd, J = 8.8, 2.1 Hz, 1H), 5.99 (t, J = 3.5 Hz, 1H), 3.94 (s, 3H), 3.01 (dt, J = 18.6, 4.6 Hz, 1H), 2.96 - 2.78 (m, 1H), 2.38 - 2.28 (m, 1H), 2.09 - 1.88 (m, 2H), 1.86 - 1.76 (m, 1H). MS-ESI (m/z) calc’d for CwHisCINeO [M+H]+: 381.1. Found 381.2.
Step 7: 8-(( 1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl) oxy) -5, 6, 7,8-tetrahydrocinnoline-
3-carbonitrile, enantiomer 1 and 2
Figure imgf000369_0002
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17/-pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 3-chloro-8-((l-(l-methyl-17/-pyrazol-4- yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydrocinnoline in place of 6-((5-bromo-6-chloro-2,3- dihydro-17/-inden-l-yl)oxy)-l-(l -methyl- 17/-pyrazol -4-yl)- 17/-indazole. The material was subjected to chiral preparative HPLC using Method FY to afford 8-(( l -( l-methyl-IT/- pyrazol-4-yl)-l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydrocinnoline-3-carbonitrile. enantiomer 1 (2.4 mg, 2%) as a white solid. 'H NMR (400 MHz, Acetone- e) 6 8.14 (d, J = 0.8 Hz, 1H), 8.12 (t, J = 1.2 Hz, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.74 (d, J = 0.6 Hz, OH), 7.71 (d, J = 0.6 Hz, OH), 7.61 - 7.58 (m, 1H), 6.99 (dd, J = 8.8, 2.1 Hz, 1H), 6.02 (t, J = 3.4 Hz, 1H), 3.99 (s, 3H), 3.22 - 3.12 (m, 1H), 3.07 - 2.95 (m, 1H), 2.56 - 2.46 (m, 1H), 2.21 - 2.10 (m, 2H), 2.01 - 1.92 (m, 1H). MS-ESI (m/z) calc’d for C20H18N7O [M+H]+: 372.2. Found 372.4. A later eluting fraction was also isolated to afford 8-((l-(l-methyl-17/- pyrazol-4-yl)-IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydrocinnoline-3-carbonitrile. enantiomer 2 (2.4, 2%) as a white solid. 'H NMR (400 MHz, Acetone-cL) 6 8.14 (d, J = 0.8 Hz, 1H), 8.12 (d, J = 1.1 Hz, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 8.8, 2.1 Hz, 1H), 6.03 (t, J = 3.4 Hz, 1H), 3.99 (s, 3H), 3.21 - 3.12 (m, 1H), 3.06 - 2.96 (m, 1H), 2.55 - 2.47 (m, 1H), 2.24 - 2.12 (m, 2H), 2.00 - 1.93 (m, 1H). MS-ESI (m/z) calc’d for C20H18N7O [M+H]+: 372.2. Found 372.4.
Example 192: 5-((l-(l-(2-Hydroxy-2-methyIpropyl)-lH-pyrazol-4-yI)-LH-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000370_0001
To a solution of 4-iodopyrazole (969.85 mg, 5 mmol) in MeCN (16.67 mL) were added cesium carbonate (4.89 g, 15 mmol) and 2,2-dimethyloxirane (0.66 mL, 7.5 mmol), then the mixture was stirred at 80 °C for 5 hrs. The mixture was diluted with H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (1.33 g, 100%) as an off-white solid. 'H NMR (400 MHz, DMSO- e) 6 7.79 (d, J = 0.7 Hz, 1H), 7.50 (d, J = 0.7 Hz, 1H), 4.68 (s, 1H), 4.02 (s, 2H), 1.03 (s, 6H). MS-ESI (m/z) calc’d for C7H12IN2O [M+H]+: 267.0. Found 267.1.
Figure imgf000370_0002
To a solution of triphenylphosphine (1.84 g, 7 mmol) in toluene (35 mL) was added DIAD (1.38 mL, 7 mmol) and the mixture was stirred at 25 °C for 15 minutes. l//-lndazol-6- ol (0.94 g, 7 mmol) and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.21 g, 7 mmol) were then added and the suspension was stirred at 25 °C for 30 minutes. The solvent was evaporated, the residue was purified by silica gel chromatography on a 25 g silica gel column, using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (332 mg, 16%) as an orange oil. 'H NMR (400 MHz, DMSO- e) 6 12.81 (s, 1H), 7.96 (s, 1H), 7.71 - 7.62 (m, 3H), 7.54 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.83 (dd, J = 8.8, 2.1 Hz, 1H), 5.62 (t, J = 5.1 Hz, 1H), 2.90 (dt, J = 17.0, 5.8 Hz, 1H), 2.79 (dt, J = 16.9, 6.9 Hz, 1H), 2.04 (dq, J = 12.2, 7.0, 5.7 Hz, 2H), 1.85 (ddd, J = 24.9, 11.8, 7.0 Hz, 2H). MS-ESI (m/z) calc’d for CisHieNsO [M+H]+: 290.1. Found 290.2.
Step 3: 5-((l-(l-(2-Hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000371_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 1 -(4-iodopyrazol-l - yl)-2-methyl-propan-2-ol in place of 4-iodo-l-methylpyrazole. The material was subjected to chiral preparative HPLC using Method FZ to afford 5-((l-(l-(2-hydroxy-2-methylpropyl)- l//-pyrazol-4-yl)-l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (25 mg, 25%) as a white solid. 1 H NMR (400 MHz, DMSO- e) 6 8.22 (d, J = 0.8 Hz, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.64 (dd, J = 8.0, 1.7 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.28 - 7.23 (m, 1H), 6.97 (dd, J = 8.8, 2.1 Hz, 1H), 5.76 (t, J = 5.0 Hz, 1H), 4.75 (s, 1H), 4.10 (s, 2H), 2.91 (dt, J = 17.2, 5.7 Hz, 1H), 2.85 - 2.72 (m, 1H), 2.11 - 1.98 (m, 2H), 1.96 - 1.73 (m, 2H), 1.12 (s, 6H). MS-ESI (m/z) calc’d for C25H26N5O2 [M+H]+: 428.2. Found 428.4. A later eluting fraction was also isolated to afford 5-((l -(l -(2-hydroxy-2-methylpropyl)-l//-pyrazol- 4-yl)- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (23, 23%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.22 (d, J = 0.8 Hz, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.64 (dd, J = 8.0, 1.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.29 - 7.22 (m, 1H), 6.97 (dd, J = 8.8, 2.0 Hz, 1H), 5.76 (t, J = 4.9 Hz, 1H), 4.75 (s, 1H), 4.10 (s, 2H), 2.91 (dt, J = 17.2, 5.7 Hz, 1H), 2.86 - 2.71 (m, 1H), 2.04 (q, J = 5.2, 4.4 Hz, 2H), 1.96 - 1.71 (m, 2H), 1.12 (s, 6H). MS-ESI (m/z) calc’d for C25H26N5O2 [M+H]+: 428.2. Found 428.4.
Example 193: 5-((l-(2-(MethoxymethyI)pyridin-4-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitriIe, enantiomer 1 and 2
Figure imgf000372_0001
Step 1: (4-Iodopyridin-2-yl)methanol
Figure imgf000372_0002
To a solution of methyl 4-iodopyridine-2-carboxylate (2.63 g, 10 mmol) in MeOH (33.33 mL) was added sodium borohydride (1.51 g, 40 mmol) and the mixture was stirred at 25 °C for 30 minutes. The solvent was evaporated; the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (2.35 g, 100%) as a yellow oil. JH NMR (400 MHz, DMSO- e) 6 8.18 (dd, J = 5.2, 0.6 Hz, 1H), 7.84 (dd, J = 1.7, 0.8 Hz, 1H), 7.68 (ddd, J = 5.2, 1.7, 0.8 Hz, 1H), 5.49 (t, J = 5.9 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H) MS-ESI (m/z) calc’d for CeFLINO [M+H]+: 236.2. Found 236.2.
Step 2: 4-Iodo-2-(methoxymethyl)pyridine
Figure imgf000372_0003
To a solution of (4-iodopyridin-2-yl)methanol (2.35 g, 10 mmol) in THF (33.33 mL) was added 60% sodium hydride (800 mg, 20 mmol) and the mixture was stirred at 25 °C for 15 minutes, iodomethane (0.75 mL, 12 mmol) was added and the mixture was stirred at 25 °C for 30 minutes. The solvent was evaporated; the residue was taken up in H2O and the solid that formed was collected by filtration, washed with H2O, and dried to afford the title compound (1.977 g, 79%) as a beige solid. 'H NMR (400 MHz, DMSO- e) 6 8.22 (d, J = 5.1 Hz, 1H), 7.79 (d, J = 1.3 Hz, 1H), 7.73 (dd, J = 5.1, 1.7 Hz, 1H), 4.45 (s, 2H), 3.36 (s, 3H) MS-ESI (m/z) calc’d for C HdNO [M+H]+: 250.1. Found 250.2.
Step 3: 5-((l-(2-(Methoxymethyl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-
Figure imgf000373_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 4-Iodo-2- (methoxymethyl)pyridine in place of 4-iodo-l-methylpyrazole. The material was subjected to chiral preparative HPLC using Method GA to afford 5-((l-(2-(methoxymethyl)pyridin-4- yl)- IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (17 mg, 18%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.64 (d, J = 5.4 Hz, 1H), 8.40 (d, J = 0.8 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.82 (dd, J = 5.5, 2.3 Hz, 1H), 7.70 (s, 1H), 7.65 (dd, J = 8.1, 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.8, 2.0 Hz, 1H), 5.81 (t, J = 5.0 Hz, 1H), 4.59 (s, 2H), 3.42 (s, 3H), 2.92 (dt, J = 17.3, 5.8 Hz, 1H), 2.80 (ddd, J = 17.2, 8.1, 6.0 Hz, 1H), 2.13 - 2.02 (m, 2H), 1.97 - 1.74 (m, 2H). MS-ESI (m/z) calc’d for C25H23N4O2 [M+H]+: 411.2. Found 411.4. A later eluting fraction was also isolated to afford 5-((l-(2-(methoxymethyl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (17, 18%) as a white solid. XH-NMR (400 MHz, DMSO- e) 6 8.63 (dd, J = 5.4, 0.7 Hz, 1H), 8.40 (d, J = 0.8 Hz, 1H), 7.88 - 7.84 (m, 2H), 7.82 (dd, J = 5.5, 2.3 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 8.0, 1.7 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.8, 2.0 Hz, 1H), 5.81 (t, J = 5.0 Hz, 1H), 4.59 (s, 2H), 3.42 (s, 3H), 2.92 (dt, J = 17.2, 5.7 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.12 - 2.02 (m, 2H), 1.99 - 1.75 (m, 2H). MS-ESI (m/z) calc’d for C25H23N4O2 [M+H]+: 411.2. Found 411.4.
Example 194: 5-((l-(l-(l,l-Dioxidothietan-3-yl)-lff-pyrazol-4-yl)-lff-indazol-6-yl)oxy)-
5,6,7,8-tetrahydronaphthalene-2-carbonitriIe, enantiomer 1 and 2
Figure imgf000374_0001
Step 1: 3-(4-Iodo-lH-pyrazol-l-yl)thietane 1,1-dioxide
Figure imgf000374_0002
To a solution of 4-iodopyrazole (261.86 mg, 1.35 mmol) and 3-bromothietane 1,1- dioxide (249.8 mg, 1.35 mmol) in MeCN (9 mL) was added cesium carbonate (1.32 g, 4.05 mmol) and the mixture was stirred at 75 °C under N2 for 2 hrs. The mixture was diluted with H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (206 mg, 51%) as an off-white solid. 'H NMR (400 MHz, DMSO- e) 6 8.12 (d, J = 0.7 Hz, 1H), 7.69 (d, J = 0.6 Hz, 1H), 5.35 (tt, J = 8.9, 5.3 Hz, 1H), 4.81 - 4.71 (m, 2H), 4.68 - 4.59 (m, 2H). MS-ESI (m/z) calc’d for C6H8IN2O2S [M+H]+: 298.9. Found 299.0.
Figure imgf000374_0003
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 3-(4-iodo-l//- pyrazol-l-yl)thietane 1,1 -di oxide in place of 4-iodo-l-methylpyrazole. The material was subjected to chiral preparative HPLC using Method GB to afford 5-((l-(l-(l,l- dioxidothietan-3-yl)- IT/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene- 2-carbonitrile, enantiomer 1 (16 mg, 15%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.53 (d, J = 0.9 Hz, 1H), 8.21 (d, J = 0.9 Hz, 1H), 8.14 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.62 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.8, 2.0 Hz, 1H), 5.78 (t, J = 5.0 Hz, 1H), 5.43 (tt, J = 8.7, 5.5 Hz, 1H), 4.88 - 4.74 (m, 4H), 2.90 (dt, J = 11.3, 5.6 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.10 - 1.99 (m, 2H), 1.98 - 1.72 (m, 2H). MS-ESI (m/z) calc’d for C24H22N5O3S [M+H]+: 460.5. Found 460.4. A later eluting fraction was also isolated to afford 5-(( l -( l-( l. l -dioxidothietan-3-yl)- IT/-pyrazol-4- yl)- IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (16 mg, 15%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.53 (s, 1H), 8.21 (d, J = 0.9 Hz, 1H), 8.14 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.64 (dd, J = 8.0, 1.7 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.8, 2.0 Hz, 1H), 5.78 (t, J = 5.0 Hz, 1H), 5.43 (tt, J = 8.7, 5.5 Hz, 1H), 4.91 - 4.73 (m, 4H), 2.91 (dt, J = 17.2, 5.5 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.05 (dd, J = 9.3, 4.8 Hz, 2H), 1.98 - 1.74 (m, 2H). MS-ESI (m/z) calc’d for C24H22N5O3S [M+H]+: 460.5. Found 460.4.
Example 195: 8-((l-(2-ChIoropyridin-4-yI)-lH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000375_0001
In a sealed vial, a mixture of 17/-indazol-6-ol (500.0 mg, 3.73 mmol), 2-chloro-4- iodopyridine (981.75 mg, 4.1 mmol), (17?,27?)-Al,A2-dimethylcyclohexane-l,2-diamine (265.1 mg, 1.86 mmol), copper(I) iodide (141.98 mg, 0.750 mmol) and tripotassium phosphate (2.37 g, 11.18 mmol) in dry 1,4-dioxane (10 mL) was stirred at 90 °C for 2 hrs. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (540 mg, 59%) as an orange solid. 'H NMR (400 MHz, DMSO-d6) δ 8.82 (1 H, d, J=1.98 Hz) 8.03 - 8.11 (1 H, m) 5.39 (1 H, d, J=4.62 Hz) 4.59 (1 H, q, J=4.47 Hz) 2.78 - 2.90 (1 H, m) 2.64 - 2.77 (1 H, m) 1.81 - E96 (3 H, m) 1.63 - E78 (1 H, m). MS-ESI (m/z) calc’d for C12H9CIN3O [M+H]+: 246.0. Found 246.1.
Step 2: 8-((l-(2-Chloropyridin-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-tetrahydroquinoline-3- carbonitrile, enantiomer 1 and 2
Figure imgf000376_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 1 -(2-chloropyridin-4- yl)-lH-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl- 17/-indazol-6-ol and 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile in place of 5- hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. The material was subjected to chiral preparative HPLC using Method GC to afford 8-((l-(2-chloropyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (15.1 mg, 22%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.88 (1 H, d, J=2.20 Hz) 8.54 (1 H, d, J=5.72 Hz) 8.44 (1 H, d, J=0.66 Hz) 8.23 (1 H, d, J=1.98 Hz) 7.98 (1 H, dd, J=5.50, 1.98 Hz) 7.94 (1 H, d, J=1.76 Hz) 7.80 - 7.89 (2 H, m) 7.13 (1 H, dd, J=8.69, 2.09 Hz) 5.83 (1 H, t, J=3.74 Hz) 2.94 - 3.05 (1 H, m) 2.79 - 2.92 (1 H, m) 2.23 - 2.33 (1 H, m) 1.92 - 2.15 (2 H, m) 1.78 - 1.90 (1 H, m). MS-ESI (m/z) calc’d for C22H17CIN5O [M+H]+: 402.1. Found 402.2. A later eluting fraction was also isolated to afford 8-(( l-(2-chloropyridin-4-yl)-l7/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (16.4 mg, 24%). 'H NMR (400 MHz, DMSO- e) 6 8.88 (1 H, d, J=1.98 Hz) 8.54 (1 H, d, J=5.50 Hz) 8.44 (1 H, s) 8.23 (1 H, d, J=1.98 Hz) 7.98 (1 H, dd, J=5.50, 1.98 Hz) 7.94 (1 H, d, J=1.76 Hz) 7.82 - 7.88 (2 H, m) 7.13 (1 H, dd, J=8.69, 2.09 Hz) 5.83 (1 H, t, J=3.85 Hz) 2.94 - 3.04 (1 H, m) 2.80 - 2.91 (1 H, m) 2.24 - 2.32 (1 H, m) 1.92 - 2.14 (2 H, m) 1.79 - 1.91 (1 H, m). MS-ESI (m/z) calc’d for C22H17CIN5O [M+H]+: 402. E Found 402.2.
Example 196: 8-((l-(6-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000377_0001
2-Chl oro-5 -iodopyridine (483.08 mg, 2.02 mmol) was added to a suspension of 2- oxa-6-azaspiro[3.3]heptane (200.0 mg, 2.02 mmol) and potassium carbonate (278.85 mg, 2.02 mmol) in MeCN (5 mL) and the mixture was stirred at 60 °C overnight and then at 85 °C for 20 hrs.
The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with H2O (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-50% EtOAc/cyclochexane gradient eluent to afford the title compound (340 mg, 56%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.21 (1 H, d, J=1.76 Hz) 7.75 (1 H, dd, J=8.69, 2.31 Hz) 6.29 (1 H, d, J=8.14 Hz) 4.70 (4 H, s) 4.07 (4 H, s). MS-ESI (m/z) calc’d for C10H12IN2O [M+H]+: 303.0. Found 303.0.
Figure imgf000377_0002
In a sealed vial, a mixture of 17/-indazol-6-ol (50.0 mg, 0.370 mmol), 6-(5- iodopyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (123.87 mg, 0.410 mmol), (1R,2R)-N1 ,N2- dimethylcyclohexane-l,2-diamine (26.51 mg, 0.19 mmol), copper(I) iodide (14.2 mg, 0.070 mmol) and tripotassium phosphate (0.24 g, 1.12 mmol) in dry 1,4-dioxane (2 mL) was stirred at 90 °C for 2 hrs. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0- 100% EtOAc/cyclochexane gradient eluent to afford the title compound (45 mg, 39%) as an orange solid. 'H NMR (400 MHz, DMSO-d6) δ 9.82 (1 H, br. s.) 8.33 (1 H, d, J=1.98 Hz) 8.10 (1 H, d, J=0.88 Hz) 7.78 (1 H, dd, J=8.80, 2.64 Hz) 7.63 (1 H, d, J=8.58 Hz) 6.81 (1 H, s) 6.74 (1 H, dd, J=8.80, 1.98 Hz) 6.57 (1 H, d, J=8.36 Hz) 4.75 (4 H, s) 4.18 (4 H, s). MS- ESI (m/z) calc’d for C17H17CIN4O2 [M+H]+: 309.1. Found 309.2.
Step 3: 8-( l-( 6-(2-Oxa-6-azaspiro[3.3 ]heptan-6-yl)pyridin-3-yl)-lH-indazol-6-yl)oxy)-
5.6. 7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000378_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 1 -(6-(2-oxa-6- azaspiro[3.3]heptan-6-yl)pyridin-3-yl)-17/-indazol-6-ol in place of l-(l- (bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol 8-hy droxy-5, 6,7,8- tetrahydroquinoline-3-carbonitrile in place of 5-hy droxy-5, 6,7, 8-tetrahydronaphthalene-2- carbonitrile. The material was subjected to chiral preparative HPLC using Method GD to afford 8-((l-(6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)-17/-indazol-6-yl)oxy)- 5, 6, 7, 8 -tetrahydroquinoline-3 -carbonitrile, enantiomer 1 (10.2 mg, 15%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.83 (1 H, d, J=2.20 Hz) 8.41 (1 H, d, J=2.64 Hz) 8.19 (2 H, s) 7.85 (1 H, dd, J=8.80, 2.64 Hz) 7.73 (1 H, d, J=8.80 Hz) 7.30 (1 H, s) 6.93 (1 H, dd, J=8.80, 2.20 Hz) 6.59 (1 H, d, J=9.02 Hz) 5.64 (1 H, t, J=3.85 Hz) 4.74 (4 H, s) 4.19 (4 H, s) 2.90 - 3.00 (1 H, m) 2.74 - 2.87 (1 H, m) 2.14 - 2.27 (1 H, m) 1.73 - 2.06 (3 H, m). MS-ESI (m/z) calc’d for C27H25N6O2 [M+H]+: 465.2. Found 465.3. A later eluting fraction was also isolated to afford 8-((l-(6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (10.4 mg, 15%). Tf NMR (400 MHz, DMSO-d6) δ 8.83 (1 H, d, J=1.98 Hz) 8.41 (1 H, d, J=2.64 Hz) 8.19 (2 H, s) 7.85 (1 H, dd, J=8.80, 2.64 Hz) 7.73 (1 H, d, J=8.80 Hz) 7.30 (1 H, s) 6.93 (1 H, dd, J=8.69, 2.09 Hz) 6.59 (1 H, d, J=9.02 Hz) 5.64 (1 H, t, J=3.96 Hz) 4.74 (4 H, s) 4.19 (4 H, s) 2.90 - 3.00 (1 H, m) 2.75 - 2.86 (1 H, m) 2.17 - 2.26 (1 H, m) 1.75 - 2.06 (3 H, m). MS-ESI (m/z) calc’d for C27H25N6O2 [M+H]+: 465.2. Found 465.3.
Example 197: 8-((l-(2-(3-Hydroxyazetidin-l-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-
5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000379_0001
2-Fluoro-4-iodopyridine (500.0 mg, 2.24 mmol) was added to a suspension of 3- azetidinol hydrochloride (245.64 mg, 2.24 mmol) and potassium carbonate (619.8 mg, 4.48 mmol) in MeCN (6 mL), and the mixture was stirred at 85 °C for 3 hrs. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with water (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-50% EtOAc/cyclochexane gradient eluent to afford the title compound (430 mg, 69%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 7.74 (1 H, d, J=5.28 Hz) 6.95 (1 H, dd, J=5.28, 1.32 Hz) 6.77 (1 H, d, J=1.10 Hz) 5.64 (1 H, d, J=6.38 Hz) 4.50 - 4.58 (1 H, m) 4.10 - 4.16 (2 H, m) 3.65 (2 H, dd, J=9.35, 4.73 Hz). MS-ESI (m/z) calc’d for C8HioIN20 [M+H]+: 277.0. Found 277.0.
Step 2: 8-((l-(2-(3-Hydroxyazetidin-l-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-
Figure imgf000380_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 1 -(4-iodopyridin-2- yl)azetidin-3-ol in place of 4-iodo-l-methylpyrazole. The material was subjected to chiral preparative HPLC using Method GE to afford 8-((l-(2-(3-hydroxyazetidin-l-yl)pyridin-4- yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (16 mg, 15%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.53 (d, J = 0.9 Hz, 1H), 8.21 (d, J = 0.9 Hz, 1H), 8.14 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.62 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.8, 2.0 Hz, 1H), 5.78 (t, J = 5.0 Hz, 1H), 5.43 (tt, J = 8.7, 5.5 Hz, 1H), 4.88 - 4.74 (m, 4H), 2.90 (dt, J = 11.3, 5.6 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.10 - 1.99 (m, 2H), 1.98 - 1.72 (m, 2H). MS-ESI (m/z) calc’d for C24H22N5O3S [M+H]+: 460.5. Found 460.4. A later eluting fraction was also isolated to afford 8-((l-(2-(3-hydroxyazetidin-l-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)- 5, 6, 7, 8 -tetrahydroquinoline-3 -carbonitrile, enantiomer 2 (16 mg, 15%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.53 (s, 1H), 8.21 (d, J = 0.9 Hz, 1H), 8.14 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.64 (dd, J = 8.0, 1.7 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.8, 2.0 Hz, 1H), 5.78 (t, J = 5.0 Hz, 1H), 5.43 (tt, J = 8.7, 5.5 Hz, 1H), 4.91 - 4.73 (m, 4H), 2.91 (dt, J = 17.2, 5.5 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.05 (dd, J = 9.3, 4.8 Hz, 2H), 1.98 - 1.74 (m, 2H). MS-ESI (m/z) calc’d for C24H22N5O3S [M+H]+: 460.5. Found 460.4.
Example 198: 8-((l-(2-Methylpyridin-4-yl)-lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000380_0002
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 4-iodo-2-methyl- pyridine in place of 4-iodo-l-methylpyrazole. The material was subjected to chiral preparative HPLC using Method GF to afford 8-((l-(2-methylpyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (15.3 mg, 23%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.87 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 0.9 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.71 - 7.68 (m, 1H), 7.09 (dd, J = 8.8, 2.0 Hz, 1H), 5.79 (t, J = 4.0 Hz, 1H), 3.02 - 2.92 (m, 1H), 2.90 - 2.78 (m, 1H), 2.58 (s, 3H), 2.31 - 2.22 (m, 1H), 2.12 - 2.02 (m, 1H), 2.01 - 1.89 (m, 1H), 1.89 - 1.77 (m, 1H). MS-ESI (m/z) calc’d for C23H20N5O [M+H]+: 382.4. Found 382.5. A later eluting fraction was also isolated to afford 8-((l-(2- methylpyridm-4-yl)-l7/-mdazol-6-yl)oxy)-5.6.7.8-tetrahydroc|uinolme-3-carbonitrile. enantiomer 2 (15.1 mg, 23%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.87 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 0.8 Hz, 1H), 8.27 - 8.16 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.70 (dd, J = 5.5, 2.2 Hz, 1H), 7.09 (dd, J = 8.8, 2.0 Hz, 1H), 5.79 (t, J = 4.0 Hz, 1H), 2.97 (dt, J = 17.7, 4.8 Hz, 1H), 2.90 - 2.79 (m, 1H), 2.58 (s, 3H), 2.31 - 2.22 (m, 1H), 2.12 - 2.02 (m, 1H), 2.01 - 1.90 (m, 1H), 1.89 - 1.78 (m, 1H). MS-ESI (m/z) calc’d for C23H20N5O [M+H]+: 382.4. Found 382.5.
Example 199: 8-((l-(l-(Oxetan-3-ylmethyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-
5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000381_0001
To a solution of 4-iodopyrazole (1.17 g, 6.03 mmol) in THF (20 mL) was added sodium hydride (60% dispersion in oil, 482.12 mg, 12.05 mmol) and the mixture was stirred at 25 °C for 15 minutes. 3-(Bromomethyl)oxetane (910.0 mg, 6.03 mmol) was added and the mixture was stirred at 25 °C for 15 hrs. The solvent was evaporated, the residue obtained was purified by silica gel chromatography using a 0-50% EtOAc/cyclochexane gradient eluent to afford the title compound (242 mg, 15%) as a yellow oil. 'H NMR (400 MHz, DMSO- e) 6 7.95 (d, J = 0.7 Hz, 1H), 7.53 (d, J = 0.7 Hz, 1H), 4.62 (dd, J = 7.8, 6.2 Hz, 2H), 4.42 (d, J = 7.3 Hz, 2H), 4.38 (t, J = 6.1 Hz, 2H), 3.38 (pt, J = 7.6, 6.0 Hz, 1H). MS-ESI (m/z) calc’d for C7H10IN2O [M+H]+: 265.0. Found 265.1.
Step 2: 8-((l-(l-(Oxetan-3-ylmethyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-
Figure imgf000382_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 4-iodo-l-(oxetan-3- ylmethyl)- IT/-pyrazole in place of 4-iodo-l-methylpyrazole. The material was subjected to chiral preparative HPLC using Method GG to afford 8-((l-(l-(oxetan-3-ylmethyl)-17/- pyrazol-4-yl)-IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroquinoline-3-carbonitrile. enantiomer 1 (13 mg, 13%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.85 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 0.8 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.41 - 7.32 (m, 1H), 6.95 (dd, J = 8.8, 2.1 Hz, 1H), 5.74 (t, J = 4.0 Hz, 1H), 4.68 (dd, J = 7.8, 6.2 Hz, 2H), 4.52 - 4.49 (m, 2H), 4.47 (td, J = 6.0, 1.4 Hz, 2H), 3.49 (tt, J = 7.7, 6.0 Hz, 1H), 2.96 (dt, J = 17.2, 4.9 Hz, 1H), 2.83 (ddd, J = 16.9, 9.7, 6.0 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.04 (tt, J = 13.7, 3.6 Hz, 1H), 1.99 - 1.77 (m, 2H). MS- ESI (m/z) calc’d for C24H23N6O2 [M+H]+: 427.2. Found 427.2. A later eluting fraction was also isolated to afford 8-((l-(l-(oxetan-3-ylmethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)- 5, 6, 7, 8 -tetrahydroquinoline-3 -carbonitrile, enantiomer 2 (13 mg, 13%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.85 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 0.8 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.41 - 7.32 (m, 1H), 6.95 (dd, J = 8.8, 2.1 Hz, 1H), 5.74 (t, J = 4.0 Hz, 1H), 4.68 (dd, J = 7.8, 6.2 Hz, 2H), 4.52 - 4.49 (m, 2H), 4.47 (td, J = 6.0, E4 Hz, 2H), 3.49 (tt, J = 7.7, 6.0 Hz, 1H), 2.96 (dt, J = 17.2, 4.9 Hz, 1H), 2.83 (ddd, J = 16.9, 9.7, 6.0 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.04 (tt, J = 13.7, 3.6 Hz, 1H), E99 - E77 (m, 2H). MS-ESI (m/z) calc’d for C24H23N6O2 [M+H]+: 427.2. Found 427.2.
Example 200: 4-Methoxy-8-((5-methyI-l-(l-methyI-tH-pyrazol-4-yI)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000383_0001
To a solution of 3-bromo-5,6,7,8-tetrahydroquinoline (1.0 g, 4.71 mmol) in DCM (14.29 mL) was added MCPBA (976.4 mg, 5.66 mmol). The reaction was stirred at 25 °C for 18 hrs. Then polymer bound PPhs was added to quench the reaction. The solid was removed by vacuum filtration and washed with DCM (10 mL). The combined filtrates were diluted with saturated aqueous NaHCOs and stirred for 10 min. Then the organic phase was passed through a phase separator and concentrated in vacuo to afford the title compound (1.07 g, 99%) as a white solid which was used without further purification. JH NMR (400 MHz, DMSO- e) 6 8.42 (d, J = 1.8 Hz, 1H), 7.39 (s, 1H), 2.73 (t, J = 6.2 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 1.83 - 1.74 (m, 2H), 1.70 - 1.61 (m, 2H). MS-ESI (m/z) calc’d for CsHnBrNO [M+H]+: 228.1, 230.0. Found 228.1, 230.1.
Figure imgf000383_0002
To a solution of 3-bromo-5,6,7,8-tetrahydroquinoline 1-oxide (1.0 g, 4.38 mmol) in concentrated sulfuric acid (10.0 mL, 187.6 mmol) was added potassium nitrate (5.32 g, 52.61 mmol) portionwise and the reaction mixture was heated at 110 °C for 15 minutes. The reaction mixture was slowly poured onto ice and then extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography using a 0- 100% EtOAc/cyclohexane gradient eluent to afford the title compound (400 mg, 33%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.80 (s, 1H), 2.71 - 2.61 (m, 4H), 1.84 - 1.76 (m, 2H), 1.73 - 1.65 (m, 2H). MS-ESI (m/z) calc’d for CoHioBrNCh [M+H]+: 273.1, 275.0. Found 273.0, 275.0.
Figure imgf000384_0001
A I M methanolic solution of sodium methoxide (1.87 mL, 1.87 mmol) was added to a solution of 3-bromo-4-nitro-5,6,7,8-tetrahydroquinoline 1-oxide (400.0 mg, 1.22 mmol) in MeOH (3 mL) that was cooled in an ice-bath. The resulting mixture was stirred at r.t. for 1 hr. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in DCM (100 mL) and H2O (100 mL). The layers were separated and the organic layer was dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a 0-25% MeOH/EtOAc gradient eluent to afford the title compound (240 mg, 76%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.48 (s, 1H), 3.79 (s, 3H), 2.71 (t, J = 6.1 Hz, 2H), 2.65 (t, J = 6.5 Hz, 2H), 1.81 - 1.72 (m, 2H), 1.71 - 1.62 (m, 2H). MS-ESI (m/z) calc’d for CioHuBrNCL [M+H]+: 258.0, 260.0. Found 258.1, 260.1.
Figure imgf000384_0002
In a sealed microwave reaction vial, a solution of 3-bromo-4-methoxy-5, 6,7,8- tetrahydroquinoline 1-oxide (240.0 mg, 0.90 mmol) and trifluoroacetic anhydride (0.25 mL, 1.8 mmol) in DCM (3.341 mL), was stirred at 25 °C for 6 hrs under nitrogen atmosphere. The reaction mixture was then concentrated under reduced pressure. MeOH (20 mL) and potassium carbonate (124.66 mg, 0.900 mmol) were added to the reaction mixture and the resulting suspension was stirred at r.t. for 30 min. Then the solvent was removed under reduced pressure and the residue was diluted with saturated aqueous NaHCOs (100 mL) and DCM (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under vacuum. The residue was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (184 mg, 79%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.53 (s, 1H), 5.19 (d, J = 4.3 Hz, 1H), 4.52 (q, J = 4.5 Hz, 1H), 3.83 (s, 3H), 2.87 - 2.75 (m, 1H), 2.69 - 2.57 (m, 1H), 1.95 - 1.77 (m, 3H), 1.76 - 1.61 (m, 1H). MS-ESI (m/z) calc’d for CioHuBrNCL [M+H]+: 258.1, 260.0. Found 258.2, 260.2.
Step 5: 3-Bromo-4-methoxy-8-( (5-methyl-l-( 1 -methyl- lH-pyrazol-4-yl)- lH-indazol-6- yl)oxy)-5, 6, 7,8-tetrahydroquinoline
Figure imgf000385_0001
2-(Tributylphosphoranylidene)acetonitrile (0.1 mL, 0.390 mmol) was added to a solution of 3-bromo-4-methoxy-5,6,7,8-tetrahydroquinolin-8-ol (100.0 mg, 0.390 mmol) and 5-methyl-l-(l-methylpyrazol-4-yl)indazol-6-ol (88.43 mg, 0.390 mmol) in dry toluene (3.87 mL). The resulting mixture was stirred at 90 °C for 5 hrs. Additional 2- (tributylphosphoranylidene)acetonitrile (0.1 mL, 0.390 mmol) was then added and the mixture was stirred at 90 °C for 5 hrs. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain material which was purified by flash silica gel chromatography using a 0-80% EtOAc/cyclohexane gradient eluent to afford the title compound (104 mg, 57%) as an orange oil. JH NMR (400 MHz, DMSO- e) 6 8.59 (s, 1H), 8.29 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 0.9 Hz, 1H), 7.92 (d, J = 0.9 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.51 (s, 1H), 5.73 - 5.65 (m, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.03 - 2.93 (m, 1H), 2.81 - 2.70 (m, 1H), 2.30 - 2.20 (m, 1H), 2.14 (d, J = 1.0 Hz, 3H), 2.04 - 1.80 (m, 3H). MS- ESI (m/z) calc’d for C22H23BrN5O2 [M+H]+: 468.3, 470.1. Found 468.2, 470.2.
Step 6: 4-Methoxy-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000385_0002
Prepared as described for 6-chl oro- !-((!-( 1 -methyl- 17/-pyrazol-4-y l)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile using 3-bromo-4-methoxy-8-((5-methyl-l-(l- methyl- l//-pyrazol-4-yl)- l//-indazol-6-yl)oxy)-5.6, 7,8-tetrahydroquinoline in place of
6-((5-bromo-6-chloro-2,3-dihydro-17/-inden-l-yl)oxy)-l-(l-methyl-17/-pyrazol-4-yl)-17/- indazole. The material was subjected to chiral preparative HPLC using Method GH to afford 4-methoxy-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (5.2 mg, 6%) as a white solid. XH NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.29 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 0.9 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 7.50 (s, 1H), 5.76 - 5.71 (m, 1H), 4.28 (s, 3H), 3.94 (s, 3H), 2.93 - 2.79 (m, 1H), 2.65 - 2.54 (m, 1H), 2.27 - 2.19 (m, 1H), 2.13 (s, 3H), 2.03 - 1.77 (m, 3H). MS-ESI (m/z) calc’d for C22H21N6O2 [M+H]+: 415.5. Found 415.5. A later eluting fraction was also isolated to afford 4-methoxy-8-((5-methyl- l-(l -methyl- IT/- pyrazol-4-yl)-IT/-indazol-6-yl)oxy)-5.6.7.8-tetrahydroquinoline-3-carbonitrile. enantiomer 2 (5.2, 6%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.29 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.50 (s, 1H), 5.76 - 5.70 (m, 1H), 4.28 (s, 3H), 3.94 (s, 3H), 2.93 - 2.80 (m, 1H), 2.65 - 2.54 (m, 1H), 2.22 (d, J = 11.4 Hz, 1H), 2.13 (d, J = 1.0 Hz, 3H), 2.02 - 1.80 (m, 3H). MS-ESI (m/z) calc’d for C22H21N6O2 [M+H]+: 415.5. Found 415.5.
Example 201: 8-((l-(2-(4-(Dimethylphosphoryl)piperidin-l-yl)pyridin-4-yl)-lH-indazol-
6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000386_0001
2-Fluoro-4-iodopyridine (345.87 mg, 1.55 mmol) was added to a suspension of 4- dimethylphosphorylpiperidine (250.0 mg, 1.55 mmol) and potassium carbonate (214.37 mg, 1.55 mmol) in MeCN (5 mL) and the mixture was stirred at 85 °C overnight. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with H2O (lx), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-25% MeOH/EtOAc gradient eluent to afford the title compound (335 mg, 59%) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 7.79 (1 H, d, J=5.28 Hz) 7.22 (1 H, d, J=l.10 Hz) 6.95 (1 H, dd, J=5.06, 1.32 Hz) 4.40 (2 H, d, J=10.56 Hz) 2.78 (2 H, t, J=11.77 Hz) E75 - E91 (3 H, m) E36 - E45 (2 H, m) E34 (3 H, s) 1.31 (3 H, s). MS-ESI (m/z) calc’d for C12H19IN2OP [M+H]+: 365.0. Found 365.1.
Step 2: 8-((l-(2-(4-(Dimethylphosphoryl)piperidin-l-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-
Figure imgf000387_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using (1 -(4-iodopyri din-2 - yl)piperidin-4-yl)dimethylphosphine oxide in place of 4-iodo-l-methylpyrazole. The resulting material was subjected to chiral preparative HPLC using Method GI to afford 8-((l- (2-(4-(dimethylphosphoryl)piperi din- 1-y l)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (5.2 mg, 7%) as a white solid. XH NMR
(400 MHz, DMSO-d6) δ 8.87 (1 H, d, J=1.98 Hz) 8.32 (1 H, s) 8.26 (1 H, d, J=5.50 Hz) 8.22 (1 H, d, J=1.98 Hz) 7.79 (1 H, d, J=8.80 Hz) 7.71 (1 H, s) 7.15 (1 H, d, J=1.54 Hz) 7.11 (1 H, dd, J=5.61, 1.65 Hz) 7.02 (1 H, dd, J=8.80, 2.20 Hz) 5.75 (1 H, t, J=4.18 Hz) 4.50 (2 H, d, J=13.20 Hz) 2.79 - 3.06 (4 H, m) 2.23 - 2.31 (1 H, m) 2.03 - 2.18 (1 H, m) 1.75 - 2.01 (5 H, m) 1.43 - 1.59 (2 H, m) 1.35 (3 H, s) 1.32 (3 H, s). MS-ESI (m/z) calc’d for C29H32N6O2P [M+H]+: 527.2. Found 527.2. A later eluting fraction was also isolated to afford 8-((l-(2-(4- (dimethylphosphoryl)piperidin-l-yl)pyri din-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (5.6 mg, 8%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, d, J=1.98 Hz) 8.32 (1 H, d, J=0.66 Hz) 8.26 (1 H, d, J=5.50 Hz) 8.22 (1 H, d, J=1.98 Hz) 7.79 (1 H, d, J=8.80 Hz) 7.71 (1 H, s) 7.15 (1 H, d, J=1.54 Hz) 7.11 (1 H, dd, J=5.50, 1.76 Hz) 7.02 (1 H, dd, J=8.80, 1.98 Hz) 5.75 (1 H, t, J=4.18 Hz) 4.50 (2 H, d, J=11.66 Hz) 2.79 - 3.05 (4 H, m) 2.24 - 2.32 (1 H, m) 2.02 - 2.17 (1 H, m) 1.75 - 2.02 (5 H, m) 1.42 - 1.59 (2 H, m) 1.35 (3 H, s) 1.32 (3 H, s). MS-ESI (m/z) calc’d for C29H32N6O2P [M+H]+: 527.2. Found 527.2.
Example 202: 8-((l-(2-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-lH- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1
Figure imgf000388_0001
A solution of 2-(bromomethyl)-4-iodo-pyridine (0.3 g, 1 mmol) in MeCN (2 mL) was added dropwise to a suspension of 2-oxa-6-azaspiro[3.3]heptane (0.09 mL, 1 mmol) and potassium carbonate (0.14 mL, 1 mmol) in MeCN (2 mL) and the mixture was stirred at 25 °C for 1 hr. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel chromatography using a 0- 10% MeOH/DCM gradient eluent to afford the title compound (273 mg, 86%) as a yellow oil. 'H NMR (400 MHz, DMSO- e) 6 8.17 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 5.1, 1.7 Hz, 1H), 4.61 (s, 4H), 3.56 (s, 2H), 3.36 (s, 4H). MS-ESI (m/z) calc’d for C11H14IN2O [M+H]+: 317.1. Found 317.3.
Step 2: 1-(T etrahydro-2H-pyran-2-yl)-6-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH- indazole
Figure imgf000388_0002
To a solution of 6-bromo-l-tetrahydropyran-2-yl-indazole (2.5 g, 8.89 mmol) in 1,4- dioxane (25 mL) were added potassium acetate (2.62 g, 26.68 mmol) and bis(pinacolato)diborane (4.52 g, 17.78 mmol). The mixture was degassed with N2 then Pd(dppf)C12*DCM (0.73 g, 0.890 mmol) was added and the reaction was stirred at 100 °C for 2 hrs. The reaction mixture was partitioned between H2O and DCM. The phases were separated and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (lx) passed through a phase separator and evaporated to dryness. The residue was purified on a silica gel pad, using a 1 : 1 EtOAc/cyclohexane eluent to afford the title compound as a dark brown oil. JH NMR (400 MHz, DMSO-d6) δ 8.14 (1 H, s) 8.00 (1
H, d, J=0.88 Hz) 7.77 (1 H, dd, J=8.14, 0.88 Hz) 7.45 (1 H, dd, J=8.03, 0.55 Hz) 5.97 (1 H, dd, J=9.46, 2.64 Hz) 3.74 - 3.89 (2 H, m) 2.36 - 2.47 (1 H, m) 1.92 - 2.11 (2 H, m) 1.69 -
I.89 (1 H, m) 1.49 - 1.66 (2 H, m) 1.33 (12 H, s). MS-ESI (m/z) calc’d for C18H26BN2O3 [M+H]+: 329.1. Found 329.2.
Step 3: l-(Tetrahydro-2H-pyran-2-yl)-lH-indazol-6-ol
Figure imgf000389_0001
To a solution of l-(tetrahydro-27f-pyran-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-17f-indazole (2.92 g, 8.89 mmol) in MeOH (50 mL) was added hydrogen peroxide (4.54 mL, 44.46 mmol) and the mixture was stirred at r.t. for 1.5 hrs. The solvent was evaporated, the residue was taken up in H2O and extracted with EtOAc. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with H2O (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (2.8 g) as a brown oil. 'H NMR (400 MHz, DMSO-d6) δ 9.66 (1 H, s) 7.89 (1 H, s) 7.54 (1 H, d, J=8.58 Hz) 6.89 - 6.94 (1 H, m) 6.70 (1 H, dd, J=8.69, 2.09 Hz) 5.65 (1 H, dd, J=9.46, 2.64 Hz) 3.83 - 3.90 (1 H, m) 3.65 - 3.75 (1 H, m) 2.31 - 2.43 (1 H, m) 2.00 - 2.08 (1 H, m) 1.94 (1 H, dq, J=13.15, 3.39 Hz) 1.69 - 1.82 (1 H, m) 1.53 - 1.61 (2 H, m). MS-ESI (m/z) calc’d for C12H15N2O2 [M+H]+: 219.2. Found 219.1.
Step 4: 8-( ( 1 -(T etrahydro-2H-pyran-2-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahydroquinoline- 3-carbonitrile
Figure imgf000389_0002
To a solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (700.0 mg, 4.02 mmol), l-(tetrahydro-27/-pyran-2-yl)-17/-indazol-6-ol (1.25 g, 4.02 mmol) and triphenylphosphine (2.11 g, 8.04 mmol) in THF (25 mL) was added diisopropyl azodicarboxylate (0.95 mL, 4.82 mmol) dropwise and the mixture was stirred at r.t. overnight. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with brine (lx), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent. The residue obtained was further purified by silica gel chromatography on a 55 g NH silica gel column using a 0-40% EtOAc/cyclohexane gradient eluent to afford the title compound (960 mg, 64%) as a white solid. JH NMR (400 MHz, DMSO-de) 8 8.86 (1 H, s) 8.22 (1 H, d, J=1.98 Hz) 7.99 (1 H, s) 7.65 (1 H, dd, J=8.80, 1.76 Hz) 7.43 (1 H, d, J=9.02 Hz) 6.90 (1 H, ddd, J=8.69, 5.28, 2.09 Hz) 5.81 (1 H, dd, J=9.68, 1.98 Hz) 5.66 (1 H, q, J=3.81 Hz) 3.89 (1 H, dd, J=11.11, 2.97 Hz) 3.69 - 3.80 (1 H, m) 2.93 - 3.07 (1 H, m) 2.78 - 2.91 (1 H, m) 2.35 - 2.47 (1 H, m) 2.21 - 2.31 (1 H, m) 2.00 - 2.11 (2 H, m) 1.90 - 1.98 (2 H, m) 1.69 - 1.88 (2 H, m) 1.53 - 1.66 (2 H, m). MS-ESI (m/z) calc’d for C22H23N4O [M+H]+: 374.4. Found 375.3.
Step 5: 8-((lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000390_0001
To a solution of 8-((l-(Tetrahy dro-27/-pyran-2-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile (960.0 mg, 2.56 mmol) in DCM (30 mL) was added trifluoroacetic acid (5 mL) and the mixture was stirred at r.t. overnight. Volatiles were then removed under reduced pressure and the residue was purified by silica gel chromatography using a 0-80% EtOAc/cyclohexane gradient eluent. This material was further purified by preparative HPLC using Method GK after which the enantiomers were separated by chiral chromatography using Method GL to give 8-((17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (120 mg, 16%) as a white solid. XH NMR (400 MHz, DMSO-de) 8 12.81 (1 H, br. s.) 8.86 (1 H, d, J=1.98 Hz) 8.21 (1 H, d, J=1.98 Hz) 7.95 (1 H, d, J=0.88 Hz) 7.63 (1 H, d, J=8.80 Hz) 7.23 (1 H, s) 6.81 (1 H, dd, J=8.69, 2.09 Hz) 5.58 (1 H, t, J=3.85 Hz) 2.92 - 3.03 (1 H, m) 2.74 - 2.90 (1 H, m) 2.19 - 2.31 (1 H, m) 1.75 - 2.09 (3 H, m). MS-ESI (m/z) calc’d for C17H15N4O [M+H]+: 291.3. Found 291.2. A second eluting enantiomer was also isolated to give 8-((17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (121 mg, 16%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 12.81 (1 H, br. s.) 8.86 (1 H, d, J=1.98 Hz) 8.21 (1 H, d, J=1.98 Hz) 7.95 (1 H, d, J=0.88 Hz) 7.63 (1 H, d, J=9.24 Hz) 7.23 (1 H, s) 6.81 (1 H, dd, J=8.69, 2.09 Hz) 5.58 (1 H, t, J=3.85 Hz) 2.91 - 3.03 (1 H, m) 2.76 - 2.90 (1 H, m) 2.19 - 2.31 (1 H, m) 1.78 - 2.13 (3 H, m). MS-ESI (m/z) calc’d for C17H15N4O [M+H]+: 29E3. Found 29E2.
Step 6: 8-((l-(2-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-lH-indazol-6- yl)oxy)-5, 6, 7,8-tetrahydroquinoline-3-carbonitrile
Figure imgf000391_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 8-(( l//-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 in place of
Figure imgf000391_0002
pyrazolo[4,3-b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-((4- iodopyridin-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane in place of 4-iodo-l-methylpyrazole to afford 8-((l-(2-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (29 mg, 59%) as a beige solid. 'H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 0.8 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.77 - 7.73 (m, 2H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 5.76 (t, J = 4.0 Hz, 1H), 4.58 (s, 4H), 3.72 (s, 2H), 3.42 (s,4H), 2.97 (dt, J = 17.4, 4.9 Hz, 1H), 2.90 - 2.78 (m, 1H), 2.31 - 2.23 (m, 1H), 2.12 - 2.01 (m, 1H), 2.01 - E91 (m, 1H), E90 - E79 (m, 1H). MS-ESI (m/z) calc’d for C28H27N6O2 [M+H]+: 479.5. Found 479.4.
Example 203 : 8-((l-(2-((2-Oxa-6- azaspiro [3.3] heptan-6-yl)methyl)pyridin-4-yl)- 1H- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2
Figure imgf000392_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 8-(( l//-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 in place of
Figure imgf000392_0002
pyrazolo[4,3-b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-((4- iodopyridin-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane in place of 4-iodo-l-methylpyrazole to afford 8-((l-(2-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (29 mg, 59%) as a beige solid. 'H NMR (400 MHz, CDCh) 8 8.80 - 8.76 (m, 1H), 8.64 (d, J = 5.5 Hz, 1H), 8.15 (d, J = 0.9 Hz,lH), 7.82 - 7.80 (m, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.64 (dd, J = 5.5, 2.2 Hz, 1H),7.O8 (dd, J = 8.8, 2.0 Hz, 1H), 5.56 (t, J = 3.8 Hz, 1H), 4.73 (s, 4H), 3.79 (d, J = 2.7 Hz, 2H), 3.52 (d, J =1.3 Hz, 4H), 3.02 (dt, J = 17.4, 4.9 Hz, 1H), 2.86 (ddd, J = 17.0, 10.1, 5.9 Hz, 1H), 2.48 - 2.38 (m, 1H), 2.26 - 2.13 (m, 1H), 2.03 (ddt, J = 14.1, 11.9, 3.6 Hz, 1H), 1.98 - 1.87 (m, 1H). MS-ESI (m/z) calc’d for C28H27N6O2 [M+H]+: 479.5. Found 479.4.
Example 204: 4-(Methoxymethyl)-8-((5-methyl-l-(l-methyl-lff-pyrazol-4-yl)-lff- indazol-6-yI)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitriIe, enantiomer 1 and 2
Figure imgf000392_0003
To a solution of 4-(cyclohexen-l-yl)morpholine (3.35 g, 20 mmol) and triethylamine (3.9 mL, 28 mmol) in toluene (40 mL) was added 2-methoxyacetyl chloride (1.83 mL, 20 mmol) dropwise and the mixture was stirred at 25 °C for 2 hrs. The mixture was diluted with DCM and washed with water. The organic layer was evaporated to dryness and taken up in 1 M HC1 and stirred for 30 minutes. The solution was extracted with DCM (3x). Tthe combined organic layers were passed through a phase separator and evaporated to afford the title compound (2.92 g, 86%) as a yellow oil which was used without further purification. JH NMR (400 MHz, DMSO- e) 64.28 - 4.00 (m, 2H), 3.47 - 3.21 (m, 4H), 2.38 - 2.13 (m, 3H), 2.04 - 1.48 (m, 5H). MS-ESI (m/z) calc’d for C9H15O3 [M+H]+: 171.1. Found 171.1.
Step 2: 1 -(Methoxymethyl) -3-oxo-2, 3, 5 ,6, 7,8-hexahydroisoquinoline-4-carbonitrile and 4-
Figure imgf000393_0001
To a solution of 2-(2-methoxyacetyl)cyclohexanone (2.92 g, 17.16 mmol) in EtOH (42.89 mL) were added 2-cyanoacetamide (1.44 g, 17.16 mmol) and piperidine (1.69 mL, 17.16 mmol) and the mixture was stirred at 75 °C for 3 hrs. The solvent was evaporated and the residue was taken up in H2O and extracted with EtOAc (4x). The combined organic layers were passed through a phase separator and evaporated to obtain a mixture of the title compounds (2.92 g, 78%) as a dark oil, which was used without further purification. 'H NMR (400 MHz, DMSO- e) 6 12.17 (d, J = 89.7 Hz, 1H), 4.45 - 4.27 (m, 2H), 3.64 - 3.19 (m, 3H), 2.83 - 2.11 (m, 2H), 1.79 - 1.32 (m, 6H). MS-ESI (m/z) calc’d for C12H15N2O2 [M+H]+: 219.3. Found 219.3.
Step 3: 3-Chloro-l-(methoxymethyl)-5,6, 7,8-tetrahydroisoquinoline-4-carbonitrile and 2-
Figure imgf000393_0002
A suspension of l-(methoxymethyl)-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4- carbonitrile and 4-(methoxymethyl)-2-oxo-l,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (2.92 g, 13.38 mmol) in phosphoryl chloride (44.6 mL) was stirred at 100 °C for 3 hrs. The excess POCh was evaporated to give a residue that was carefully quenched by addition of K2COs(aq) and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-25% EtOAc/cyclohexane gradient eluent to afford the title compounds (1.03 g, 32%) as an orange oil. Minor isomer: JH NMR (400 MHz, DMSO- e) 6 4.56 (s, 2H), 3.34 (s, 3H), 2.95 - 2.86 (m, 2H), 2.76 (dt, J = 19.3, 5.8 Hz, 2H), 1.77 (qd, J = 6.2, 2.5 Hz, 4H). Major isomer: 'H NMR (400 MHz, DMSO- e) 64.52 (s, 2H), 3.31 (s, 3H), 2.96 - 2.86 (m, 2H), 2.76 (dt, J = 19.3, 5.8 Hz, 2H), 1.77 (qd, J = 6.2, 2.5 Hz, 4H). MS-ESI (m/z) calc’d for C12H14CIN2O [M+H]+: 239.1. Found 239.7.
Step 4: l-(Methoxymethyl)-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile and 4-
Figure imgf000394_0001
To a suspension of 3-chloro-l-(methoxymethyl)-5,6,7,8-tetrahydroisoquinoline-4- carbonitrile and 2-chloro-4-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (1.03 g, 4.33 mmol) in EtOH (5 mL), H2O (5 mL), and acetic acid (0.500 mL) was added zinc (566.25 mg, 8.66 mmol) and the mixture was stirred at 95 °C for 6 hrs. The mixture was filtered through a Celite pad and the filtrate was evaporated to dryness to obtain a residue which was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a mixture of the title compounds (700 mg, 80%) as ayellow oil 'H NMR (400 MHz, DMSO- e) 6 8.71 - 8.60 (m, 1H), 4.59 - 4.53 (m, 2H), 3.39 - 3.19 (m, 3H), 2.98 - 2.64 (m, 4H), 1.78 (dq, J = 6.6, 3.3 Hz, 4H). MS-ESI (m/z) calc’d for C12H15N2O [M+H]+: 203.2. Found 203.1.
Step 5: 4-Cyano-l -(methoxymethyl) -5, 6, 7,8-tetrahydroisoquinoline 2-oxide and 3-Cyano-4-
Figure imgf000394_0002
To a solution of l-(methoxymethyl)-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile and 4-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (700.0 mg, 3.46 mmol) in DCM (34.61 mL) was added MCPBA (853.22 mg, 3.46 mmol) and the mixture was stirred at 25 °C for 3 hrs. The reaction was quenched by addition of polymer bound triphenylphosphine and stirred for 15 minutes. The resin was filtered under vacuum and the filtrate was washed with K2CO3(aq). The aqueous layer was extracted with DCM (2x) and the combined organic layers were dried over Na2SC>4 and evaporated to obtain a mixture of the title compounds (755.4 mg, 100%) as a yellow oil. 'H NMR (400 MHz, DMSO-rie) 6 8.81 - 8.69 (m, 1H), 4.77 - 4.43 (m, 2H), 3.39 - 3.26 (m, 3H), 2.87 - 2.62 (m, 4H), 1.89 - 1.63 (m, 4H). MS-ESI (m/z) calc’d for C12H15N2O2 [M+H]+: 219.2. Found 219.2.
Figure imgf000395_0001
To a solution of mixed 4-cyano-l-(methoxymethyl)-5,6,7,8-tetrahydroisoquinoline 2- oxide and 3-cyano-4-(methoxymethyl)-5,6,7,8-tetrahydroquinoline 1-oxide (755.4 mg, 3.46 mmol) in DCM (34.61 mL) was added trifluoroacetic anhydride (0.96 mL, 6.92 mmol) and the mixture was stirred at 25 °C for 15 hrs. The solvent was evaporated and the residue was taken up in MeOH. Solid K2CO3 was added and the suspension was stirred for 30 minutes. Water was added and the suspension was extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by flash silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (100 mg, 13%) as a yellow oil. JH NMR (400 MHz, DMSO-de) 6 8.75 (d, J = 11.9 Hz, 1H), 5.65 (d, J = 6.1 Hz, 1H), 4.78 (dd, J = 6.1, 3.9 Hz, 1H), 4.58 (d, J = 11.9 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 3.30 (s, 3H), 2.87 (dt, J = 17.6, 4.5 Hz, 1H), 2.64 (ddd, J = 16.9, 9.4, 5.6 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.83 - 1.67 (m, 2H). MS- ESI (m/z) calc’d for C12H15N2O2 [M+H]+: 219.2. Found 219.2.
Step 7: 4-(Methoxymethyl)-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-
Figure imgf000395_0002
Prepared as described for 5-((l-(l-(bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5- methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using 5-methyl-l- (1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-ol in place of l-(l-(bicyclo[l.l.l]pentan-l-yl)- 17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-ol and 8-hydroxy-4-(methoxymethyl)-5,6,7,8- tetrahydroquinoline-3-carbonitrile in place of 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carbonitrile. The material was subjected to chiral preparative HPLC using Method GM to afford 4-(methoxymethyl)-8-((5-methyl- l-( l-methyl- IT/-pyrazol-4-yl)-l7/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (22.2 mg, 11%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.88 (s, 1H), 8.28 (d, J = 0.8 Hz, 1H), 8.08 (d, J = 0.8 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 6.00 (t, J = 3.9 Hz, 1H), 4.69 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 3.94 (s, 3H), 3.35 (s, 3H), 3.00 (dt, J = 17.5, 4.6 Hz, 1H), 2.77 (ddd, J = 17.1, 10.0, 5.7 Hz, 1H), 2.21 (s, 1H), 2.15 (d, J = 1.0 Hz, 3H), 2.09 - 1.94 (m, 1H), 1.84 (d, J = 16.1 Hz, 2H). MS-ESI (m/z) calc’d for C24H25N6O2 [M+H]+: 429.5. Found 429.3. A later eluting fraction was also isolated to afford 4-(methox meth l)-8-((5-meth l- l-( l-meth l- IT/-pyrazol-4- l)-l7/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (20.6 mg, 10%). XH NMR (400 MHz, DMSO- e) 6 8.89 (s, 1H), 8.29 (d, J = 0.8 Hz, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.60 (d, J = 1.1 Hz, 1H), 7.36 (s, 1H), 6.00 (t, J = 3.9 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 12.1 Hz, 1H), 3.95 (s, 3H), 3.36 (s, 3H), 3.01 (dt, J = 17.7, 4.6 Hz, 1H), 2.77 (ddd, J = 17.1, 10.1, 5.7 Hz, 1H), 2.25 - 2.17 (m, 1H), 2.17 (s, 3H), 2.02 (tt, J = 14.5, 3.8 Hz, 1H), 1.94 - 1.75 (m, 2H). MS-ESI (m/z) calc’d for C24H25N6O2 [M+H]+: 429.5. Found 429.3.
Example 205: 8-((l-(2-(l-(Hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)- lff-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, isomer 1; 8-((l-(2-(l- (Hydroxymethyl)-3- azabicyclo [3.1.0] hexan-3-yl)pyridin-4-yl)- 1 Jf-indazol-6-y l)oxy )- 5,6,7,8-tetrahydroquinoline-3-carbonitrile, isomer 2; 8-((l-(2-(l-(Hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-tH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, isomer 3; 8-((l-(2-(l-(Hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-tH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, isomer 4
Figure imgf000397_0001
2-Fluoro-4-iodopyridine (372.59 mg, 1.67 mmol) was added to a suspension of (3- azabicyclo[3.1.0]hexan-l-yl)methanol hydrochloride (250.0 mg, 1.67 mmol) and potassium carbonate (461.87 mg, 3.34 mmol) in MeCN (5 mL) and the mixture was stirred at 85 °C overnight. The reaction mixture was partitioned between H2O and EtOAc and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases were washed with H2O (lx), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using a 0-100% EtOAc/ cyclohexane gradient eluent to afford the title compound (190 mg, 36%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) δ 7.74 (1 H, d, J=5.06 Hz) 6.90 (1 H, dd, J=5.28, 1.32 Hz) 6.79 (1 H, d, J=0.88 Hz) 4.67 (1 H, t, J=5.61 Hz) 3.57 - 3.64 (2 H, m) 3.49 - 3.56 (2 H, m) 3.32 - 3.41 (2 H, m) 1.52 (1 H, dt, J=8.20, 4.15 Hz) 0.79 (1 H, dd, J=8.03, 4.51 Hz) 0.35 (1 H, t, J=4.29 Hz). MS-ESI (m/z) calc’d for C11H14IN2O [M+H]+: 317.1. Found 317.1.
Step 2: 8-(( l-(2-(l-(Hydroxymethyl)-3-azabicyclo [3.1 ,0]hexan-3-yl)pyridin-4-yl)- 1H- indazol-6-yl)oxy)-5,6, 7,8-tetrahydroquinoline-3-carbonitrile, isomer 1; 8-((l-(2-(l- (Hydroxymethyl)-3-azabicyclo[3.1.0 ]hexan-3-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydroquinoline-3-carbonitrile, isomer 2; 8-((l-(2-(l-(Hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydroquinoline- 3-carbonitrile, isomer 3; 8-((l-(2-(l-(Hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-tetrahydroquinoline-3-carbonitrile, isomer 4
Figure imgf000398_0001
Prepared as described for 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-pyrazolo[4,3- b]pyridin-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile using (3-(4-iodopyridin-2- yl)-3-azabicyclo[3.1.0]hexan-l-yl)methanol in place of 4-iodo-l-methylpyrazole. The material was subjected to chiral preparative HPLC using Method GN to afford 8-((l-(2-(l- (hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, isomer 1 (8.2 mg, 7% ) as a white solid. JH NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, d, J=1.98 Hz) 8.31 (1 H, s) 8.22 (1 H, d, J=1.76 Hz) 8.19 (1 H, d, J=5.50 Hz) 7.79 (1 H, d, J=8.80 Hz) 7.73 (1 H, s) 6.99 - 7.09 (2 H, m) 6.75 (1 H, d, J=1.76 Hz) 5.74 (1 H, t, J=4.07 Hz) 4.68 (1 H, t, J=5.50 Hz) 3.63 - 3.81 (2 H, m) 3.56 (2 H, d, J=5.50 Hz) 3.44 - 3.52 (2 H, m) 2.92 - 3.02 (1 H, m) 2.76 - 2.91 (1 H, m) 2.22 - 2.32 (1 H, m) 2.03 - 2.17 (1 H, m) 1.96 (1 H, br. s.) 1.80 - 1.90 (1 H, m) 1.57 (1 H, dt, J=8.09, 3.99 Hz) 0.83 (1 H, dd, J=7.81, 4.51 Hz) 0.43 (1 H, t, J=4.18 Hz). MS-ESI (m/z) calc’d for C28H27N6O2 [M+H]+: 479.5. Found 479.4. A second eluting isomer gave 8-((l-(2-(l- (hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, isomer 2 (9.6 mg, 8%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, d, J=2.20 Hz) 8.31 (1 H, d, J=0.66 Hz) 8.22 (1 H, d, J=1.98 Hz) 8.19 (1 H, d, J=5.72 Hz) 7.78 (1 H, d, J=8.80 Hz) 7.73 (1 H, s) 7.00 - 7.09 (2 H, m) 6.76 (1 H, d, J=1.76 Hz) 5.74 (1 H, t, J=4.07 Hz) 4.68 (1 H, t, J=5.61 Hz) 3.64 - 3.77 (2 H, m) 3.54 - 3.61 (2 H, m) 3.43 - 3.51 (2 H, m) 2.93 - 3.04 (1 H, m) 2.80 - 2.91 (1 H, m) 2.23 - 2.32 (1 H, m) 2.03 - 2.15 (1 H, m) 1.91 - 2.03 (1 H, m) 1.81 - 1.90 (1 H, m) 1.56 (1 H, dt, J=7.98, 4.04 Hz) 0.83 (1 H, dd, J=7.81, 4.51 Hz) 0.44 (1 H, t, J=4.29 Hz). MS-ESI (m/z) calc’d for C28H27N6O2 [M+H]+: 479.5. Found 479.4. A third eluting isomer gave 8-((l-(2-(l- (hydroxymethyl)-3-azabicyclo[3.E0]hexan-3-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, isomer 3 ( 9.8 mg, 8%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, d, J=1.98 Hz) 8.31 (1 H, s) 8.22 (1 H, d, J=1.98 Hz) 8.19 (1 H, d, J=5.50 Hz) 7.78 (1 H, d, J=8.80 Hz) 7.73 (1 H, s) 7.00 - 7.10 (2 H, m) 6.76 (1 H, d, J=1.54 Hz) 5.74 (1 H, t, J=4.07 Hz) 4.68 (1 H, t, J=5.39 Hz) 3.65 - 3.77 (2 H, m) 3.54 - 3.62 (2 H, m) 3.43 - 3.51 (2 H, m) 2.93 - 3.02 (1 H, m) 2.79 - 2.90 (1 H, m) 2.23 - 2.32 (1 H, m) 2.04 - 2.15 (1 H, m) 1.97 (1 H, d, J=11.88 Hz) 1.81 - 1.91 (1 H, m) 1.56 (1 H, dt, J=8.09, 4.21 Hz) 0.83 (1 H, dd, J=7.81, 4.29 Hz) 0.44 (1 H, t, J=4.29 Hz). MS-ESI (m/z) calc’d for C28H27N6O2 [M+H]+: 479.5. Found 479.4. A fourth eluting isomer gave 8-((l-(2-(l- (hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile, isomer 4 (9.3 mg, 8%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (1 H, d, J=2.20 Hz) 8.31 (1 H, s) 8.22 (1 H, d, J=1.98 Hz) 8.19 (1 H, d, J=5.72 Hz) 7.78 (1 H, d, J=8.80 Hz) 7.73 (1 H, s) 7.00 - 7.09 (2 H, m) 6.75 (1 H, d, J=1.76 Hz) 5.74 (1 H, t, J=4.18 Hz) 4.68 (1 H, t, J=5.61 Hz) 3.65 - 3.78 (2 H, m) 3.56 (2 H, d, J=5.72 Hz) 3.44 - 3.53 (2 H, m) 2.92 - 3.02 (1 H, m) 2.79 - 2.91 (1 H, m) 2.22 - 2.32 (1 H, m) 2.03 - 2.16 (1 H, m) 1.91 - 2.03 (1 H, m) 1.82 - 1.90 (1 H, m) 1.57 (1 H, dt, J=8.09, 4.21 Hz) 0.83 (1 H, dd, J=7.59, 4.51 Hz) 0.43 (1 H, t, J=4.18 Hz). MS-ESI (m/z) calc’d for C28H27N6O2 [M+H]+: 479.5. Found 479.4.
Example 206: 5-Cyaiio-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6-yl)-6- (trifluoromethyl)picolinamide
Figure imgf000399_0001
Step 1: 5-Chloro-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl) -6- (trifluoromethyl)picolinamide
Figure imgf000399_0002
To a mixture of l-(l-methylpyrazol-4-yl)indazol-6-amine (37.82 mg, 0.18 mmol), 5- chloro-6-(trifhioromethyl)pyridine-2-carboxylic acid (40.0 mg, 0.18 mmol) and triethylamine (0.02 mL, 0.18 mmol) in MeCN (E85 mL) was added HATU (67.43 mg, 0.18 mmol) and the reaction was stirred at 25 °C for 18 hrs. The reaction mixture was concentrated under reduced pressure and the residue was taken up in DCM and H2O. The organic phase was separated, concentrated under reduced pressure, and the residue obtained was purified by flash silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (55 mg, 74%) as an off-white solid. JH NMR (400 MHz, DMSO- e) 6 10.60 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 8.26 - 8.22 (m, 2H), 7.86 (d, J = 0.8 Hz, 1H), 7.86 - 7.83 (m, 1H), 7.65 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for CisHuClFsNeO [M+H]+: 421.1. Found 421.1.
Step 2: 5-Cyano-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)-6-
(trifluoromethyl)picolinamide
Figure imgf000400_0001
Prepared as described for 3-cyano-2,6-dimethyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)benzamide using 5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6- (trifluoromethyl)picolinamide in place of 3-bromo-2,6-dimethyl-/V-(l-(l-methyl-17/-pyrazol- 4-yl)-17/-indazol-6-yl)benzamide to afford a residue which was purified by silica gel chromatography using a 0-100% EtOAc/cyclohexane gradient eluent to afford 25 mg of a solid which was further purified by preparative HPLC using Method GO to afford the title compound (5.2 mg, 10%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.79 (s, 1H), 8.91 (d, J = 8.2 Hz, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 8.28 - 8.21 (m, 2H), 7.90 - 7.81 (m, 2H), 7.67 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (s, 3H). MS-ESI (m/z) calc’d for C19H13F3N7O [M+H]+: 412.1. Found 412.2.
Example 207: 4-Cyano-3-isopropyl-7V-(l-(l-methyI-lH-pyrazol-4-yI)-lH-indazol-6- yl)picolinamide
Figure imgf000400_0002
To a suspension of 4-cyano-/V-[l-(l-methylpyrazol-4-yl)indazol-6-yl]-3-prop-l-en-2- ylpyridine-2-carboxamide (50.0 mg, 0.13 mmol) in EtOH (1 mL) and MeOH (5 mL) was added sodium borohydride (3.7 mg, 0.10 mmol) and the mixture was stirred at 80 °C for 15 hrs. The solvent was evaporated to obtain a residue (52 mg) which was dissolved in H2O (1 mL). Then 10% Pd/C (13.88 mg, 0.01 mmol) and ammonium formate (16.45 mg, 0.26 mmol) were added and the mixture was stirred at 80 °C for 30 minutes. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness. The material was suspended in phosphoryl chloride (10 mL) and heated at 100 °C for 2 hrs. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford material which was purified by preparative HPLC using Method GQ to obtain the title compound (13 mg, 26%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.92 (s, 1H), 8.75 (d, J = 4.9 Hz, 1H), 8.28 - 8.26 (m, 1H), 8.23 (d, J = 1.0 Hz, 2H), 8.02 (d, J = 4.9 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.43 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 3.48 (hept, J = 7.0 Hz, 1H), 1.43 (d, J = 7.1 Hz, 6H). MS-ESI (m/z) calc’d for C21H20N7O [M+H]+: 386.2. Found 386.2.
Example 208: 3-Cyano-7V-(l-(l-methyI-LH-pyrazol-4-yI)-LH-indazol-6-yI)-2- vinylbenzamide
Figure imgf000401_0001
A microwave reaction vial was charged with 3-cyano-2-iodo-/V-[l-(l-methylpyrazol- 4-yl)indazol-6-yl]benzamide (100.0 mg, 0.21 mmol), triphenylphosphine (1.63 mg, 0.01 mmol), tributyl(vinyl)stannane (0.07 mL, 0.25 mmol) and toluene (0.65 mL) under N2. The reaction mixture was degassed with N2 for 10 min, then Pd(PPhs)4 (2.39 mg, 0.002 mmol) was added and the mixture was heated to reflux for 6 hrs. The reaction mixture was filtered and diluted with H2O (150 mL) and EtOAc (150 mL). The organic phase was separated, washed with brine, dried over Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-60% EtOAc/cyclohexane gradient eluent to afford a solid which was further purified by preparative HPLC using Method GR to afford the title compound (6.7 mg, 9%) as a white solid. 'H NMR (400 MHz, DMSO-<A) 6 10.72 (s, 1H), 8.25 (s, 1H), 8.23 - 8.19 (m, 2H), 8.01 (dd, J = 7.8, 1.3 Hz, 1H), 7.86 (dd, J = 7.8, 1.3 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 8.7, 1.7 Hz, 1H), 6.98 (dd, J = 17.7, 11.6 Hz, 1H), 5.82 (dd, J = 17.7, 0.8 Hz, 1H), 5.69 (dd, J = 11.5, 0.8 Hz, 1H), 3.95 (s, 3H). MS-ESI (m/z) calc’d for C21H17N6O [M+H]+: 369.1. Found 369.1.
Example 209: 3-Cyano-2-ethyl-W-(l-(l-methyl-l/f-pyrazol-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000402_0001
A mixture of 3-cyano-2-ethenyl-/V-[l-(l-methylpyrazol-4-yl)indazol-6-yl]benzamide (10.0 mg, 0.03 mmol) and 10% Pd/C (44.43 mg, 0.04 mmol) in MeOH (8.349 mL) was stirred under an H2 atmosphere for 2 hrs. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford a residue which was purified by HPLC using Method GS to afford the title compound (2.4 mg, 25%) as a white solid. JH NMR (400 MHz, MeOD) 6 8.34 (s, OH), 8.15 (d, J = 1.0 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.83 (dd, J = 7.8, 1.4 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.29 (dd, J = 8.7, 1.8 Hz, 1H), 4.01 (s, 3H), 3.03 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H). MS-ESI (m/z) calc’d for C21H19N6O [M+H]+: 371.1. Found 371.2.
Example 210: 3-Cyano-2-isopropyl- \-( l-(pyridaziii-4-yl)-l//-indazol-6-yl)benzamide
Figure imgf000402_0002
Step 1: l-( 6-Chloropyridazin-4-yl)-6-nitro-lH-indazole; 2-( 6-Chloropyridazin-4-yl)-6-nitro- 2H-indazole
Figure imgf000402_0003
To a solution of 6-nitroindazole (163.13 mg, 1 mmol) in DMF (5 mL) was added potassium carbonate (0.14 mL, 1 mmol) and the mixture was stirred at 25 °C for 10 minutes. 3,5-Dichloropyridazine (148.98 mg, 1 mmol) was added and stirring was continued at 25 °C for 24 hours. Water was added and the solid formed was collected by filtration, washed with H2O, and dried to obtain a 60:40 mixture of l-(6-chloropyridazin-4-yl)-6- nitroindazole and 2-(6-chloropyridazin-4-yl)-6-nitroindazole (256 mg, 93%) as a brown solid. Major isomer: 'H NMR (400 MHz, DMSO-de) 6 9.91 (d, J = 2.3 Hz, 1H), 9.02 (dt, J = 1.8, 1.0 Hz, 1H), 8.87 (d, J = 1.0 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.24 - 8.17 (m, 2H). Minor isomer: 'H NMR (400 MHz, DMSO-de) 8 10.12 (d, J = 2.3 Hz, 1H), 9.68 (d, J = 1.1 Hz, 1H), 8.80 - 8.74 (m, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 9.2, 0.8 Hz, 1H), 7.90 (dd, J = 9.3, 2.0 Hz, 1H). Major isomer: r.t. 0.91 min, MS-ESI (m/z) calc’d for C11H10N5 [M+H]+: 276.1. Found 276.1. Minor isomer: r.t. 0.97 min, MS-ESI (m/z) calc’d for C11H10N5 [M+H]+: 276.1. Found 276.1.
Step 2: l-(Pyridazin-4-yl)-lH-indazol-6-amine
Figure imgf000403_0001
To a suspension of l-(6-chloropyridazin-4-yl)-6-nitro-17/-indazole; 2-(6- chloropyridazin-4-yl)-6-nitro-27/-indazole (256.0 mg, 0.930 mmol) in MeOH (9.287 mL) was added 10% Pd/C (98.83 mg, 0.090 mmol) and ammonium formate (351.39 mg, 5.57 mmol). The mixture was stirred at 65 °C for 1 hr. After cooling the mixture was filtered through a Celite pad, the filtrate was evaporated to obtain a yellow residue which was taken up in H2O and stirred for 10 minutes. The solid formed was collected by filtration, washed with H2O, and dried to afford the title compound (56 mg, 29%) as an orange solid. 1 H NMR (400 MHz, DMSO- e) 8 9.76 (dd, J = 2.9, 1.0 Hz, 1H), 9.26 (dd, J = 5.9, 1.0 Hz, 1H), 8.24 (d, J = 0.9 Hz, 1H), 7.96 (dd, J = 5.9, 2.9 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 1.7, 0.8 Hz, 1H), 6.70 (dd, J = 8.6, 1.7 Hz, 1H), 5.74 (s, 2H). MS-ESI (m/z) calc’d for C11H10N5 [M+H]+: 212.1. Found 212.1.
Step 3: Ethyl 2-iodo-3-methylbenzoate
Figure imgf000403_0002
To a solution of 2-iodo-3-methylbenzoic acid (8.05 g, 30.72 mmol) in DMF (101.77 mL) were added potassium carbonate (8.49 mL, 61.44 mmol) and iodoethane (4.94 mL, 61.44 mmol). The mixture was then stirred at 25 °C for 2 hrs. The reaction was diluted with H2O (500 mL) and extracted with Et20 (3x). The combined organic layers were washed with H2O, dried over Na2SC>4, and evaporated to obtain the title compound (8.912 g, 100%) as a clear oil. 'H NMR (400 MHz, DMSO- e) 6 7.46 (dd, J = 7.5, 1.6 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.30 (dd, J = 7.6, 1.8 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). MS-ESI (m/z) calc’d for C10H12IO2 [M+H]+: 291.0. Found 291.1.
Step 4: 3-(Ethoxycarbonyl)-2-iodobenzoic acid
Figure imgf000404_0001
To a solution of ethyl 2-iodo-3-methylbenzoate (8.91 g, 30.72 mmol) in pyridine (80 mL) and H2O (80 mL) was added KMnCU (21.85 g, 138.24 mmol) and the mixture was stirred at 100 °C for 3 hrs. The dark solid formed was filtered under vacuum while still hot and washed with warm H2O. The filtrate was diluted with H2O and washed with Et20 (2x). The combined organic layers were discarded and the aqueous layer was acidified by addition of HC1 until pH 1 and then extracted with Et20 (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (6.55 g, 67%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 13.50 (s, 1H), 7.63 (dd, J = 7.2, 2.1 Hz, 1H), 7.58 - 7.52 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). MS-ESI (m/z) calc’d for C10H10IO4 [M+H]+: 321.0. Found 321.0.
Step 5: Ethyl 3-carbamoyl-2-iodobenzoate
Figure imgf000404_0002
A suspension of 3-ethoxycarbonyl-2-iodobenzoic acid (6.55 g, 16.17 mmol) in thionyl chloride (40.93 mL) was stirred at 75 °C for 2 hrs. The solvent was evaporated to obtain a yellow oil which was taken up in DCM and added dropwise to a cold solution of ammonium hydroxide (39.5 mL, 584.6 mmol). The biphasic mixture was stirred for 15 minutes, then the 2 phases were separated. The organic layer was concentrated to afford the title compound (5.16 g, 100%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.87 (s, 1H), 7.57 (s, 1H), 7.53 - 7.45 (m, 2H), 7.38 (dd, J = 5.6, 3.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). MS-ESI (m/z) calc’d for C10H11INO3 [M+H]+: 320.0. Found 320.0.
Step 6: Ethyl 3-cyano-2-iodobenzoate
Figure imgf000405_0001
A suspension of ethyl 3-carbamoyl-2-iodobenzoate (5.16 g, 16.17 mmol) in POCk (100 mL) was heated at 100 °C for 1 hr. The excess of POCh was removed under vacuum, the residue oil was taken up in DCM, washed with aqueous K2CO3 (3x). The organic layer was passed through a short silica pad and then evaporated to afford the title compound (4.87 g, 100%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 7.97 (dd, J = 7.7, 1.6 Hz, 1H), 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). MS-ESI (m/z) calc’d for C10H9INO2 [M+H]+: 302.4. Found 302.4.
Figure imgf000405_0002
To a solution of ethyl 3-cyano-2-iodobenzoate (1.2 g, 4 mmol) in THF (20 mL)/H20 (20 mL) was added potassium carbonate (552.84 mg, 4 mmol), isopropenylboronic acid pinacol ester (0.75 mL, 4 mmol) and XPhos Pd G3 (338.58 mg, 0.40 mmol). The mixture was stirred at 100 °C for 30 minutes. The solvent was evaporated and the residue was taken up in H2O and extracted with EtOAc (3x). The combined organic layers were passed through an alumina pad and evaporated to obtain a residue which was purified by silica gel chromatography on a 50 g silica gel column using a 0-100% EtOAc/cyclohexane gradient eluent to afford the title compound (842 mg, 98%) as an orange oil. 1 H NMR (400 MHz, DMSO- e) 6 8.05 (dd, J = 7.8, 1.4 Hz, 1H), 8.03 (dd, J = 8.0, 1.4 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 5.33 (p, J = 1.5 Hz, 1H), 4.88 (p, J = 1.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.10 (dd, J = 1.5, 0.9 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). MS-ESI (m/z) calc’d for C13H14NO2 [M+H]+: 216.1. Found 216.1.
Step 8: Ethyl 3-carbamoyl-2-(prop-l-en-2-yl)benzoate
Figure imgf000406_0001
To a solution of ethyl 3-cyano-2-(prop-l-en-2-yl)benzoate (842.0 mg, 3.91 mmol) in DMSO (9.779 mL) were added potassium carbonate (180.03 mg, 1.3 mmol) and hydrogen peroxide (0.96 mL, 9.39 mmol). The mixture was stirred at 25 °C for 17 hrs. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with H2O, dried over Na2SC>4, and evaporated to afford the title compound (754 mg, 82%) as an orange solid. 'H NMR (400 MHz, DMSO-tL) 6 7.69 (dd, J = 7.7, 1.4 Hz, 1H), 7.62 (s, 1H), 7.51 (dd, J = 7.6, 1.5 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.36 (s, 1H), 5.06 (p, J = 1.5 Hz, 1H), 4.70 (dd, J = 2.0, 1.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.04 (t, J = 1.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H). MS-ESI (m/z) calc’d for C13H16NO3 [M+H]+: 234,1. Found 234.1.
Figure imgf000406_0002
To a solution of ethyl 3-carbamoyl-2-(prop-l-en-2-yl)benzoate (754.0 mg, 3.23 mmol) in MeOH (32.32 mL) was added 10% Pd/C (1.03 g, 0.97 mmol) and the mixture was hydrogenated at 6 bar for 48 hrs. The catalyst was filtered through a Celite pad and the filtrate was evaporated to dryness to afford the title compound (760.5 mg, 100%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 7.81 (s, 1H), 7.45 (s, 1H), 7.41 (dd, J = 7.2, 2.0 Hz, 1H), 7.33 (dd, J = 7.6, 2.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.31 (hept, J = 7.0 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.30 (d, J = 7.2 Hz, 6H). MS-ESI (m/z) calc’d for C13H18NO3 [M+H]+: 236.3. Found 236.3.
Step 10: Ethyl 3-cyano-2-isopropylbenzoate
Figure imgf000406_0003
A suspension of ethyl 3-carbamoyl-2-propan-2-ylbenzoate (760.5 mg, 3.23 mmol) in POCh (32.32 mL) was stirred at 100 °C for 30 minutes. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were dried over Na2SC>4 and evaporated to afford the title compound (560 mg, 80%) as a light brown oil. 'H NMR (400 MHz, DMSO- e) 6 7.96 (dd, J = 7.7, 1.5 Hz, 1H), 7.80 (dd, J = 7.8, 1.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.50 (hept, J = 7.2 Hz, 1H), 1.40 (d, J = 7.2 Hz, 6H), 1.31 (t, J = 7.1 Hz, 3H). MS-ESI (m/z) calc’d for C13H16NO2 [M+H]+: 218.1. Found 218.1.
Step 11 : 3-Cyano-2-isopropylbenzoic acid
Figure imgf000407_0001
To a solution of ethyl 3-cyano-2-propan-2-ylbenzoate (560.0 mg, 2.58 mmol) in THF (12.89 mL) and H2O (12.89 mL) was added LiOH’FbO (108.15 mg, 2.58 mmol) and the mixture was stirred at 25 °C for 6 hrs. The organic solvent was evaporated and the aqueous layer was acidified by addition of HC1 (37%) and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (474 mg, 97%) as a beige solid. JH NMR (400 MHz, DMSO- e) 6 13.53 (s, 1H), 7.92 (dd, J = 7.7, 1.5 Hz, 1H), 7.80 (dd, J = 7.8, 1.5 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 3.61 (hept, J = 7.2 Hz, 1H), 1.41 (d, J = 7.2 Hz, 6H). MS-ESI (m/z) calc’d for C11H12NO2 [M+H]+: 190.0. Found 190.0.
Figure imgf000407_0002
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide using 3-cyano-2-isopropylbenzoic acid in place of 4- cyano-2-(prop-l-en-2-yl)benzoic acid and l-(pyridazin-4-yl)-17/-indazol-6-amine in place of 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine to afford the title compound (28 mg, 8%) as a beige solid. 'H-NMR (400 MHz, DMSO- e) 6 10.95 (s, 1H), 9.82 (dd, J = 2.9, 1.0 Hz, 1H), 9.38 (dd, J = 5.9, 1.0 Hz, 1H), 8.75 (s, 1H), 8.57 (d, J = 0.9 Hz, 1H), 8.05 (dd, J = 5.9, 2.9 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.78 (dd, J = 7.7, 1.4 Hz, 1H), 7.63 (dd, J = 8.7, 1.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 3.38 (hept, J = 6.9 Hz, 1H), 1.44 (d, J = 7.1 Hz, 6H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.1. Found 383.2.
Example 211: 3-Cyano-2-isopropyl-7V-(l-(6-methylpyridazin-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000408_0001
Step 1: l-(6-Methylpyridazin-4-yl)-lH-indazol-6-amine
Figure imgf000408_0002
To a solution of l-(6-chloropyridazin-4-yl)-6-nitroindazole and 2-(6-chloropyridazin- 4-yl)-6-nitroindazole (551.3 mg, 2 mmol) in 1,4-dioxane (15 mL) and H2O (5 mL) were added potassium carbonate (552.84 mg, 4 mmol), trimethylboroxin (0.56 mL, 4 mmol) and Pd(PPh3)4 (462.22 mg, 0.40 mmol). The mixture was then stirred at 100 °C for 15 hrs. After cooling, the reaction was diluted with H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel chromatography using a 0-20% EtOH/DCM gradient eluent to afford the title compound (58 mg, 13%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 9.59 (d, J = 2.6 Hz, 1H), 8.22 (d, J = 0.9 Hz, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 1.7, 0.9 Hz, 1H), 6.69 (dd, J = 8.6, 1.7 Hz, 1H), 5.72 (s, 2H), 2.71 (s, 3H). MS-ESI (m/z) calc’d for C12H12N5 [M+H]+: 226.1. Found 226.1.
Figure imgf000408_0003
Prepared as described for 4-cyano-/V-[l-(l-methylpyrazol-4-yl)indazol-6-yl]-3-prop- l-en-2-ylpyridine-2-carboxamide using 3-cyano-2-isopropylbenzoic acid in place of 4- cyano-2-(prop-l-en-2-yl)benzoic acid and l-(6-methylpyridazin-4-yl)-17/-indazol-6-amine in place of 1-(1 -methyl- l7/-pyrazol-4-yl)-l7/-indazol-6-amine to afford the title compound (33.6 mg, 33%) as a beige solid. 'H NMR (400 MHz, DMSO- e) 6 10.93 (s, 1H), 9.66 (d, J = 2.5 Hz, 1H), 8.67 (s, 1H), 8.55 (d, J = 0.9 Hz, 1H), 8.00 - 7.90 (m, 3H), 7.78 (dd, J = 7.7, 1.4 Hz, 1H), 7.69 (dd, J = 8.7, 1.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 3.38 (hept, J = 6.6 Hz, 1H), 2.74 (s, 3H), 1.44 (d, J = 7.1 Hz, 6H). MS-ESI (m/z) calc’d for C23H21N6O [M+H]+: 397.2. Found 397.2.
Example 212:3-Cyaiio-2-isopropyl-/V-(l-(6-methoxypyridazin-4-yl)-l//-indazol-6- yl)benzamide
Figure imgf000409_0001
Step 1: l-(6-Chloropyridazin-4-yl)-lH-indazol-6-amine; 2-(6-chloropyridazin-4-yl)-2H- indazol-6-amine
Figure imgf000409_0002
To a suspension of l-(6-chloropyridazin-4-yl)-6-nitroindazole; 2-(6-chloropyridazin- 4-yl)-6-nitroindazole (275.65 mg, 1 mmol) in EtOH (9 mL)/ H2O (1 mL) was added NH4CI (53.49 mg, 1 mmol) and iron powder (223.4 mg, 4 mmol). The mixture was then stirred at 80 °C for 1 hr. After cooling the mixture was diluted with EtOAc and filtered through a Celite pad. The filtrate was washed with H2O (3x), passed through a phase separator, and evaporated to obtain a 7:3 mixture of the title compounds (170 mg, 69%) as a yellow solid. Major isomer: 'H NMR (400 MHz, DMSO- e) 69.76 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.25 - 7.22 (m, 1H), 6.72 (dd, J = 8.6, 1.7 Hz, 1H), 5.82 (s, 2H). Minor isomer: 'H NMR (400 MHz, DMSO- e) 6 9.92 (d, J = 2.3 Hz, 1H), 9.10 (d, J = 1.0 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 6.68 (dd, J = 9.1, 1.8 Hz, 1H), 6.44 - 6.40 (m, 1H), 5.66 (s, 2H). Major isomer: r.t. 0.76 min, MS- ESI (m/z) calc’d for C11H9 CINs [M+H]+: 246.0. Found 246.0. Minor isomer: r.t. 0.97 min, MS-ESI (m/z) calc’d for C11H10N5 [M+H]+: 246.0. Found 246.0.
Step 2: l-(6-Methoxypyridazin-4-yl)-lH-indazol-6-amine
Figure imgf000410_0001
Sodium hydride (60% dispersion in oil, 55.36 mg, 1.38 mmol) was carefully added to MeOH (10 mL) and stirred at 25 °C for 15 minutes. A suspension of l-(6-chloropyridazin-4- yl)indazol-6-amine and 2-(6-chloropyridazin-4-yl)indazol-6-amine (170.0 mg, 0.69 mmol) in MeOH (5 mL) was added and the mixture was stirred at 65 °C for 3 hrs. The solvent was evaporated and the residue was purified by silica gel chromatography using a 0-5% MeOH/DCM gradient eluent to afford the title compound (54 mg, 32%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 9.47 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 0.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.21 - 7.16 (m, 1H), 6.69 (dd, J = 8.6, 1.7 Hz, 1H), 5.75 (d, J = 1.5 Hz, 2H), 4.11 (s, 3H). MS-ESI (m/z) calc’d for C12H12N5O [M+H]+: 242.1. Found 242.1.
Figure imgf000410_0002
Prepared as described for 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-3-(prop-l-en-2-yl)picolinamide using 3-cyano-2-isopropylbenzoic acid in place of 4- cyano-2-(prop-l-en-2-yl)benzoic acid and l-(6-methoxypyridazin-4-yl)-17/-indazol-6-amine in place of 1-(1 -methyl- l//-pyrazol-4-yl)-l7/-indazol-6-amme to afford the title compound (19 mg, 21%) as a beige solid. 'H NMR (400 MHz, DMSO- e) 6 10.93 (s, 1H), 9.51 (d, J = 2.2 Hz, 1H), 8.66 (s, 1H), 8.54 (d, J = 0.9 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.78 (dd, J = 7.7, 1.4 Hz, 1H), 7.69 (dd, J = 8.7, 1.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 4.12 (s, 3H), 3.38 (hept, J = 7.0 Hz, 1H), 1.44 (d, J = 7.1 Hz, 6H). MS-ESI (m/z) calc’d for C23H21N6O2 [M+H]+: 413.2. Found 413.2. Example 213: (£')-2-(Biit-2-eii-2-yl)-3-cyano-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//- indazol-6-yI)benzamide
Figure imgf000411_0001
Step 1: Ethyl (E)-2-(but-2-en-2-yl)-3-cyanobenzoate
Figure imgf000411_0002
To a solution of ethyl 3-cyano-2-iodobenzoate (100.0 mg, 0.33 mmol) in THF (1.661 mL) and water (1.661 mL) were added 2-[(Z)-but-2-en-2-yl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (60.47 mg, 0.33 mmol) and potassium carbonate (45.9 mg, 0.33 mmol). The mixture was degassed with N2 for 15 min, then XPhos Pd G3 (28.11 mg, 0.03 mmol) was added and the reaction was stirred at 100 °C for 45 min. The solvent was evaporated and the residue was taken up in H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and evaporated to obtain a residue which was purified by silica gel chromatography using a 0-5% MeOH/DCM gradient eluent to afford the the title compound (24 mg, 31%) as a colorless oil. JH NMR (400 MHz, CDCh) 8 7.97 (dd, J = 7.9, 1.4 Hz, 1H), 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 5.50 - 5.38 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.03 (t, J = 1.3 Hz, 3H), 1.85 - 1.76 (m, 3H), 1.34 (t, J = 7.2 Hz, 3H), MS-ESI (m/z) calc’d for C14H16NO2 [M+H]+: 230.1 Found 230.1.
Step 2: (E)-2-(But-2-en-2-yl)-3-cyano-N-( 1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000411_0003
Prepared as described for 6-chloro-3-cyano-2-fluoro-/V-(l-(l-methyl-17/-pyrazol-4- yl)-17/-indazol-6-yl)benzamide using ethyl (E)-2-(but-2-en-2-yl)-3 -cyanobenzoate in place of methyl 6-chloro-3-cyano-2-fluorobenzoate to afford the title compound (11 mg, 25%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.55 (s, 1H), 8.20 (d, J = 1.0 Hz, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.95 (dd, J = 7.7, 1.3 Hz, 1H), 7.83 (dd, J = 7.7, 1.3 Hz, 1H), 7.81 - 7.80 (m, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.33 (dd, J = 8.7, 1.7 Hz, 1H), 5.61 - 5.52 (m, 1H), 3.95 (s, 3H), 1.99 - 1.92 (m, 3H), 1.66 (dd, J = 6.8, 1.3 Hz, 3H). MS-ESI (m/z) calc’d for C23H21N6O [M+H]+: 397.2. Found 397.2.
Example 214: 2-(v<?c-Biityl)-3-cyano-/V-(l-(l-methyl-l//-pyrazol-4-yl)-l//-indazol-6- yl)benzamide
Figure imgf000412_0001
A mixture of (E')-2-(but-2-en-2-yl)-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)benzamide (11.0 mg, 0.03 mmol) and 10% Pd/C (2.95 mg, 0.003 mmol) in MeOH (10 mL) was stirred under an H2 atmosphere for 4 hrs. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to afford a residue which was purified by preparative HPLC using Method GT to afford the title compound (3.4 mg, 31%) as a white solid. ‘H NMR (400 MHz, DMSO- e) 6 10.76 (s, 1H), 8.28 - 8.25 (m, 1H), 8.23 - 8.19 (m, 2H), 7.94 (dd, J = 7.7, 1.4 Hz, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.75 (dd, J = 7.7, 1.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.39 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 3.08 (h, J = 7.2 Hz, 1H), 2.03 - 1.87 (m, 1H), 1.76 (dp, J = 14.4, 7.3 Hz, 1H), 1.41 (d, J = 7.2 Hz, 3H), 0.78 (t, J = 7.4 Hz, 3H). MS-ESI (m/z) calc’d for C23H23N6O [M+H]+: 399.2. Found 399.2.
Example 215: 5-Cyano-4-isopropyl-N-(l-(l-methyI-lH-pyrazol-4-yI)-lH-indazol-6- yl)nicotinamide
Figure imgf000412_0002
Step 1: Methyl 4-hydroxynicotinate OH O (V - N
To a solution of 4-hydroxypyridine-3-carboxylic acid (5.8 g, 41.69 mmol) in MeOH (100 mL) was added sulfuric acid (0.22 mL, 4.17 mmol) and the mixture was stirred at 65 °C for 72 hrs. The solvent was evaporated, the residue was taken up in Na2COs solution and stirred for 5 minutes. The solid that formed was collected by filtration, washed with H2O, and dried to obtain the title compound (2.88 g, 45%) as a beige solid. JH NMR (400 MHz, DMSO- e) 6 11.66 (s, 1H), 8.21 (s, 1H), 7.63 (s, 1H), 6.20 (s, 1H), 3.70 (s, 3H), MS-ESI (m/z) calc’d for CvHsINOs [M+H]+: 154.0. Found 154.0.
Step 2: Methyl 4-hydroxy-5-iodonicotinate
Figure imgf000413_0001
To a suspension of methyl 4-hydroxynicotinate (2.88 g, 18.81 mmol) in MeCN (15 mL) and acetic acid (9 mL) was added /V-iodosuccinimide (4.23 g, 18.81 mmol) and the mixture was stirred at 60 °C for 5 hrs. The solvent was evaporated and the residue was taken up in acetone. The solid formed was collected by filtration, washed with acetone, and dried to obtain the title compound (4.43 g, 84%) as a white solid. 1 H NMR (400 MHz, DMSO- e) 6 12.04 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 3.72 (s, 3H). MS-ESI (m/z) calc’d for C7H7INO3 [M+H]+: 280.0. Found 280.0.
Step 3: Methyl 4-chloro-5 -iodonicotinate
Cl O
'TY- N
A suspension of methyl 4-hydroxy-5-iodonicotinate (1.12 g, 4 mmol) in POCh (20 mL) was stirred at 100 °C for 2 hrs. The solvent was evaporated and the residue was taken up in saturated aqueous NaHCOs and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain the title compound (1.19 g, 100%) as a pale yellow solid. ‘H NMR (400 MHz, DMSO-Je) 6 9.14 (s, 1H), 8.83 (s, 1H), 3.90 (s, 3H). MS-ESI (m/z) calc’d for C9H9CINO2 [M+H]+: 298.0. Found 298.0. Step 4: Methyl 4-chloro-5-vinylnicotinate
Figure imgf000414_0001
To a suspension of methyl 4-chl oro-5 -iodonicotinate (1.21 g, 4 mmol) in toluene (40 mL) was added tributyl(vinyl)stannane (1.17 mL, 4 mmol) and bis(triphenylphosphine)palladium(II) dichloride (281.56 mg, 0.400 mmol). The mixture was then stirred at 100 °C for 15 hrs. The solvent was evaporated and the residue was purified by silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (790.48 mg, 100%) as ayellow solid. 'H NVIR (400 MHz, DMSO- e) 6 9.00 (d, J = 0.8 Hz, 1H), 8.81 (s, 1H), 7.01 (dd, J = 17.6, 11.2 Hz, 1H), 6.10 (dd, J = 17.6, 0.8 Hz, 1H), 5.65 (dd, J = 11.2, 0.8 Hz, 1H), 3.90 (s, 3H). MS-ESI (m/z) calc’d for C9H9CINO2 [M+H]+: 198.0, 200.0. Found 198.0, 200.0.
Step 5: Methyl 4-chloro-5-formylnicotinate
Figure imgf000414_0002
To a solution of methyl 4-chloro-5-vinylni cotinate (790.48 mg, 4 mmol) in 1,4- di oxane (10 mL) and water (10 mL) was added sodium periodate (1.71 g, 8 mmol) and 4% osmium tetroxide (1.27 mL, 0.200 mmol). The mixture was then stirred at 25 °C for 2 hrs. The suspension was diluted with water and extracted with DCM (4x). The combined organic layers were passed through a phase separator and evaporated to obtain the title compound (798.35 mg, 100%) as a dark oil. 'H NMR (400 MHz, DMSO- e) 6 10.39 (s, 1H), 9.12 (s, 1H), 9.04 (s, 1H), 3.94 (s, 3H). MS-ESI (m/z) calc’d for C9H7CINO3 [M+H]+: 200.0. Found 200.0.
Figure imgf000414_0003
To a suspension of methyl 4-chloro-5-formylpyridine-3-carboxylate (698.57 mg, 3.5 mmol) in EtOH (35 mL) was added hydroxylamine (0.21 mL, 3.5 mmol) and the mixture was stirred at 25 °C for 30 minutes. The solvent was evaporated under reduced pressure to afford the title compound (10 mg, 89%) as a brown solid. 'H-NMR (400 MHz, DMSO- e) 6 11.16 (s, 1H), 10.11 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 3.72 (s, 3H). MS-ESI (m/z) calc’d for CsHsC Os [M+H]+: 215.0. Found 197 [M-H2O].
Step 7: Methyl 4-chloro-5 -cyanonicotinate
Figure imgf000415_0001
A suspension of methyl 4-chloro-5-((hydroxyimino)methyl)nicotinate (610.0 mg, 3.11 mmol) in POCh (31.1 mL) was stirred at 100 °C for 2 hrs. The excess POCh was evaporated and the residue was taken up in saturated aqueous NaHCOs and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain the title compound (350 mg, 57%) as a yellow solid. 1 H NMR (400 MHz, DMSO- e) 6 9.25 (s, 1H), 9.20 (s, 1H), 3.93 (s, 3H). MS-ESI (m/z) calc’d for C8H6CIN2O2 [M+H]+: 197.0. Found 197.0.
Figure imgf000415_0002
To a solution of methyl 4-chloro-5-cyanonicotinate (350.0 mg, 1.78 mmol) in THF (8.309 mL) and water (8.309 mL) were added potassium carbonate (246.06 mg, 1.78 mmol), isopropenylboronic acid pinacol ester (0.33 mL, 1.78 mmol) and XPhos Pd G3 (150.7 mg, 0.180 mmol). The mixture was then stirred at 100 °C for 1 hr. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to obtain a residue which was purified by silica gel chromatography using a 0-50% EtOAc/cyclohexane gradient eluent to afford the title compound (77 mg, 21%) as a yellow oil. 'H NMR (400 MHz, DMSO- e) 6 9.20 (s, 1H), 9.14 (s, 1H), 5.42 (p, J = 1.5 Hz, 1H), 5.02 (p, J = 1.0 Hz, 1H), 3.86 (s, 3H), 2.08 (t, J = 1.5, 1.0 Hz, 3H). MS-ESI (m/z) calc’d for C11H11N2O2 [M+H]+: 203.0. Found 203.0. Step 9: 5-Cyano-4-(prop-l-en-2-yl)nicotinic acid
Figure imgf000416_0001
To a solution of methyl 5-cyano-4-(prop-l-en-2-yl)nicotinate (77.0 mg, 0.38 mmol) in THF (1.904 mL) and H2O (1.904 mL) was added LiOH’FhO (15.98 mg, 0.380 mmol) and the mixture was stirred at 25 °C for 1 hr. The mixture was then diluted with H2O and extracted with Et20. The aqueous layer was acidified by addition of 1 M HC1 until pH 3-4, then extracted with EtOAc (2x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (45 mg, 63%) as a yellow oil. 'H NMR (400 MHz, DMSO- e) 6 13.80 (s, 1H), 9.15 (s, 1H), 9.11 (s, 1H), 5.40 (p, J = 1.5 Hz, 1H), 5.01 (p, J = 0.9 Hz, 1H), 2.08 (dd, J = 1.6, 1.0 Hz, 3H). MS-ESI (m/z) calc’d for C10H9N2O2 [M+H]+: 189.0. Found 189.0.
Step 10: 5-Cyano-N-(l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-4-(prop-l-en-2- yl)nicotinamide
Figure imgf000416_0002
To a suspension of 5-cyano-4-(prop-l-en-2-yl)nicotinic acid (45.0 mg, 0.240 mmol), l-(l-methylpyrazol-4-yl)indazol-6-amine (50.99 mg, 0.240 mmol) and triethylamine (33.33 uL, 0.240 mmol) in MeCN (2.391 mL) was added HATU (90.93 mg, 0.240 mmol) and the mixture was stirred at 25 °C for 3 hrs. The solvent was evaporated and the residue was taken up in H2O and extracted with DCM (3x). The combined organic layers were passed through a phase separator and evaporated to afford the title compound (92 mg, 100%) as a beige solid which was used without further purification. 'H NMR (400 MHz, DMSO- e) 6 10.84 (s, 1H), 9.16 (s, 1H), 9.03 (s, 1H), 8.22 (d, J = 1.0 Hz, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.84 - 7.79 (m, 2H), 7.34 (dd, J = 8.7, 1.7 Hz, 1H), 5.45 (t, J = 1.5 Hz, 1H), 5.14 (s, 1H), 3.95 (s, 3H), 2.10 (s, 3H). MS-ESI (m/z) calc’d for C21H18N7O [M+H]+: 384.2. Found 384.2.
Step 11: 5-Cyano-4-isopropyl-N-( 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6- yl)nicotinamide
Figure imgf000417_0001
Prepared as described for 3-isopropyl-/V4-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol- 6-yl)pyridine-2,4-dicarboxamide, using 5-cyano-N-(l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)-4-(prop-l-en-2-yl)nicotinamide in place of 2-cyano-/V-(l-(l-methyl-17/- pyrazol-4-yl)-17/-indazol-6-yl)-3-(prop-l-en-2-yl)isonicotinamide to afford the title compound (14.1 mg, 15%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 11.00 (s, 1H), 9.08 (s, 1H), 8.90 (s, 1H), 8.27 (s, 1H), 8.25 - 8.20 (m, 2H), 7.85 - 7.80 (m, 2H), 7.37 (dd, J = 8.7, 1.7 Hz, 1H), 3.95 (s, 3H), 3.36 (hept, J = 7.2 Hz, 1H), 1.42 (d, J = 7.0 Hz, 6H). MS- ESI (m/z) calc’d for C21H20N7O [M+H]+: 386.2. Found 386.2.
Example 216: 5-((l-(l-(2-Methoxyethyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1
Figure imgf000417_0002
A mixture of 5-(( 17/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (30 mg, 103.69 umol), 4-bromo-l-(2-methoxyethyl)-17/-pyrazole (21.26 mg, 103.69 umol), Cui (3.95 mg, 20.74 umol), K3PO4 (66.03 mg, 311.06 umol) and (15, 25)- /Vl,/V2-dimethylcyclohexane-l,2-diamine (7.37 mg, 51.84 umol) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C and then the mixture was stirred at 110 °C for 24 hrs under an N2 atmosphere. The mixture was concentrated to give a residue which was purified by HPLC using Method GT to afford the title compound (5.18 mg, 11%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.31 (s, 1 H), 8.17 (d, J=0.63 Hz, 1 H), 7.96 (d, J=0.63 Hz, 1 H), 7.75 (d, J=8.76 Hz, 1 H), 7.69 (s, 1 H), 7.64 (d, J=8.00 Hz, 1 H), 7.55 (d, J=8.00 Hz, 1 H), 7.27 (s, 1 H), 6.97 (dd, J=8.76, 2.00 Hz, 1 H), 5.78 (t, J=4.82 Hz, 1 H), 4.34 (t, J=5.32 Hz, 2 H), 3.75 (t, J=5.32 Hz, 2 H), 3.25 (s, 3 H), 2.86 - 2.94 (m, 1 H), 2.74 - 2.83 (m, 1 H), 2.01 - 2.06 (m, 2 H), 1.76 - 1.93 (m, 2 H). MS-ESI (m/z) calc’d for C24H24N5O2 [M+H]+: 414.2 Found 414.1. Example 217 : 5-((l-(4-Methylthiazol-5-yl)-lff-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000418_0001
To a solution of l-(17/-indazol-6-yloxy)tetralin-6-carbonitrile (40.00 mg, 138.25 umol), 5-bromo-4-methyl-thiazole (24.62 mg, 138.25 umol) in dioxane (1 mL) were added Cui (5.27 mg, 27.65 umol), (lS,2S)- ,/V2-dimethylcyclohexane-l,2-diamine (9.83 mg, 69.13 umol) and K3PO4 (88.04 mg, 414.75 umol) at 20 °C. The mixture was stirred at 100 °C for 48 hrs under an N2 atmosphere. The residue was purified via Method GU. The material was further separated by chiral separation using Method GV to afford 5-((l-(4-methylthiazol-5- yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (1.72 mg, 3%) as an off-white solid. 'H NMR (400 MHz, MeOD) 6 9.05 (s, 1 H), 8.24 (d, J=0.83 Hz, 1 H), 7.78 (d, J=8.70 Hz, 1 H), 7.55 (s, 1 H), 7.46 - 7.53 (m, 2 H), 7.02 (dd, J=8.82, 2.15 Hz, 1 H), 6.89 (s, 1 H), 5.58 (t, J=4.95 Hz, 1 H), 2.89 - 2.98 (m, 1 H), 2.78 - 2.87 (m, 1 H), 2.29 (s, 3 H), 2.07 - 2.14 (m, 2 H), 1.95 - 2.03 (m, 1 H), 1.80 - 1.91 (m, 1 H). MS-ESI (m/z) calc’d for C22H19N4OS [M+H]+: 387.1. Found 387.0. A later eluting fraction was also isolated to afford 5-((l-(4-methylthiazol-5-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (2.02 mg, 4%) as an off-white solid. 'H NMR (400 MHz, MeOD) 6 9.06 (s, 1 H), 8.24 (d, J=0.83 Hz, 1 H), 7.78 (d, J=8.82 Hz, 1 H), 7.56 (s, 1 H), 7.47 - 7.53 (m, 2 H), 7.02 (dd, J=8.76, 2.09 Hz, 1 H), 6.89 (s, 1 H), 5.59 (t, J=4.95 Hz, 1 H), 2.89 - 2.99 (m, 1 H), 2.76 - 2.88 (m, 1 H), 2.30 (s, 3 H), 2.07 - 2.15 (m, 2 H), 1.95 - 2.04 (m, 1 H), 1.82 - 1.91 (m, 1 H). MS-ESI (m/z) calc’d for C22H19N4OS [M+H]+: 387.1. Found 387.0.
Example 218: 5-((l-(2-Methoxythiazol-5-yI)-lH-indazol-6-yI)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000419_0001
To a solution of 5-iodo-2-methoxythiazole (12.50 mg, 51.84 umol) and
Figure imgf000419_0002
indazol-6-yl)oxy)-5,6,7,8-tetiahydronaphthalene-2-carbonitrile, enantiomer 2 (15 mg, 51.84 umol) in dioxane (1 mL) were added Cui (1.97 mg, 10.37 umol), K3PO4 (33.01 mg, 155.53 umol) and (lS,2S)- ,/V2-dimethylcyclohexane-l,2-diamine (3.69 mg, 25.92 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method GW to afford the title compound (5.9 mg, 25%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 8.26 (s, 1 H), 7.78 (d, J=8.80 Hz, 1 H), 7.69 (s, 1 H), 7.62- 7.66 (m, 2 H), 7.53 (d, J=7.95 Hz, 1 H), 7.39 (s, 1 H), 7.00 (dd, J=1.83, 8.68 Hz, 1 H), 5.83 (t, J=4.83 Hz, 1 H), 4.07 (s, 3 H), 2.73-2.94 (m, 2 H), 1.99-2.08 (m, 2 H), 1.77-1.92 (m, 2 H). MS-ESI (m/z) calc’d for C22H19N4O2S [M+H]+: 403.1. Found 403.1.
Example 219: 5-((l-(4,5,6,7-Tetrahydropyrazolo[l,5-a]pyridin-3-yI)-LH-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000419_0003
Prepared as described for 5-((l-(2-methoxythiazol-5-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 3-bromo-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyridine in place of 5 -iodo-2-methoxy thiazole. The compound was purified by HPLC using Method GX to afford the title compound (960 ug, 4%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.16 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, J=8.8 Hz, 1 H), 7.68 (s, 1 H), 7.63 (d, J=7.6 Hz, 1 H), 7.51 (d, J=8.0 Hz, 1 H), 7.04 (s, 1 H), 6.92 (dd, J=2.0, 8.8 Hz, 1 H), 5.69 (t, J=4.8 Hz, 1 H), 4.15 (t, J=6.1 Hz, 2 H), 2.97 - 2.70 (m, 2 H), 2.70 - 2.67 (m, 2 H), 2.01 (br d, J=5.4 Hz, 4 H), 1.87 - 1.76 (m, 4 H). MS-ESI (m/z) calc’d for C25H24N5O [M+H]+: 410.2. Found: 410.1. Example 220: 5-((l-(2-Isopropylthiazol-5-yl)-Lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000420_0001
Prepared as described for 5-((l-(2-methoxythiazol-5-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 5-bromo-2- isopropylthiazole in place of 5-iodo-2-methoxythiazole. The compound was purified by HPLC using Method GY to afford the title compound (2.17 mg, 15%) as ayellow solid. JH NMR (400 MHz, DMSO- e) 6 8.30 (s, 1 H), 8.10 (s, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 7.70 (s, 1 H), 7.65 (d, J=8.0 Hz, 1 H), 7.55 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.02 (dd, J=2.0, 8.8 Hz, 1 H), 5.86 (t, J=4.7 Hz, 1 H), 3.30 - 3.27 (m, 1 H), 2.96 - 2.86 (m, 1 H), 2.84 - 2.74 (m, 1 H), 2.10 - 1.97 (m, 2 H), 1.93 - 1.77 (m, 2 H), 1.37 (d, J=6.9 Hz, 6 H) MS-ESI (m/z) calc’d for C24H23N4OS [M+H]+: 415.2. Found: 415.0.
Example 221 : 5-((l-(Pyrazolo [ 1,5-a] py ridin-3-y 1)-17/-indazol-6-y l)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000420_0002
Prepared as described for 5-((l-(2-methoxythiazol-5-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 3-iodopyrazolo[l,5- a]pyridine in place of 5-iodo-2-methoxythiazole. The compound was purified by HPLC using Method GW to afford the title compound (4.11 mg, 33%) as a white solid. 1 H NMR (400 MHz, DMSO- e) 6 8.79 (d, J=6.97 Hz, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 7.79 (d, J=8.68 Hz, 1H), 7.66 (br d, J=4.77 Hz, 2H), 7.62 (br d, J=8.07 Hz, 1H), 7.50 (d, J=8.07 Hz, 1H), 7.30-7.36 (m, 1H), 7.18 (s, 1H), 7.03 (t, J=6.48 Hz, 1H), 6.96 (dd, J=1.71, 8.68 Hz, 1H), 5.70 (br t, J=4.71 Hz, 1H), 2.83-2.92 (m, 1H), 2.71-2.80 (m, 1H), 1.95-2.05 (m, 2H), 1.71-1.91 (m, 2H). MS-ESI (m/z) calc’d for C25H20N5O [M+H]+: 406.2. Found 406.2. Example 222: 5-((l-(5-Methyl-l,3,4-oxadiazol-2-yl)-Lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000421_0001
Prepared as described for 5-((l-(2-methoxythiazol-5-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 2-bromo-5-methyl-l,3,4- oxadiazole in place of 5 -iodo-2-methoxy thiazole. The compound was purified by HPLC using Method GZ to afford the title compound (2.34 mg, 11%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.52 (s, 1H), 7.89 (d, J=8.68 Hz, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.65 (d, J=8.07 Hz, 1H), 7.56 (d, J=8.07 Hz, 1H), 7.18 (dd, J=2.14, 8.74 Hz, 1H), 5.74 (t, J=4.77 Hz, 1H), 2.88-2.97 (m, 1H), 2.75-2.85 (m, 1H), 2.59 (s, 3H), 2.05-2.13 (m, 2H), 1.78-1.94 (m, 2H). MS-ESI (m/z) calc’d for C21H18N5O2 [M+H]+: 372.1. Found 372.1.
Example 223: 5-((l-(2-Methylthiazol-4-yl)-Lff-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2
Figure imgf000421_0002
Prepared as described for 5-((l-(2-methoxythiazol-5-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 using 4-bromo-2-methylthiazole in place of 5-iodo-2-methoxythiazole. The compound was purified by HPLC using Method HA to afford the title compound (4.87 mg, 17%) as a yellow solid. 1 H NMR (400 MHz, DMSO- e) 6 8.27 (s, 1H), 7.96 (d, J=1.8 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.70 (s, 1H), 7.62- 7.67 (m, 1H), 7.54-7.58 (m, 1H), 7.46 (s, 1H), 7.06 (dd, J=8.8, 2.2 Hz, 1H), 5.67 (t, J=4.8 Hz, 1H), 2.87-2.97 (m, 1H), 2.78-2.84 (m, 1H), 2.77 (s, 3H), 2.06-2.10 (m, 2H), 1.78-1.92 (m, 2H). MS-ESI (m/z) calc’d for C22H19N4OS [M+H]+: 387.1. Found 387.0.
Example 224: 5-((l-(2-Morpholinopyridin-4-yl)-LH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000422_0001
Step 1: 5-((l-(2-Morpholinopyridin-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000422_0002
To a solution of 4-(4-bromopyridin-2-yl)morpholine (70 mg, 287.95 umol) in dioxane (7 mL) were added 5-(( l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile (99.98 mg, 345.54 umol), Cui (10.97 mg, 57.59 umol), /Vl,JV2-dimethylcyclohexane-l,2- diamine (20.48 mg, 143.98 umol) and K3PO4 (183.37 mg, 863.85 umol) at 20 °C. The mixture was then stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method HB to afford the title compound (36.75 mg, 28%) as a white solid. MS- ESI (m/z) calc’d for C27H26N5O2 [M+H]+: 452.2. Found 452.3.
Step 2: 5-((l-(2-Morpholinopyridin-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-
Figure imgf000422_0003
The enantiomers of 5-((l-(2-morpholinopyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile were separated by chiral HPLC using Method HC to afford 5-((l-(2-morpholinopyri din-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (18.55 mg, 45%) as a pale pink solid. 'H NMR (400 MHz, DMSO- e) 6 8.33 (s, 1H), 8.26 (d, J=5.38 Hz, 1H), 7.82 (d, J=8.80 Hz, 1H), 7.70 (s, 1H), 7.64 (br d, J=8.07 Hz, 1H), 7.53-7.59 (m, 2H), 7.16 (br d, J=5.50 Hz, 1H), 7.13 (s, 1H), 7.05 (br d, J=8.80 Hz, 1H), 5.78 (br t, J=4.77 Hz, 1H), 3.71 (br t, J=4.46 Hz, 4H), 3.52 (br d, J=4.89 Hz, 4H), 2.86-2.95 (m, 1H), 2.75-2.84 (m, 1H), 2.00-2.14 (m, 2H), 1.74- 1.95 (m, 2H). MS-ESI (m/z) calc’d for C27H26N5O2 [M+H]+: 452.2. Found 452.1. A later eluting fraction was also isolated to afford 5-(( I -(2-morpholinopyridin-4-yl)-IT/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (17.35 mg, 43%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.33 (s, 1H), 8.26 (d, J=5.48 Hz, 1H), 7.81 (d, J=8.77 Hz, 1H), 7.69 (s, 1H), 7.62-7.66 (m, 1H), 7.53-7.57 (m, 2H), 7.16 (d, J=5.70 Hz, 1H), 7.13 (s, 1H), 7.04 (dd, J=1.64, 8.66 Hz, 1H), 5.78 (t, J=4.82 Hz, 1H), 3.71 (t, J=4.71 Hz, 4H), 3.45-3.57 (m, 4H), 2.84-2.94 (m, 1H), 2.74-2.84 (m, 1H), 1.99-2.14 (m, 2H), 1.77-1.92 (m, 2H). MS-ESI (m/z) calc’d for C27H26N5O2 [M+H]+: 452.2. Found 452.1.
Example 225: 5-((l-(Pyrimidin-4-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000423_0001
Step 1: 6-Bromo-l-(pyrimidin-4-yl)-lH-indazole
Figure imgf000423_0002
To a solution of 6-bromo-17/-indazole (383.09 mg, 1.94 mmol) in NMP (12 mL) was added NaH (175.75 mg, 4.39 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. 4-chloropyrimidine hydrochloride (320 mg, 2.12 mmol) was then added at 0 °C and the mixture was stirred at 80 °C for 12 hrs. The reaction mixture was quenched by addition of saturated aqueous NH4CI at 0 °C and then extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (430 mg, 80%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.14 (s, 1 H), 8.02 (dd, J=5.75, 1.25 Hz, 1 H), 7.94 (d, J=8.50 Hz, 1 H), 7.75 - 7.82 (m, 2 H), 7.60 (dd, J=8.44, 1.69 Hz, 1 H), 7.26 - 7.29 (m, 1 H). MS-ESI (m/z) calc’d for CnH8BrN4 [M+H]+: 274.9, 276.9. Found 275.1, 277.1. Step 2: l-(Pyrimidin-4-yl)-6-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-indazole
Figure imgf000424_0001
A mixture of 6-bromo-l-pyrimidin-4-yl-indazole (200 mg, 727.00 umol), bis(pinacolato)diboron (221.53 mg, 872.40 umol), Pd(dppf)Ch (53.19 mg, 72.70 umol), and AcOK (214.05 mg, 2.18 mmol) in dioxane (8 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 120 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiCh, petroleum ether/EtOAc = 3/1, Rf = 0.29) to afford the title compound (230 mg, 98%) as a white solid. JH NMR (400 MHz, CDCh) 8 9.21 (d, J=0.63 Hz, 1 H), 9.12 (s, 1 H), 9.02 - 9.09 (m, 1 H), 8.66 (d, J=5.75 Hz, 1 H), 8.19 (d, J=0.75 Hz, 1 H), 7.70 (d, J=0.63 Hz, 2 H), 1.34 (s, 12 H), MS-ESI (m/z) calc’d for Ci7H2oBN402[M+H]+: 323.1. Found 323.2.
Step 3: l-(Pyrimidin-4-yl)-lH-indazol-6-ol
Figure imgf000424_0002
To a solution of l-pyrimidin-4-yl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indazole (230 mg, 713.91 umol) in THF (2 mL) and H2O (2 mL) was added sodium perborate tetrahydrate (329.53 mg, 2.14 mmol) at 20 °C. The mixture was stirred at 50 °C for 1 hr. The reaction mixture was then diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous NaiSOr. filtered, and the filtrate was concentrated under vacuum to afford the title compound (140 mg, 70%) as a yellow solid. MS-ESI (m/z) calc’d for C11H9N4O [M+H]+: 213.1. Found 213.2.
Step 4:5-((l-(Pyrimidin-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-tetrahydronaphthalene-2- carbonitrile
Figure imgf000425_0001
A mixture of l-(pyrimidin-4-yl)-17/-indazol-6-ol (130 mg, 612.61 umol), 5-hydroxy- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile (106.11 mg, 612.61 umol) and (tributylphosphoranylidene)acetonitrile (295.71 mg, 1.23 mmol) in toluene (4 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue. The residue was purified by HPLC using Method GW to afford the title compound (11.2 mg, 5%) as white solid. MS-ESI (m/z) calc’d for C22H18N5O [M+H]+: 368.1. Found 368.2.
Step 5: 5-((l-(Pyrimidin-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 1 and 2
Figure imgf000425_0002
The enantiomers of 5-((l -(pyrimidin-4-y l)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile were separated by chiral HPLC using Method HD to afford 5-(( l-(pyrimidin-4-yl)- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2- carbonitrile, enantiomer 1 (1.26 mg, 14%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 69.12 (s, 1 H), 8.83 (d, J=5.75 Hz, 1 H), 8.49 (s, 1 H), 8.45 (d, J=1.63 Hz, 1 H), 7.98 (d, J=5.75 Hz, 1 H), 7.86 (d, J=8.63 Hz, 1 H), 7.72 (s, 1 H), 7.62 - 7.68 (m, 1 H), 7.54 - 7.61 (m, 1 H), 7.20 (dd, J=8.75, 2.13 Hz, 1 H), 5.73 (t, J=4.82 Hz, 1 H), 2.89 - 2.97 (m, 1 H), 2.77 - 2.86 (m, 1 H), 2.10 (q, J=5.46 Hz, 2 H), 1.78 - 1.94 (m, 2 H). MS-ESI (m/z) calc’d for C22H18N5O [M+H]+: 368.1. Found 368.1. A later eluting fraction was also isolated to afford 5-((l-(pyrimidin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (1.26 mg, 13%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 9.12 (s, 1 H), 8.83 (d, J=5.75 Hz, 1 H), 8.49 (s, 2 H), 7.98 (d, J=5.88 Hz, 1 H), 7.86 (d, J=8.75 Hz, 1 H), 7.72 (s, 1 H), 7.62 - 7.68 (m, 1 H), 7.54 - 7.61 (m, 1 H), 7.20 (dd, J=8.76, 2.00 Hz, 1 H), 5.74 (t, J=4.88 Hz, 1 H), 2.88 - 2.98 (m, 1 H), 2.76 - 2.87 (m, 1 H), 2.10 (q, J=5.46 Hz, 2 H), 1.79 - 1.95 (m, 2 H). MS-ESI (m/z) calc’d for C22H18N5O [M+H]+: 368.1. Found 368.1. Example 226: 3-Cyano-2-(prop-l-en-2-yI)-N-(l-(pyrimidin-4-yI)-LH-indazol-6- yl)benzamide (226A) and 3-Cyano-2-isopropyl-N-( l-(pyrimidin-4-yl)-l//-indazol-6- yl)benzamide (226B)
Figure imgf000426_0001
Step 1: 6-Nitro-l-(pyrimidin-4-yl)-lH-indazole
Figure imgf000426_0002
To a solution of 6-nitro-17/-indazole (648.24 mg, 3.97 mmol) in DMF (10 mL) was added NaH (635.79 mg, 15.89 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hrs. Then 4-chloropyrimidine (600 mg, 3.97 mmol) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was quenched with H2O at 0 °C, then the mixture was extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-12% EtOAc/petroleum ether gradient eluent to afford the title compound (320 mg, 32%) as a yellow solid. JH NMR (400 MHz, DMSO- d6) 89.58 (s, 1 H), 9.26 (s, 1 H), 8.92 (d, J=5.75 Hz, 1 H), 8.80 (s, 1 H), 8.16-8.23 (m, 2 H), 8.04 (d, J=5.63 Hz, 1 H). MS-ESI (m/z) calc’d for CnHsNsCL [M+H]+: 242.1. Found 242.2
Step 2: l-(Pyrimidin-4-yl)-lH-indazol-6-amine
Figure imgf000426_0003
To a stirred solution of 6-nitro-l-(pyrimidin-4-yl)-17/-indazole (160 mg, 663.34 umol) in H2O (3 mL) and EtOH (3 mL) was added Fe (185.22 mg, 3.32 mmol) and NH4CI (177.41 mg, 3.32 mmol) at 20 °C, the reaction mixture was stirred at 80 °C for 2 hrs. The reaction mixture was combined with an additional, identical reaction mixture and the combined mixtures were filtered and the filtrate was concentrated under vacuum. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (240 mg, 85%) as a yellow solid. 1 H NMR (400 MHz, DMSO- e) 6 9.07 (s, 1 H), 8.78 (br d, J=5.62 Hz, 1 H), 8.23 (s, 1 H), 7.89-7.93 (m, 2 H), 7.53 (br s, 1 H), 6.72 (br d, J=8.07 Hz, 1 H), 5.94 (br s, 2 H). MS-ESI (m/z) calc’d for C11H10N5 [M+H]+: 212.1. Found 212.3.
Figure imgf000427_0001
To a solution of l-(pyrimidin-4-yl)-17/-indazol-6-amine (240 mg, 1.14 mmol), 3- cyano-2-(prop-l-en-2-yl)benzoic acid (212.70 mg, 1.14 mmol) in DMF (5 mL) was added EDCI (261.38 mg, 1.36 mmol) and HOBt (184.24 mg, 1.36 mmol), EtsN (344.93 mg, 3.41 mmol). The mixture was stirred at 20 °C for 12 hrs and then diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-26% EtOAc/petroleum ether gradient eluent to afford the title compound (270 mg, 51%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 10.82 (s, 1 H), 9.28 (s, 1 H), 9.13 (s, 1 H), 8.85 (d, J=5.95 Hz, 1 H), 8.53 (s, 1 H), 7.98-8.03 (m, 2 H), 7.86- 7.93 (m, 2 H), 7.62-7.68 (m, 2 H), 5.36 (s, 1 H), 5.06 (s, 1 H), 2.13 (s, 3 H). MS-ESI (m/z) calc’d for C22H17N6O [M+H]+: 381.1. Found 381.0.
Figure imgf000427_0002
A mixture of 3-cyano-2-(prop-l-en-2-yl)-N-(l-(pyrimidin-4-yl)-17/-indazol-6- yl)benzamide (240 mg, 630.91 umol) and Pd(OH)2 (443.01 mg) in EtOAc (2 mL) was degassed and purged with H2 (3x) and then the mixture was stirred at 20 °C for 2 hrs under an H2 atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under vacuum to give a residue that was purified by HPLC using Method HE to afford the title compound (15.01 mg, 6%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1 H), 9.37 (s, 1 H), 9.13 (s, 1 H), 8.85 (d, J=5.73 Hz, 1 H), 8.54 (d, J=0.88 Hz, 1 H), 8.01 (dd, J=1.21, 5.84 Hz, 1 H), 7.95 (dd, J=1.32, 7.72 Hz, 1 H), 7.90 (d, J=8.82 Hz, 1 H), 7.80 (dd, J=1.32, 7.72 Hz, 1 H), 7.71 (dd, J=1.76, 8.60 Hz, 1 H), 7.54 (t, J=7.72 Hz, 1 H), 3.37 (s, 1 H), 1.44 (d, J=7.06 Hz, 6 H). MS-ESI (m/z) calc’d for C22H19N6O [M+H]+: 383.2. Found 383.0.
Example 227 : 3-Cyano-2-isopropyl-7V-(l-(2-methoxythiazol-5-yI)-LH-indazol-6- yl)benzamide
Figure imgf000428_0001
Step 1: 5-Iodo-2-methoxythiazole
Figure imgf000428_0002
To a solution of 2-methoxythiazole (1 g, 8.68 mmol) in THF (17.5 mL) was added n- BuLi (2.5 M, 3.47 mL) at -78 °C and the mixture was stirred at -78 °C for 2 hrs under N2. Another solution of I2 (2.20 g, 8.68 mmol) in THF (17.5 mL) was added at -78 °C and the mixture was stirred at 20 °C for 1 hr under N2. The reaction mixture was quenched with saturated aqueous NH4CI at 0 °C and then extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-1% EtOAc/petroleum ether gradient eluent to afford the title compound (1.68 g, 80%) as a red oil. 'H NMR (400 MHz, CDCh) 8 7.20 (s, 1 H), 4.04-4.11 (m, 3 H). MS-ESI (m/z) calc’d for C4H5INOS [M+H]+: 241.9. Found 241.8.
Step 2: 3-Cyano-2-isopropyl-N-( 1 -(2-methoxythiazol-5-yl)-lH-indazol-6-yl)benzamide To a solution of 5-io
Figure imgf000429_0001
65.71 umol), 3-cyano-N-(1H- indazol-6-yl)-2-isopropylbenzamide (20 mg, 65.71 umol) in dioxane (1 mL) was added CuI (2.50 mg, 13.14 umol), K3PO4 (41.85 mg, 197.14 umol), and (1S,2S)-N1,N2- dimethylcyclohexane-1,2-diamine (4.67 mg, 32.86 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method HG to afford the title compound (5.03 mg, 17%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1 H), 8.41 (s, 1 H), 8.33 (d, J=0.73 Hz, 1 H), 7.94 (dd, J=1.22, 7.70 Hz, 1 H), 7.84 (d, J=8.68 Hz, 1 H), 7.76 (dd, J=1.22, 7.70 Hz, 1 H), 7.51-7.57 (m, 2 H), 7.42 (dd, J=1.47, 8.68 Hz, 1 H), 4.10 (s, 3 H), 3.35 (td, J=7.18, 14.24 Hz, 1 H), 1.42 (d, J=7.09 Hz, 6 H). MS- ESI (m/z) calc’d for C22H20N5O2S [M+H]+: 418.1. Found 418.0 Example 228: 3-Cyano-N-(1-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- isopropylbenzamide Prepared as described
Figure imgf000429_0002
for 3-cyano-2-isopropyl-N-(1-(2-methoxythiazol-5-yl)-1H- indazol-6-yl)benzamide using 1-(2-fluoroethyl)-4-iodo-1H-pyrazole in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HH to afford the title compound (33 mg, 22%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1 H), 8.29 (s, 2 H), 8.24 (d, J=0.8 Hz, 1 H), 7.96 - 7.90 (m, 2 H), 7.81 (d, J=8.6 Hz, 1 H), 7.75 (dd, J=1.3, 7.6 Hz, 1 H), 7.53 (t, J=7.7 Hz, 1 H), 7.40 (dd, J=1.6, 8.7 Hz, 1 H), 4.91 (t, J=4.7 Hz, 1 H), 4.79 (t, J=4.7 Hz, 1 H), 4.58 (t, J=4.7 Hz, 1 H), 4.51 (t, J=4.7 Hz, 1 H), 3.38 - 3.34 (m, 1 +: 417.2. Found: 417.1. Example 229: 3-Cyano-2-isopropyl-N-(1-(2-methoxypyrimidin-4-yl)-1H-indazol-6- yl)benzamide Prepared as describ
Figure imgf000430_0001
ed for 3-cyano-2-isopropyl-N-(1-(2-methoxythiazol-5-yl)-1H- indazol-6-yl)benzamide using 4-bromo-2-methoxypyrimidine in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HI to afford the title compound (21.97 mg, 19%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 9.10 (s, 1 H), 8.52 (s, 1 H), 8.26 (d, J=7.23 Hz, 1 H), 7.91-7.96 (m, 2 H), 7.86-7.90 (m, 1 H), 7.76-7.80 (m, 1 H), 7.53 (t, J=7.67 Hz, 1 H), 7.06 (d, J=7.23 Hz, 1 H), 3.46 (s, 3 H), 3.37- 3.40 (m, 1 H), 1.43 (d, J=7.23 Hz, 6 H). MS-ESI (m/z) calc’d for C23H21N6O2 [M+H]+: 413.2. Found: 413.1. Example 230: 3-Cyano-2-isopropyl-N-(1-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-1H- indazol-6-yl)benzamide Prepared as described
Figure imgf000430_0002
for 3-cyano-2-isopropyl-N-(1-(2-methoxythiazol-5-yl)-1H- indazol-6-yl)benzamide using 4-iodo-3-methoxy-1-methyl-1H-pyrazole in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HJ to afford the title compound (3.84 mg, 13%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1 H), 8.17 (s, 1 H), 8.04 (br s, 2 H), 7.92 (br d, J=7.58 Hz, 1 H), 7.74 (br t, J=8.62 Hz, 2 H), 7.49- 7.55 (m, 1 H), 7.30 (br d, J=8.31 Hz, 1 H), 3.81 (br d, J=5.38 Hz, 6 H), 3.33 (s, 1 H), 1.41 (br d, J=7.09 Hz, 6 H). MS-ESI (m/z) calc’d for C23H23N6O2 [M+H]+: 415.2. Found: 415.1.
Example 231: 3-Cyano-A (l-(l,5-dimethyl-l/f-pyrazol-4-yl)-Lff-indazol-6-yl)-2- isopropylbenzamide
Figure imgf000431_0001
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/- indazol-6-yl)benzamide using 4-bromo-l,5-dimethyl-pyrazole in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HK to afford the title compound (3.21 mg, 15%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.78 (s, 1 H), 8.23 (d, J=0.75 Hz, 1 H), 8.08 (s, 1 H), 7.93 (d, J=6.50 Hz, 1 H), 7.80 (d, J=8.76 Hz, 1 H), 7.74 (dd, J=7.69, 1.31 Hz, 1 H), 7.69 (s, 1 H), 7.52 (t, J=7.75 Hz, 1 H), 7.32 (dd, J=8.69, 1.56 Hz, 1 H), 3.86 (s, 3 H), 2.19 (s, 3 H), 1.41 (d, J=7.13 Hz, 6 H).MS-ESI (m/z) calc’d for C23H23N6O [M+H]+: 399.1. Found 399.1.
Example 232: 3-Cyaiio-2-isopropyl-/V-(l-(5-methyloxazol-2-yl)-l//-indazol-6- yl)benzamide
Figure imgf000431_0002
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/- indazol-6-yl)benzamide using 2-bromo-5 -methyloxazole in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HL to afford the title compound (9.62 mg, 29%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.97 (s, 1H), 9.00 (s, 1H), 8.44 (s, 1H), 7.95 (dd, J=1.32, 7.72 Hz, 1H), 7.88 (d, J=8.60 Hz, 1H), 7.78 (dd, J=1.32, 7.72 Hz, 1H), 7.51-7.57 (m, 2H), 7.05 (d, J=1.32 Hz, 1H), 3.36 (quin, J=7.28 Hz, H). MS-ESI (m/z) calc’d for C22H20N5O2 [M+H]+: 386.2. Found 386.1. Example 233: 3-Cyano-2-isopropyl-N-(1-(2-morpholinopyridin-4-yl)-1H-indazol-6- yl)benzamide
Figure imgf000432_0001
Prepared as described for 3-cyano-2-isopropyl-N-(1-(2-methoxythiazol-5-yl)-1H- indazol-6-yl)benzamide using 4-(4-bromopyridin-2-yl)morpholine in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HM to afford the title compound (14.28 mg, 37%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 8.26-8.31 (m, 1H), 7.96 (dd, J=1.32, 7.72 Hz, 1H), 7.90 (d, J=8.82 Hz, 1H), 7.75-7.79 (m, 1H), 7.52-7.57 (m, 1H), 7.48 (dd, J=1.43, 8.71 Hz, 1H), 7.18- 7.35 (m, 2H), 3.73-3.78 (m, 4H), 3.58-3.63 (m, 4H), 3.38 (quin, J=7.11 Hz, 1H), 1.40-1.45 (m, 6H). MS-ESI (m/z) calc’d for C27H27N6O2 [M+H]+: 467.2. Found 467.1. Example 234: 3-Cyano-2-isopropyl-N-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H- indazol-6-yl)benzamide Prepared as described
Figure imgf000432_0002
for 3-cyano-2-isopropyl-N-(1-(2-methoxythiazol-5-yl)-1H- indazol-6-yl)benzamide using 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole in place of 5-iodo- 2-methoxythiazole. The material was purified by HPLC using Method HN to afford the title compound (6.77 mg, 26%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=0.73 Hz, 1H), 8.04 (s, 1H), 7.94 (dd, J=1.22, 7.70 Hz, 1H), 7.82 (d, J=8.56 Hz, 1H), 7.75 (dd, J=1.28, 7.64 Hz, 1H), 7.54 (t, J=7.70 Hz, 1H), 7.41 (dd, J=1.47, 8.80 Hz, 1H), 5.28 (q, J=9.13 Hz, 2H), 3.32-3.36 (m, 1H), 1.42 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C23H20F3N6O [M+H]+: 453.2. Found 453. E
Example 235: 3-Cyano-2-isopropyl-7V-(l-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-3- yl)- 1 //-indazol-6-y 1 )benzamide
Figure imgf000433_0001
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/- indazol-6-yl)benzamide using 3-bromo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine in place of 5 -iodo-2-methoxy thiazole. The material was purified by HPLC using Method HO to afford the title compound (2.05 mg, 8%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.79 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.93 (d, J=7.45 Hz, 1H), 7.79 (d, J=8.77 Hz, 1H), 7.71- 7.77 (m, 2H), 7.52 (t, J=7.78 Hz, 1H), 7.33 (d, J=8.77 Hz, 1H), 4.18 (t, J=5.70 Hz, 2H), 3.25- 3.31 (m, 1H), 2.67 (t, J=6.14 Hz, 2H), 2.03 (br s, 2H), 1.81 (br s, 2H), 1.40 (d, J=7.23 Hz, 6H). MS-ESI (m/z) calc’d for C25H25N6O [M+H]+: 425.2. Found 425.1.
Example 236: 3-Cyano-2-isopropyl-7V-(l-(2-isopropylthiazol-5-yl)-LH-indazol-6- yl)benzamide
Figure imgf000433_0002
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/- indazol-6-yl)benzamide using 5-bromo-2 -isopropylthiazole in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HP to afford the title compound (8.3 mg, 35%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.92 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 7.95 (d, J=8.11 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J=8.77 Hz, 1H), 7.77 (d, J=7.45 Hz, 1H), 7.54 (t, J=7.67 Hz, 1H), 7.48 (d, J=8.77 Hz, 1H), 3.35-3.39 (m, 1H), 3.29-3.33 (m, 1H), 1.42 (d, J=7.23 Hz, 6H), 1.38 (d, J=7.02 Hz, 6H). MS-ESI (m/z) calc’d for C24H24N5OS [M+H]+: 430.2. Found 430.1.
Example 237 : 3-Cyano-2-isopropyl-7V-(l-(l-methyI-6-oxo-l,6-dihydropyridin-3-yI)-LH- indazol-6-yl)benzamide
Figure imgf000434_0001
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/- indazol-6-yl)benzamide using 5-iodo-l-methylpyridin-2(177)-one in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HQ to afford the title compound (18.74 mg, 27%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.31 (s, 1H), 8.21 (s, 1H), 8.16 (d, J=2.75 Hz, 1H), 7.79-7.90 (m, 3H), 7.69 (dd, J=1.19, 7.69 Hz, 1H), 7.45-7.52 (m, 1H), 7.28 (dd, J=1.56, 8.69 Hz, 1H), 6.75 (d, J=9.63 Hz, 1H), 3.69 (s, 3H), 3.43 (td, J=7.18, 14.29 Hz, 1H), 1.50 (d, J=7.13 Hz, 6H). MS-ESI (m/z) calc’d for C24H22N5O2 [M+H]+:412.2. Found 412.1
Exampe 238: 3-Cyano-2-isopropyl-/V-(l-(2-(trifluoromethyl)pyrimidin-5-yl)-l//-indazol-
6-yl)benzamide
Figure imgf000434_0002
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-lH- indazol-6-yl)benzamide using 5-bromo-2-(trifluoromethyl)pyrimidine in place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method HR to afford the title compound (3.77 mg, 16%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.94 (s, 1H), 9.53 (s, 2H), 8.71 (s, 1H), 8.57 (s, 1H), 7.91-8.01 (m, 2H), 7.76 (dd, J=l.19, 7.69 Hz, 1H), 7.51-7.62 (m, 2H), 1.43 (d, J=7.13 Hz, 6H). MS-ESI (m/z) calc’d for C23H18F3N6O
[M+H]+:451.1. Found 45 EE
Exampe 239 : 3-Cyano-2-isopropyl-N-(l-(4-methyloxazol-2-yl)- lff-indazol-6- yl)benzamide
Figure imgf000435_0001
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/- indazol-6-yl)benzamide using 2-bromo-4-methyloxazole in place of place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method GT to afford the title compound (5.18 mg, 13%) as ayellow solid. 'H NMR (400 MHz, CDCh) 8 8.65 (s, 1H), 8.23 (s, 1H), 7.75-7.82 (m, 3H), 7.70 (dd, J=8.7, 1.6 Hz, 1H), 7.66 (dd, J=7.6, 1.2 Hz, 1H), 7.36-7.42 (m, 2H), 3.49-3.58 (m, 1H), 2.26 (d, J=1.1 Hz, 3H), 1.54 ppm (d, J=7.2 Hz, 6H). MS-ESI (m/z) calc’d for C22H20N5O2 [M+H]+: 386.2. Found: 386.1.
Exampe 240: 3-Cyano-2-isopropyl-/V-(l-(2-methylthiazol-4-yl)-l//-indazol-6- yl)benzamide
Figure imgf000435_0002
Prepared as described for 3-cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/- indazol-6-yl)benzamide using 4-bromo-2-methylthiazole in place of place of 5-iodo-2- methoxythiazole. The material was purified by HPLC using Method GX to afford the title compound (6.58 mg, 16%) as ayellow solid. JH NMR (400 MHz, DMSO- e) 6 10.85 (s, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 7.94 (dd, J=7.8, 1.3 Hz, 1H), 7.76-7.83 (m, 2H), 7.53-7.59 (m, 2H), 7.49 (s, 1H), 3.37 (br d, J=7.1 Hz, 1H), 2.78 (s, 3H), 1.44 ppm (d, J=7.1 Hz, 6H). MS-ESI (m/z) calc’d for C22H20N5OS [M+H]+: 402.1. Found: 402.0.
Example 241: 3-Cyano-2-isopropenyl-6-methyl-7V-[l-(l-methylpyrazol-4-yl)indazol-6- yl] benzamide
Figure imgf000436_0001
Step 1: 6-Bromo-2-chloro-3-cyano-benzoic acid
Figure imgf000436_0002
To a solution of 4-bromo-2-chlorobenzonitrile (5 g, 23.10 mmol) in THF (50 mL) was added a 2 M solution of LDA in THF (17.32 mL, 34.6 mM) at -78 °C and the mixture was stirred at -78 °C for 0.5 hr. Carbon dioxide (10.17 g, 230.99 mmol) (dry ice) was added and the mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of saturated aqueous NH4CI at 0 °C and then extracted with EtOAc (3x). The organic phase was discarded; the aqueous phase was acidified with 1 M HC1 to pH =2 and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.6 g, 20%) as brown solid. 'H NMR (400 MHz, CDCh) 8 7.65 - 7.71 (m, 1 H), 7.57 - 7.62 (m, 1 H).
Step 2: 6-Bromo-2-chloro-3-cyano-N-[ 1 -( 1 -methylpyrazol-4-yl)indazol-6-yl ]benzamide
Figure imgf000436_0003
To a solution of 6-bromo-2-chloro-3-cyano-benzoic acid (1 g, 3.84 mmol) in DCM (20 mL) were added 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (818.66 mg, 3.84 mmol), 2-bromo-l-ethyl-pyridinium tetrafluoroborate (1.16 g, 4.22 mmol) and DIEA (1.24 g, 9.60 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with CH2CI2 (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-46% EtOAc/petroleum ether gradient eluent to afford the title compound (676 mg, 19%) as a yellow solid. JH NMR (400 MHz, CDCh) 6 8.34 (s, 1 H), 8.12 (s, 1 H), 7.88 (s, 1 H), 7.82 (s, 1 H), 7.76 (d, J=8.68 Hz, 1 H), 7.65 - 7.70 (m, 1 H), 7.57 (d, J=8.31 Hz, 1 H), 7.31 - 7.35 (m, 1 H), 7.14 (d, J=8.56 Hz, 1 H), 4.01 (s, 3 H) MS-ESI (m/z) calc’d for CwHnBrCINeO [M+H]+: 454.9, 456.9 Found 455.1, 457.1.
Step 3: 2-Chloro-3-cyano-6-methyl-N-[l-( 1 -methylpyrazol-4-yl)indazol-6-yl ]benzamide
Figure imgf000437_0001
A mixture of 6-bromo-2-chloro-3-cyano-/V-[l-(l-methylpyrazol-4-yl)indazol-6- yl]benzamide (730 mg, 1.60 mmol), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (221.21 mg, 1.76 mmol), K2CO3 (664.22 mg, 4.81 mmol), and Pd(dppf)C12«CH2C12 (130.82 mg, 160.19 umol) in dioxane (15 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-46% EtOAc/petroleum ether gradient eluent to afford the title compound (140 mg, 22%) as a yellow oil. 'H NMR (400 MHz, CDCh) 6 8.35 (s, 1 H), 8.12 (s, 1 H), 7.89 (s, 1 H), 7.83 (s, 1 H), 7.74 - 7.78 (m, 1 H), 7.66 (d, J=7.95 Hz, 2 H), 7.33 (d, J=7.95 Hz, 1 H), 7.08 (dd, J=8.62, 1.65 Hz, 1 H), 4.02 (s, 3 H), 2.53 (s, 3 H). MS-ESI (m/z) calc’d for C20H16CIN6O [M+H]+: 391.1. Found 391.2.
Step 4: 3-Cyano-2-isopropenyl-6-methyl-N-[l-( 1 -methylpyrazol-4-yl)indazol-6-yl Jbenzamide
Figure imgf000437_0002
A mixture of 2-chloro-3-cyano-6-methyl-A-[l-(l-methylpyrazol-4-yl)indazol-6- yl]benzamide (10 mg, 25.59 umol), 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.30 mg, 25.59 umol), Pd(dppf)Ch (936.11 ug, 1.28 umol), and CS2CO3 (25.01 mg, 76.76 umol) in dioxane (0.4 mL) and H2O (0.1 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 100 °C for 12 hrs under an N2 atmosphere and concentrated to give a residue. The residue was purified by HPLC using Method HS to afford the title compound (3.23 mg, 31%) as ayellow solid JH NMR (400 MHz, DMSO- e) 6 10.66 (s, 1 H), 8.21 (s, 1 H), 8.20 (s, 2 H), 7.85 (d, J=7.88 Hz, 1 H), 7.81 (s, 1 H), 7.78 (d, J=8.63 Hz, 1 H), 7.48 (d, J=8.13 Hz, 1 H), 7.31 (dd, J=8.69, 1.44 Hz, 1 H), 5.33 (s, 1 H), 5.04 (s, 1 H), 3.95 (s, 3 H), 2.40 (s, 3 H), 2.07 (s, 3 H). MS-ESI (m/z) calc’d for C23H21N6O [M+H]+: 397.1 Found 397.1.
Example 242: (E)-3-Cyano-2-isopropyl-A-(l-(2-(pyridin-4-yl)vinyl)-lff-indazol-6- yl)benzamide
Figure imgf000438_0001
Step 1: (E)-4-(2-(4, 4, 5, 5-Tetramethyl-l, 3, 2-dioxaborolan-2-yl)vinyl)pyridine
Figure imgf000438_0002
To a solution of 4-bromopyridine (6 g, 37.98 mmol) in toluene (40 mL) was added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (7.02 g, 45.57 mmol), tn-tert- butylphosphonium tetrafluoroborate (1.10 g, 3.80 mmol), DIPEA (9.82 g, 75.95 mmol), and Pd2(dba)3 (1.74 g, 1.90 mmol) at 20 °C. The mixture was stirred at 85 °C for 3 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (1.39 g, 15%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.89 (d, J=6.63 Hz, 2H), 8.21 (d, J=6.75 Hz, 2H), 7.48 (d, J=18.51 Hz, 1H), 6.82 (d, J=18.51 Hz, 1H), 1.26 (s, 12H).
Step 2: (E)-(2-(Pyridin-4-yl)vinyl)boronic acid
Figure imgf000439_0001
To a solution of (E)-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)pyridine (1.3 g, 5.63 mmol) in acetone (140 mL) and H2O (7 mL) were added NH4OAC (1 M, 25.31 mL) and NalCL (3.61 g, 16.88 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hrs and then concentrated to give a residue. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-100% EtOAc/petroleum ether gradient eluent to afford the title compound (760 mg, 84%) as a brown oil. MS-ESI (m/z) calc’d for C7H9BNO2 [M+H]+: 150.1. Found 150.2.
Figure imgf000439_0002
To a solution of 3-cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (100 mg, 328.57 umol) in DCE (5 mL) was added (E)-(2-(pyridin-4-yl)vinyl)boronic acid (58.73 mg, 394.29 umol), CU(OAC)2 (59.68 mg, 328.57 umol), 2-(2-pyridyl)pyridine (51.32 mg, 328.57 umol) and Na2COs (69.65 mg, 657 umol) at 20 °C. The mixture was stirred at 70 °C for 3 hrs. The er reduced pressure to remove solvent. The residue was purified by HPLC using Method HT to afford the title compound (35.7 mg, 24%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.70 (s, 1H), 8.40-8.66 (m, 3H), 8.36 (s, 1H), 7.96 (dd, J=1.13, 7.69 Hz, 1H), 7.81 (d, J=8.58 Hz, 1H), 7.77 (dd, J=1.25, 7.69 Hz, 1H), 7.72 (br s, 2H), 7.55 (t, J=7.69 Hz, 1H), 7.32 (dd, J=1.37, 8.64 Hz, 1H), 7.12 (d, J=13.95 Hz, 1H), 3.36-3.43 (m, 1H), 1.45 (d, J=7.03 Hz, 6H). MS-ESI (m/z) calc’d for C25H22N5O [M+H]+: 408.2. Found 408.1. Example 243: 3-Cyano-N-(1-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- isopropylbenzamide To a solution of 4-b
Figure imgf000440_0001
le (20 mg, 111.74 umol) in dioxane (1 mL) was added 3-cyano-N-(1H-indazol-6-yl)-2-isopropylbenzamide (40.81 mg, 134.09 umol), CuI (4.26 mg, 22.35 umol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (7.95 mg, 55.87 umol) and K3PO4 (71.16 mg, 335.21 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method GW to afford the title compound (1.32 mg, 2%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.23-8.30 (m, 2H), 8.15 (s, 1H), 7.93 (d, J=7.23 Hz, 1H), 7.81 (d, J=8.77 Hz, 1H), 7.74 (d, J=8.11 Hz, 1H), 7.49-7.56 (m, 1H), 7.34 (d, J=8.33 Hz, 1H), 3.86 (s, 3H), 1.40 (d, J=7.02 Hz, 6H). MS-ESI (m/z) calc’d for C22H20FN6O [M+H]+: 403.2. Found 403.1. Example 244: 4-Cyano-2-isopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide
Figure imgf000440_0002
To a solution of 4-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-(prop- l-en-2-yl)benzamide (80 mg, 209.20 umol) in EtOAc (4 mL) was added Pd(OH)2 (80.79 mg, 115.06 umol) at 20 °C. The mixture was stirred at 20 °C for 2 hrs under H2 atmosphere (15 psi). The mixture was filtered and filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method HW to afford the title compound (14.63 mg, 36%) as a white solid. ‘H NMR (400 MHz, DMSO- e) 6 10.53 (s, 1H), 8.34 (s, 1H), 8.15-8.25 (m, 2H), 7.82 (s, 1H), 7.76 (d, J=8.76 Hz, 1H), 7.39-7.46 (m, 1H), 7.23-7.33 (m, 2H), 7.10 (d, J=7.63 Hz, 1H), 3.95 (s, 3H), 3.24 (td, J=6.83, 13.73 Hz, 1H), 2.31-2.39 (m, 3H), 1.20 (d, J=6.88 Hz, 6H). MS-ESI (m/z) calc’d for C22H24N5O [M+H]+:374.2. Found 374.1.
Example 245: 3-Cyano-A-(5-methyl-l-(l-methyl-l/7-pyrazol-4-yl)-l/7-indazol-6-yl)-2- (prop-l-en-2-yl)benzamide (245A) and 3-Cyano-2-isopropyl-7V-(5-methyI-l-(l-methyI- lH-pyrazol-4-yI)- 1 H-indazol-6-y l)benzamide (245B)
Figure imgf000441_0001
To a solution of 5-methyl-6-nitro-17/-indazole (300 mg, 1.69 mmol), 4-iodo-l- methyl- l//-pyrazole (352.22 mg, 1.69 mmol) in dioxane (15 mL) was added K3PO4 (1.08 g, 5.08 mmol) and (l<S',2<S)-/Vl,/V2-dimethylcyclohexane-l,2-diamine (120.44 mg, 846.69 umol), Cui (64.50 mg, 338.68 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0- 21% EtOAc/petroleum ether gradient eluent to afford the title compound (176.7 mg, 40%) as a pale yellow solid. MS-ESI (m/z) calc’d for C12H12N5O2 [M+H]+: 258.1. Found 258.2.
Step 2: 5-Methyl-l-( 1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-amine
Figure imgf000442_0001
To a solution of 5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-6-nitro-17/-indazole (190 mg, 738.59 umol) in EtOH (5 mL) and H2O (1 mL) was added Fe (206.23 mg, 3.69 mmol) and NH4CI (197.54 mg, 3.69 mmol) at 20 °C. The mixture was stirred at 80 °C for 1 hrs. The mixture was filtered and the filtrate was diluted with H2O and extracted with EtOAc (5x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford the title compound (148.95 mg, 88%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.10 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.34 (s, 1H), 6.80 (s, 1H), 5.23 (br s, 2H), 3.91 (s, 3H), 2.16 (s, 3H). MS-ESI (m/z) calc’d for C12H14N5 [M+H]+:228.1. Found 228.3.
Step 3: 3-Cyano-N-(5-methyl-l-( 1 -methyl- IH-pyr azol-4-yl)-l H-indazol-6-yl)-2-(prop- l-en-2- yl)benzamide (245A)
Figure imgf000442_0002
To a solution of 5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-amine (140 mg, 616.02 umol), 3-cyano-2-(prop-l-en-2-yl)benzoic acid (126.85 mg, 677.62 umol) in DCM (4 mL) was added a 50 wt % solution of T3P in EtOAc (1.18 g, 1.85 mmol) at 20 °C. The mixture was then stirred at 30 °C for 0.5 hr. EtsN (187.00 mg, 1.85 mmol) was then added and the mixture was stirred at 30 °C for an additional 5 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0-61% EtOAc/petroleum ether gradient eluent to afford the title compound (124.5 mg, 54%) as a white solid. Then the residue (30 mg) was further purified by HPLC using Method HX to afford the title compound (16.58 mg, 54%) as a white solid. XH NMR (400 MHz, DMSO- e) 6 9.96 (s, 1H), 8.21 (d, J=17.54 Hz, 2H), 7.98 (t, J=7.02 Hz, 2H), 7.84 (s, 2H), 7.69 (s, 1H), 7.64 (t, J=7.78 Hz, 1H), 5.41 (s, 1H), 5.09 (s, 1H), 3.95 (s, 3H), 2.36 (s, 3H), 2.14 (s, 3H).MS-ESI (m/z) calc’d for C23H2iN6O[M+H]+: 397.2. Found 397.1. Step 4: 3-Cyano-2-isopropyl-N-(5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6- yl)benzamide (245B)
Figure imgf000443_0001
To a mixture of 3-cyano-/V-(5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)-2-(prop-l-en-2-yl)benzamide (100 mg, 252.24 umol) in EtOAc (5 mL) was added Pd(OH)2 (97.42 mg, 138.73 umol) and the mixture was stirred at 20 °C for 2 hrs under an H2 atmosphere (15 psi). The mixture was filtered and filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method HT to afford the title compound (21 mg, 20%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.12 (s, 1H), 8.25 (s, 1H), 8.20 (d, J=0.88 Hz, 1H), 7.93 (dd, J=1.32, 7.67 Hz, 1H), 7.83-7.89 (m, 3H), 7.72 (s, 1H), 7.54 (t, J=7.67 Hz, 1H), 3.95 (s, 3H), 3.45 (quin, J=7.18 Hz, 1H), 2.39 (s, 3H), 1.46 (d, J=7.23 Hz, 6H). MS-ESI (m/z) calc’d for C23H23NeO[M+H]+: 399.2. Found: 399.1.
Example 246: l-Methoxy-5-((l-(l-methyI-LH-pyrazol-4-yI)-lH-indazol-6-yI)amino)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000443_0002
Step 1: 6-Bromo-5-hydroxy-3,4-dihydronaphthalen-l(2H)-one
Figure imgf000443_0003
To a solution of 5-hydroxy-3.4-dihydronaphthalen- l(27/)-one (1 g, 6.17 mmol) in DCM (60 mL) was added JV-isopropylpropan-2-amine (436.74 mg, 4.32 mmol) under an N2 atmosphere. Then NBS (1.10 g, 6.17 mmol) in DCM (60 mL) was added and the mixture was stirred at 20 °C for 4 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and purified by silica gel column chromatography using a 0-18% EtOAc/petroleum ether gradient eluent to afford the title compound (1.2 g, 80%) as a yellow solid. 'H NMR (400 MHz, CDCh) 7.54 (d, J=8.33 Hz, 1 H) 7.43 (d, J=8.55 Hz, 1 H) 5.73 - 5.75 (m, 1 H) 2.98 (t, J=6.25 Hz, 2 H) 2.60 - 2.68 (m, 2 H) 2.11 - 2.19 (m, 2 H). MS-ESI (m/z) calc’d for CioHioBrCh [M+H]+: 241.0, 243.0 Found 241.1, 243.1.
Step 2: l-Hydroxy-5-oxo-5, 6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000444_0001
A mixture of 6-bromo-5-hydroxy-3.4-dihydronaphthalen-l (27/)-one (300 mg, 1.24 mmol), Zn(CN)2 (292.25 mg, 2.49 mmol), Zn (162.74 mg, 2.49 mmol), dppf (137.97 mg, 248.88 umol) and Pd2(dba)s (227.90 mg, 248.88 umol) in DMA (7 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 100 °C for 2 hrs under an N2 atmosphere, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0-22% EtOAc/petroleum ether gradient eluent to afford the title compound (200 mg, 85%) as a yellow gum. MS-ESI (m/z) calc’d for C11H10NO2 [M+H]+: 188.1. Found 188.2.
Step 3: 1 -Methoxy-5-oxo-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000444_0002
To a solution of l-hydroxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (300 mg, 1.60 mmol) in DMF (5 mL) was added CS2CO3 (783.24 mg, 2.40 mmol) and Mel (341.21 mg, 2.40 mmol). The mixture was stirred at 20 °C for 2 hrs under an N2 atmosphere. The reaction mixture was diluted with saturated aqueous NH4CI and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (200 mg, 62%) as a white solid. MS-ESI (m/z) calc’d for C12H12NO2 [M+H]+:
202.1 Found 202.2.
Step 4: 5-Hydroxy-l-methoxy-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000445_0001
To a solution of l-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (200 mg, 993.93 umol) in MeOH (3 mL) was added NaBH4 (45.12 mg, 1.19 mmol) and the mixture was stirred at 20 °C for 1 hr. The reaction mixture was then diluted with H2O and the mixture was concentrated under reduced pressure to remove MeOH. Then the mixture was extracted with EtOAc (3x) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (166.6 mg, 82%) as a yellow oil. MS-ESI (m/z) calc’d for C12H14NO2 [M+H]+: 204.1. Found 204.3.
Step 5: N-( 6-Cyano-5 -methoxy- 1 , 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( 1-(1 -methyl-lH- pyrazol-4-yl)-lH-indazol-6-yl)-2-nitrobenzenesulfonamide
Figure imgf000445_0002
To a solution of /V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- nitrobenzenesulfonamide (200 mg, 502.01 umol) in toluene (5 mL) was added (tributylphosphoranylidene)acetonitrile (363.49 mg, 1.51 mmol) and 5 -hydroxy-1 -methoxy - 5,6,7,8-tetrahydronaphthalene-2-carbonitrile (122.43 mg, 602.42 umol) at 20 °C. The mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel column chromatography using a 0-100% EtOAc/petroleum ether gradient eluent to afford the title compound (260 mg, 88%) as a brown gum. MS-ESI (m/z) calc’d for C29H26N7O5S [M+H]+: 584.2. Found 584.0. Step 6: l-Methoxy-5-( (1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000446_0001
To a solution of /V-(6-cyano-5-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-(l-(l- methyl- l7/-pyrazol-4-yl)- l 7/-indazol-6-yl)-2-nitrobenzenesulfonamide (100 mg, 171.35 umol) in DMF (2 mL) was added PhSH (90 mg, 816.87 umol) and K2CO3 (71.04 mg, 514.04 umol). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by HPLC using Method HY to afford the title compound (18.78 mg, 27%) as a pale yellow solid. MS-ESI (m/z) calc’d for C23H23NO6 [M+H]+: 399.2. Found 399.0.
Step 7: l-Methoxy-5-((l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000446_0002
The enantiomers of I -methoxy-5-(( l -( l -methyl- IT/-pyrazol-4- l)- IT/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile were separated by chiral HPLC using Method HZ. The material was further purified by HPLC using Method IA to afford 1- methoxy-5-((l-(l -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (2.74 mg, 30%) as a colorless gum. 'H NMR (400 MHz, MeOD) 7.99 (s, 1 H), 7.91 (s, 1 H), 7.76 (s, 1 H), 7.50 (br d, J=8.78 Hz, 1 H), 7.41 (br d, J=7.91 Hz, 1 H), 7.28 (br d, J=7.91 Hz, 1 H), 6.70 (br d, J=8.66 Hz, 1 H), 6.57 (s, 1 H), 4.76 (br s, 1 H), 3.98 (dd, J=7.34, 1.82 Hz, 6 H), 2.71 - 2.92 (m, 2 H), 1.83 - 2.06 (m, 4 H). MS-ESI (m/z) calc’d for C23H23NO6 [M+H]+: 399.2 Found 399.1. A later eluting fraction from chiral separation was also isolated to give l -methoxy-5-(( l -( l -methyl- IT/- pyrazol-4-yl)- l //-indazol-6-yl)amino)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 2 (3.04 mg, 33%) as a colorless gum. 'H NMR (400 MHz, MeOD) 7.99 (s, 1 H) 7.91 (s, 1 H) 7.77 (s, 1 H) 7.50 (d, J=8.78 Hz, 1 H) 7.41 (d, J=8.16 Hz, 1 H) 7.28 (d, J=8.16 Hz, 1 H) 6.70 (dd, J=8.78, 1.63 Hz, 1 H) 6.57 (s, 1 H) 4.76 (br t, J=5.40 Hz, 1 H) 3.97 (d, J=7.28 Hz, 6 H) 2.70 - 2.91 (m, 2 H) 1.82 - 2.04 (m, 4 H). MS-ESI (m/z) calc’d for C23H23NO6 [M+H]+: 399.2 Found 399.1.
Example 247: l-Isopropyl-5-((l-(l-methyl-LH-pyrazol-4-yl)-LH-indazol-6-yl)amino)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000447_0001
To a solution of 5-hydroxytetralin-l-one (5 g, 30.83 mmol) in DCM (100 mL) was added A-isopropylpropan-2-amine (2.18 g, 21.58 mmol) under an N2 atmosphere. Then 1- bromopyrrolidine-2,5-dione (5.49 g, 30.83 mmol) in DCM (100 mL) was added and the mixture was stirred at 20 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (1.8 g, 24%) as a white solid. JH NMR (CDCh) 8 7.50 - 7.56 (m, 1 H), 7.42 (d, J=8.44 Hz, 1 H), 5.70 (d, J=1.47 Hz, 1 H), 2.97 (t, J=6.11 Hz, 2 H), 2.64 (t, J=6.60 Hz, 2 H), 2.14 (quin, J=6.11 Hz, 2 H).MS-ESI (m/z) calc’d for CioHioBrCh [M+H]+: 240.9, 242.9. Found: 241.1, 243.1.
Step 2: l-Hydroxy-5-oxo-5, 6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000447_0002
A mixture of 6-bromo-5-hydroxy-3.4-dihydronaphthalen-l (27/)-one (1.8 g, 7.47 mmol), Zn(CN)2 (1.80 g, 15.31 mmol), Zn (976.45 mg, 14.93 mmol), dppf (827.84 mg, 1.49 mmol) and Pd2(dba)s (1.37 g, 1.49 mmol) in DMA (20 mL) was degassed and purged with N2 (3x) at 20 °C and then stirred at 100 °C for 2 hrs under an N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers dried over Na2SOi, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (1.2 mg, 85%) as a brown solid. MS-ESI (m/z) calc’d for C11H10NO2 [M+H]+: 188.0. Found 188.2.
Step 3: 2-Cyano-5-oxo-5,6, 7,8-tetrahydronaphthalen-l-yl trifluoromethanesulfonate
Figure imgf000448_0001
To a solution of l-hydroxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (600 mg, 3.21 mmol) in CH2CI2 (5 mL) were added pyridine (760.60 mg, 9.62 mmol) and triflic anhydride (1.36 g, 4.81 mmol) at 0 °C for 5 minutes. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The material was purified by silica gel chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (390 mg, 38%) as a yellow solid.
Step 4: 5-Oxo-l-(prop-l-en-2-yl)-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000448_0002
A mixture of 2-cyano-5-oxo-5,6,7,8-tetrahydronaphthalen-l-yl trifluoromethanesulfonate (720 mg, 2.26 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (568.46 mg, 3.38 mmol), Pd(dppt)Ch (165.02 mg, 225.52 umol), CS2CO3 (2.20 g, 6.77 mmol) in dioxane (10 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 95 °C for 2 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (400 mg, 83%) as a white solid. 'H NMR (DMSO- e) 6 7.93 (d, J=8.19 Hz, 1 H), 7.82 (d, J=8.19 Hz, 1 H), 5.51 (s, 1 H), 5.01 (s, 1 H), 2.90 (br t, J=5.62 Hz, 2 H), 2.61 - 2.73 (m, 2 H), 2.00 - 2.10 (m, 5 H), MS-ESI (m/z) calc’d for CMHMNO [M+H]+: 212.1. Found 212.2.
Step 5: 5-Hydroxy-l-(prop-l-en-2-yl)-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000449_0001
To a solution of 5-oxo-l-(prop-l-en-2-yl)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile (400 mg, 1.89 mmol) in MeOH (5 mL) was added NaBH4 (85.95 mg, 2.27 mmol) at 0 °C and the mixture was stirred at 20 °C for 2 hrs. The reaction mixture was quenched by addition of H2O and extracted with EtOAC (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue to afford the title compound (330 mg, 83%) as a yellow oil. 'H NMR (DMSO- e) 6 7.60 - 7.64 (m, 1 H), 7.52 (d, J=8.19 Hz, 1 H), 5.40 - 5.45 (m, 2 H), 4.89 (s, 1 H), 4.59 (q, J=5.83 Hz, 1 H), 2.55 - 2.77 (m, 2 H), 1.98 - 2.01 (m, 3 H), 1.80 - 1.95 (m, 2 H), 1.60 - 1.72 (m, 2 H), MS-ESI (m/z) calc’d for C14H16NO [M+H]+: 214.1. Found 214.2.
Step 6: N-( 6-Cyano-5-isopropenyl-tetralin-l-yl)-N-[l-( 1 -methylpyrazol-4-yl)indazol-6-yl ]-2- ni tro-benzenes ulfonamide
Figure imgf000449_0002
To a solution of 5-hydroxy-l-(prop-l-en-2-yl)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile (220 mg, 1.03 mmol) and 7V-(1-(1 -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-yl)-2- nitrobenzenesulfonamide (405 mg, 1.02 mmol) in toluene (5 mL) was added (tributylphosphoranylidene)acetonitrile (497.93 mg, 2.06 mmol) at 20 °C. The mixture was degassed and purged with N2 (3x) and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0-35% EtOAc/petroleum ether gradient eluent to afford the title compound (460 mg, 75%) as a yellow oil. MS-ESI (m/z) calc’d for C31H28N7SO4 [M+H]+: 594.1 Found 594.3.
Step 7: 5-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-l-(prop-l-en-2-yl)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000450_0001
To a solution of /V-(6-cyano-5-isopropenyl-tetralin-l-yl)-/V-[l-(l-methylpyrazol-4- yl)indazol-6-yl]-2-nitro-benzenesulfonamide (460 mg, 774.86 umol) in MeCN (5 mL) were added thiophenol (420 mg, 3.81 mmol) and K2CO3 (535.45 mg, 3.87 mmol). The mixture was stirred at 20 °C for 3 hrs and then adjusted to pH = 10 by saturated aqueous Na2CC>3. The mixture was then diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-45% EtOAc/petroleum ether gradient eluent to afford the title compound (186 mg, 58%) as a yellow solid. MS-ESI (m/z) calc’d for C25H25N6 [M+H]+: 409.2. Found 409.3.
Step 8: l-Isopropyl-5-( <1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)amino) -5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000450_0002
To a solution of 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-l-(prop-l- en-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (50 mg, 122.40 umol) in MeOH (2 mL) was added Mg (59.50 mg, 2.45 mmol) at 0 °C. The mixture was stirred at 50 °C for 2 hrs. The mixture was filtered and filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method IB to afford the title compound (9 mg, 17%) as a white solid. MS-ESI (m/z) calc’d for C25H27N6 [M+H]+: 411.2. Found 411.3.
Step 9: l-Isopropyl-5-( <1-(1 -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)amino) -5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000451_0001
The enantiomers of l-isopropyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile were separated by chiral HPLC using Method IC to afford l-isopropyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (0.61 mg, 9%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 8.17 (s, 1 H), 7.93 (s, 1 H), 7.79 (s, 1 H), 7.56 (d, J=7.89 Hz, 1 H), 7.47 (d, J=8.77 Hz, 1 H), 7.33 (d, J=8.11 Hz, 1 H), 6.64 - 6.72 (m, 2 H), 6.48 (d, J=8.77 Hz, 1 H), 4.84 (br s, 1 H), 3.90 (s, 3 H), 3.49 - 3.56 (m, 1 H), 2.72 - 2.91 (m, 2 H), 1.86 (br d, J=16.22 Hz, 4 H), 1.40 (dd, J=7.13, 2.08 Hz, 6 H),MS-ESI (m/z) calc’d for C25H27N6 [M+H]+: 411.2. Found 411.1. A later eluting fraction was also isolated to afford 1-isopropyl- 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile, enantiomer 2 (0.91 mg, 15%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.14 (s, 1 H), 7.90 (s, 1 H), 7.76 (s, 1 H), 7.53 (d, J=7.89 Hz, 1 H), 7.44 (d, J=8.77 Hz, 1 H), 7.30 (d, J=8.11 Hz, 1 H), 6.67 (dd, J=8.88, 1.64 Hz, 1 H), 6.63 (s, 1 H), 6.46 (d, J=8.77 Hz, 1 H), 4.75 - 4.89 (m, 1 H), 3.87 (s, 3 H), 3.46 - 3.50 (m, 1 H), 2.69 - 2.89 (m, 2 H), 1.75 - 1.88 (m, 4 H), 1.37 (dd, J=7.13, 2.08 Hz, 6 H). MS-ESI (m/z) calc’d for C25H27N6 [M+H]+: 411.2. Found 411.1.
Example 248: 5-((l-(l-MethyI-tH-pyrazol-4-yI)-tH-indazol-6-yI)amino)-l- (trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000451_0002
Step 1: 6-Amino-5-(trifluoromethyl)-3, 4-dihydronaphthalen-l(2H)-one
Figure imgf000451_0003
A mixture of 6-amino-3,4-dihydronaphthalen-l(277)-one (1 g, 6.20 mmol), 1- trifluoromethyl-l,2-benziodoxol-3-(lH)-one (3.92 g, 12.41 mmol) and K2CO3 (1.29 g, 9.31 mmol) in CH3CN (40 mL) at 20 °C was degassed and purged with N2 (3x). The mixture was then stirred at 100 °C for 18 hrs under an N2 atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (370 mg, 26%) as a yellow solid. JH NMR (400 MHz, CDCh) 8 8.02 (d, J=8.7 Hz, 1 H), 6.60 (d, J=8.8 Hz, 1 H), 4.81 (br s, 2 H), 3.11 - 2.95 (m, 2 H), 2.65 - 2.47 (m, 2 H), 2.11 - 2.03 (m, 2 H). MS-ESI (m/z) calc’d for C11H11F3NO [M+H]+: 230.1. Found 230.2.
Figure imgf000452_0001
A mixture of 6-amino-5-(trifluoromethyl)-3.4-dihydronaphthalen- l(27/)-one (370 mg, 1.61 mmol), tert-butyl nitrite (332.94 mg, 3.23 mmol) and CuBr (463.15 mg, 3.23 mmol) in MeCN (5 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 60 °C for 3 hrs under an N2 atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was diluted with EtOAc and filtered. The solid was washed with EtOAc; the solid was discarded and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-6% EtOAc/petroleum ether gradient eluent to afford the title compound (340 mg, 71%) as a pale yellow solid. MS-ESI (m/z) calc’d for CnHgBrFsO [M+H]+: 293.0, 295.0. Found 293.1, 295.1.
Figure imgf000452_0002
A mixture of 6-bromo-5-(trifluoromethyl)-3.4-dihydronaphthalen- 1 (27/)-one (500 mg, 1.71 mmol), Zn(CN)2 (600.99 mg, 5.12 mmol), Zn (111.56 mg, 1.71 mmol), dppf (283.73 mg, 511.81 umol), and Pd2(dba)3 (156.22 mg, 170.60 umol) in DMA (6 mL) in a sealed micro wave reaction vial under N2 was heated at 100 °C for 2 hrs using micro wave irradiation. The mixture was then filtered and the filtrate was concentrated under vacuum. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-3% EtOAc/petroleum ether gradient eluent to afford the title compound (290 mg, 71%) as a yellow solid.
Figure imgf000453_0001
To a solution of 5-oxo-l-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile (290 mg, 1.21 mmol) in MeOH (10 mL) was added NaBEU (55.04 mg, 1.45 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 hrs and then additional NaBEU (45.87 mg, 1.21 mmol) was added to the mixture at 0 °C and stirring was continued at 20 °C for 2 hrs. The reaction mixture was quenched with H2O at 0 °C and the mixture was concentrated under vacuum. The residue was diluted with H2O and extracted with EtOAc (4x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (190 mg, 53%) as a red oil. JH NMR (400 MHz, CDCh) 8 7.85 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 4.83 (br s, 1H), 3.12 - 2.83 (m, 2H), 2.21 - 2.07 (m, 1H), 2.06 - 1.90 (m, 2H), 1.89 - 1.78 (m, 1H), 1.89 - 1.78 (m, 1H).
Step 5: N-( 6-Cyano-5-(trifluoromethyl)-l , 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( 1-(1 -methyl-
Figure imgf000453_0002
A mixture of 5-hydroxy-l-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile (87.18 mg, 361.45 umol), 7V-(1-(1 -methyl- l//-pyrazol-4-y l)-17/-indazol-6-yl)-2- nitrobenzenesulfonamide (72 mg, 180.73 umol) and (tributylphosphoranylidene)acetonitrile (87.24 mg, 361.45 umol) in toluene (4 mL) was degassed and purged with N2 (3x) at 20 °C.
The mixture was then stirred at 100 °C for 12 hrs under N2. The reaction mixture was concentrated under reduced pressure to remove solvent and the residue was purified by preparative TLC (SiCh, petroleum ether/EtOAc = 0/1, Rf = 0.41) to afford the title compound (52 mg, 46%) as a yellow oil. MS-ESI (m/z) calc’d for C29H23F3N7O4S [M+H]+: 622.1.
Found 622.2.
Step 6: 5-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-l-( trifluoromethyl)-
Figure imgf000454_0001
To a solution of -(6-cyano-5-(trifluoromethyl)- l .2.3.4-tetrahydronaphthalen- l -yl)- -( l -( I -methyl- IT/-pyrazol-4-yl)- IT/-indazol-6-yl)-2-nitrobenzenesulfonamide (100 mg, 160.88 umol) and K2CO3 (111.17 mg, 804.39 umol) in MeCN (4 mL) was added thiophenol (88.63 mg, 804.39 umol). The mixture was stirred at 20 °C for 2 hrs and then diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiCh, petroleum ether/EtOAc = 0/1, Rf = 0.34) and further purified by HPLC using Method ID to afford the title compound (17 mg, 23%) as a pale yellow solid. MS-ESI (m/z) calc’d for C23H20F3N6 [M+H]+: 437.2. Found 437.3.
Step 7: 5-( (1-(1 -Methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-l-( trifluoromethyl)-
5,6, 7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000454_0002
5-((l -( 1 -Methyl- 1/7-py razol-4-y 1)- 1 //-indazol -6-y l)amino)- 1 -(trifluoromethy 1)-
5.6.7.8-tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method IE to afford 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-l-(trifluoromethyl)-
5.6.7.8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (4.23 mg, 46%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.16 (s, 1 H), 7.95 (s, 1 H), 7.90 (d, J=7.9 Hz, 1 H), 7.81 (s, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.50 (d, J=8.8 Hz, 1 H), 6.72 - 6.67 (m, 2 H), 6.57 (d, J=8.8 Hz, 1 H), 4.95 (br d, J=7.5 Hz, 1 H), 3.90 (s, 3 H), 3.09 - 2.85 (m, 2 H), 2.04 - 1.74 (m, 4 H). MS-ESI (m/z) calc’d for C23H20F3N6 [M+H]+: 437.2. Found 437.2. A later eluting fraction was also isolated to afford 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-l- (trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (4.46 mg, 49%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.16 (s, 1 H), 7.95 (s, 1 H), 7.90 (d, J=7.9 Hz, 1 H), 7.81 (s, 1 H), 7.76 (d, J=7.9 Hz, 1 H), 7.50 (d, J=9.0 Hz, 1 H), 6.73 - 6.67 (m, 2 H), 6.57 (d, J=9.0 Hz, 1 H), 5.00 - 4.89 (m, 1 H), 3.90 (s, 3 H), 3.06 - 2.85 (m, 2 H), 2.03 - 1.81 (m, 4 H). MS-ESI (m/z) calc’d for C23H20F3N6 [M+H]+: 437.2. Found 437.2.
Example 249: 3-Cyano-/V-(l-(5-fliioro-l-methyl-l H-pyrazol-4-yl)-l//-indazol-6-yl)-2- isopropylbenzamide
Figure imgf000455_0001
To a solution of 3-cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (20 mg, 65.71 umol) in dioxane (1 mL) were added 4-bromo-5-fluoro-l-methyl-17/-pyrazole (11.76 mg, 65.71 umol), Cui (2.50 mg, 13.14 umol), K3PO4 (41.85 mg, 197.14 umol) and/Vl,/V2- dimethylcyclohexane-l,2-diamine (4.67 mg, 32.86 umol) at 20 °C. The mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere and then concentrated under vacuum to give a residue. The residue was purified by HPLC using Method IF to afford the title compound (4.53 mg, 17%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.83 (s, 1H), 8.27 (d, J=0.73 Hz, 1H), 8.18 (s, 1H), 7.93 (dd, J=1.22, 7.70 Hz, 1H), 7.86 (d, J=2.57 Hz, 1H), 7.81 (d, J=8.56 Hz, 1H), 7.74 (dd, J=1.34, 7.70 Hz, 1H), 7.52 (t, J=7.70 Hz, 1H), 7.35 (dd, J=1.59, 8.68 Hz, 1H), 3.86 (s, 3H), 3.31-3.36 (m, 1H), 1.41 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C22H20FN6O [M+H]+: 403.2. Found 403.1.
Example 250: 3-Cyano-6-fluoro-7V-(l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-2- (prop-l-en-2-yl)benzamide (250A) and 3-Cyano-6-fluoro-2-isopropyl-7V-(l-(l-methyl- lH-pyrazol-4-yl)- 1 H-indazol-6-y l)benzamide (250B)
Figure imgf000456_0001
Step 1: 2-Bromo-3-cyano-6-fluorobenzoic acid
Figure imgf000456_0002
To a solution of 2-bromo-4-fluorobenzonitrile (1 g, 5.00 mmol) in THF (10 mL) was added a 2 M solution of LDA in THF (2.50 mL, 5.00 mmol) at -78 °C. The mixture was stirred at -78 °C for 0.5 h under an N2 atmosphere. Then CO2 (2.20 g, 50.00 mmol) (dry ice) was added. The mixture was warmed to 20 °C and stirred for 1 hr under an N2 atmosphere (15 psi). The reaction mixture was diluted with saturated aqueous NH4CI and extracted with EtOAc (3x). The combined organic phases were discarded. The aqueous phase was diluted with 1 M HC1 to pH = 3 and then extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (850 mg, 69%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- e) 6 8.12 (dd, J=8.77, 5.48 Hz, 1 H) 7.63 (t, J=8.77 Hz, 1 H). MS-ESI (m/z) calc’d for C8H4BrFNO2 [M+H]+: 243.9, 245.9 Found 243.9, 245.9.
Step 2: 2-Bromo-3-cyano-6-fluoro-N-( 1-(1 -methyl- IH-pyr azol-4-yl)-l H-indazol-6- yl)benzamide
Figure imgf000456_0003
To a solution of 2-bromo-3-cyano-6-fluorobenzoic acid (300 mg, 1.23 mmol) in DMF (10 mL) were added HATU (560.96 mg, 1.48 mmol) and DIEA (476.68 mg, 3.69 mmol). The mixture was stirred at 20 °C for 0.5 hr. Then 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6- amine (262.16 mg, 1.23 mmol) was added and the mixture was stirred at 20 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a 0-88% EtOAc/petroleum ether gradient eluent to afford the title compound (130 mg, 24%) as a yellow oil. MS-ESI (m/z) calc’d for CwHuBrFNeO [M+H]+: 439.0, 441.0. Found 439.1, 441.1.
Step 3: 3-Cyano-6-fluoro-N-( l-(l -methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)-2-(prop-l-en-2- yl)benzamide (250A)
Figure imgf000457_0001
To a solution of 2-bromo-3-cyano-6-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/- indazol-6-yl)benzamide (105 mg, 239.05 umol) in dioxane (4 mL) and H2O (1 mL) were added 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (40.17 mg, 239.05 umol), Pd(dppf)Ch (8.75 mg, 11.95 umol) and CS2CO3 (233.66 mg, 717.15 umol) at 20 °C. The mixture was stirred at 100 °C for 2 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a 0-82% EtOAc/petroleum ether gradient eluent to afford the title compound (90 mg, 65%) was as a yellow gum. Further purification of 10 mg of the yellow gum by HPLC using Method IH afforded the title compound (3.56 mg, 35%) as a white solid. JH NMR (400 MHz, DMSO- e) 6 10.92 (s, 1 H), 8.21 - 8.24 (m, 2 H), 8.16 (s, 1 H), 8.07 - 8.12 (m, 1 H), 7.79 - 7.84 (m, 2 H), 7.58 (t, J=8.77 Hz, 1 H), 7.28 (dd, J=8.55, 1.53 Hz, 1 H), 5.40 (s, 1 H), 5.09 (s, 1 H), 3.95 (s, 3 H), 2.08 (s, 3 H). MS-ESI (m/z) calc’d for C22H18FN6O [M+H]+: 401.1. Found 401.0.
Step 4: 3-Cyano-6-fluoro-2-isopropyl-N-( 1-(1 -methyl- IH-pyr azol-4-yl)-l H-indazol-6- yl)benzamide (250B)
Figure imgf000458_0001
To a solution of 3-cyano-6-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)- 2-(prop-l-en-2-yl)benzamide (80 mg, 199.80 umol) in EtOAc (10 mL) was added Pd(OH)2 (160 mg) at 20 °C. The mixture was stirred at 50 °C for 20 minutes under an H2 atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC using Method IJ to afford the title compound (10.14 mg, 12%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.82 (br s, 1 H) 8.18 - 8.21 (m, 2 H) 8.15 (s, 1 H) 7.98 (dd, J=8.71, 5.62 Hz, 1 H) 7.79 - 7.83 (m, 2 H) 7.38 - 7.45 (m, 2 H) 3.96 (s, 3 H) 3.28 - 3.36 (m, 1 H) 1.44 (d, J=7.06 Hz, 6 H). MS-ESI (m/z) calc’d for C22H20FN6O [M+H]+: 403.2. Found 403.1.
Example 251: 3-Cyano-7V-(l-(l-(2-cyanopropan-2-yI)-lH-pyrazol-4-yI)-lH-indazol-6-yI)- 2-isopropylbenzamide
Figure imgf000458_0002
To a solution of 4-iodo-17/-pyrazole (10 g, 51.55 mmol) in DMF (100 mL) was added
K2CO3 (14.25 g, 103.11 mmol) and 2-bromoacetonitrile (6.8 g, 56.71 mmol) at 20 °C. The mixture was then stirred at 50 °C for 3 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue that was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (10 g, 83%) as ayellow solid. H NMR (400 MHz, CDCh) 8 7.60 (d, J=3.5 Hz, 2H), 5.13 - 5.04 (m, 2H).
Figure imgf000459_0001
A solution of NaH (2.06 g, 51.50 mmol) was added to DMSO (16 mL) at 0 °C. The mixture was stirred at 20 °C for 20 min. Then a solution of 2-(4-iodo-17/-pyrazol-l- yl)acetonitrile (3 g, 12.88 mmol) and iodomethane (5.48 g, 38.63 mmol) in DMSO (5 mL) was added to the mixture at 20 °C. The mixture was stirred at 20 °C for 8 hrs. The reaction mixture was quenched with saturated aqueous NH4CI at 0 °C, then the mixture was extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 100% petroleum ether gradient eluent to afford the title compound (130 mg, 3%) as a white solid. 'H NMR (400 MHz, CDCh) 8 7.72 (s, 1 H), 7.61 (s, 1 H), 1.99 (s, 6 H).
Step 3: 3-Cyano-N-( 1-(1 -(2-cyanopropan-2-yl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)-2- isopropylbenzamide
Figure imgf000459_0002
3-Cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (20 mg, 65.71 umol), 2-(4-iodo- 17/-pyrazol-l-yl)-2-methylpropanenitrile (17.16 mg, 65.71 umol), 3,4,7,8-tetramethyl-l,10- phenanthroline (1.55 mg, 6.57 umol), CS2CO3 (42.82 mg, 131.43 umol) and (Bu4NCuI)2 (3.68 mg, 3.29 umol) in DMA in a sealed micro wave reaction vial under N2 were heated at 130 °C for 5 hours using micro wave irradiation. The temperature was then increased to 150 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method IK to afford the title compound (5.32 mg, 17%) as ayellow solid. 'H NMR (400MHz, DMSO-d6) δ 10.84 (s, 1 H), 8.57 (s, 1 H), 8.28 (d, J=4.6 Hz, 2 H), 8.09 (s, 1 H), 7.94 (d, J=7.5 Hz, 1 H), 7.83 (d, J=8.8 Hz, 1 H), 7.75 (d, J=7.7 Hz, 1 H), 7.54 (t, J=7.8 Hz, 1 H), 7.45 (br d, J=8.8 Hz, 1 H), 2.06 (s, 6 H), 1.42 (d, J=7.0 Hz, 6 H). MS-ESI (m/z) calc’d for C25H24N7O [M+H]+: 438.2. Found: 438.1.
Example 252: 3-Cyano-2-isopropyl-7V-(l-(l-methyI-LH-imidazol-4-yI)-LH-indazol-6- yl)benzamide
Figure imgf000460_0001
Prepared as described for 3-cyano-/V-(l-(l-(2-cyanopropan-2-yl)-17/-pyrazol-4-yl)- 17/-indazol-6-yl)-2-isopropylbenzamide using 4-iodo-l -methyl- 177-imidazole in place of 2- (4-iodo- 1 //-pyrazol- 1 -y I )-2-methy I propanenitrile. The material was purified by HPLC using Method IL to afford the title compound (3.27 mg, 8%) as a pink solid. JH NMR (CDCh) 8 10.79 (s, 1 H), 8.81 (s, 1 H), 8.20 (br s, 1 H), 7.93 (d, J=7.63 Hz, 1 H), 7.70 - 7.81 (m, 3 H), 7.52 (t, J=7.69 Hz, 1 H), 7.36 - 7.45 (m, 2 H), 3.76 (s, 3 H), 3.36 (dt, J=14.13, 6.94 Hz, 1 H), 1.43 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C22H21N6O [M+H]+: 385.1. Found 385.1.
Example 253: 3-Cyano-2-isopropyl-7V-(l-(l-(tetrahydro-2/f-pyran-4-yl)-lH-pyrazol-4- yl)- 1 //-indazol-6-y 1 )benzamide
Figure imgf000460_0002
Prepared as described for 3-cyano-/V-(l-(l-(2-cyanopropan-2-yl)-17/-pyrazol-4-yl)- 17/-indazol-6-yl)-2-isopropylbenzamide using 4-bromo-l -(tetrahydro-27/-py ran-4-yl)- 17/- pyrazole in place of 2-(4-iodo- 17/-pyrazol- 1 -yl)-2 -methylpropanenitrile. The material was purified by HPLC using Method IM to afford the title compound (4.83 mg, 10%) as a white solid. 'H NMR (DMSO-d6) δ 10.81 (s, 1 H), 8.32 (s, 1 H), 8.28 (s, 1 H), 8.23 (s, 1 H), 7.94 (dd, J=7.78, 0.99 Hz, 1 H), 7.88 (s, 1 H), 7.80 (d, J=8.55 Hz, 1 H), 7.73 - 7.76 (m, 1 H), 7.53 (t, J=7.78 Hz, 1 H), 7.41 (dd, J=8.66, 1.43 Hz, 1 H), 4.47 - 4.58 (m, 1 H), 3.99 (br d, J=11.40 2 (d, J=7.23 Hz, 6 H). MS-ESI (m/z) calc’d for C26H27N6O2 [M+H]+: 455.2. Found 455.1. Example 254: 3-Cyano-2-isopropyl-N-(1-(2-methyloxazol-5-yl)-1H-indazol-6- yl)benzamide Prepared as describe
Figure imgf000461_0001
opan-2-yl)-1H-pyrazol-4-yl)- 1H-indazol-6-yl)-2-isopropylbenzamide using 5-bromo-2-methyloxazole in place of 2-(4- iodo-1H-pyrazol-1-yl)-2-methylpropanenitrile. The material was purified by HPLC using Method IN to afford the title compound (1.64 mg, 4%) as a white solid.1H NMR (400 MHz, DMSO-d6) 10.92 (s, 1 H), 8.42 (s, 1 H), 8.29 (s, 1 H), 7.94 (d, J=6.88 Hz, 1 H), 7.86 (d, J=8.63 Hz, 1 H), 7.75 (d, J=6.88 Hz, 1 H), 7.53 (t, J=7.75 Hz, 1 H), 7.46 (dd, J=8.63, 1.25 Hz, 1 H), 7.34 (s, 1 H), 3.30 (br s, 1 H), 2.52 (br s, 3 H), 1.42 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C22H20N5O2 [M+H]+: 386.2. Found 386.1. Example 255: 3-Cyano-2-isopropyl-N-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6- yl)benzamide Prepared as described
Figure imgf000461_0002
for 3-cyano-N-(1-(1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)- 1H-indazol-6-yl)-2-isopropylbenzamide using 2-bromo-4-methylpyrimidine in place of 2-(4- iodo-1H-pyrazol-1-yl)-2-methylpropanenitrile. The material was purified by HPLC using Method IO to afford the title compound (5.71 mg, 14%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.31 (s, 1H), 8.75 (d, J=5.01 Hz, 1H), 8.40 (s, 1H), 7.94 (dd, J=1.04, 7.64 Hz, 1H), 7.85 (d, J=8.68 Hz, 1H), 7.79 (dd, J=1.16, 7.64 Hz, 1H), 7.65 (dd, J=1.65, 8.62 Hz, 1H), 7.54 (t, J=7.70 Hz, 1H), 7.31 (d, J=5.01 Hz, 1H), 3.35-3.40 (m, 1H), O [M+H]+: 397.2. Found 397.1. Example 256: 3-Cyano-2-isopropyl-N-(1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indazol-6- yl)benzamide Prepared as describe
Figure imgf000462_0001
d for 3-cyano-N-(1-(1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)- 1H-indazol-6-yl)-2-isopropylbenzamide using 2-bromo-5-methyl-1,3,4-oxadiazole in place of 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanenitrile. The material was purified by HPLC using Method IP to afford the title compound (6.45 mg, 31%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.97 (s, 1H), 8.56 (s, 1H), 7.89-8.00 (m, 2H), 7.76-7.82 (m, 1H), 7.63 (dd, J=1.53, 8.62 Hz, 1H), 7.54 (t, J=7.76 Hz, 1H), 3.37-3.41 (m, 1H), 2.60 (s, 3H), 1.43 (d, J=7.21 Hz, 6H). MS-ESI (m/z) calc’d for C21H19N6O2 [M+H]+: 387.2. Found 387.1. Example 257: N-(1-(1-Benzyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-3-cyano-2- isopropylbenzamide Prepared as describe
Figure imgf000462_0002
d for 3-cyano-N-(1-(1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)- 1H-indazol-6-yl)-2-isopropylbenzamide using 1-benzyl-4-iodo-1H-pyrazole in place of 2-(4- iodo-1H-pyrazol-1-yl)-2-methylpropanenitrile. The material was purified by HPLC using Method IQ to afford the title compound (9.23 mg, 20%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.23 (d, J=0.7 Hz, 1H), 7.94 (dd, J=7.8, 1.2 Hz, 1H), 7.89 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.75 (dd, J=7.6, 1.3 Hz, 1H), 7.53 (t, J=7.7 461 Hz, 1H), 7.29-7.40 (m, 6H), 5.44 (s, 2H), 3.34-3.39 (m, 1H), 1.42 ppm (d, J=7.1 Hz, 6H).
MS-ESI (m/z) calc’d for C28H25N6O [M+H]+: 461.2. Found: 461.2.
Example 258: 5-((l-(l-(2-Cyanopropan-2-yl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000463_0001
Step 1: 5-((l-(l-(2-Cyanopropan-2-yl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000463_0002
To a solution of 2-(4-iodo-17/-pyrazol-l-yl)-2-methylpropanenitrile (35 mg, 134.07 umol) in dioxane (1.5 mL) were added Cui (5.11 mg, 26.81 umol), K3PO4 (85.37 mg, 402.20 umol), ,/V2-dimethylcyclohexane-l,2-diamine (9.54 mg, 67.03 umol), and 5-((17/-indazol- 6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (38.79 mg, 134.07 umol) at 20 °C. The mixture was stirred at 110 °C for 2 hrs under an N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method IR to afford the title compound (15 mg, 26%) as a white solid. MS-ESI (m/z) calc’d for C25H23N6O [M+H]+:423.2. Found 423.0.
Step 2: 5-((l-(l-(2-Cyanopropan-2-yl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-
Figure imgf000463_0003
5-((l-(l-(2-Cyanopropan-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method IS to afford 5-((l-(l-(2-cyanopropan-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (4.33 mg, 45%) as a white solid. XH NMR (400 MHz, MeOD) 6 8.37 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.73 (d, J=8.80 Hz, 1H), 7.48- 7.56 (m, 3H), 7.19 (s, 1H), 6.98 (dd, J=1.96, 8.80 Hz, 1H), 5.65 (t, J=5.01 Hz, 1H), 2.78-2.97 (m, 2H), 2.10-2.16 (m, 2H), 2.08 (s, 6H), 1.96-2.05 (m, 1H), 1.82-1.92 (m, 1H). MS-ESI (m/z) calc’d for C25H23N6O [M+H]+:423.2. Found 423.1. A later eluting fraction was also isolated to afford 5-((l-(l-(2-cyanopropan-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (3.74 mg, 40%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.37 (s, 1H), 8.12 (d, J=0.73 Hz, 1H), 8.03 (s, 1H), 7.74 (d, J=8.80 Hz, 1H), 7.50-7.58 (m, 3H), 7.19 (s, 1H), 6.98 (dd, J=2.02, 8.86 Hz, 1H), 5.66 (t, J=5.01 Hz, 1H), 2.80-2.98 (m, 2H), 2.11-2.16 (m, 2H), 2.09 (s, 6H), 1.97-2.06 (m, 1H), 1.83- 1.93 (m, 1H). MS-ESI (m/z) calc’d for C25H23N6O [M+H]+:423.2. Found 423.1.
Example 259: 5-((l-(5-FIuoro-l-methyI-lH-pyrazol-4-yI)-LH-indazol-6-yI)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitriIe, enantiomer 1 and 2
Figure imgf000464_0001
Step 1: 5-((l-(5-Fluoro-l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000464_0002
To a solution of 4-bromo-5 -fluoro- 1 -methyl- 1 //-pyrazole (50 mg, 279.34 umol) and 5-((17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (67.35 mg, 232.79 umol) in dioxane (3 mL) were added Cui (8.87 mg, 46.56 umol), K3PO4 (148.24 mg, 698.36 umol), and (15,2S)-/Vi,/V2-dimethylcyclohexane-l,2-diamine (16.56 mg, 116.39 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method IT to afford the title compound (25 mg, 25%) as a white solid. MS-ESI (m/z) calc’d for C22H19FN5O [M+H]+: 388.2. Found 388.2.
Step 2: 5-((l-(5-Fluoro-l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5, 6, 7,8-
Figure imgf000465_0001
5-((l-(5-Fluoro-l -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method IU to afford 5-((l-(5-fluoro-l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (3.24 mg, 35%) as a white solid. XH NMR (400 MHz, DMSO- e) 6 8.21 (s, 1 H), 7.88 (d, J=2.65 Hz, 1 H), 7.75 (d, J=8.60 Hz, 1 H), 7.68 (s, 1 H), 7.63 (d, J=7.50 Hz, 1 H), 7.51 (d, J=7.94 Hz, 1 H), 7.16 (s, 1 H), 6.95 (dd, J=1.98, 8.82 Hz, 1 H), 5.71 (t, J=4.85 Hz, 1 H), 3.82 (s, 3 H), 2.85-2.94 (m, 1 H), 2.73-2.82 (m, 1 H), 1.99-2.04 (m, 2 H), 1.76-1.89 (m, 2 H). MS-ESI (m/z) calc’d for C22H19FN5O [M+H]+: 388.2. Found 388.2. A later eluting fraction was also isolated to afford 5-((l-(5- nuoro-l -methyl- IT/-pyrazol-4-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2- carbonitrile, enantiomer 2 (4.19 mg, 43%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.22 (s, 1 H), 7.88 (d, J=2.65 Hz, 1 H), 7.75 (d, J=8.60 Hz, 1 H), 7.69 (s, 1 H), 7.64 (d, J=7.94 Hz, 1 H), 7.51 (d, J=7.94 Hz, 1 H), 7.17 (s, 1 H), 6.95 (dd, J=1.98, 8.82 Hz, 1 H), 5.71 (t, J=4.96 Hz, 1 H), 3.83 (d, J=0.66 Hz, 3 H), 2.83-2.95 (m, 1 H), 2.73-2.82 (m, 1 H), 1.99-2.04 (m, 2 H), 1.75-1.90 (m, 2 H). MS-ESI (m/z) calc’d for C22H19FN5O [M+H]+: 388.2. Found 388.2.
Example 260: 5-((l-(l-MethyI-6-oxo-l,6-dihydropyridin-3-yI)-LH-indazol-6-yI)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000466_0001
Step 1: 5-(( l-( l-Methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)- lH-indazol-6-yl)oxy)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000466_0002
A mixture of 5-iodo-l-methylpyridin-2(177)-one (16.25 mg, 69.13 umol),
Figure imgf000466_0003
indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (20 mg, 69.13 umol), Cui (2.63 mg, 13.83 umol), K3PO4 (44.02 mg, 207.38 umol) and /Vl,JV2-dimethylcyclohexane- 1,2-diamine (4.92 mg, 34.56 umol) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 105 °C for 24 hr under an N2 atmosphere. The reaction was combined together with another 20 mg scale reaction before work up. The final mixture was concentrated to give a residue. The residue was purified by HPLC using Method IW to afford the title compound (10 mg, 18%) as a white solid. MS-ESI (m/z) calc’d for C24H21N4O2 [M+H]+: 397.1. Found 397.2.
Step 2: 5-( (1-(1 -Methyl-6-oxo-l, 6-dihydropyridin-3-yl)-lH-indazol-6-yl)oxy)-5, 6, 7, 8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000466_0004
l-[l-(l-Methyl-6-oxo-3-pyridyl)indazol-6-yl]oxytetralin-6-carbonitrile was subject to chiral separation using Method IX to afford 5-((l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)- l7/-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (3.13 mg, 34%) as a gray solid. 'H NMR (400 MHz, DMSO- e) 6 7.38 (s, 2 H), 6.92 (td, J=6.32, 2.88 Hz, 2 H), 6.86 (s, 1 H), 6.81 (br d, J=7.88 Hz, 1 H), 6.69 (d, J=7.88 Hz, 1 H), 6.46 (s, 1 H), 6.14 (dd, J=8.69, 1.56 Hz, 1 H), 5.73 (d, J=9.63 Hz, 1 H), 4.89 (br t, J=4.44 Hz, 1 H), 2.69 (s, 3 H), 2.02 - 2.11 (m, 1 H), 1.90 - 2.00 (m, 1 H), 1.17 - 1.23 (m, 2 H), 0.94 - 1.08 (m, 2 H). MS-ESI (m/z) calc’d for C24H21N4O2 [M+H]+: 397.1. Found 397.0. A later eluting fraction was also isolated to afford 5-((l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (2.8 mg, 31%) as a gray solid. 'H NMR (400 MHz, DMSO- e) 6 7.38 (s, 2 H), 6.89 - 6.94 (m, 2 H), 6.86 (s, 1 H), 6.81 (br d, J=8.00 Hz, 1 H), 6.69 (d, J=8.00 Hz, 1 H), 6.46 (s, 1 H), 6.14 (br d, J=8.88 Hz, 1 H), 5.73 (d, J=9.63 Hz, 1 H), 4.89 (br t, J=4.63 Hz, 1 H), 2.69 (s, 3 H), 2.03 - 2.09 (m, 1 H), 1.92 - 1.98 (m, 1 H), 1.20 (q, J=5.29 Hz, 2 H), 0.95 - 1.06 (m, 2 H). MS-ESI (m/z) calc’d for C24H21N4O2 [M+H]+: 397. E Found 397.1.
Example 261: 5-(( l-(2-(2-()xaspiro|3.3|lieptaii-6-yl)pyridin-4-yl)-l//-indazol-6-yl)oxy)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000467_0001
Step 1: 6-(4-Iodopyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane
Figure imgf000467_0002
To a solution of 2-fluoro-4-iodopyridine (200 mg, 896.92 umol) in DMSO (4 mL) were added K2CO3 (371.88 mg, 2.69 mmol) and 2-oxa-6-azaspiro[3.3]heptane (133.37 mg, 1.35 mmol) at 20 °C. The mixture was then stirred at 70 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford the title compound (200 mg, 73%) as a white solid. 'H NMR (400 MHz, CDCh) 7.75 (d, J=5.48 Hz, 1 H), 6.93 (dd, J=5.37, 1.21 Hz, 1 H), 6.65 (d, J=0.88 Hz, 1 H), 4.82 (s, 4 H), 4.14 (s, 4 H). MS-ESI (m/z) calc’d for C10H12IN2O [M+H]+: 303.0. Found 303.1. Step 2: 5-((l-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)- 5, 6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000468_0001
To a solution of 6-(4-iodopyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (20 mg, 66.20 umol) in dioxane (2 mL) were added 5-((17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile (19.15 mg, 66.20 umol), Cui (2.52 mg, 13.24 umol), and/Vl,/V2-dimethylcyclohexane-l,2-diamine (4.71 mg, 33.10 umol), K3PO4 (42.16 mg, 198.60 umol) at 20 °C. The mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative-TLC (100% EtOAc, Rf = 0.55) to afford the title compound (13.5 mg, 44%) as a white solid. MS-ESI (m/z) calc’d for C26H26N5O2 [M+H]+: 464.2. Found 464.0.
Step 3: 5-((l-(2-(2-Oxaspiro[3.3]heptan-6-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5,6, 7,8-
Figure imgf000468_0002
The enantiomers of 5-((l-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile were separated by chiral HPLC using Method IY to afford 5-((l-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl)- l//-indazol-6-yl)oxy)-5.6.7.8-tetrahydronaphthalene-2-carbonitrile. enantiomer 1 (3.9 mg, 43%) as a white solid. 'H NMR (400 MHz, DMSO- e) 8.33 (s, 1 H), 8.18 (d, J=5.48 Hz, 1 H), 7.82 (d, J=8.77 Hz, 1 H), 7.71 (s, 1 H), 7.66 (d, J=8.11 Hz, 1 H), 7.53 - 7.57 (m, 2 H), 7.13 (dd, J=5.59, 1.64 Hz, 1 H), 7.05 (dd, J=8.66, 1.64 Hz, 1 H), 6.69 (d, J=1.32 Hz, 1 H), 5.79 (t, J=5.15 Hz, 1 H), 4.72 (s, 4 H), 4.16 (s, 4 H), 2.87 - 2.95 (m, 1 H), 2.76 - 2.86 (m, 1 H), 2.03 - 2.14 (m, 2 H), 1.78 - 1.93 (m, 2 H). MS-ESI (m/z) calc’d for C26H26N5O2 [M+H]+: 464.2 Found 464.1. A later eluting fraction was also isolated to afford 5-((l-(2-(2-oxa-6- azaspiro[3.3]heptan-6-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile, enantiomer 2 (4.36 mg, 47%) as a white solid. 'H NMR (400 MHz, DMSO- e) 8.33 (s, 1 H), 8.18 (d, J=5.70 Hz, 1 H), 7.82 (d, J=8.77 Hz, 1 H), 7.70 (s, 1 H), 7.66 (d, J=8.55 Hz, 1 H), 7.53 - 7.58 (m, 2 H), 7.13 (dd, J=5.59, 1.64 Hz, 1 H), 7.02 - 7.07 (m, 1 H), 6.69 (s, 1 H), 5.78 (t, J=5.04 Hz, 1 H), 4.72 (s, 4 H), 4.16 (s, 4 H), 2.86 - 2.95 (m, 1 H), 2.74 - 2.85 (m, 1 H), 2.04 - 2.12 (m, 2 H), 1.80 - 1.91 (m, 2 H). MS-ESI (m/z) calc’d for C26H26N5O2 [M+H]+: 464.2. Found 464.1.
Example 262: 5-((l-(2-(6-Oxa-3-azabicyclo[3.1.1 |lieptaii-3-yl)pyridin-4-yl)-l//-indazol-
6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000469_0001
Step 1: 3-(4-Iodo-2-pyridyl)-6-oxa-3-azabicyclo[3. 1. 1 ]heptane
Figure imgf000469_0002
To a solution of 6-oxa-3-azabicyclo[3.1.1]heptane (200.66 mg, 1.48 mmol) in dioxane (2 mL) was added EtsN (1.36 g, 13.45 mmol) at 20 °C. The mixture was stirred at 20 °C for 0.5 hr and then 2-fluoro-4-iodopyridine (300 mg, 1.35 mmol) was added to the mixture and stirring was continued at 110 °C for 37.5 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-21% EtOAc/petr oleum ether gradient eluent to afford the title compound (130 mg, 31%) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 7.89 (d, J=5.25 Hz, 1 H), 7.01 (br d, J=5.00 Hz, 1 H), 6.96 (br s, 1 H), 4.77 (br d, J=6.50 Hz, 2 H), 3.66 - 3.78 (m, 4 H), 3.26 - 3.34 (m, 1 H), 1.97 (d, J=8.88 Hz, 1 H). MS-ESI (m/z) calc’d for C10H12IN2O [M+H]+: 302.9. Found 303.1. Step 2: 5-( ( 1 -(2-( 6-Oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)- 5, 6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000470_0001
A mixture of 5-((17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (20 mg, 69.13 umol), 3-(4-iodo-2-pyridyl)-6-oxa-3-azabicyclo[3.1.1]heptane (20.88 mg, 69.13 umol), Cui (2.63 mg, 13.83 umol), K3PO4 (44.02 mg, 207.38 umol) and ,A2- dimethylcyclohexane-l,2-diamine (4.92 mg, 34.56 umol) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction was combined together with another 20 mg scale reaction before work up. The final mixture was concentrated to give a residue. The residue was purified by HPLC using Method IZ to afford the title compound (30 mg, 47%) as a white solid. MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2. Found 464.3.
Step 3: 5-( ( 1 -(2-( 6-Oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-
Figure imgf000470_0002
The enantiomers of 5-((l-(2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-4-yl)-lH- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile were separated by chiral HPLC using Method JA to afford 5-((l-(2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyridin-4- yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (3.76 mg, 40%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.34 (s, 1 H), 8.27 (d, J=5.50 Hz, 1 H), 7.82 (d, J=8.88 Hz, 1 H), 7.70 (s, 1 H), 7.64 (br d, J=3.00 Hz, 2 H), 7.54 - 7.58 (m, 1 H), 7.16 (br d, J=5.13 Hz, 1 H), 7.05 (dd, J=8.76, 1.75 Hz, 1 H), 6.97 (s, 1 H), 5.80 (t, J=4.94 Hz, 1 H), 4.72 (br d, J=6.38 Hz, 2 H), 3.75 - 3.81 (m, 2 H), 3.65 (br dd, J=11.88, 5.38 Hz, 2 H), 3.14 (q, J=7.05 Hz, 1 H), 2.86 - 2.95 (m, 1 H), 2.75 - 2.84 (m, 1 H), 2.03 - 2.11 (m, 2 H), 1.77 - 1.93 (m, 3 H). MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2 Found
464.1. A later eluting fraction was also isolated to afford 5-((l-(2-(6-oxa-3- azabicyclo[3. l.l]heptan-3-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (4.2 mg, 44%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.33 (s, 1 H), 8.26 (d, J=5.63 Hz, 1 H), 7.82 (d, J=8.76 Hz, 1 H), 7.69 (s, 1 H), 7.61 - 7.67 (m, 2 H), 7.53 - 7.57 (m, 1 H), 7.14 (dd, J=5.50, 1.50 Hz, 1 H), 7.04 (dd, J=8.76, 1.75 Hz, 1 H), 6.95 (s, 1 H), 5.80 (br t, J=4.94 Hz, 1 H), 4.71 (br d, J=6.38 Hz, 2 H), 3.77 (br d, J=12.26 Hz, 2 H), 3.58 - 3.69 (m, 2 H), 3.10 - 3.17 (m, 1 H), 2.85 - 2.94 (m, 1 H), 2.74 - 2.83 (m, 1 H), 2.03 - 2.11 (m, 2 H), 1.75 - 1.92 (m, 3 H). MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2. Found 464. E
Example 263: 5-((l-(l-MethyI-lH-pyrazol-4-yI)-lH-indazol-6-yI)amino)-l-(prop-l-en-2- yI)-5,6,7,8-tetrahydronaphthalene-2-carbonitriIe, enantiomer 1 and 2
Figure imgf000471_0001
Step 1: 5-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-l-(prop-l-en-2-yl)-5,6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000471_0002
To a solution of /V-(6-cyano-5-isopropenyl-tetralin-l-yl)-/V-[l-(l-methylpyrazol-4- yl)indazol-6-yl]-2-nitro-benzenesulfonamide (460 mg, 774.86 umol) in MeCN (5 mL) were added thiophenol (420 mg, 3.81 mmol) and K2CO3 (535.45 mg, 3.87 mmol) and the mixture was stirred at 20 °C for 3 hrs. The reaction mixture was adjusted to pH = 10 by addition of saturated aqueous NaiCOs and then diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The material was purified by silica gel chromatography using a 0- 45% EtOAc/petroleum ether gradient eluent to afford the title compound (186 mg, 58%) as a yellow solid. MS-ESI (m/z) calc’d for C25H25N6 [M+H]+: 409.2. Found: 409.3. Step 2: 5-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-l-(prop-l-en-2-yl)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 and 2
Figure imgf000472_0001
The enantiomers of 5-isopropenyl-l-[[l-(l-methylpyrazol-4-yl)indazol-6- yl]amino]tetralin-6-carbonitrile were separated by chiral HPLC using Method JB to afford 5- ((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-l -(prop-1 -en-2-yl)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (1.98 mg, 35%) as a yellow solid. JH NMR (400 MHz, MeOD) 6 8.01 (s, 1 H), 7.95 (s, 1 H), 7.77 (s, 1 H), 7.53 (d, J=8.76 Hz, 1 H), 7.45 - 7.51 (m, 2 H), 6.74 (d, J=8.76 Hz, 1 H), 6.62 (s, 1 H), 5.45 (s, 1 H), 4.93 (s, 1 H), 4.68 (br s, 1 H), 3.97 (s, 3 H), 2.69 - 2.88 (m, 2 H), 2.08 (s, 3 H), 1.83 - 1.98 (m, 4 H) MS- ESI (m/z) calc’d for C25H25N6 [M+H]+: 409.2. Found: 409.1. A later eluting fraction was also isolated to afford 5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-l-(prop-l- en-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (4.16 mg, 96%) as a gray solid. 'H NMR (400 MHz, MeOD) 6 8.01 (s, 1 H), 7.91 (s, 1 H), 7.76 (s, 1 H), 7.45 - 7.53 (m, 3 H), 6.71 (dd, J=8.80, 1.47 Hz, 1 H), 6.58 (s, 1 H), 5.45 (s, 1 H), 4.92 (br s, 1 H), 4.77 (br t, J=5.68 Hz, 1 H), 3.96 (s, 3 H), 2.76 (br s, 2 H), 2.07 (s, 3 H), 1.86 - 2.04 (m, 4 H). MS-ESI (m/z) calc’d for C25H25N6 [M+H]+: 409.2. Found: 409.1.
Example 264 : 3-Cy ano-2-isop ropy l- \- [ 1- [2-(4-methylpiperazin- l-yl)-4-pyridyl]indazol-
6-yl] benzamide
Figure imgf000472_0002
Step 1: l-(4-Iodo-2-pyridyl)-4-methyl-piperazine
Figure imgf000472_0003
To a solution of 2-fluoro-4-iodopyridine (200 mg, 896.92 umol) in DMSO (2 mL) was added K2CO3 (247.92 mg, 1.79 mmol) and 1 -methylpiperazine (134.75 mg, 1.35 mmol) and the mixture was stirred at 60 °C for 12 hrs. The mixture was concentrated to give a residue that was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were washed with brine (3x), dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (250 mg, 92%) as white solid. 'H NMR (DMSO- e) 6 7.79 (d, J=5.13 Hz, 1 H), 7.20 (s, 1 H), 6.98 (dd, J=5.13, 1.00 Hz, 1 H), 3.44 - 3.49 (m, 4 H), 2.33 - 2.37 (m, 4 H), 2.19 (s, 3 H). MS-ESI (m/z) calc’d for C10H15IN3 [M+H]+: 304.0. Found 304.1.
Step 2: 3-Cyano-2-isopropyl-N-(l-(2-(4-methylpiperazin-l-yl)pyridin-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000473_0001
3-Cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (100.40 mg, 329.88 umol), l-(4- iodo-2-pyridyl)-4-methyl-piperazine (100 mg, 329.88 umol), 3,4,7,8-tetramethyl-l,10- phenanthroline (7.80 mg, 32.99 umol), CS2CO3 (214.96 mg, 659.76 umol), and bis [(tetrabutylammonium iodide)copper(I) iodide] (18.47 mg, 16.49 umol) in DMA (4 mL) under N2 in a sealed micro wave reaction vial were heated at 100 °C for 3 hrs using microwave irradiation. The mixture was concentrated to give a residue. The residue was purified by HPLC using Method JC to afford the title compound (21.64 mg, 10%) as a white solid. 'H NMR (DMSO- e) 6 10.96 (s, 1 H), 8.83 (s, 1 H), 8.41 (s, 1 H), 8.35 (d, J=5.50 Hz, 1 H), 7.95 (dd, J=7.69, 1.31 Hz, 1 H), 7.88 (d, J=8.63 Hz, 1 H), 7.76 (dd, J=7.69, 1.31 Hz, 1 H), 7.55 (t, J=7.75 Hz, 1 H), 7.41 (dd, J=8.69, 1.44 Hz, 1 H), 7.32 (s, 1 H), 7.19 (dd, J=5.38, 1.50 Hz, 1 H), 4.53 (br d, J=13.51 Hz, 2 H), 3.11 - 3.26 (m, 3 H), 2.85 (d, J=4.38 Hz, 3 H), 1.49 - 1.83 (m, 2 H), 1.42 (d, J=7.13 Hz, 6 H), 1.14 - 1.38 (m, 2 H). MS-ESI (m/z) calc’d for C28H30N7O [M+H]+: 480.2. Found 480.2.
Example 265: 3-Cyano-2-isopropyl-/V-(l-methyl-l//-indazol-6-yl)benzamide
Figure imgf000474_0001
Step 1: 3-Cyano-N-(l-methyl-lH-indazol-6-yl)-2-(prop-l-en-2-yl)benzamide
Figure imgf000474_0002
To a solution of 1 -methyl- 17/-indazol-6-amine (100 mg, 679.45 umol), 3-cyano-2- (prop-l-en-2-yl)benzoic acid (127.19 mg, 679.45 umol) in DMF (3 mL) were added HATU (387.52 mg, 1.02 mmol) and DIEA (263.44 mg, 2.04 mmol) at 20 °C and the mixture was stirred for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The material was purified by silica gel chromatography using a 0-35% EtOAc/petroleum ether gradient eluent to afford the title compound (200 mg, 93%) as a brown oil. 'H NMR (400 MHz, DMSO- e) 6 10.61 (s, 1 H), 8.18 (s, 1 H), 7.93 - 8.04 (m, 2 H), 7.83 - 7.91 (m, 1 H), 7.59 - 7.72 (m, 2 H), 7.18 (dd, J=8.63, 1.25 Hz, 1 H), 5.36 (s, 1 H), 5.04 (s, 1 H), 3.96 - 4.02 (m, 3 H), 2.12 (s, 3 H) MS-ESI (m/z) calc’d for C19H17N4O [M+H]+: 317.1. Found 317.2.
Step 2: 3-Cyano-2-isopropyl-N-( 1 -methyl- lH-indazol-6-yl)benzamide
Figure imgf000474_0003
A mixture of 3-cyano-/V-(l-methyl-17/-indazol-6-yl)-2-(prop-l-en-2-yl)benzamide (100 mg, 316.10 umol) and Pd(OH)2 (500.00 mg, 712.05 umol) in EtOAc (3 mL) was degassed and purged with H2 (3x) and then the mixture was stirred at 20 °C for 1 hr under an H2 atmosphere (15 psi). The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method JD to afford the title compound (28.35 mg, 26%) as white solid. 'H NMR (400 MHz, DMSO- e) 6 10.77 (s, 1 H), 8.27 (s, 1 H), 7.98 (s, 1 H), 7.94 (dd, J=7.69, 1.19 Hz, 1 H), 7.75 (dd, J=7.63, 1.25 Hz, 1 H), 7.70 (d, J=8.63 Hz, 1 H), 7.53 (t, J=7.69 Hz, 1 H), 7.21 (dd, J=8.69, 1.56 Hz, 1 H), 4.01 (s, 3 H), 3.37 - 3.41 (m, 1 H), 1.43 (d, J=7.13 Hz, 6 H) MS-ESI (m/z) calc’d for C19H19N4O [M+H]+: 319.1. Found 319.1. Example 266: 3-Cyano-2-isopropyl-/V-(l-(l-(2-morpholinoethyl)-l//-pyrazol-4-yl)-l//- indazol-6-yI)benzamide
Figure imgf000475_0001
To a solution of 4-iodo-17/-pyrazole (200 mg, 1.03 mmol), 4-(2- chloroethyl)morpholine (231.40 mg, 1.55 mmol) in DMF (5 mL) was added K2CO3 (427.51 mg, 3.09 mmol) at 20 °C. The mixture was stirred at 90 °C for 12 hrs. The mixture was diluted with H2O and extracted with EtOAc (5x). The combined organic layers were washed with brine (5x), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (250 mg, 78%) as a white solid. MS-ESI (m/z) calc’d for C9H15IN3O [M+H]+:308.0. Found 308.2. Step 2: 3-Cyano-2-isopropyl-N-(l-(l-(2-morpholinoethyl)-lH-pyrazol-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000475_0002
To a solution of 4-(2-(4-iodo-17/-pyrazol-l-yl)ethyl)morpholine (40 mg, 130.24 umol) in dioxane (2.5 mL) was added Cui (4.96 mg, 26.05 umol) and K3PO4 (82.94 mg, 390.71 umol), (17?,27?)- ,A2-dimethylcyclohexane-l,2-diamine (9.26 mg, 65.12 umol), 3- cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (39.64 mg, 130.24 umol) at 20 °C. The mixture was stirred at 110 °C for 2 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method JE to afford the title compounds (7.3 mg, 9%) as a white solid. JH NMR (400 MHz, CDCh) 8 8.50 (br s, 1H), 8.10 (br d, J=7.88 Hz, 3H), 8.00 (s, 1H), 7.75 (br t, J=8.69 Hz, 2H), 7.57-7.68 (m, 2H), 7.37 (br t, J=7.57 Hz, 1H), 4.75 (br s, 2H), 3.93 (br s, 4H), 3.66 (br s, 2H), 3.51 (td, J=6.94, 14.13 Hz, 1H), 3.01 (br s, 4H), 1.52 (d, J=7.00 Hz, 6H). MS-ESI (m/z) calc’d for C27H30N7O [M+H]+:484.2. Found 484.1.
Example 267 : 3-Cyano-2-isopropyl-7V-(l-(l-((l-methylpiperidin-4-yl)methyl)-lH- pyrazol-4-yl)- l//-iiidaz()l-6-yl)benzainide
Figure imgf000476_0001
Step 1: 4-((4-Iodo-lH-pyrazol-l-yl)methyl)-l -methylpiperidine
Figure imgf000476_0002
A mixture of (l-methylpiperidin-4-yl)methanol (200 mg, 1.55 mmol), 4-iodo-1 /- pyrazole (300.27 mg, 1.55 mmol), (tributylphosphoranylidene)acetonitrile (747.23 mg, 3.10 mmol) in toluene (5 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 50 °C for 2 hrs under an N2 atmosphere. The mixture was concentrated under vacuum to give a residue that was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 100% EtOAc gradient eluent to afford material of insufficient purity (350 mg). The material was further purified by prep-TLC (SiO2, EtOAc/EtOH = 3/1, Rf = 0.54) to afford the title compound (230 mg, 48%) as a yellow gum. JH NMR (400 MHz, DMSO- e) 6 7.89 (s, 1H), 7.45-7.53 (m, 1H), 3.98 (d, J=7.3 Hz, 2H), 2.70 (br d, J=11.5 Hz, 2H), 2.10 (s, 3H), 1.68-1.79 (m, 3H), 1.38 (br d, J=12.5 Hz, 2H), 1.16 ppm (br dd, J=12.3, 3.4 Hz, 2H). MS-ESI (m/z) calc’d for C10H17IN3 [M+H]+: 306.0. Found 306.1.
Step 2: 3-Cyano-2-isopropyl-N-( 1 -(!-((! -methylpiperidin-4-yl)methyl)-lH-pyrazol-4-yl)-lH- indazol-6-yl)benzamide
Figure imgf000477_0001
To a mixture of 4-((4-iodo-17f-pyrazol-l-yl)methyl)-l -methylpiperidine (30.08 mg, 98.57 umol), 3-cyano-/V-(17f-indazol-6-yl)-2-isopropylbenzamide (30 mg, 98.57 umol) in dioxane (1 mL) were added Cui (3.75 mg, 19.71 umol), K3PO4 (62.77 mg, 295.72 umol) and ATA6-dimethylcyclohexane-l .2-diamine (7.01 mg, 49.29 umol) at 20 °C. The mixture was heated at 100 °C for 2 hrs under an N2 atmosphere and then filtered, and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method JE to afford the title compound (18.17 mg, 38%) as a red oil. 'H NMR (400 MHz, DMSO- e) 6 10.85 (s, 1H), 9.48 (br s, 1H), 8.38 (s, 1H), 8.28-8.32 (m, 1H), 8.23 (s, 1H), 7.94 (dd, J=7.7, 1.1 Hz, 1H), 7.90 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.74 (dd, J=7.6, 1.2 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.35 (dd, J=8.8, 1.3 Hz, 1H), 4.39-4.89 (m, 6H), 4.17 (d, J=6.8 Hz, 2H), 3.43 (br d, J=12.1 Hz, 2H), 3.29-3.38 (m, 1H), 2.85-3.01 (m, 2H), 2.70-2.82 (m, 3H), 2.14 (br d, J=3.7 Hz, 1H), 1.77 (br d, J=13.2 Hz, 2H), 1.45-1.54 (m, 2H), 1.42 ppm (d, J=7.0 Hz, 6H). MS-ESI (m/z) calc’d for C28H32N7O [M+H]+: 482.3. Found 482.1. Example 268: 3-Cyano-2-isopropyl-7V-(l-(2-(4-methylmorpholin-2-yl)pyridin-4-yl)-lH- indazol-6-yl)benzamide, enantiomer 1 and 2
Figure imgf000478_0001
Step 1: l-(4-Bromopyridin-2-yl)ethanone
Figure imgf000478_0002
To a solution of 2,4-dibromopyridine (10 g, 42.21 mmol) in toluene (90 mL) was added «-BuLi (2.5 M, 18.57 mL) at -78 °C under an N2 atmosphere. The mixture was stirred at -78 °C for 1 hr. Then JV-methoxy-JV-methylacetamide (8.71 g, 84.43 mmol) was added and the mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by addition of saturated aqueous NH4CI at 0 °C and extracted with EtOAc (4x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-10% EtOAc/petroleum ether gradient eluent to afford the title compound (2.85 g, 33%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.61 (d, J=5.25 Hz, 1H), 8.06 (d, J=1.88 Hz, 1H), 7.95 (dd, J=1.94, 5.19 Hz, 1H), 2.62 (s, 3H). MS-ESI (m/z) calc’d for C tEBrNO [M+H]+: 200.0, 202.0. Found 200.1, 202.1.
Step 2: 2-Bromo-l-(4-bromopyridin-2-yl)ethanone
Figure imgf000478_0003
To a mixture of 1 -(4-bromopyri din-2 -yl)ethanone (540 mg, 2.70 mmol) in HBr/AcOH (5 mL, 33% purity) was added Bn (647.13 mg, 4.05 mmol) at 0 °C, then the mixture was stirred 2 hrs. The reaction mixture was filtered and the solid was washed with EtOAc and dried in vacuum to afford the title compound (613.8 mg, 81%) as a white solid. MS-ESI (m/z) calc’d for C7H5Br2NO [M+H]+: 277.9, 279.9, 281.9. Found 278.0, 280.0, 282.0.
Step 3: l-(4-Bromopyridin-2-yl)-2-((2-hydroxyethyl)(methyl)amino)ethanone
Figure imgf000479_0001
To a solution of 2-bromo-l -(4-bromopyri din-2 -yl)ethanone (260 mg, 932.14 umol) in THF (5 mL) were added K2CO3 (193.24 mg, 1.40 mmol) and 2-(methylamino)ethanol (70.01 mg, 932.14 umol) at 20 °C. The mixture was stirred at 20 °C for 30 minutes and then concentrated under reduced pressure to afford the title compound (142.2 mg, 27%) as a white solid. MS-ESI (m/z) calc’d for CioHi4BrN202 [M+H]+: 273.0, 275.0. Found 273.2, 275.2.
Step 4: l-(4-Bromopyridin-2-yl)-2-((2-hydroxyethyl)(methyl)amino)ethanol
Figure imgf000479_0002
To a solution of 1 -(4-bromopyri din-2-yl)-2-((2-hydroxyethyl)(methyl)amino)ethanone
(180 mg, 659.04 umol) in MeOH (2 mL) was added NaBFL (37.40 mg, 988.56 umol) at 20
°C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O and concentrated under reduced pressure to remove MeOH. The mixture was extracted with EtOAc (4x) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (150 mg, 82%) as an orange oil. MS-ESI (m/z) calc’d for CioHi6BrN202 [M+H]+: 275.0, 277.0. Found 275.2, 277.2.
Step 5: 2-(4-Bromopyridin-2-yl)-4-methylmorpholine
Figure imgf000479_0003
To a solution of l-(4-bromopyridin-2-yl)-2-((2-hydroxyethyl)(methyl)amino)ethanol (150 mg, 545.17 umol) in toluene (3 mL) were added (tributylphosphoranylidene)acetonitrile (263.16 mg, 1.09 mmol) at 20 °C. The solution was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by preparative TLC (SiO2, petroleum ether/EtOAc = 3/1, Rf = 0.15) to afford the title compound (36 mg, 25%) as a pale yellow oil. MS-ESI (m/z) calc’d for CioHi4BrN20 [M+H]+: 257.0, 259.0. Found 257.1, 259.2.
Step 6: 2-(4-Bromopyridin-2-yl)-4-methylmorpholine, enantiomer 1 and 2
Figure imgf000480_0001
2-(4-Bromopyridin-2-yl)-4-methylmorpholine was subjected to chiral separation using Method JF to afford 2-(4-bromopyridin-2-yl)-4-methylmorpholine, enantiomer 1 (19 mg, 36%) as a white solid. MS-ESI (m/z) calc’d for CioHi4BrN20 [M+H]+: 257.0, 259.0. Found 257.2, 259.2. A later eluting fraction was also isolated to afford 2-(4-bromopyridin-2- yl)-4-methylmorpholine, enantiomer 2 (18 mg, 36%) was obtained as a white solid. MS-ESI (m/z) calc’d for CioHi4BrN20 [M+H]+: 257.0, 259.0. Found 257.1, 259.2.
Step 7: 3-Cyano-2-isopropyl-N-(l-(2-(4-methylmorpholin-2-yl)pyridin-4-yl)-lH-indazol-6- yl)benzamide, enantiomer 1
Figure imgf000480_0002
To a solution of 2-(4-bromopyridin-2-yl)-4-methylmorpholine, enantiomer 1 (19.00 mg, 73.89 umol) in dioxane (1.5 mL) were added Cui (2.81 mg, 14.78 umol), K2PO4 (47.06 mg, 221.68 umol), (77?,27?)- ,A2-dimethylcyclohexane-l,2-diamine (5.26 mg, 36.95 umol), and 3-cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (22.49 mg, 73.89 umol) at 20 °C. The mixture was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and the residue was purified by HPLC using Method JG to afford material of insufficient purity (5 mg). Then material was further purified by HPLC using Method JH to afford the title compounds (1.76 mg, 4%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.94 (s, 1H), 8.76 (s, 1H), 8.68 (d, J=5.50 Hz, 1H), 8.45 (s, 1H), 7.85-7.99 (m, 3H), 7.70-7.81 (m, 2H), 7.49-7.60 (m, 2H), 4.62 (dd, J=2.38, 10.09 Hz, 1H), 4.00 (br d, J=9.17 Hz, 1H), 3.71-3.79 (m, 1H), 3.15 (br d, J=11.25 Hz, 1H), 2.67-2.72 (m, 1H), 2.23 (s, 3H), 2.10 (dt, J=3.30, 11.49 Hz, 1H), 1.95 (t, J=10.70 Hz, 1H), 1.43 (d, J=7.21 Hz, 6H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.3.
Step 8: 3-Cyano-2-isopropyl-N-(l-(2-(4-methylmorpholin-2-yl)pyridin-4-yl)-lH-indazol-6- yl)benzamide, enantiomer 2
Figure imgf000481_0001
To a solution of 2-(4-bromopyridin-2-yl)-4-methylmorpholine, enantiomer 2 (18 mg, 70.00 umol) in dioxane (1.5 mL) were added Cui (2.67 mg, 14.00 umol), K3PO4 (44.58 mg, 210.01 umol), (7J?,2J?)-/Vi,/V2-dimethylcyclohexane-l,2-diamine (4.98 mg, 35.00 umol), and 3-cyano-7V-(177-indazol-6-yl)-2-isopropylbenzamide (21.31 mg, 70.00 umol) at 20 °C. The mixture was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method JI to afford a residue (4.5 mg). Then the residue (4.5 mg) was further purified by HPLC using Method JJ to afford the title compound (1.62 mg, 4%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.94 (s, 1H), 8.76 (s, 1H), 8.68 (d, J=5.50 Hz, 1H), 8.45 (s, 1H), 7.88-7.98 (m, 3H), 7.71-7.81 (m, 2H), 7.50-7.58 (m, 2H), 4.62 (dd, J=2.38, 10.09 Hz, 1H), 4.00 (br d, J=9.54 Hz, 1H), 3.70-3.80 (m, 1H), 3.15 (br d, J=11.74 Hz, 1H), 2.66-2.72 (m, 1H), 2.23 (s, 3H), 2.10 (dt, J=2.93, 11.37 Hz, 1H), 1.95 (t, J=10.70 Hz, 1H), 1.43 (d, J=7.09 Hz, 6H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.3.
Example 269: 3-Cyano-2-isopropyl-/V-(l-(2-(4-methylmorpholin-3-yl)pyridin-4-yl)-l//- indazol-6-yl)benzamide, enantiomer 1 and 2
Figure imgf000482_0001
Step 1: tert-Butyl (2-(2-(4-bromopyridin-2-yl)-2-oxoethoxy)ethyl)carbamate
Figure imgf000482_0003
A solution of 2,4-dibromopyridine (2 g, 8.44 mmol) in toluene (60 mL) was degassed and purged with N2 (3x) at -70 °C and then «-BuLi (2.5 M, 3.38 mL) was added to the mixture and the mixture was stirred at -70 °C for 0.5 hr under an N2 atmosphere. Then tertbutyl 3-oxomorpholine-4-carboxylate (1.70 g, 8.44 mmol) in toluene (10 mL) was added to the mixture at -70 °C and stirring was continued for 1 hr. The mixture was then warmed to 20 °C and stirred for 2 hrs. The reaction mixture was diluted with saturated aqueous NH4CI and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-9% EtOAc/petroleum ether gradient eluent to afford the title compound (477 mg, 15%) as a yellow oil. JH NMR (400 MHz, CDCh) 8 8.49 (d, J=5.13 Hz, 1 H), 8.24 (d, J=1.71 Hz, 1 H), 7.71 (dd, J=5.26, 1.96 Hz, 1 H), 5.29 (br s, 1 H),
5.10 (s, 2 H), 3.72 (t, J=5.01 Hz, 2 H), 3.44 (br d, J=4.89 Hz, 2 H), 1.49 (s, 9 H). MS-ESI (m/z) calc’d for Ci4H2oBrN204 [M+H]+: 359.1, 361.1. Found 359.1, 361.1.
Step 2: 5-(4-Bromopyridin-2-yl)-3,6-dihydro-2H-l,4-oxazine
Figure imgf000482_0002
A solution of tert-butyl (2-(2-(4-bromopyridin-2-yl)-2-oxoethoxy)ethyl)carbamate (120 mg, 334.06 umol) in TFA (0.3 mL) and CH2CI2 (3 mL) was stirred at 20 °C for 0.5 hr. The mixture was concentrated to afford the title compound (80 mg, 95%) as a yellow oil. MS-ESI (m/z) calc’d for CoHioBrl [M+H]+: 241.0, 243.0. Found 241.1, 243.1.
Step 3: 3-(4-Bromopyridin-2-yl)morpholine
Figure imgf000483_0001
To a solution of 5-(4-bromopyridin-2-yl)-3,6-dihydro-27/-l,4-oxazine (80 mg, 331.83 umol) in MeOH (3 mL) was added NaBHsCN (83.41 mg, 1.33 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (80 mg, 95%) as a yellow solid. MS-ESI (m/z) calc’d for CsHnBrlSbO [M+H]+: 243.0, 245.0. Found 243.2, 245.2.
Step 4: 3-(4-Bromopyridin-2-yl)-4-methylmorpholine
Figure imgf000483_0002
To a solution of 3-(4-bromopyridin-2-yl)morpholine (80 mg, 329.08 umol), a 37 wt% solution of formaldehyde (587.60 mg, 7.24 mmol, 539.08 uL) and acetic acid (13.83 mg, 230.36 umol) in MeOH (3 mL) was added NaBHsCN (66.17 mg, 1.05 mmol) at 0 °C. The mixture was stirred at 20 °C for 5 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether/EtOAc = 0/1, Rf = 0.38) to afford the title compound (36 mg, 42%) as a white solid. MS-ESI (m/z) calc’d for CioHuBrlSbO [M+H]+: 257.0, 259.0. Found 257.2, 259.2. Step 5: 3-Cyano-2-isopropyl-N-(l-(2-(4-methylmorpholin-3-yl)pyridin-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000484_0001
A mixture of 3-cyano-A-(17/-indazol-6-yl)-2-isopropylbenzamide (40 mg, 131.43 umol), 3-(4-bromopyridin-2-yl)-4-methylmorpholine (26 mg, 101.12 umol), Cui (3.85 mg, 20.22 umol), (15,2<S)-/Vi,A2-dimethylcyclohexane-l,2-diamine (7.19 mg, 50.56 umol) and K3PO4 (64.39 mg, 303.35 umol) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method JE to afford the title compound (30 mg, 45%) as a white solid. MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.3.
Step 6: 3-Cyano-2-isopropyl-N-(l-(2-(4-methylmorpholin-3-yl)pyridin-4-yl)-lH-indazol-6- yl)benzamide, enantiomer 1 and 2
Figure imgf000484_0002
The enantiomers of 3-cyano-2-isopropyl-A-(l-(2-(4-methylmorpholin-3-yl)pyridin-4- yl)- 17/-indazol-6-y I (benzamide were separated by chiral HPLC using Method JK to afford 3- cyano-2-isopropyl-A-(l-(2-(4-methylmorpholin-3-yl)pyridin-4-yl)-17/-indazol-6- yl)benzamide, enantiomer 1 (3.05 mg, 41%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.90 (s, 1 H), 8.67 (d, J=5.62 Hz, 1 H), 8.34 (s, 1 H), 8.10 (d, J=2.08 Hz, 1 H), 7.84 - 7.91 (m, 3 H), 7.75 (dd, J=7.70, 1.22 Hz, 1 H), 7.52 (t, J=7.76 Hz, 1 H), 7.38 (dd, J=8.62, 1.53 Hz, 1 H), 3.89 - 3.96 (m, 2 H), 3.81 - 3.88 (m, 1 H), 3.62 (t, J=10.82 Hz, 1 H), 3.48 - 3.54 (m, 1 H), 3.42 - 3.47 (m, 1 H), 2.95 (br d, J=11.74 Hz, 1 H), 2.45 - 2.58 (m, 1 H), 2.24 (s, 3 H), 1.54 (d, J=7.09 Hz, 6 H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.1. A later eluting fraction was also isolated to afford 3-cyano-2-isopropyl-/V-(l-(2-(4-methylmorpholin- 3-yl)pyridin-4-yl)-17/-indazol-6-yl)benzamide, enantiomer 2 (3.31 mg, 45%) as a yellow solid. 'H NMR (400 MHz, MeOD) 6 8.90 (s, 1 H), 8.67 (d, J=5.62 Hz, 1 H), 8.34 (s, 1 H), 8.10 (d, J=1.96 Hz, 1 H), 7.84 - 7.90 (m, 3 H), 7.74 (d, J=7.46 Hz, 1 H), 7.49 - 7.55 (m, 1 H), 7.38 (d, J=8.68 Hz, 1 H), 3.88 - 3.96 (m, 2 H), 3.81 - 3.88 (m, 1 H), 3.61 (t, J=10.76 Hz, 1 H), 3.50 (dt, J=14.27, 7.11 Hz, 1 H), 3.43 (dd, J=10.27, 3.42 Hz, 1 H), 2.94 (br d, J=11.86 Hz, 1 H), 2.50 (td, J=11.71, 3.48 Hz, 1 H), 2.23 (s, 3 H), 1.54 (d, J=7.21 Hz, 6 H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 48E2. Found 48E1.
Example 270: Cyaiio-/V-(l-(6-(3-(2-hydroxypropaii-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)- l//-iiidazol-6-yl)-2-isopropylbenzaniide. enantiomer 1 and 2
Figure imgf000485_0001
Step 1 : 2-(Pyrrolidin-3-yl)propan-2-ol
Figure imgf000485_0002
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)pyrrolidine-l -carboxylate (400 mg, E74 mmol) in EtOAc (3 mL) was added a 4 M solution of HC1 in EtOAc (1.00 mL) at 20 °C and the mixture was stirred for 2 hrs. The reaction mixture was concentrated under vacuum to afford the title compound (220 mg, 95%) as a white solid. MS-ESI (m/z) calc’d for C HieNO [M+H]+: 130.1. Found: 130.2.
Step 2: 2-( 1 -( 6-Chloropyrimidin-4-yl)pyrrolidin-3-yl)propan-2-ol
Figure imgf000486_0001
To a solution of 4,6-dichloropyrimidine (230 mg, 1.54 mmol) in DMSO (4 mL) was added DIEA (498.83 mg, 3.86 mmol) and 2-(py rroli din-3 -yl)propan-2-ol (219.41 mg, 1.70 mmol) at 20 °C. The mixture was then stirred at 90 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The material was purified by silica gel chromatography using a 0-18% EtOAc/petroleum ether gradient eluent to afford the title compound (308 mg, 82%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 8.30 (s, 1 H), 6.57 (s, 1 H), 4.44 (s, 1 H), 3.62 - 3.86 (m, 1 H), 3.40 - 3.56 (m, 1 H), 3.15 - 3.34 (m, 2 H), 2.16 - 2.32 (m, 1 H), 1.76 - 1.98 (m, 2 H), 1.15 (br s, 6 H),MS- ESI (m/z) calc’d for C11H17CIN3O [M+H]+: 242.1. Found 242.2.
Step 3: 3-Cyano-N-(l-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-lH- indazol-6-yl)-2-isopropylbenzamide
Figure imgf000486_0002
A mixture of 2-(l-(6-chloropyrimidin-4-yl)pyrrolidin-3-yl)propan-2-ol (79.42 mg, 328.57 umol), 3-cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (100 mg, 328.57 umol), CS2CO3 (160.58 mg, 492.86 umol), and Josiphos SL-J009-1 Pd G3 (20 mg) and in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 80 °C for 12 hrs under an N2 atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue that was purified by HPLC using Method JL to afford the title compound (70 mg, 40%) as white solid. 'H NMR (400 MHz, DMSO- e) 6 10.88 (s, 1 H), 9.31 (s, 1 H), 8.49 (s, 1 H), 8.41 (s, 1 H), 7.94 (dd, J=7.70, 1.10 Hz, 1 H), 7.84 (d, J=8.68 Hz, 1 H), 7.78 (dd, J=7.70, 1.22 Hz, 1 H), 7.65 (br d, J=8.68 Hz, 1 H), 7.53 (t, J=7.70 Hz, 1 H), 6.85 (br s, 1 H), 4.42 (br s, 1 H), 3.53 - 3.91 (m, 1 H), 3.34 - 3.42 (m, 3 H), 3.30 (br s, 1 H), 2.19 - 2.39 (m, 1 H), 1.95 (br s, 2 H), 1.44 (d, J=7.09 Hz, 6 H), 1.15 (s, 6 H) MS-ESI (m/z) calc’d for C29H32N7O2 [M+H]+: 510.2. Found 510.3 Step 4: 3-Cyano-N-(l-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-lH- indazol-6-yl)-2-isopropylbenzamide, enantiomer 1 and 2
Figure imgf000487_0001
The enantiomers of 3-cyano-/V-(l -(6-(3-(2-hy droxypropan-2-yl)pyrroli din-1 - yl)pyrimidin-4-yl)-17/-indazol-6-yl)-2-isopropylbenzamide were separated by chiral HPLC using Method JM to afford 3-cyano-/V-(l-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-l- yl)pyrimidin-4-yl)-17/-indazol-6-yl)-2-isopropylbenzamide, enantiomer 1 (8.22 mg, 46%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.88 (s, 1 H), 9.31 (s, 1 H), 8.49 (d, J=0.63 Hz, 1 H), 8.41 (s, 1 H), 7.94 (dd, J=7.69, 1.31 Hz, 1 H), 7.84 (d, J=8.76 Hz, 1 H), 7.77 (dd, J=7.69, 1.31 Hz, 1 H), 7.65 (br d, J=8.63 Hz, 1 H), 7.53 (t, J=7.69 Hz, 1 H), 6.85 (br s, 1 H), 4.42 (br s, 1 H), 3.42 - 3.94 (m, 2 H), 3.35 - 3.39 (m, 2 H), 3.30 (br s, 1 H), 2.32 - 2.42 (m, 1 H), 1.95 (br s, 2 H), 1.44 (d, J=7.13 Hz, 6 H), 1.12 - 1.21 (m, 6 H) MS-ESI (m/z) calc’d for C29H32N7O2 [M+H]+: 510.2. Found 510.1. A later eluting fraction was also isolated to afford 3-cyano-/V-(l-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6-yl)- 2-isopropylbenzamide, enantiomer 2 (8.69 mg, 49%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.88 (s, 1 H), 9.31 (s, 1 H), 8.49 (d, J=0.75 Hz, 1 H), 8.41 (s, 1 H), 7.94 (dd, J=7.75, 1.25 Hz, 1 H), 7.84 (d, J=8.76 Hz, 1 H), 7.77 (dd, J=7.75, 1.38 Hz, 1 H), 7.62 - 7.70 (m, 1 H), 7.53 (t, J=7.69 Hz, 1 H), 6.85 (br s, 1 H), 4.42 (br s, 1 H), 3.42 - 3.95 (m, 2 H), 3.35 - 3.40 (m, 2 H), 3.27 - 3.31 (m, 1 H), 2.32 - 2.42 (m, 1 H), 1.95 (br s, 2 H), 1.44 (d, J=7.13 Hz, 6 H), 1.11 - 1.20 (m, 6 H). MS-ESI (m/z) calc’d for C29H32N7O2 [M+H]+: 510.2. Found 510.2.
Example 271: 3-Cyano-A-(l-(l-methyl-l/7-pyrazol-4-yl)-l/f-indazol-6-yl)-2-(l,l,l- trifluoropropan-2-yl)benzamide, enantiomer 1 and 2
Figure imgf000488_0001
Step 1: Methyl 3-cyano-2-(3,3,3-trifluoroprop-l-en-2-yl)benzoate
Figure imgf000488_0002
A mixture of methyl 3-cyano-2-iodobenzoate (4.44 g, 15.46 mmol), 4,4,6-trimethyl-2- (3,3,3-trifluoroprop-l-en-2-yl)-l,3,2-dioxaborinane (5.15 g, 23.20 mmol), Pd(Amphos)C12 (1.10 g, 1.55 mmol), and AcOK (4.55 g, 46.39 mmol) in EtOH (50 mL) and H2O (6.5 mL) was degassed and purged with N2 (3x) at 20 °C and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue that was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-4% EtOAc/petroleum ether gradient eluent to afford the title compound (1.29 g, 32%) as a yellow oil. JH NMR (400 MHz, CDCh) 8 8.16 (dd, J=8.00, 1.38 Hz, 1 H), 7.84 (dd, J=7.82, 1.31 Hz, 1 H), 7.56 (t, J=7.88 Hz, 1 H), 6.26 (d, J=0.75 Hz, 1 H), 5.69 (s, 1 H), 3.82 (s, 3 H).
Step 2: 3-Cyano-2-(3,3,3-trifluoroprop-l-en-2-yl)benzoic acid
Figure imgf000488_0003
To a solution of methyl 3-cyano-2-(3,3,3-trifluoroprop-l-en-2-yl)benzoate (500 mg, 1.96 mmol) in THF (10 mL) and H2O (10 mL) was added LiOHHLO (164.44 mg, 3.92 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hrs. THF was removed under vacuum, then the aqueous layer was extracted with EtOAc (3x). The organic layer was discarded. The aqueous layer was acidified with 1 M HC1 to pH = 1 and extracted with EtOAc (5x). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (430 mg, 90%) as a white solid. 1 H NMR (400 MHz, CDCh) 8 8.16 (dd, J=8.00, 1.38 Hz, 1 H), 7.84 (dd, J=7.82, 1.31 Hz, 1 H), 7.56 (t, J=7.88 Hz, 1 H), 6.26 (d, J=0.75 Hz, 1 H), 5.69 (s, 1 H), 3.82 (s, 3 H). 'H NMR (400 MHz, DMSO-d6) δ 13.68 (br s, 1 H), 8.27 (dd, J=7.95, 1.34 Hz, 1 H), 8.23 (dd, J=7.76, 1.28 Hz, 1 H), 7.82 (t, J=7.89 Hz, 1 H), 6.42 (s, 1 H), 6.03 (s, 1 H).
Step 3: 3-Cyano-N-( 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)-2-( 3, 3, 3-trifluoroprop-l- en-2-yl)benzamide
Figure imgf000489_0001
To a solution of 3-cyano-2-(3,3,3-trifluoroprop-l-en-2-yl)benzoic acid (88 mg, 364.89 umol) and 1-(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-amine (93.37 mg, 437.87 umol) in DCM (3 mL) was added a 50 wt % solution of T3P in EtOAc (464.41 mg, 729.79 umol). The mixture was stirred at 40 °C for 0.5 hr. Then EtsN (92.31 mg, 912.24 umol) was added to the mixture at 40 °C and the mixture was stirred at 40 °C for 2 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether / EtOAc = 0/1, Rf = 0.78) to give 50 mg of material of insufficient purity. The material was further purified by HPLC using Methods JQ and JR to afford the title compound (8.72 mg, 5%) as a colorless gum. 'H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.23 - 8.19 (m, 2H), 8.18 - 8.12 (m, 2H), 8.04 (dd, J=1.0, 7.8 Hz, 1H), 7.87 - 7.74 (m, 3H), 7.35 (dd, J=1.5, 8.7 Hz, 1H), 6.49 (s, 1H), 6.12 (s, 1H), 3.96 - 3.92 (m, 3H). MS-ESI (m/z) calc’d for C22H16F3N6O [M+H]+: 437.1. Found 436.9.
Step 4: 3-Cyano-N-( l-(l -methyl- !H-pyrazol-4-yl)-lH-indazol-6-yl)-2-( 1, 1, 1-trifluoropropan- 2-yl)benzamide
Figure imgf000490_0001
A mixture of 3-cyano-A-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-(3,3,3- trifluoroprop-l-en-2-yl)benzamide (100 mg, 229.15 umol) and Pd/C (300 mg, 10% purity) in EtOAc (4 mL) and MeOH (8 mL) was degassed and purged with H2 (3x) at 20 °C. The reaction mixture was then stirred at 40 °C for 1 hr under an H2 atmosphere (50 psi). The reaction mixture was combined with an additional, identical reaction mixture and the combined mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method JN to afford the title compound (10 mg, 5%) as a white solid. MS-ESI (m/z) calc’d for C22H18F3N6O [M+H]+: 439.1 Found 439.0.
Step 5: 3-Cyano-N-( 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indazol-6-yl)-2-( 1, 1, 1-trifluoropropan-
2-yl)benzamide, enantiomer 1 and 2
Figure imgf000490_0002
The enantiomers of 3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- (l,l,l-trifluoropropan-2-yl)benzamide were separated by chiral HPLC using Method JO. The first eluting fraction was further purified by HPLC using Method JP to afford 3-cyano-A- (1 -( 1 -methyl- 1 Ef-py razol-4-y 1)- 1 J/-indazol-6-y l)-2-( 1,1,1 -trifluoropropan-2-y l)benzamide, enantiomer 1 (3.31 mg, 36%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.24 (s, 1 H), 8.07 (d, J=1.00 Hz, 1 H), 8.02 (s, 1 H), 7.88 (dd, J=7.75, 1.13 Hz, 1 H), 7.76 - 7.81 (m, 2 H), 7.71 (d, J=8.76 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.19 (dd, J=8.69, 1.56 Hz, 1 H), 4.29 - 4.42 (m, 1 H), 3.93 (s, 3 H), 1.75 (br d, J=6.38 Hz, 3 H). MS-ESI (m/z) calc’d for C22H18F3N6O [M+H]+: 439.1 Found 439.0. A second eluting fraction from the chiral separation was also isolated to afford 3-cyano-N-(l -(I -methyl- l//-pyrazol-4-yl)- l//-indazol-6-yl)-2-(l . 1. 1- trifluoropropan-2-yl)benzamide, enantiomer 2 (4.47 mg, 49%) as a white solid. 'H NMR (400 MHz, MeOD) 6 8.35 (s, 1 H), 8.18 (d, J=0.88 Hz, 1 H), 8.12 (s, 1 H), 7.99 (dd, J=7.75, 1.25 Hz, 1 H), 7.87 - 7.92 (m, 2 H), 7.82 (d, J=8.63 Hz, 1 H), 7.70 (t, J=7.75 Hz, 1 H), 7.30 (dd, J=8.63, 1.63 Hz, 1 H), 4.40 - 4.52 (m, 1 H), 4.03 (s, 3 H), 1.86 (br d, J=6.13 Hz, 3 H). MS- ESI (m/z) calc’d for C22H18F3N6O [M+H]+: 439.1. Found 439.0.
Example 272: 5-((l-(6-((A)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)- lH-indazol-6-yI)amino)-5,6,7,8-tetrahydronaphthalene-l-carbonitriIe, enantiomer 1 and 2
Figure imgf000491_0001
To a solution of I -(tetrahydro-27/-pyran-2-yl)-l7/-indazol-6-arnine (1 g, 4.60 mmol ) in pyridine (30 mL) was added 2-nitrobenzenesulfonyl chloride (2.04 g, 9.20 mmol ) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was then concentrated under reduced pressure to remove solvent. The residue was purified by silica gel column chromatography using a 0-35% EtOAc/petroleum ether gradient eluent to afford the title compound (1.16 g, 66%) as a pale yellow solid. MS-ESI (m/z) calc’d for C18H19N4SO5 [M+H]+: 403.1. Found 403.2
Step 2: N-(5-Cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-2-nitro-N-(l-(tetrahydro-2H-pyran-
Figure imgf000491_0002
A mixture of 2-nitro-AA I -(tetrahydro-27/-pyran-2-yl)- IT/-indazol-6- yl)benzenesulfonamide (1.00 g, 2.48 mmol), 5-hydroxy-5,6,7,8-tetrahydronaphthalene-l- carbonitrile (430.42 mg, 2.48 mmol), and (tributylphosphoranylidene)acetonitrile (1.20 g, 4.97 mmol) in toluene (20 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 100 °C for 2 hrs under an N2 atmosphere. The mixture was concentrated under vacuum and the residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-35% EtOAc/petroleum ether gradient eluent to afford the title compound (600 mg, 43%) as a pale yellow gum. MS-ESI (m/z) calc’d for C29H28N5SO5. [M+H]+: 558.2. Found 558.3
Step 3: N-(5-Cyano-l, 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( lH-indazol-6-yl)-2- nitrobenzenesulfonamide
Figure imgf000492_0001
To a mixture of A-(5-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-2-nitro-/V-(l- (tetrahydro-2H-pyran-2-yl)-17/-indazol-6-yl)benzenesulfonamide (620 mg, 1.11 mmol) in MeOH (4 mL) and H2O (9 mL) was added PTS A (1.91 g, 11.12 mmol) at 20 °C. The mixture was then stirred at 70 °C for 18 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH and extracted with EtOAc (5x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-51% EtOAc/petroleum ether gradient eluent to afford the title compound (250.21 mg, 47%) as a yellow solid. MS-ESI (m/z) calc’d for C24H20N5SO4. [M+H]+: 474.1. Found 474.1.
Step 4: N-(5-Cyano-l, 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( 1 -(6-( (S)-3-(2-hydroxypropan-2-
Figure imgf000492_0002
A mixture of A-(5-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-(17/-indazol-6-yl)-2- nitrobenzenesulfonamide (140 mg, 295.67 umol), (<S)-2-(l-(6-chloropyrimidin-4- yl)pyrrolidin-3-yl)propan-2-ol (71.47 mg, 295.67 umol), CS2CO3 (144.50 mg, 443.50 umol) and Josiphos SL-J009-1 Pd G3 (30 mg) in dioxane (3 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was stirred at 100 °C for 5 hrs under an N2 atmosphere after which the temperature was raised to 120 °C and stirring was continued for an additional 13 hrs. The mixture was concentrated under vacuum and the residue was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-46% EtOAc/petroleum ether gradient eluent to afford the title compound (90 mg, 44%) as a yellow solid. MS-ESI (m/z) calc’d for C35H35N8O5S. [M+H]+: 679.2. Found: 679.3.
Step 5: 5-( (l-( 6-( (S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-lH-indazol-6- yl)amino)-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile
Figure imgf000493_0001
To a solution of /V-(5-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-(l-(6-((S)-3-(2- hy droxy propan-2 -y l)py rrolidin- 1 -y l)py rimidin-4-y 1)- 17/-i ndazol -6-y I )-2- nitrobenzenesulfonamide (80.00 mg, 117.86 umol) in DMF (2 mL) were added thiophenol (170 mg, 1.54 mmol) and K2CO3 (81.45 mg, 589.31 umol ) at 20 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether/EtOAc = 2/1, Rf = 0.28, 0.35) to afford the title compound (28.08 mg, 48%) as a yellow solid. MS-ESI (m/z) calc’d for C29H32N7O. [M+H]+: 494.3. Found 494.4.
Step 6: 5-( (l-( 6-( (S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-lH-indazol-6- yl)amino)-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile, enantiomer 1 and 2
Figure imgf000494_0001
5-((l-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-l-carbonitrile was subjected to chiral separation using Method HF to afford 5-((l-(6-((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin- 4-yl)- l7/-indazol-6-yl)amino)-5.6.7.8-tetrahydronaphthalene- 1 -carbonitrile. enantiomer 1 (4.5 mg, 49%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.40 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 6.76-6.80 (m, 2H), 6.67 (d, J=8.2 Hz, 1H), 4.74 (br s, 1H), 4.41 (s, 1H), 3.48-3.88 (m, 2H), 2.84-3.06 (m, 3H), 1.76-2.06 (m, 8H), 1.14-1.17 ppm (m, 6H). MS-ESI (m/z) calc’d for C29H32N7O [M+H]+: 494.3. Found 494.3. A later eluting fraction was also isolated to afford 5-((l-(6-((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)amino)-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile, enantiomer 2 (4.48 mg, 49%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 8.40 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 6.76-6.80 (m, 2H), 6.67 (d, J=8.3 Hz, 1H), 4.74 (br s, 1H), 4.41 (br s, 1H), 3.47-3.94 (m, 2H), 2.86-3.04 (m, 3H), 1.78-2.04 (m, 8H), 1.14-1.17 ppm (m, 6H). MS-ESI (m/z) calc’d for C29H32N7O [M+H]+: 494.3. Found 494.3.
Example 273: 5-((l-(6-((7?)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)- l//-iiidazol-6-yl)ainiiio)-5.6.7.8-tetraliydroiiaplithalene-l-carbonitrile. enantiomer 1 and 2
Figure imgf000494_0002
Step 1 : N-(5-Cyano-l, 2, 3, 4-tetrahydronaphthalen-l-yl)-N-( l-(6-( ^R)-3-( 2-hydroxypropan-2-
Figure imgf000495_0001
A mixture of A-(5-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-A-(17/-indazol-6-yl)-2- nitrobenzenesulfonamide (100 mg, 211.19 umol), (R)-2-(l-(6-chloropyrimidin-4- yl)pyrrolidin-3-yl)propan-2-ol (51.05 mg, 211.19 umol), CS2CO3 (103.22 mg, 316.79 umol), and Josiphos SL-J009-1 Pd G3 (20 mg) in dioxane (2 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 13 hrs under an N2 atmosphere. The mixture was concentrated under vacuum, diluted with H2O, and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiCh, petroleum ether/EtOAc = 1/1, Rf = 0.55, 0.28) to afford the title compound (38 mg, 26%) as a yellow solid. MS-ESI (m/z) calc’d for C35H35N8O5S. [M+H]+: 679.2. Found: 679.3.
Step 2: 5-((l-(6-( ^R)-3-( 2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-lH-indazol-6-
Figure imgf000495_0002
To a solution of A-(5-cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-/V-(l-(6-((S)-3-(2- hy droxy propan-2 -y l)py rrolidin- 1 -y l)py rimidin-4-y 1)- 17/-i ndazol -6-y I )-2- nitrobenzenesulfonamide (17.00 mg, 25.05 umol) in DMF (1 mL) were added thiophenol (34 mg, 308.59 umol) and K2CO3 (17.31 mg, 125.23 umol) at 20 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether/EtOAc = 2/1, Rf = 0.28, 0.35) to afford the title compound (8.25 mg, 66%) as a pale yellow solid. MS-ESI (m/z) calc’d for C29H32N7O. [M+H]+: 494.3. Found 494.4.
Step 3: 5-((l-(6-( ^R)-3-( 2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-lH-indazol-6- yl)amino)-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile, enantiomer 1 and 2
Figure imgf000496_0001
5-((l-(6-((7?)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-l-carbonitrile was subjected to chiral separation using Method JS to afford 5-((l-(6-((7?)-3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin- 4-yl)- l7/-indazol-6-yl)amino)-5.6, 7, 8-tetrahydronaphthalene-l -carbonitrile, enantiomer 1 (3.85 mg, 42%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- e) 6 8.39 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 6.76-6.79 (m, 2H), 6.67 (d, J=8.5 Hz, 1H), 4.74 (br s, 1H), 4.29-4.56 (m, 1H), 3.55-3.94 (m, 2H), 2.88-3.03 (m, 3H), 1.84-2.01 (m, 8H), 1.14-1.16 (m, 6H). MS- ESI (m/z) calc’d for C29H32N7O [M+H]+: 494.3. Found: 494.3. A later eluting fraction was also isolated to afford 5-(( l-(6-((/?)-3-(2-hydroxypropan-2-yl)pyrrolidin- l-yl)pyrimidin-4-yl)- l7/-indazol-6-yl)amino)-5.6, 7, 8-tetrahydronaphthalene-l -carbonitrile, enantiomer 2 (4.13 mg, 45%) as a pale yellow solid. 'H NMR (400 MHz, DMSO- e) 6 8.40 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 6.76-6.80 (m, 2H), 6.66 (br d, J=8.5 Hz, 1H), 4.73 (br s, 1H), 4.42 (br s, 1H), 3.48-3.90 (m, 2H), 2.85-3.04 (m, 3H), 1.82-2.06 (m, 8H), 1.14-1.17 ppm (m, 6H). MS-ESI (m/z) calc’d for C29H32N7O [M+H]+: 494.3. Found 494.3.
Example 274: 3-Cyano-/V-(l-(l-(difluoromethyl)-l//-pyrazol-4-yl)-l//-indazol-6-yl)-6- fluoro-2-(prop-l-en-2-yI)benzamide
Figure imgf000497_0001
Step 1: l-( 1 -(Difluoromethyl)-lH-pyrazol-4-yl)-6-nitro-lH-indazole
Figure imgf000497_0002
To a solution of l-(difluoromethyl)-4-iodo-pyrazole (300 mg, 1.23 mmol) in dioxane (30 mL) was added 6-nitro-17/-indazole (240.71 mg, 1.48 mmol), Cui (46.84 mg, 245.92 umol), ,/V2-dimethylcyclohexane-l,2-diamine (87.45 mg, 614.80 umol), and K3PO4 (783.01 mg, 3.69 mmol) at 20 °C. The mixture was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-17% EtOAc/petroleum ether gradient eluent to afford the title compound (80 mg, 23%) as a yellow solid. MS-ESI (m/z) calc’d for C11H8F2N5O2 [M+H]+: 280.1. Found 280.2.
Step 2: 1-(1 -(Difluoromethyl) -lH-pyrazol-4-yl)-lH-indazol-6-amine
Figure imgf000497_0003
To a solution of 1-(1 -(difluoromethyl)- I //-pyrazol-4- l)-6-nitro- 1 //-indazole (80 mg, 286.53 umol) in EtOH (2 mL) and H2O (2 mL) were added Fe (80.01 mg, 1.43 mmol) and NH4CI (76.63 mg, 1.43 mmol) at 20 °C. The mixture was then stirred at 80 °C for 1 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (51.4 mg, 71%) as a brown solid. MS-ESI (m/z) calc’d for C11H10F2N5 [M+H]+: 250.1. Found 250.2.
Figure imgf000498_0001
To a solution of 2-bromo-3-cyano-6-fluorobenzoic acid (50 mg, 204.90 umol) in dioxane (2 mL) and H2O (0.5 mL) was added 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (34.43 mg, 204.90 umol), Pd(dppf)Ch (7.50 mg, 10.25 umol), and CS2CO3 (200.28 mg, 614.71 umol) at 20 °C. The mixture was stirred at 100 °C for 2 hrs under an N2 atmosphere. The residue was diluted with H2O and extracted with EtOAc (3x). The organic layers were discarded. The aqueous phase was acidified with 1 M HC1 to pH = 4 and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (26 mg, 61%) as a brown oil. MS-ESI (m/z) calc’d for C11H9FNO2 [M+H]+: 206.1. Found 206.2.
Step 4: 3-Cyano-N-( 1-(1 -(difluoromethyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)-6-fluoro-2- (prop-l-en-2-yl)benzamide
Figure imgf000498_0002
To a solution of 3-cyano-6-fluoro-2-(prop-l-en-2-yl)benzoic acid (14.82 mg, 72.23 umol) in DMF (1 mL) were added DIEA (23.34 mg, 180.57 umol) and HATU (27.46 mg, 72.23 umol) at 20 °C. The mixture was stirred at 20 °C for 0.5 hr. Then 1-(1- (difluoromethyl)-17/-pyrazol-4-yl)-17/-indazol-6-amine (15 mg, 60.19 umol) was added and the mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method JT to afford the title compound (12.42 mg, 45%) as ayellow solid. 'H NMR (400 MHz, DMSO- e) 6 10.98 (s, 1H), 8.80 (s, 1H), 8.32 (d, J=0.86 Hz, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.79-8.13 (m, 3H), 7.59 (t, J=8.74 Hz, 1H), 7.38 (dd, J=1.59, 8.68 Hz, 1H), 5.40 (t, J=1.41 Hz, 1H), 5.09 (s, 1H), 2.09 (s, 3H). MS-ESI (m/z) calc’d for C22H16F3N6O2 [M+H]+: 437.1 Found 437.0.
Example 275: 3-Cyano-A-(l-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l/f-indazol-6-yl)-6- fluoro-2-isopropylbenzamide
Figure imgf000499_0001
To a solution of 3-cyano-/V-(l-(l-(difluoromethyl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)-6-fluoro-2-(prop-l-en-2-yl)benzamide (50 mg, 114.58 umol) in EtOAc (3 mL) was added Pd(OH)2 (50.00 mg, 71.21 umol) at 20 °C. The mixture was stirred at 50 °C for 4 hrs under an H2 atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method JU to afford the title compound (19.62 mg, 39%) as ayellow solid. JH NMR (400 MHz, DMSO- e) 6 11.11 (s, 1H), 8.78-8.83 (m, 1H), 8.32 (d, J=1.0 Hz, 1H), 8.28 (s, 2H), 8.03-8.09 (m, 1H), 7.77-7.95 (m, 2H), 7.49 (t, J=8.6 Hz, 1H), 7.43 (dd, J=8.7, 1.6 Hz, 1H), 3.23-3.27 (m, 1H), 1.41 (d, J=7.1 Hz, 6H). MS-ESI (m/z) calc’d for C22H18F3N6O [M+H]+: 439.1. Found 439.1.
Example 276: 2-Cyaiio-/V-(l-(2-methoxy-6-methylpyridin-4-yl)-l//-indazol-6-yl)-3- (prop-l-en-2-yl)isonicotinamide (276A) and 2-Cyano-3-isopropyl-7V-(l-(2-methoxy-6- methylpyridin-4-yl)-lff-indazol-6-yl)isonicotinamide (276B)
Figure imgf000499_0002
Step 1 : l-(2-Methoxy-6-methylpyridin-4-yl)-6-nitro-lH-indazole
Figure imgf000500_0001
To a solution of 4-bromo-2-methoxy-6-methyl-pyridine (200 mg, 989.86 umol) and 6- nitro-17 -indazole (193.78 mg, 1.19 mmol) in dioxane (4 mL) were added Cui (37.70 mg, 197.97 umol), K3PO4 (630.34 mg, 2.97 mmol) and (/5'.25')- i. -di meth l c clohexane- 1.2- diamine (70.40 mg, 494.93 umol) at 20 °C. The mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 0-100% EtOAc/petroleum ether gradient eluent to afford the title compound (50 mg, 17%) as a pale yellow solid. JH NMR (400 MHz, CDCh) 8 8.73 - 8.85 (m, 1 H), 8.36 (d, J=0.86 Hz, 1 H), 8.16 (dd, J=8.86, 1.90 Hz, 1 H), 7.95 (d, J=8.80 Hz, 1 H), 7.22 (d, J=1.22 Hz, 1 H), 6.96 (d, J=1.22 Hz, 1 H), 4.04 (s, 3 H), 2.60 (s, 3 H). MS-ESI (m/z) calc’d for C14H13N4O3 [M+H]+: 285.1. Found 285.0.
Step 2: l-(2-Methoxy-6-methylpyridin-4-yl)-lH-indazol-6-amine
Figure imgf000500_0002
To a solution of 1 -(2-methoxy-6-methylpyridin-4-yl)-6-nitro- 1 //-indazole (50 mg, 175.89 umol) in EtOH (1 mL) and H2O (1 mL) was added Fe (49.11 mg, 879.45 umol) and NH4CI (47.04 mg, 879.45 umol) at 20 °C. The mixture was then stirred at 80 °C for 2 hrs and concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (35 mg, 79%) as a yellow solid. MS-ESI (m/z) calc’d for C14H15N4O [M+H]+: 255.1. Found 255.3. Step 3: 2-Cyano-N-( 1 -(2-methoxy-6-methylpyridin-4-yl)-lH-indazol-6-yl)-3-(prop-l-en-2- yl)isonicotinamide (276A)
Figure imgf000501_0001
To a solution of l-(2-methoxy-6-methylpyridin-4-yl)-17/-indazol-6-amine (8 mg, 31.46 umol) in DMF (1 mL) were added HATU (17.94 mg, 47.19 umol), DIEA (12.20 mg, 94.38 umol, 16.44 uL), and 2-cyano-3-(prop-l-en-2-yl)isonicotinic acid (5.92 mg, 31.46 umol) and the mixture was stirred at 20 °C for 12 hrs. The mixture was diluted with H2O and extracted with EtOAc(3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by HPLC using Method JV to afford the title compound (1.78 mg, 9%) as a white solid. JH NMR (400 MHz, MeOD) 6 8.78 (d, J=4.77 Hz, 1 H), 8.62 (s, 1 H), 8.28 (s, 1 H), 7.86 (d, J=8.56 Hz, 1 H), 7.83 (d, J=4.89 Hz, 1 H), 7.37 (dd, J=8.68, 1.34 Hz, 1 H), 7.33 (s, 1 H), 7.03 (s, 1 H), 5.52 (s, 1 H), 5.23 (s, 1 H), 3.99 (s, 3 H), 2.54 (s, 3 H), 2.22 (s, 3 H) MS-ESI (m/z) calc’d for C24H21N6O2 [M+H]+: 425.2. Found 425.1.
Step 4: 2-Cyano-3-isopropyl-N-(l-(2-methoxy-6-methylpyridin-4-yl)-lH-indazol-6- yl)isonicotinamide (276B)
Figure imgf000501_0002
A mixture of 2-cyano-/V-(l-(2-methoxy-6-methylpyridin-4-yl)-17/-indazol-6-yl)-3- (prop-l-en-2-yl)isonicotinamide (13 mg, 30.63 umol), Pd/C (10 mg, 11.78 umol) in EtOAc (1 mL) was degassed and purged with H2 (3x) and then the mixture was stirred at 20 °C for 12 hrs under an H2 atmosphere (15 psi). The reaction mixture was concentrated under reduced pressure to remove solvent and the residue was purified by HPLC using Method JW to afford the title compound (1.52 mg, 8%) as a colorless oil. 'H NMR (400 MHz, MeOD) 6 8.82 (s, 1 H), 8.68 (d, J=4.75 Hz, 1 H), 8.34 (d, J=0.75 Hz, 1 H), 7.89 (d, J=8.50 Hz, 1 H), 7.71 (d, J=4.75 Hz, 1 H), 7.49 (s, 1 H), 7.40 (dd, J=8.63, 1.75 Hz, 1 H), 7.22 (s, 1 H), 4.08 (s, 3 H), 3.47 - 3.51 (m, 1 H), 2.59 (s, 3 H), 1.53 (d, J=7.13 Hz, 6 H) MS-ESI (m/z) calc’d for C24H23N6O2 [M+H]+: 427.2. Found 425.1.
Example 277 : 2-Cyano-3-(prop-l -eii-2-yl)-/V-(l-(pyrimidin-4-yl)-l //-indazol-6- yl)isonicotinamide (277A) and 2-Cyano-3-isopropyl-N-( l-(pyrimidin-4-yl)-l//-indazol-6- yl)isonicotinamide (277B)
Figure imgf000502_0001
Step 1: 6-Nitro-l-(pyrimidin-4-yl)-lH-indazole
Figure imgf000502_0002
To a solution of 6-nitro-17/-indazole (297.36 mg, 1.82 mmol) in NMP (8 mL) was added NaH (164.78 mg, 4.12 mmol) at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. 4- Chloropyrimidine (300 mg, 1.99 mmol, HC1 salt) was then added at 0 °C; the mixture was then stirred at 80 °C for 12 hrs. The mixture was filtered and the filtrate was washed with H2O. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0- 100% EtOAc/petroleum ether gradient eluent to afford the title compound (130 mg, 29%) as a yellow solid. 'H NMR (400 MHz, DMSO- e) 6 9.58 - 9.64 (m, 1 H), 9.28 (d, J=1.00 Hz, 1 H), 8.94 (d, J=5.75 Hz, 1 H), 8.82 (d, J=0.88 Hz, 1 H), 8.19 - 8.25 (m, 2 H), 8.07 (dd, J=5.75, 1.25 Hz, 1 H), MS-ESI (m/z) calc’d for CnHsNsCE [M+H]+: 242.0. Found 242.2.
Step 2: l-(Pyrimidin-4-yl)-lH-indazol-6-amine
Figure imgf000503_0001
To a solution of 6-nitro-l-(pyrimidin-4-yl)-17/-indazole (100 mg, 414.58 umol) in EtOH (2 mL) and H2O (2 mL) were added Fe (115.77 mg, 2.07 mmol) and NH4CI (110.88 mg, 2.07 mmol) at 20 °C. The mixture was then stirred at 80 °C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under vacuum to remove the EtOH. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (80 mg, 91%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 9.06 (s, 1 H), 8.75 (d, J=5.75 Hz, 1 H), 8.14 - 8.28 (m, 1 H), 7.82 - 7.99 (m, 2 H), 7.50 (d, J=8.50 Hz, 1 H), 6.68 (dd, J=8.50, 1.63 Hz, 1 H), 5.83 (s, 2 H). MS-ESI (m/z) calc’d for C11H10N5 [M+H]+: 212.0. Found 212.3.
Step 3: Methyl 2-cyano-3-(prop-l-en-2-yl)isonicotinate
Figure imgf000503_0002
A mixture of methyl 3-chloro-2-cyano-pyridine-4-carboxylate (50 mg, 254.34 umol), 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (64.11 mg, 381.50 umol), Pd(dppf)C12 (18.61 mg, 25.43 umol) and CS2CO3 (248.60 mg, 763.01 umol) in dioxane (3 mL) and H2O (0.3 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 95 °C for 2 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether/EtOAc = 3/1, Rf = 0.49) to afford the title compound (32 mg, 62%) as a white oil. MS-ESI (m/z) calc’d for C11H11N2O2 [M+H]+: 203.0. Found 203.2.
Step 4: 2-Cyano-3-(prop-l-en-2-yl)isonicotinic acid
Figure imgf000504_0001
To a solution of methyl 2-cyano-3-(prop-l-en-2-yl)isonicotinate (32 mg, 158.25 umol) in THF (1 mL) and H2O (1 mL) was added LiOHHEO (26.56 mg, 633.01 umol) at 20°C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was diluted with 1 M
HC1 to adjust pH=4, and then diluted with H2O and extracted with EtOAc (3x).The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (25 mg, 86%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=4.88 Hz, 1 H), 7.96 (d, J=4.88 Hz, 1 H), 5.38 - 5.46 (m, 1 H), 5.06 (s, 1 H), 2.10 (s, 3 H). MS-ESI (m/z) calc’d for C10H9N2O2 [M+H]+: 189.0. Found 189.2.
Step 5: 2-Cyano-3-(prop-l-en-2-yl)-N-( 1 -(pyrimidin-4-yl)-lH-indazol-6-yl)isonicotinamide (277 A)
Figure imgf000504_0002
To a solution of l-(pyrimidin-4-yl)-17/-indazol-6-amine(10 mg, 47.34 umol) and 2- cyano-3-(prop-l-en-2-yl)isonicotinic acid (8.91 mg, 47.34 umol) in DMF (1 mL) were added HATU (27.00 mg, 71.02 umol) and DIEA (18.36 mg, 142.03 umol) at 20 °C. The mixture was stirred at 20 °C for 5 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method JX to afford the title compound (3.64 mg, 15%) as white solid. JH NMR (400 MHz, DMSO- d6) 8 11.02 (br s, 1 H), 9.25 (s, 1 H), 9.14 (br s, 1 H), 8.86 (br d, J=4.40 Hz, 2 H), 8.55 (s, 1 H), 7.95 - 8.06 (m, 2 H), 7.91 (br d, J=8.56 Hz, 1 H), 7.66 (br d, J=8.80 Hz, 1 H), 5.49 (br s, 1 H), 5.19 (br s, 1 H), 2.13 (s, 3 H).MS-ESI (m/z) calc’d for C21H16N7O [M+H]+: 382.1. Found 382.0.
Step 6: 2-Cyano-3-isopropyl-N-(l-(pyrimidin-4-yl)-lH-indazol-6-yl)isonicotinamide (277B)
Figure imgf000505_0001
A mixture of 2-cyano-3-isopropenyl-A-(l-pyrimidin-4-ylindazol-6-yl)pyridine-4- carboxamide (55.00 mg, 144.21 umol), 10% Pd/C (100 mg) in EtOAc (1 mL) was degassed and purged with H2 (3x), and then the mixture was stirred at 20 °C for 15 min under an H2 atmosphere (15 psi). The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method JY to afford the title compound (2.69 mg, 9%) as a white solid. 1 H NMR (400 MHz, MeOD) 6 9.41 (s, 1 H), 9.11 (s, 1 H), 8.77 (d, J=5.99 Hz, 1 H), 8.69 (d, J=4.77 Hz, 1 H), 8.39 (s, 1 H), 8.13 (d, J=5.99 Hz, 1 H), 7.88 (d, J=8.68 Hz, 1 H), 7.72 (d, J=4.77 Hz, 1 H), 7.66 (dd, J=8.62, 1.77 Hz, 1 H), 3.46 - 3.53 (m, 1 H), 1.54 (d, J=7.21 Hz, 6 H).MS-ESI (m/z) calc’d for C21H18N7O [M+H]+: 384.1 Found 384.1.
Example 278: 3-Cyano-2-isopropyl-A-(l-(2-(pyridin-4-yI)cyclopropyl)-LH-indazol-6- yl)benzamide, enantiomer 1 and 2
Figure imgf000505_0002
Step 1 : (E)-4-( 2-( 4, 4, 5, 5-Tetramethyl-l, 3, 2-dioxaborolan-2-yl)vinyl)pyridine
Figure imgf000505_0003
A mixture of 4-bromopyridine (3 g, 18.99 mmol), 4, 4,5, 5-tetramethyl-2 -vinyl-1, 3,2- dioxaborolane (3.51 g, 22.79 mmol, 3.86 mL), tri-/c/7-butylphosphanium tetrafluoroborate (550.89 mg, 1.90 mmol), Pd2(dba)3 (869.37 mg, 949.39 umol) and DIEA (4.91 g, 37.98 mmol, 6.61 mL) in toluene (15 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 85 °C for 15 hrs under an N2 atmosphere. The mixture was concentrated to give a residue that was purified by silica gel column chromatography using a 0-26% EtOAc/petroleum ether gradient eluent to afford the title compound (3.1 g, 70%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 8.61 (br d, J=5.01 Hz, 2 H), 7.34 (d, J=6.36 Hz, 2 H), 7.28 (d, J=7.21 Hz, 1 H), 6.39 (d, J=18.34 Hz, 1 H), 1.33 (s, 12 H). MS-ESI (m/z) calc’d for C13H19BNO2 [M+H]+: 232.1. Found 232.3.
Step 2: ((lS,2S)-2-(pyridin-4-yl)cyclopropyl)boronic acid
Figure imgf000506_0001
A solution of diethylzinc (1 M, 86.54 mL) was added to DCM (20 mL) under an N2 atmosphere. The solution was cooled to 0 °C and a solution of TFA (9.87 g, 86.54 mmol, 6.41 mL) in DCM (5 mL) was added and the mixture was stirred for 30 min. A solution of diiodomethane (23.18 g, 86.54 mmol) in DCM (5 mL) was then added and stirring was continued for an additional 30 min. Then a solution of (A’)-4-(2-(4.4.5.5-tetramethyl- 1.3.2- dioxaborolan-2-yl)vinyl)pyridine (1 g, 4.33 mmol) in DCM (5 mL) was added and the mixture was stirred at 20 °C for 12 hrs. The reaction mixture was quenched by addition of saturated aqueous NaHCOs at 0 °C to pH = 7, and then diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-26% MeOH/Dichloromethane gradient eluent to afford the title compound (330 mg, 46%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 8.40 (d, J=6.00 Hz, 2 H), 6.99 (d, J=5.88 Hz, 2 H), 1.91 (br s, 1 H), 1.71 (br s, 2 H), 1.21 - 1.31 (m, 3 H), 1.03 - 1.11 (m, 1 H), 0.24 - 0.33 (m, 1 H). MS-ESI (m/z) calc’d for CsHnBNCL [M+H]+: 164.1. Found 164.2.
Step 3: 3-Cyano-2-isopropyl-N-[l-[2-(4-pyridyl)cyclopropyl ]indazol-6-yl]benzamide
Figure imgf000506_0002
A mixture of ((15,2S)-2-(pyridin-4-yl)cyclopropyl)boronic acid (50.00 mg, 306.78 umol), 3-cyano-N-(IT/-indazol-6-yl)-2-isopropylbenzamide (74.69 mg, 245.43 umol), CU(OAC)2 (55.72 mg, 306.78 umol), Na2COs (65.03 mg, 613.57 umol) and 2-(2- pyridyl)pyridine (47.91 mg, 306.78 umol) in DCE (1 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 70 °C for 15 hrs under an N2 atmosphere. The reaction mixture was combined with an additional, identical reaction mixture and the combined mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method A to afford the title compound (9 mg, 4%) as a brown solid. MS-ESI (m/z) calc’d for C26H24N5O [M+H]+: 422.1. Found 422.1.
Step 4: 3-Cyano-2-isopropyl-N-(l-(2-(pyridin-4-yl)cyclopropyl)-lH-indazol-6-yl)benzamide, enantiomer 1 and 2
Figure imgf000507_0001
The enantiomers of 3-cyano-2-isopropyl-/V-[l-[2-(4-pyridyl)cyclopropyl]indazol-6- yl]benzamide were separated by chiral HPLC using Method KA to afford 3-cyano-2- isopropyl-N-(l -(2-(pyridin-4-yl)cyclopropyl)- l7/-indazol-6-y I (benzamide. enantiomer 1 (3.69 mg, 40%) as a white solid. 'H NMR (400 MHz, DMSO- e) 6 10.79 (s, 1 H), 8.49 (d, J=6.00 Hz, 2 H), 8.29 (s, 1 H), 8.02 (s, 1 H), 7.93 (d, J=7.75 Hz, 1 H), 7.73 (d, J=8.25 Hz, 2 H), 7.52 (t, J=7.75 Hz, 1 H), 7.37 (d, J=6.00 Hz, 2 H), 7.32 (dd, J=8.69, 1.44 Hz, 1 H), 4.09 (dt, J=7.25, 3.88 Hz, 1 H), 3.37 - 3.40 (m, 1 H), 2.62 - 2.68 (m, 1 H), 1.96 - 2.02 (m, 1 H), 1.79 - 1.86 (m, 1 H), 1.43 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C26H24N5O [M+H]+: 422.1 Found 422.2. A later eluting fraction was also isolated to afford 3-cyano-2-isopropyl- N-(l-(2-(pyridin-4-yl)cyclopropyl)-17/-indazol-6-yl)benzamide, enantiomer 2 (4.29 mg, 47%) as a pink solid. 'H NMR (400 MHz, DMSO- e) 6 10.80 (s, 1 H), 8.47 - 8.51 (m, 2 H), 8.29 (s, 1 H), 8.02 (s, 1 H), 7.93 (dd, J=7.76, 1.16 Hz, 1 H), 7.73 (d, J=8.31 Hz, 2 H), 7.52 (t, J=7.70 Hz, 1 H), 7.35 - 7.39 (m, 2 H), 7.31 (dd, J=8.68, 1.59 Hz, 1 H), 4.06 - 4.11 (m, 1 H), 3.33 - 3.34 (m, 1 H), 2.61 - 2.68 (m, 1 H), 1.95 - 2.02 (m, 1 H), 1.79 - 1.86 (m, 1 H), 1.42 (d, J=6.97 Hz, 6 H). MS-ESI (m/z) calc’d for C26H24N5O [M+H]+: 422.E Found 422. E
Example 279: (E)-3-Cyano-A-(l-(2-(2,6-dimethylpyridin-4-yl)vinyl)-l/f-indazol-6-yl)-2- isopropylbenzamide (279A) and (Z)-3-Cyano-A-(l-(2-(2,6-dimethylpyridin-4-yl)vinyl)- 1 //-ind azol-6-yl)-2-is op ropylbenzamide (279B)
Figure imgf000508_0001
To a solution of 4-bromo-2,6-dimethyl-pyridine (500 mg, 2.69 mmol) in toluene (15 mL) were added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (496.69 mg, 3.22 mmol), Pd2(dba)s (123.05 mg, 134.37 umol) and DIEA (694.67 mg, 5.37 mmol) at 20 °C. The mixture was then stirred at 85 °C for 3 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and the residue was purified by silica gel chromatography using a 0-42% EtOAc/petroleum ether gradient eluent to afford the title compound (110 mg, 15%) as a pale yellow solid. JH NMR (DMSO- e) 6 7.06 - 7.24 (m, 3 H), 6.36 (d, J=18.51 Hz, 1 H), 2.41 (s, 6 H), 1.24 (s, 12 H) MS-ESI (m/z) calc’d for C15H23BNO2 [M+H]+:260.2. Found 178.3.
Figure imgf000508_0002
To a solution of (E)-2,6-dimethyl-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)vinyl)pyridine (110 mg, 424.46 umol) in H2O (0.5 mL) and acetone (5 mL) were added NH4OAC (114.52 mg, 1.49 mmol) and NalCti (363.16 mg, 1.70 mmol) at 20 °C and the mixture was stirred for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford the title compound (58.8 mg, 78%) as a white solid. MS-ESI (m/z) calc’d for C9Hi3BNO2 [M+H]+: 178.1. Found 178.3.
Step 3: (E)-3-Cyano-N-(l-(2-(2,6-dimethylpyridin-4-yl)vinyl)-lH-indazol-6-yl)-2- isopropylbenzamide (279A)
Figure imgf000509_0001
To a solution of (E')-(2-(2,6-dimethylpyridin-4-yl)vinyl)boronic acid (60 mg, 284.73 umol) in DCE (3 mL) were added Cu(OAc)2 (51.72 mg, 284.73 umol), Na2COs (60.36 mg, 569.47 umol) 2-(2-pyridyl)pyridine (44.47 mg, 284.73 umol) and 3-cyano-/V-(17/-indazol-6- yl)-2-isopropylbenzamide (86.66 mg, 284.73 umol) at 20 °C. The mixture was then stirred at 70 °C for 3 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method KD to afford the title compounds (15.38 mg, 11%) as a white solid. JH NMR (400 MHz, MeOD) 6 8.78 (s, 1H), 8.71 (d, J=13.63 Hz, 1H), 8.33 (s, 1H), 7.80-7.87 (m, 4H), 7.73 (dd, J=1.38, 7.75 Hz, 1H), 7.51 (t, J=7.75 Hz, 1H), 7.22-7.28 (m, 2H), 3.50 (td, J=7.13, 14.26 Hz, 1H), 2.70 (s, 6H), 1.54 (d, J=7.13 Hz, 6H). MS-ESI (m/z) calc’d for C27H26N5O [M+H]+:436.2. Found 436.2.
Step 4: (Z)-3-Cyano-N-(l-(2-(2, 6-dimethylpyridin-4-yl)vinyl)-lH-indazol-6-yl)-2- isopropylbenzamide (279B)
Figure imgf000509_0002
To a solution of (E)-2-(2,6-dimethyl-4-pyridyl)vinyl boronic acid (22 mg, 124.29 umol), 3-cyano-/V-(17/-indazol-6-yl)-2-isopropyl-benzamide (31.52 mg, 103.58 umol) in DCE (3 mL) were added Na2COs (21.96 mg, 207.15 umol), 2-(2-pyridyl)pyridine (16.18 mg, 103.58 umol) Cu(OAc)2 (18.81 mg, 103.58 umol) at 20 °C. The mixture was then stirred at 70 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method KE and Method KF to afford the title compound (0.66 mg, 1%) as a colorless gum. JH NMR (400 MHz, MeOD) 6 8.16 (s, 1 H), 8.03 (s, 1 H), 7.82 (dd, J=7.69, 1.31 Hz, 1 H), 7.77 (d, J=8.63 Hz, 1 H), 7.64 (dd, J=7.69, 1.31 Hz, 1 H), 7.45 - 7.50 (m, 1 H), 7.40 (d, J=9.38 Hz, 1 H), 7.21 (dd, J=8.63, 1.63 Hz, 1 H), 6.88 (s, 2 H), 6.43 (d, J=9.38 Hz, 1 H), 3.31-3.40 (m, lH)2.36(s, 6 H), 1.49 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C27H26N5O [M+H]+ : 435.2. Found 435.2
Example 280: 5-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-lff-indazol-6-yl)oxy)-
5,6,7,8-tetrahydronaphthalene-l-carbonitriIe, enantiomer 1 and 2
Figure imgf000510_0001
Step 1 : 5-Methyl-6-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-indazole
Figure imgf000510_0002
A mixture of 6-bromo-5-methyl-17/-indazole (2 g, 9.48 mmol), bis(pinacolato)diboron (2.89 g, 11.37 mmol), AcOK (2.79 g, 28.43 mmol), and Pd(dppl)C12 (693.37 mg, 947.61 umol) in dioxane (40 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 120 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-6% EtOAc/petroleum ether gradient eluent to afford the title compound (1.4 g, 57%) as a yellow oil. 'H NMR (400 MHz, CDCh) 67.99 (s, 1 H), 7.52 (br s, 1 H), 7.41 (s, 1 H), 7.23 (d, J=l.13 Hz, 1 H), 2.63 (s, 3 H), 1.38 (s, 12 H). MS-ESI (m/z) calc’d for C14H20BN2O2 [M+H]+: 259.1. Found 259.3. Step 2: 5 -Methyl- lH-indazol-6-ol
Figure imgf000511_0001
To a solution of 5-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17/- indazole (1.4 g, 5.42 mmol) in THF (10 mL) and H2O (10 mL) was added sodium perborate tetrahydrate (2.50 g, 16.27 mmol) at 20 °C. The mixture was then stirred at 50 °C for 45 min. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-50% EtOAc/petroleum ether gradient eluent to afford the title compound (265 mg, 32%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 7.92 (s, 1 H), 7.48 (s, 1 H), 6.86 (s, 1 H), 2.36 (s, 3 H). MS-ESI (m/z) calc’d for C8H9N2O [M+H]+: 149.0. Found 149.2.
Step 3: 5-((5-Methyl-lH-indazol-6-yl)oxy)-5,6, 7,8-tetrahydronaphthalene-2-carbonitrile
Figure imgf000511_0002
A mixture of 5 -methyl- l//-indazol-6-ol (200 mg, 1.35 mmol), 5-hydroxy-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile (233.81 mg, 1.35 mmol), and (tributylphosphoranylidene)acetonitrile (651.59 mg, 2.70 mmol) in toluene (3 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue that was purified by silica gel column chromatography using a 0-26% EtOAc/petroleum ether gradient eluent to afford the title compound (400 mg, 97%) as a brown solid. 'H NMR (400 MHz, CDCh) 8 7.91 - 7.96 (m, 1 H), 7.52 (s, 1 H), 7.47 - 7.50 (m, 3 H), 7.02 (s, 1 H), 5.44 (t, J=5.38 Hz, 1 H), 2.92 - 3.01 (m, 1 H), 2.80 - 2.89 (m, 1 H), 2.25 (s, 3 H), 2.15 - 2.21 (m, 2 H), 2.00 - 2.04 (m, 1 H), 1.85 - 1.94 (m, 1 H). MS-ESI (m/z) calc’d for C19H18N3O [M+H]+: 304.1. Found 304.3.
Step 4: 5-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-lH-indazol-6-yl)oxy)-5, 6, 7,8- tetrahydronaphthalene-2-carbonitrile
Figure imgf000512_0001
A mixture of 5-((5-methyl-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile (400 mg, 1.32 mmol), 4-bromo-2-methoxy-6-methylpyridine (266.42 mg, 1.32 mmol), Cui (50.22 mg, 263.72 umol), K3PO4 (839.67 mg, 3.96 mmol) and A6.A6- dimethylcyclohexane-l,2-diamine (93.78 mg, 659.29 umol) in dioxane (5 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 105 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue that was purified by HPLC using Method KG to afford the title compound (50 mg, 7%) as a yellow solid. JH NMR (400 MHz, CDCh) 6 8.12 (s, 1 H), 7.58 (d, J=0.75 Hz, 1 H), 7.52 (s, 1 H), 7.48 (s, 2 H), 7.35 (s, 1 H), 7.31 (s, 1 H), 7.05 (s, 1 H), 5.46 - 5.52 (m, 1 H), 4.08 (s, 3 H), 2.94 - 3.03 (m, 1 H), 2.82 - 2.91 (m, 1 H), 2.66 (s, 3 H), 2.27 (s, 3 H), 2.17 - 2.25 (m, 2 H), 2.04 - 2.13 (m, 1 H), 1.92 (br d, J=9.51 Hz, 1 H). MS-ESI (m/z) calc’d for C26H25N4O2 [M+H]+: 425.2. Found 425.3.
Step 5: 5-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-lH-indazol-6-yl)oxy)-5, 6, 7,8-
Figure imgf000512_0002
The enantiomers of 5-(( l-(2-methoxy-6-methylpyridin-4-yl)-5-methyl- l//-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile were separated by chiral HPLC using Method KH. The first eluting compound was further purified by HPLC using Method KI to afford 5-((l-(2-methoxy-6-methylpyridin-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 1 (2.62 mg, 19%) as a pale yellow solid. 'H NMR (400 MHz, MeOD) 6 8.12 (s, 1 H), 7.60 (d, J=6.24 Hz, 2 H), 7.52 (d, J=0.86 Hz, 2 H), 7.47 (s, 1 H), 7.29 (s, 1 H), 6.96 (s, 1 H), 5.70 (t, J=5.01 Hz, 1 H), 3.98 (s, 3 H), 2.93 - 3.04 (m, 1 H), 2.81 - 2.91 (m, 1 H), 2.52 (s, 3 H), 2.23 (s, 3 H), 2.13 - 2.22 (m, 2 H), 2.02 - 2.10 (m, 1 H), 1.87 - 1.96 (m, 1 H). MS-ESI (m/z) calc’d for C26H25N4O2 [M+H]+: 425.2. Found 425.1. A second eluting fraction from the chiral separation was also isolated to afford 5-((l- (2-methoxy-6-methylpyridin-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, enantiomer 2 (4.18 mg, 39%) as a yellow solid. JH NMR (400 MHz, DMSO- e) 6 8.26 (s, 1 H), 7.71 (s, 1 H), 7.63 - 7.67 (m, 2 H), 7.60 (s, 1 H), 7.55 (d, J=8.00 Hz, 1 H), 7.35 (d, J=1.25 Hz, 1 H), 7.02 (d, J=l.13 Hz, 1 H), 5.89 (t, J=4.94 Hz, 1 H), 3.90 (s, 3 H), 2.89 - 2.97 (m, 1 H), 2.76 - 2.86 (m, 1 H), 2.48 - 2.49 (m, 3 H), 2.17 (s, 3 H), 2.05 - 2.11 (m, 2 H), 1.81 - 1.93 (m, 2 H). MS-ESI (m/z) calc’d for C26H25N4O2 [M+H]+: 425.2. Found 425.1.
Example 281: l-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-lff-indazol-6-yl)oxy)-
2,3-dihydro-LH-indene-5-carbonitriIe, enantiomer 1 and 2
Figure imgf000513_0001
To a solution of 6-bromo-5-methyl-17/-indazole (2.8 g, 13.27 mmol) in dioxane (60 mL) was added Pd(dppf)Ch (970.71 mg, 1.33 mmol), AcOK (3.91 g, 39.80 mmol), and bis(pinacolato)diboron (4.04 g, 15.92 mmol) at 20 °C. The mixture was then stirred at 120 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (4x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-12% EtOAc/petroleum ether gradient eluent to afford the title compound (1.62 g, 47%) as a yellow oil. MS-ESI (m/z) calc’d for C14H20BN2O2 [M+H]+: 259.2. Found 259.3.
Step 2: 5 -Methyl- lH-indazol-6-ol
Figure imgf000513_0002
To a solution of 5-methyl-6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)- 1H- indazole (2.6 g, 6.31 mmol) in THF (20 mL) and H2O (20 mL) was added sodium perborate tetrahydrate (2.91 g, 18.92 mmol) at 20 °C. The mixture was then stirred at 50 °C for 50 min. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-50% EtOAc/petroleum ether gradient eluent to afford the title compound (409.2 mg, 43%) as a pale yellow solid. MS-ESI (m/z) calc’d for C8H9N2O [M+H]+:149.1. Found 149.3. Step 3: 1-((5-Methyl-1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile To a solution of 1-hyd -carbonitrile (75 mg,471.15
Figure imgf000514_0001
umol) in toluene (3 mL) were added (tributylphosphoranylidene)acetonitrile (227.43 mg, 942.30 umol) and 5-methyl-1H-indazol-6-ol (62.83 mg, 424.04 umol) at 20 °C. The mixture was then stirred at 110 °C for 2 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by preparative TLC (SiO2, petroleum ether / EtOAc= 1/2, Rf = 0.4) to afford the title compound (20 mg, 14%) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.62 (s, 1H), 7.54- 7.58 (m, 2H), 7.51 (s, 1H), 7.03 (s, 1H), 5.82 (t, J=6.17 Hz, 1H), 3.17-3.24 (m, 1H), 2.99-3.06 (m, 1H), 2.73-2.81 (m, 1H), 2.26-2.31 (m, 1H), 2.24 (s, 3H). MS-ESI (m/z) calc’d for C18H16N3O [M+H]+: 290.1. Found 290.3. Step 4: 1-((1-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-1H-indazol-6-yl)oxy)-2,3-dihydro- 1H-indene-5-carbonitrile To a solution of 1-
Figure imgf000514_0002
-dihydro-1H-indene-5- carbonitrile (20 mg, 69.13 umol) in dioxane (1.5 mL) were added CuI (2.63 mg,13.83 umol), K3PO4 (44.02 mg), N1,N2-dimethylcyclohexane-1,2-diamine (4.92 mg), and 4-bromo-2- methoxy-6-methylpyridine (13.97 mg, 69.13 umol) at 20 °C. The mixture was then stirred at 105 °C for 12 hrs under an N2 atmosphere. The reaction was combined with an additional 18 mg scale reaction before work up. The final mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method KJ to afford the title compounds (14.29 mg, 26%) as a light brown solid.1H NMR (400 MHz, MeOD) δ 8.13 (s, 1H), 7.72 (s, 1H), 7.58-7.64 (m, 3H), 7.48 (s, 1H), 7.30 (d, J=1.25 Hz, 1H), 6.98 (d, J=1.25 Hz, 1H), 6.04-6.09 (m, 1H), 3.98 (s, 3H), 3.17-3.26 (m, 1H), 3.03-3.13 (m, 1H), 2.73-2.83 (m, 1H), 2.53 (s, 3H), 2.27-2.35 (m, 1H), 2.24 (s, 3H) MS-ESI (m/z) calc’d for C25H23N4O2 [M+H]+: 411.2. Found 411.1. Step 5: 1-((1-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-1H-indazol-6-yl)oxy)-2,3-dihydro- 1H-indene-5-carbonitrile, enantiomer 1 and 2
Figure imgf000515_0001
,3-dihydro- 1H-indene-5-carbonitrile was subjected to chiral separation using Method KK to afford 1-((1- (2-methoxy-6-methylpyridin-4-yl)-5-methyl-1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5- carbonitrile, enantiomer 1 (3.65 mg, 40%) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.55 (s, 1H), 7.42-7.52 (m, 3H), 7.15-7.22 (m, 2H), 6.81 (s, 1H), 5.79 (t, J=6.07 Hz, 1H), 3.92 (s, 3H), 3.10-3.20 (m, 1H), 2.93-3.03 (m, 1H), 2.62-2.74 (m, 1H), 2.47 (s, 3H), 2.16-2.29 (m, 4H). MS-ESI (m/z) calc’d for C25H23N4O2 [M+H]+: 411.2. Found 411.2. A later eluting fraction was also isolated to afford 1-((1-(2-methoxy-6-methylpyridin-4-yl)-5-methyl- 1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 2 (4.21 mg, 46%) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.55 (s, 1H), 7.43-7.51 (m, 3H), 7.10-7.23 (m, 2H), 6.81 (s, 1H), 5.79 (t, J=6.07 Hz, 1H), 3.92 (s, 3H), 3.09-3.20 (m, 1H), 2.92-3.04 (m, 1H), 2.62-2.73 (m, 1H), 2.47 (s, 3H), 2.15-2.26 (m, 4H). MS-ESI (m/z) calc’d for C25H23N4O2 [M+H]+: 411.2. Found 411.2. Example 282: 3-Cyano-2-isopropyl-N-(1-(2-(2-methoxyethoxy)-6-methylpyridin-4-yl)- 1H-indazol-6-yl)benzamide
Figure imgf000516_0001
Step 1: 4-Bromo-2-(2-methoxyethoxy)-6-methylpyridine
Figure imgf000516_0002
DIAD (806.59 mg, 3.99 mmol) was added to a solution of 4-bromo-6-methylpyridin- 2-ol (500 mg, 2.66 mmol), 2-methoxyethanol (254.97 mg, 3.35 mmol), and PPhs (1.05 g, 3.99 mmol) in THF (5 mL). The solution was degassed and purged with N2 (3x) at 20 °C and then the mixture was stirred for 12 hrs under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (430 mg, 64%) as a yellow oil. JH NMR (400 MHz, CDCh) 8 6.90 (s, 1 H), 6.81 (s, 1 H), 4.43 - 4.49 (m, 2 H), 3.70 - 3.75 (m, 2 H), 3.44 (s, 3 H), 2.41 (s, 3 H). MS-ESI (m/z) calc’d for CsHuBrNCh [M+H]+: 246.0. Found 246.2.
Step 2: 3-Cyano-2-isopropyl-N-(l-(2-(2-methoxyethoxy)-6-methylpyridin-4-yl)-lH-indazol-6- yl)benzamide
Figure imgf000516_0003
A mixture of 4-bromo-2-(2-methoxyethoxy)-6-methylpyridine (50 mg, 203.17 umol), 3-cyano-/V-(17/-indazol-6-yl)-2-isopropylbenzamide (61.83 mg, 203.17 umol), Cui (7.74 mg, 40.63 umol), K3PO4 (129.38 mg, 609.51 umol) and Ai,A2-dimethylcyctohexane-l,2-diamine (14.45 mg, 101.58 umol) in dioxane (2 mL) was degassed and purged with N2 (3x) at 20 °C and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method KL to afford the title compound (24.31 mg, 24%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1 H), 8.54 (s, 1 H), 8.42 (s, 1 H), 7.95 (d, J=6.75 Hz, 1 H), 7.89 (d, J=8.63 Hz, 1 H), 7.79 (d, J=7.75 Hz, 1 H), 7.66 - 7.71 (m, 1 H), 7.55 (t, J=7.75 Hz, 1 H), 7.34 (s, 1 H), 6.96 (s, 1 H), 4.41 - 4.48 (m, 2 H), 3.65 - 3.71 (m, 2 H), 3.30 (s, 3 H), 3.28 (br s, 1 H), 2.48 (s, 3 H), 1.43 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C27H28N5O3 [M+H]+: 470.2. Found 470.1. Example 283: (E)-2-Cyano-3-isopropyl-N-(1-(2-(oxazol-4-yl)vinyl)-1H-indazol-6- yl)isonicotinamide
Figure imgf000517_0001
Step 1: (E)-4-(2-(4,4,5,5-Yetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)oxazole To a solution of 2,2,6,6-tetram
Figure imgf000517_0002
e (843.42 mg, 5.97 mmol) in THF(10 mL) at -30 °C was added n-BuLi (2.5 M, 2.39 mL) under an N2 atmosphere, and the mixture was stirred for 0.5 hr. The mixture was then cooled to -78 °C and a solution of bis(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methane (1.6 g, 5.97 mmol) in THF (4 mL) was added and stirring was continued for 0.5 hr. A solution of oxazole-4-carbaldehyde (193.20 mg, 1.99 mmol) in THF(4 mL) was then added at -78 °C. The mixture was allowed to warm to 20 °C and stirred for 12 hrs. The reaction mixture was quenched by addition saturated aqueous NH4Cl (20 ml) at 0 °C to pH = 7, the mixture was stirred at 20 °C for 1 hr. and then diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (430 mg, 95%) as a yellow oil. MS-ESI (m/z) calc’d for C11H17BNO3 [M+H]+: 222.1. Found 222.3. Step 2: (E)-(2-(Oxazol-4-yl)vinyl)boronic acid To a solution of (E)-4-(2-(4,4,5,5-tetra
Figure imgf000518_0001
dioxaborolan-2-yl)vinyl)oxazole (1 g, 4.52 mmol) in acetone (20 mL) and H2O (1 mL) were added NH4OAc (1 M, 20.36 mL) and NaIO4 (2.90 g, 13.57 mmol) at 0 °C. The mixture was then stirred at 40 °C for 5 hrs. The reaction was filtered and the filtrate was concentrated under vacuum. The material was purified by silica gel chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (100 mg, 15%) as a yellow oil. MS-ESI (m/z) calc’d for C5H7BNO3 [M+H]+: 140.0. Found 140.3. Step 3: (E)-2-Cyano-3-isopropyl-N-(1-(2-(oxazol-4-yl)vinyl)-1H-indazol-6-yl)isonicotinamide A mixture of (E)-(2
Figure imgf000518_0002
.95 mg, 294.76 umol), 2- cyano-N-(1H-indazol-6-yl)-3-isopropylisonicotinamide (30 mg, 98.25 umol), Cu(OAc)2 (17.85 mg, 98.25 umol), 2-(2-pyridyl)pyridine (15.35 mg, 98.25 umol) and Na2CO3 (20.83 mg, 196.51 umol) in DCE (1 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 70 °C for 12 hrs under an N2 atmosphere and concentrated to give a residue. The residue was purified by HPLC using Method B to afford the title compound (6.33 mg, 12%) as pink solid.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1 H), 8.77 (d, J=4.75 Hz, 1 H), 8.48 (s, 1 H), 8.42 - 8.44 (m, 1 H), 8.33 (s, 1 H), 8.23 (s, 1 H), 8.02 (d, J=13.88 Hz, 1 H), 7.80 - 7.88 (m, 2 H), 7.31 (dd, J=8.69, 1.56 Hz, 1 H), 7.04 (d, J=13.76 Hz, 1 H), 1.45 (d, J=7.13 Hz, 6 H). MS-ESI (m/z) calc’d for C22H19N6O2.[M+H]+: 399.1. Found 399.1. Example 284: (E)-2-Cyano-3-isopropyl-N-(1-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-1H- indazol-6-yl)isonicotinamide
Figure imgf000519_0001
A mixture of 4-iodo-l -methyl- 17/-pyrazole (1 g, 4.81 mmol), 4,4,5,5-tetramethyl-2- vinyl-l,3,2-dioxaborolane (888.54 mg, 5.77 mmol), Pd2(dba)s (220.12 mg, 240.38 umol ), DIPEA (1.24 g, 9.62 mmol), and tri-/c/7-buty 1 phosphonium tetrafluoroborate (139.49 mg, 480.77 umol) in toluene (15 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 90 °C for 12 hrs under an N2 atmosphere and concentrated under reduced pressure to remove solvent. The residue was purified by silica gel column chromatography using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (640 mg, 56%) as a red oil. 'H NMR (400 MHz, CDCh) 8 7.58 - 7.48 (m, 1 H), 7.35 (s, 1 H), 7.21 - 7.16 (m, 1 H), 5.73 (d, J=18.5 Hz, 1 H), 3.81 (s, 3 H), 1.22 (s, 12 H). MS-ESI (m/z) calc’d for C12H20BN2O2 [M+H]+: 235.2. Found 235.1.
Figure imgf000519_0002
To a solution of (E)-l-methyl-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)vinyl)-17/-pyrazole (200 mg, 854.33 umol) in acetone (4 mL) and H2O (0.25 mL) was added NH4OAC (1 M, 3.84 mL) and NaICU (548.20 mg, 2.56 mmol) at 0 °C. The mixture was then stirred at 20 °C for 12 hrs. The mixture was filtered and the filtrate was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with Na2SC>4, filtered, and the filtrate was concentrated under vacuum to afford the title compound (120 mg, 93%) as a yellow solid.1H NMR (400MHz, DMSO-d6) δ 7.76 (s, 1 H), 7.58 - 7.54 (m, 1 H), 6.54 (br s, 2 H), 5.44 (dd, J=1.6, 17.6 Hz, 1 H), 4.98 (dd, J=1.6, 11.0 Hz, 1 H), 3.79 (s, 3 H). MS-ESI (m/z) calc’d for C6H10BN2O2 [M+H]+: 153.1. Found 153.1. Step 3: (E)-2-Cyano-3-isopropyl-N-(1-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-1H-indazol-6- yl)isonicotinamide A mixture of (E)-(2
Figure imgf000520_0001
ronic acid (100 mg, 658.07 umol), 2-cyano-N-(1H-indazol-6-yl)-3-isopropylisonicotinamide (100.47 mg, 329.04 umol), Cu(OAc)2 (119.53 mg, 658.07 umol), Na2CO3 (139.50 mg, 1.32 mmol) and 2-(2- pyridyl)pyridine (102.78 mg, 658.07 umol) in DCE (4 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 70 °C for 12 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method KM to afford the title compound (8.19 mg, 3%) as a pale yellow solid.1H NMR (400MHz, DMSO-d6) δ 11.03 (s, 1 H), 8.79 (d, J=4.6 Hz, 1 H), 8.50 (s, 1 H), 8.27 (s, 1 H), 8.00 (s, 1 H), 7.96 (d, J=14.1 Hz, 1 H), 7.87 (d, J=4.8 Hz, 1 H), 7.84 - 7.80 (m, 2 H), 7.27 (d, J=10.0 Hz, 1 H), 7.01 (d, J=14.2 Hz, 1 H), 3.86 (s, 3 H), 1.48 (d, J=7.1 Hz, 6 H). MS-ESI (m/z) calc’d for C23H22N7O [M+H]+: 412.2. Found 412.1. Example 285: 5-((1-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)- 1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, enantiomer 1 and 2 Step 1: 5-((1-
Figure imgf000520_0002
( etra y ro- -pyran- -y )- -in azo-6-y )oxy)-5,6,7,8- tetrahydronaphthalene-1-carbonitrile To a solution of 1-(
Figure imgf000521_0001
tetra ydro-2H-pyran-2-y )-1H-ndazol-6-ol (100 mg, 458.19 umol) in toluene (4 mL) was added (tributylphosphoranylidene)acetonitrile (221.17 mg, 916.38 umol) and 5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (79.36 mg, 458.19 umol) at 20 °C. The mixture was stirred at 100 °C for 2 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by silica gel chromatography using a 0-20% EtOAc/petroleum ether gradient eluent to afford the title compound (110 mg, 64%) as a white oil. MS-ESI (m/z) calc’d for C23H23N3O2 [M+H]+: 374.2. Found: 374.3. Step 2: 5-((1H-Indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile To a solution of 5-(( dazol-6-yl)oxy)-5,6,7,8-
Figure imgf000521_0002
tetrahydronaphthalene-1-carbonitrile (110 mg, 294.55 umol) in MeOH (2 mL) and H2O (2 mL) was added PTSA (253.61 mg, 1.47 mmol) at 20 °C. The mixture was then stirred at 70 °C for 12 hrs and concentrated under reduced pressure to remove solvent. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether/EtOAc = 1/1, Rf=0.5) to afford the title compound (35 mg, 41%) as a white solid. MS-ESI (m/z) calc’d for C18H16N3O [M+H]+: 290.1. Found 290.2. Step 3: 5-((1-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile To a solution of
Figure imgf000522_0001
5-((1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1- carbonitrile (22 mg, 76.04 umol) in dioxane (2 mL) was added (S)-2-(1-(6-chloropyrimidin- 4-yl)pyrrolidin-3-yl)propan-2-ol (18.38 mg, 76.04 umol), Cs2CO3 (37.16 mg, 114.06 umol), and Josiphos SL-J009-1 Pd G3 (0.4 mg) at 20 °C. The mixture was stirred at 100 °C for 5 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by preparative TLC, (SiO2, petroleum ether/EtOAc = 1/1, Rf = 0.3) to afford the title compound (16.9 mg, 45%) as a white solid. MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found: 495.4. Step 4: 5-((1-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, enantiomer 1 and 2 T yl)pyrimidin- 4-yl)-1H
Figure imgf000522_0002
-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile were separated by chiral HPLC using Method KK to afford 5-((1-(6-((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, enantiomer 1 (4.35 mg, 46 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.45 (d, J=1.75 Hz, 1H), 8.37 (s, 1H), 7.80 (d, J=8.76 Hz, 2H), 7.73 (d, J=7.75 Hz, 1H), 7.42 (t, J=7.75 Hz, 1H), 7.11 (dd, J=2.19, 8.82 Hz, 1H), 6.83 (s, 1H), 5.67 (t, J=4.25 Hz, 1H), 4.43 (br s, 1H), 3.41-3.91 (m, 4H), 3.00-3.09 (m, 1H), 2.84-2.94 (m, 1H), 2.32 (d, J=1.75 Hz, 1H), 1.85-2.18 (m, 6H), 1.12-1.20 (m, 6H). MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.2. A later eluting fraction was also isolated to afford 5-((1-(6-((S)-3-(2- hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-1-carbonitrile, enantiomer 2 (4.45 mg, 48%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.46 (d, J=1.75 Hz, 1H), 8.37 (s, 1H), 7.81 (d, J=8.63 Hz, 2H), 7.73 (d, J=7.63 Hz, 1H), 7.42 (t, J=7.69 Hz, 1H), 7.12 (dd, J=2.13, 8.76 Hz, 1H), 6.84 (s, 1H), 5.68 (t, J=4.25 Hz, 1H), 4.44 (br s, 1H), 3.38-3.96 (m, 4H), 3.01-3.10 (m, 1H), 2.84-2.95 (m, 1H), 2.22-2.34 (m, 1H), 1.78-2.20 (m, 6H), 1.12-1.21 (m, 6H). MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.1. Example 286: 5-((1-(6-((R)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)- 1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, enantiomer 1 and 2 Step 1: 5-((1-
Figure imgf000523_0001
(6-(( )-3-( - y roxypropan- -y )pyrro i in- -y )pyrimi in-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile To a solution of 5-((1H
Figure imgf000523_0002
-n azo-6-y )oxy)-5,6,7,8-tetrahydronaphthalene-1- carbonitrile (22 mg, 76.04 umol) in dioxane (1 mL) were added (R)-2-(1-(6-chloropyrimidin- 4-yl)pyrrolidin-3-yl)propan-2-ol (18.38 mg, 76.04 umol), Cs2CO3 (37.16 mg, 114.06 umol) and Josiphos SL-J009-1 Pd G3 (0.4 mg) at 20 °C. The mixture was then stirred at 100 °C for 5 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by preparative TLC (SiO2, petroleum ether/EtOAc = 1/1, Rf = 0.35) to afford the title compound (17.6 mg, 46%) as a white solid. MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.4. Step 2: 5-((1-(6-((R)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, enantiomer 1 and 2 The e 1-yl)pyrimidin-
Figure imgf000524_0001
4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile were separated by chiral HPLC using Method KO to afford 5-((1-(6-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, enantiomer 1 (4.4 mg, 47%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.45 (d, J=1.63 Hz, 1H), 8.36 (s, 1H), 7.80 (d, J=8.50 Hz, 2H), 7.72 (d, J=7.75 Hz, 1H), 7.42 (t, J=7.75 Hz, 1H), 7.11 (dd, J=2.13, 8.76 Hz, 1H), 6.83 (s, 1H), 5.67 (t, J=4.25 Hz, 1H), 4.42 (br s, 1H), 3.39-3.91 (m, 4H), 2.99-3.10 (m, 1H), 2.84-2.95 (m, 1H), 2.21-2.36 (m, 1H), 1.84- 2.19 (m, 6H), 1.11-1.20 (m, 6H). MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.2. A later eluting fraction was also isolated to afford 5-((1-(6-((R)-3-(2-hydroxypropan- 2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1- carbonitrile, enantiomer 2 (4.51 mg, 49%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.45 (d, J=1.75 Hz, 1H), 8.37 (s, 1H), 7.80 (d, J=8.63 Hz, 2H), 7.72 (d, J=7.50 Hz, 1H), 7.42 (t, J=7.75 Hz, 1H), 7.11 (dd, J=2.19, 8.82 Hz, 1H), 6.83 (s, 1H), 5.67 (t, J=4.13 Hz, 1H), 4.43 (br s, 1H), 3.47-4.07 (m, 4H), 3.05 (td, J=4.96, 17.60 Hz, 1H), 2.85-2.93 (m, 1H), 2.21-2.33 (m, 1H), 1.87-2.16 (m, 6H), 1.12-1.20 (m, 6H). MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.2. Example 287: 5-((1-(2-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-1H-indazol- 6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, isomers 1, 2, 3, and 4
Figure imgf000525_0001
Step 1: 5-(4-Iodopyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane To a solution of 2-fluoro-4-iodopyridin
Figure imgf000525_0002
.03 mmol), 2-oxa-5- azabicyclo[2.2.1]heptane (202.79 mg, 1.50 mmol) in DMSO (2 mL) was added K2CO3 (427.67 mg, 3.09 mmol) at 20 °C. The mixture was then stirred at 70 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (4x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (280 mg, 89%) as a white solid. MS-ESI (m/z) calc’d for C10H12IN2O [M+H]+: 303.0. Found 303.1. Step 2: 5-((1-(2-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-1H-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile To a solution of 5-(4-iodopy
Figure imgf000525_0003
.2.1]heptane (30 mg, 99.30 umol) and 5-((1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (28.73 mg, 99.30 umol) in dioxane (1 mL) were added CuI (3.78 mg, 19.86 umol), K3PO4 (63.23 mg, 297.90 umol), and N1,N2-dimethylcyclohexane-1,2-diamine (7.06 mg, 49.65 umol) at 20 °C. The mixture was then stirred at 110 °C for 2 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and the residue was purified by HPLC using Method KP to afford the title compound (25 mg, 54%) as a white solid. MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2. Found 464.3. Step 3: 5-((1-(2-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-1H-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-1-carbonitrile, isomers 1, 2, 3, and 4 5-((1-(2-(2-Oxa-5-azabicy
Figure imgf000526_0001
clo[2.2.1]heptan 5 yl)pyridin 4 yl) 1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile was subjected to chiral separation using Method KQ to afford 5-((1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-1H-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-1-carbonitrile, isomer 1 (2.69 mg, 22%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.19 (d, J=5.63 Hz, 1H), 7.81 (d, J=8.75 Hz, 1H), 7.64-7.71 (m, 2H), 7.54-7.60 (m, 2H), 7.02-7.10 (m, 2H), 6.83 (br s, 1H), 5.79 (br t, J=4.82 Hz, 1H), 4.92 (br s, 1H), 4.67 (s, 1H), 3.66-3.79 (m, 2H), 3.51 (br d, J=9.51 Hz, 1H), 3.29 (br s, 1H), 2.65-2.97 (m, 2H), 2.07 (br d, J=5.00 Hz, 2H), 1.78-1.95 (m, 4H). MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2. Found 464.2. A second eluting fraction was also isolated to afford 5-((1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, isomer 2 (2.95 mg, 24%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.19 (d, J=5.63 Hz, 1H), 7.81 (d, J=8.76 Hz, 1H), 7.70 (s, 1H), 7.62-7.67 (m, 1H), 7.51-7.58 (m, 2H), 6.99-7.10 (m, 2H), 6.83 (s, 1H), 5.78 (t, J=4.88 Hz, 1H), 4.92 (br s, 1H), 4.67 (s, 1H), 3.68-3.82 (m, 2H), 3.52 (d, J=9.01 Hz, 1H), 3.29 (br d, J=9.88 Hz, 1H), 2.73-2.96 (m, 2H), 2.03-2.11 (m, 2H), 1.79-1.96 (m, 4H). MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2. Found 464.2. A third eluting fraction was also isolated to afford 5-((1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-1H- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, isomer 3 (2.49 mg, 20%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.19 (d, J=5.63 Hz, 1H), 7.81 (d, J=8.88 Hz, 1H), 7.70 (s, 1H), 7.65 (dd, J=1.50, 8.00 Hz, 1H), 7.52-7.57 (m, 2H), 7.00-7.10 (m, 2H), 6.83 (s, 1H), 5.78 (t, J=4.88 Hz, 1H), 4.92 (br s, 1H), 4.67 (s, 1H), 3.69-3.81 (m, 2H), 3.52 (d, J=8.88 Hz, 1H), 3.29 (br d, J=10.13 Hz, 1H), 2.85-2.96 (m, 1H), 2.81 (br t, J=7.19 Hz, 1H), 2.01-2.11 (m, 2H), 1.75-1.95 (m, 4H). MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2. Found 464.2. The last eluting fraction was also isolated to afford 5-((1-(2-(2- oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-1-carbonitrile, isomer 4 (3.24 mg, 27%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.19 (d, J=5.62 Hz, 1H), 7.81 (d, J=8.80 Hz, 1H), 7.61- 7.72 (m, 2H), 7.51-7.60 (m, 2H), 7.01-7.11 (m, 2H), 6.83 (s, 1H), 5.79 (t, J=4.95 Hz, 1H), 4.92 (s, 1H), 4.67 (s, 1H), 3.68-3.79 (m, 2H), 3.51 (d, J=8.80 Hz, 1H), 3.31 (br s, 1H), 2.76- 2.95 (m, 2H), 2.03-2.12 (m, 2H), 1.74-1.97 (m, 4H). MS-ESI (m/z) calc’d for C28H26N5O2 [M+H]+: 464.2. Found 464.2. Example 288: 5-((1-(6-(3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomers 1, 2, 3 and 4
Figure imgf000527_0001
Step 1: 2-(1-(6-Chloropyrimidin-4-yl)pyrrolidin-3-yl)propan-2-ol, enantiomer 1 and 2
Figure imgf000527_0002
The enantiomers of 2-(1-(6-chloropyrimidin-4-yl)pyrrolidin-3-yl)propan-2-ol were separated by chiral HPLC using Method KK to afford 2-(1-(6-chloropyrimidin-4- yl)pyrrolidin-3-yl)propan-2-ol, enantiomer 1 (150 mg, 38%) as a yellow oil. A later eluting fraction was also isolated to afford 2-(1-(6-chloropyrimidin-4-yl) pyrrolidin-3-yl)propan-2-ol, enantiomer 2 (140 mg, 34%) as a yellow oil. MS-ESI (m/z) calc’d for C11H17ClN3O [M+H]+: 242.1. Found 242.2. Step 2: 5-((1-(6-(-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomers 1 and 2 A mixture of 2-(1-(6-chl 2-ol, enantiomer 1 (20 mg,
Figure imgf000528_0001
82.74 umol), 1-(1H-indazol-6-yloxy)tetralin-6-carbonitrile (23.94 mg, 82.74 umol), Cs2CO3 (40.44 mg, 124.11 umol), Josiphos SL-J0009-1 Pd G3 (5 mg) in dioxane (4 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 13 hrs under an N2 atmosphere. The solution was concentrated under reduced pressure to give a residue. The residue was purified via Method KR to afford the title compound (13.2 mg, 32%) as yellow oil. MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.3. Step 3: 5-((1-(6-(3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomers 1 and 2 5-((1-(6-(3-(2-Hydroxy yl)-1H-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaph
Figure imgf000528_0002
thalene-2-carbonitrile, isomers 1 and 2 were separated using Method KS to afford 5-((1-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol- 6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomer 1 (4.45 mg, 46%) as a yellow solid.1H NMR (400 MHz, MeOD) δ 8.49 (d, J=1.63 Hz, 1 H), 8.42 (s, 1 H), 8.17 (s, 1 H), 7.69 (d, J=8.76 Hz, 1 H), 7.54 (d, J=8.13 Hz, 2 H), 7.47 - 7.51 (m, 1 H), 7.00 (dd, J=8.69, 2.06 Hz, 1 H), 6.87 (s, 1 H), 5.60 (t, J=5.00 Hz, 1 H), 3.33 - 3.49 (m, 3 H), 3.19 - 3.28 (m, 2 H), 2.71 - 2.95 (m, 3 H), 2.13 - 2.20 (m, 2 H), 1.98 - 2.09 (m, 2 H), 1.81 - 1.92 (m, 1 H), 1.27 (d, J=3.75 Hz, 6 H). MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2 Found 495.1. A later eluting fraction was also isolated to afford 5-((1-(6-(3-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile, isomer 2 (4.46 mg, 47%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J=0.75 Hz, 1 H), 8.46 (d, J=2.00 Hz, 1 H), 8.37 (s, 1 H), 7.81 (d, J=8.76 Hz, 1 H), 7.72 (s, 1 H), 7.62 - 7.68 (m, 1 H), 7.54 - 7.59 (m, 1 H), 7.12 (dd, J=8.76, 2.25 Hz, 1 H), 6.84 (s, 1 H), 5.65 - 5.71 (m, 1 H), 4.44 (br s, 1 H), 3.43 - 3.91 (m, 3 H), 2.89 - 2.98 (m, 1 H), 2.76 - 2.86 (m, 1 H), 2.19 - 2.34 (m, 1 H), 2.06 - 2.14 (m, 2 H), 1.75 - 2.05 (m, 5 H), 1.13 - 1.20 (m, 6 H). MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.1. Step 4: 5-((1-(6-(-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomers 3 and 4 A mixture of 2-(-1-(6-c n-2-ol, enantiomer 2 (20
Figure imgf000529_0001
mg, 82.74 umol), 1-(1H-indazol-6-yloxy)tetralin-6-carbonitrile (23.94 mg, 82.74 umol), Cs2CO3 (40.44 mg, 124.11 umol), Josiphos SL-J0009-1 Pd G3 (5 mg) in dioxane (4 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 13 hrs under an N2 atmosphere. The solution was concentrated under reduced pressure to give a residue. The residue was purified via Method KT to afford the title compound (9.5 mg, 23%) as yellow oil. MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.4. Step 5: 5-((1-(6-(-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomers 3 and 4
Figure imgf000530_0001
(( ( ( ( y yp p y )py y)py y ) ol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomers 3 and 4 were separated using Method KT to afford 5-((1-(6-(-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H- indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomer 3 (3.32 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1 H), 8.45 (d, J=1.88 Hz, 1 H), 8.37 (s, 1 H), 7.81 (d, J=8.76 Hz, 1 H), 7.71 (s, 1 H), 7.62 - 7.67 (m, 1 H), 7.53 - 7.59 (m, 1 H), 7.12 (dd, J=8.75, 2.13 Hz, 1 H), 6.83 (s, 1 H), 5.68 (t, J=4.75 Hz, 1 H), 4.45 (br s, 1 H), 3.44 - 3.95 (m, 4 H), 2.87 - 2.98 (m, 1 H), 2.74 - 2.85 (m, 1 H), 2.33 (br d, J=1.75 Hz, 1 H), 2.06 - 2.13 (m, 2 H), 1.76 - 2.00 (m, 4 H), 1.09 - 1.20 (m, 6 H). MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.2. A later eluting fraction was also isolated to afford 5-((1-(6-(-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile, isomer 4 (2.94 mg, 33%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1 H), 8.43 - 8.46 (m, 1 H), 8.37 (s, 1 H), 7.80 (d, J=8.76 Hz, 1 H), 7.71 (s, 1 H), 7.62 - 7.68 (m, 1 H), 7.53 - 7.59 (m, 1 H), 7.08 - 7.14 (m, 1 H), 6.81 - 6.85 (m, 1 H), 5.64 - 5.71 (m, 1 H), 4.39 - 4.48 (m, 1 H), 2.87 - 2.92 (m, 1 H), 2.80 - 2.84 (m, 1 H), 2.21 - 2.30 (m, 1 H), 2.04 - 2.13 (m, 2 H), 1.79 - 1.98 (m, 4 H), 1.13 - 1.19 (m, 6 H) . MS-ESI (m/z) calc’d for C29H31N6O2 [M+H]+: 495.2. Found 495.2. Example 289: 1-((1-(2-(3-(2-Hydroxypropan-2-yl)azetidin-1-yl)pyridin-4-yl)-1H-indazol- 6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2 St
Figure imgf000530_0002
To a solution of 1-ox
Figure imgf000531_0001
o 2,3 dihydro 1H indene 5 carbonitrile (2 g, 12.73 mmol) in MeOH (20 mL) was added NaBH4 (577.67 mg, 15.28 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 hrs and concentrated to give a residue. Water was added and a white solid formed. The solid was collected by filtration, washed with H2O (2x), and dried under vacuum to afford the title compound (1.42 g, 68%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1 H), 7.68 (d, J=7.82 Hz, 1 H), 7.52 (d, J=7.70 Hz, 1 H), 5.56 (br s, 1 H), 5.10 (t, J=7.03 Hz, 1 H), 2.91 - 3.01 (m, 1 H), 2.78 (dt, J=16.29, 8.18 Hz, 1 H), 2.35 - 2.45 (m, 1 H), 1.74 - 1.87 (m, 1 H). Step 2: 1-((1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5- carbonitrile A mixture of 1-(te ol (2.16 g, 9.91 mmol), 1- hydroxy-2,3-dihydro-1H-
Figure imgf000531_0002
indene-5-carbonitrile (1.42 g, 8.92 mmol), and (tributylphosphoranylidene)acetonitrile (2.39 g, 9.91 mmol) in toluene (50 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue which was purified by silica gel column chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to afford the title compound (1.55 g, 41%) as a yellow oil. MS-ESI (m/z) calc’d for C22H22N3O2 [M+H]+: 360.2. Found 360.3. Step 3: 1-((1H-Indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile To a solution of 1-((
Figure imgf000531_0003
zol-6-yl)oxy)-2,3-dihydro- 1H-indene-5-carbonitrile (1.5 g, 4.17 mmol) in EtOH (20 mL) and H2O (20 mL) was added PTSA (2.16 g, 12.52 mmol) at 20 °C. The mixture was then stirred at 70 °C for 12 hrs and concentrated to give a residue. The mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-87% EtOAc/petroleum ether gradient eluent to afford the title compound (490 mg, 31%) as a yellow oil. MS-ESI (m/z) calc’d for C17H14N3O [M+H]+: 276.1. Found 276.3. Step 4: 2-(Azetidin-3-yl)propan-2-ol
Figure imgf000532_0001
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate (1.5 g, 6.97 mmol) in DCM (25 mL) was added a 4 M solution of HCl in EtOAc (13.93 mL) at 0 °C. The mixture was then stirred at 20 °C for 12 hrs. The mixture was concentrated to afford the title compound (1 g, 90%) as a white solid. MS-ESI (m/z) calc’d for C6H14NO [M+H]+: 116.1. Found 116.2. Step 5: 2-(1-(4-Iodopyridin-2-yl)azetidin-3-yl)propan-2-ol To a solution of 2-(azetidin-3
Figure imgf000532_0002
-yl)propan-2-ol (100 mg, 659.48 umol) in DMF (1 mL) were added DIEA (170.47 mg, 1.32 mmol, 229.74 uL) and 2-fluoro-4-iodopyridine (176.47 mg, 791.38 umol) at 20 °C. The mixture was stirred at 80 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether/EtOAc = 1/1, Rf = 0.34) to afford the title compound (110 mg, 50%) as a white solid. MS-ESI (m/z) calc’d for C11H16IN2O [M+H]+: 319.0. Found 319.1. Step 6: 1-((1-(2-(3-(2-Hydroxypropan-2-yl)azetidin-1-yl)pyridin-4-yl)-1H-indazol-6-yl)oxy)- 2,3-dihydro-1H-indene-5-carbonitrile A mixture of 1-((1H-
Figure imgf000533_0001
indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile (30 mg, 108.97 umol), 2-(1-(4-iodopyridin-2-yl)azetidin-3-yl)propan-2-ol (34.67 mg, 108.97 umol), CuI (4.15 mg, 21.79 umol), K3PO4 (69.39 mg, 326.91 umol) and (1S,2S)-N1,N2- dimethylcyclohexane-1,2-diamine (7.75 mg, 54.49 umol) in dioxane (2 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 100 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method KU to afford the title compound (30 mg, 47%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1 H), 8.14 (d, J=6.85 Hz, 1 H), 7.91 (d, J=8.80 Hz, 1 H), 7.88 (s, 1 H), 7.73 - 7.77 (m, 1 H), 7.66 - 7.70 (m, 2 H), 7.40 (dd, J=6.85, 1.59 Hz, 1 H), 7.16 (dd, J=8.80, 1.83 Hz, 1 H), 6.99 (s, 1 H), 6.19 - 6.24 (m, 1 H), 4.12 - 4.26 (m, 5 H), 3.12 - 3.20 (m, 1 H), 2.95 - 3.05 (m, 1 H), 2.71 - 2.86 (m, 2 H), 2.16 - 2.25 (m, 1 H), 1.10 (d, J=2.69 Hz, 6 H). MS-ESI (m/z) calc’d for C28H28N5O2 [M+H]+: 466.2. Found 466.3. Step 7: 1-((1-(2-(3-(2-Hydroxypropan-2-yl)azetidin-1-yl)pyridin-4-yl)-1H-indazol-6-yl)oxy)- 2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2 The
Figure imgf000533_0002
enantiomers of 1-((1-(2-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)pyridin-4-yl)- 1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile were separated by chiral HPLC using Method KV to afford 1-((1-(2-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)pyridin-4-yl)- 1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 (4.38 mg, 48%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1 H), 8.18 (d, J=5.63 Hz, 1 H), 7.81 - 7.86 (m, 2 H), 7.70 - 7.75 (m, 1 H), 7.62 - 7.67 (m, 1 H), 7.55 (s, 1 H), 7.11 (dd, J=5.63, 1.75 Hz, 1 H), 7.04 (dd, J=8.76, 1.88 Hz, 1 H), 6.69 (d, J=1.38 Hz, 1 H), 6.13 - 6.20 (m, 1 H), 4.47 (s, 1 H), 3.88 - 3.99 (m, 4 H), 3.08 - 3.17 (m, 1 H), 2.93 - 3.03 (m, 1 H), 2.68 - 2.78 (m, 2 H), 2.13 - 2.23 (m, 1 H), 1.07 (d, J=3.63 Hz, 6 H). MS-ESI (m/z) calc’d for C28H28N5O2 [M+H]+: 466.2. Found 466.1. A later eluting fraction was also isolated to afford 1-((1-(2-(3- (2-hydroxypropan-2-yl)azetidin-1-yl)pyridin-4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H- indene-5-carbonitrile, enantiomer 2 (4.15 mg, 46%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1 H), 8.18 (d, J=5.63 Hz, 1 H), 7.81 - 7.87 (m, 2 H), 7.70 - 7.74 (m, 1 H), 7.63 - 7.66 (m, 1 H), 7.55 (s, 1 H), 7.11 (dd, J=5.63, 1.75 Hz, 1 H), 7.04 (dd, J=8.76, 2.00 Hz, 1 H), 6.68 (d, J=1.63 Hz, 1 H), 6.13 - 6.19 (m, 1 H), 4.46 (s, 1 H), 3.89 - 3.97 (m, 4 H), 3.08 - 3.17 (m, 1 H), 2.93 - 3.03 (m, 1 H), 2.68 - 2.77 (m, 2 H), 2.13 - 2.23 (m, 1 H), 1.07 (d, J=3.63 Hz, 6 H). MS-ESI (m/z) calc’d for C28H28N5O2 [M+H]+: 466.2. Found 466.3. Example 290: 1-((1-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)- 1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2 Step 1: 1-((1
Figure imgf000534_0001
-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile
Figure imgf000534_0002
A mixture of (S)-2-(1-(6-chloropyrimidin-4-yl)pyrrolidin-3-yl)propan-2-ol (20 mg, 82.74 umol), 1-((1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile (22.78 mg, 82.74 umol), Cs2CO3 (40.44 mg, 124.11 umol), and Josiphos SL-J0009-1 Pd G3 (10 mg) in dioxane (2 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 80 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue which was purified by preparative TLC (petroleum ether/EtOAc = 1/2, Rf = 0.41) to afford the title compound (12 mg, 26%) as a yellow oil. MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.3. Step 2: 1-((1-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2
Figure imgf000535_0001
The enantiomers of 1-((1-(6-((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin- 4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile were separated by chiral HPLC using Method KW to afford 1-((1-(6-((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 (3.80 mg, 42%) as a white solid.1H NMR (400 MHz, MeOD) δ 8.58 (d, J=1.83 Hz, 1 H), 8.47 (s, 1 H), 8.21 (s, 1 H), 7.70 - 7.76 (m, 2 H), 7.64 (q, J=8.11 Hz, 2 H), 7.01 (dd, J=8.80, 2.20 Hz, 1 H), 6.94 (s, 1 H), 6.01 - 6.07 (m, 1 H), 4.66 (br s, 1 H), 3.38 - 3.91 (m, 3 H), 3.16 - 3.27 (m, 1 H), 3.01 - 3.12 (m, 1 H), 2.74 - 2.86 (m, 1 H), 2.47 (br s, 1 H), 2.24 - 2.33 (m, 1 H), 1.93 - 2.19 (m, 2 H), 1.31 (d, J=3.91 Hz, 6 H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.1. A later eluting fraction was also isolated to afford 1-((1-(6-((S)- 3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro- 1H-indene-5-carbonitrile, enantiomer 2 (3.34 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2 H), 8.37 (s, 1 H), 7.86 (s, 1 H), 7.80 (d, J=8.88 Hz, 1 H), 7.70 - 7.74 (m, 1 H), 7.63 - 7.67 (m, 1 H), 7.07 (dd, J=8.76, 2.13 Hz, 1 H), 6.84 (s, 1 H), 6.06 (dd, J=6.57, 4.69 Hz, 1 H), 4.44 (br s, 1 H), 3.41 - 3.95 (m, 4 H), 3.10 - 3.19 (m, 1 H), 2.97 - 3.06 (m, 1 H), 2.68 - 2.76 (m, 1 H), 2.28 - 2.42 (m, 1 H), 2.14 - 2.23 (m, 1 H), 1.96 (br s, 2 H), 1.14 - 1.20 (m, 6 H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.1. Example 291: 1-((1-(6-((R)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)- 1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2 Step 1: 1-((1
Figure imgf000536_0001
-(6-((R)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile
Figure imgf000536_0002
A mixture of (R)-2-(1-(6-chloropyrimidin-4-yl)pyrrolidin-3-yl)propan-2-ol (20 mg, 82.74 umol), 1-((1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile (22.78 mg, 82.74 umol), Cs2CO3 (40.44 mg, 124.11 umol), and Josiphos SL-J0009-1 Pd G3 (10 mg) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 80 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum to give a residue which was purified by HPLC using Method KT to afford the title compound (9 mg, 22%) as a white solid. MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.2. Step 2: 1-((1-(6-((R)-3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6- yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 and 2
Figure imgf000537_0001
The enantiomers of 1-((1-(6-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin- 4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile were separated by chiral HPLC using Method KW to afford 1-((1-(6-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)-2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 1 (2.08 mg, 23%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2 H), 8.37 (s, 1 H), 7.85 (s, 1 H), 7.80 (d, J=8.77 Hz, 1 H), 7.70 - 7.73 (m, 1 H), 7.63 - 7.66 (m, 1 H), 7.07 (dd, J=8.77, 2.19 Hz, 1 H), 6.84 (br s, 1 H), 6.03 - 6.09 (m, 1 H), 4.44 (br s, 1 H), 3.39 - 3.96 (m, 4 H), 3.12 (br dd, J=8.88, 5.59 Hz, 1 H), 2.99 - 3.05 (m, 1 H), 2.68 - 2.75 (m, 1 H), 2.22 - 2.32 (m, 1 H), 2.14 - 2.21 (m, 1 H), 1.94 (br s, 2 H), 1.15 (s, 6 H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.1. A later eluting fraction was also isolated to afford 1-((1-(6-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-6-yl)oxy)- 2,3-dihydro-1H-indene-5-carbonitrile, enantiomer 2 (1.73 mg, 19%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2 H), 8.37 (s, 1 H), 7.85 (s, 1 H), 7.80 (d, J=8.77 Hz, 1 H), 7.70 - 7.73 (m, 1 H), 7.63 - 7.66 (m, 1 H), 7.07 (dd, J=8.77, 2.19 Hz, 1 H), 6.84 (br s, 1 H), 6.03 - 6.08 (m, 1 H), 4.44 (br s, 1 H), 3.40 - 3.93 (m, 4 H), 3.09 - 3.14 (m, 1 H), 2.99 - 3.05 (m, 1 H), 2.68 - 2.73 (m, 1 H), 2.25 (s, 1 H), 2.14 - 2.21 (m, 1 H), 1.94 (br s, 2 H), 1.15 (s, 6 H). MS-ESI (m/z) calc’d for C28H29N6O2 [M+H]+: 481.2. Found 481.1. Example 292: (E)-8-((1-(2-(2-Methylpyridin-4-yl)vinyl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2 Step 1: (E)-8-
Figure imgf000537_0002
(( -( -( - et y pyri in-4-y )viny )- -in azo-6-y )oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile To a solution of 8-((1H
Figure imgf000538_0001
-n azo-6-y )oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (10 mg, 34.44 umol) in DCE (0.5 mL) was added (E)-(2-(2-methylpyridin-4-yl)vinyl)boronic acid (5.61 mg, 34.44 umol), Cu(OAc)2 (6.26 mg, 34.44 umol), 2-(2-pyridyl)pyridine (5.38 mg, 34.44 umol), and Na2CO3 (7.30 mg, 68.89 umol) at 20 °C. The mixture was then stirred at 90 °C for 12 hrs. The reaction was combined with an additional 10 mg scale reaction before work up. The combined reaction mixtures were filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method KX to afford the title compound (9 mg, 32%) as a red solid. MS-ESI (m/z) calc’d for C25H22N5O [M+H]+: 408.2. Found 408.1. Step 2: (E)-8-((1-(2-(2-Methylpyridin-4-yl)vinyl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2 The en
Figure imgf000538_0002
ant omers o ( )- -(( -( -( -met y pyr n- -y )v ny )- -ndazol-6-yl)oxy)- 5,6,7,8-tetrahydroquinoline-3-carbonitrile were separated by chiral HPLC using Method KY to afford (E)-8-((1-(2-(2-methylpyridin-4-yl)vinyl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 (2.11 mg, 23%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=1.88 Hz, 1 H), 8.52 (d, J=13.88 Hz, 1 H), 8.39 (d, J=5.25 Hz, 1 H), 8.30 (s, 1 H), 8.24 (d, J=1.88 Hz, 1 H), 7.92 (s, 1 H), 7.73 (d, J=8.76 Hz, 1 H), 7.49 (s, 1 H), 7.46 (d, J=5.38 Hz, 1 H), 7.05 (d, J=14.01 Hz, 1 H), 6.99 (dd, J=8.76, 2.00 Hz, 1 H), 5.77 (t, J=3.94 Hz, 1 H), 2.96 - 3.03 (m, 1 H), 2.82 - 2.92 (m, 1 H), 2.48 (br s, 3 H), 2.30 (br d, J=5.75 Hz, 1 H), 2.07 - 2.15 (m, 1 H), 1.81 - 2.00 (m, 2 H). MS-ESI (m/z) calc’d for C25H22N5O [M+H]+: 408.2. Found 408.0. A later eluting fraction was also isolated to afford (E)-8-((l-(2-(2-methylpyridin-4-yl)vinyl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline- 3-carbonitrile, enantiomer 2 (2 mg, 22%) as a yellow solid. 1 H NMR (400 MHz, DMSO- e) 6 8.88 (d, J=2.00 Hz, 1 H), 8.52 (d, J=14.13 Hz, 1 H), 8.39 (d, J=5.25 Hz, 1 H), 8.30 (s, 1 H), 8.24 (d, J=1.88 Hz, 1 H), 7.92 (s, 1 H), 7.73 (d, J=8.76 Hz, 1 H), 7.49 (s, 1 H), 7.47 (d, J=5.25 Hz, 1 H), 7.05 (d, J=14.01 Hz, 1 H), 6.99 (dd, J=8.76, 2.00 Hz, 1 H), 5.77 (t, J=3.94 Hz, 1 H), 2.94 - 3.03 (m, 1 H), 2.82 - 2.92 (m, 1 H), 2.48 (s, 3 H), 2.29 (br s, 1 H), 2.05 - 2.14 (m, 1 H), 1.83 - 2.00 (m, 2 H). MS-ESI (m/z) calc’d for C25H22N5O [M+H]+: 408.2. Found 408. E
Example 293: 8-[l-(2,6-Dimethoxy-4-pyridyl)indazol-6-yl]oxy-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2
Figure imgf000539_0001
Step 1: 4-Bromo-2,6-dimethoxy-pyridine
Figure imgf000539_0002
To a solution of 4-bromo-2,6-difluoropyridine (200 mg, E03 mmol) in MeOH (3 mL) was added NaOH (82.48 mg, 2.06 mmol) at 20 °C. The mixture was then stirred at 70 °C for 12 hrs. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried with Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (SiCh, petroleum ether/EtOAc = 5/1, Rf = 0.51) to afford the title compound (152 mg, 67%) as a white solid. 'H NMR (400 MHz, CDCh) 8 6.49 (s, 2 H), 3.91 (s, 6 H). MS-ESI (m/z) calc’d for CvHgBrNCE [M+H]+: 217.9, 219.9. Found 218.1, 220.1. Step 2: 8-[1-(2,6-Dimethoxy-4-pyridyl)indazol-6-yl]oxy-5,6,7,8-tetrahydroquinoline-3- carbonitrile A mixture of 4-brom
Figure imgf000540_0001
o-2,6-dimethoxy-pyridine (25 mg, 114.65 umol), 8-((1H-indazol- 6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (33.29 mg, 114.65 umol), CuI (4.37 mg, 22.93 umol), K3PO4 (73.01 mg, 343.96 umol), and N1,N2-dimethylcyclohexane-1,2-diamine (8.15 mg, 57.33 umol) in dioxane (1 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 105 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method KZ to afford the title compound (25 mg, 50%) as a white solid. MS-ESI (m/z) calc’d for C24H22N5O3 [M+H]+: 428.1. Found 428.1. Step 3: 8-[1-(2,6-Dimethoxy-4-pyridyl)indazol-6-yl]oxy-5,6,7,8-tetrahydroquinoline-3- carbonitrile, enantiomer 1 and 2
Figure imgf000540_0002
The enantiomers of 8-[1-(2,6-Dimethoxy-4-pyridyl)indazol-6-yl]oxy-5,6,7,8- tetrahydroquinoline-3-carbonitrile were separated by chiral HPLC using Method LA to afford 8-[1-(2,6-dimethoxy-4-pyridyl)indazol-6-yl]oxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (1.95 mg, 21%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1 H), 8.33 (s, 1 H), 8.21 (s, 1 H), 7.72 - 7.80 (m, 2 H), 7.01 - 7.07 (m, 1 H), 6.82 (s, 2 H), 5.70 - 5.77 (m, 1 H), 3.92 (s, 6 H), 2.92 - 3.01 (m, 1 H), 2.78 - 2.88 (m, 1 H), 2.22 - 2.31 (m, 1 H), 2.00 - 2.09 (m, 1 H), 1.79 - 1.99 (m, 2 H). MS-ESI (m/z) calc’d for C24H22N5O3 [M+H]+: 428.1. Found 428.1. A later eluting fraction was also isolated to afford 8-[1-(2,6-dimethoxy- 4-pyridyl)indazol-6-yl]oxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 2 (2.57 mg, 28%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.59 Hz, 1 H), 8.32 (s, 1 H), 8.21 (s, 1 H), 7.73 - 7.80 (m, 2 H), 7.04 (dd, J=8.80, 1.83 Hz, 1 H), 6.82 (s, 2 H), 5.74 (t, J=3.55 Hz, 1 H), 3.92 (s, 6 H), 2.92 - 3.01 (m, 1 H), 2.78 - 2.88 (m, 1 H), 2.22 - 2.31 (m, 1 H), 2.01 - 2.09 (m, 1 H), 1.80 - 1.99 (m, 2 H). MS-ESI (m/z) calc’d for C24H22N5O3 [M+H]+: 428.1. Found 428.1. Example 294: 8-((5-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-4- (trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2 Step 1: 8
Figure imgf000541_0001
romethyl)- 5,6,7,8-tetrahydroquinoline-3-carbonitrile A mixture of 8-h
Figure imgf000541_0002
hydroquinoline-3-carbonitrile (100 mg, 412.89 umol), 5-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-ol (94.24 mg, 412.89 umol), and (tributylphosphoranylidene)acetonitrile (199.30 mg, 825.77 umol) in toluene (5 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 110 °C for 12 hrs under an N2 atmosphere. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC using Method LB to afford the title compound (30 mg, 12%) as a red solid. MS-ESI (m/z) calc’d for C23H20F3N6O [M+H]+: 453.2. Found 453.3. Step 2: 8-((5-Methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-4-(trifluoromethyl)- 5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 and 2 T
Figure imgf000542_0001
yl)oxy)-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile were separated by chiral HPLC using Method LC to afford 8-((5-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H- indazol-6-yl)oxy)-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, enantiomer 1 (3.88 mg, 43%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1 H), 8.30 (s, 1 H), 8.08 (s, 1 H), 7.93 (s, 1 H), 7.57 (s, 1 H), 7.48 (s, 1 H), 5.90 (t, J=4.19 Hz, 1 H), 3.95 (s, 3 H), 3.15 (br d, J=18.14 Hz, 1 H), 2.94 - 3.04 (m, 1 H), 2.24 - 2.31 (m, 1 H), 2.15 (s, 3 H), 2.08 - 2.13 (m, 1 H), 1.93 - 2.05 (m, 2 H). MS-ESI (m/z) calc’d for C23H20F3N6O [M+H]+: 453.2. Found 453.1. A later eluting fraction was also isolated to afford 8-((5-methyl-1-(1- methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-4-(trifluoromethyl)-5,6,7,8- tetrahydroquinoline-3-carbonitrile, enantiomer 2 (3.65 mg, 40%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1 H), 8.30 (s, 1 H), 8.08 (s, 1 H), 7.93 (s, 1 H), 7.57 (s, 1 H), 7.48 (s, 1 H), 5.90 (t, J=4.06 Hz, 1 H), 3.95 (s, 3 H), 3.15 (br d, J=18.51 Hz, 1 H), 2.94 - 3.04 (m, 1 H), 2.24 - 2.30 (m, 1 H), 2.15 (s, 3 H), 2.08 - 2.13 (m, 1 H), 1.92 - 2.04 (m, 2 H). MS- ESI (m/z) calc’d for C23H20F3N6O [M+H]+: 453.2. Found 453.1. Example 295: (E)-2-Cyano-3-isopropyl-N-(1-(2-(2-methylpyridin-4-yl)vinyl)-1H- indazol-6-yl)isonicotinamide Step 1: (E)-2-Methyl-4-(2- an-2-yl)vinyl)pyridine
Figure imgf000542_0002
A mixture of 4-bromo-2-methylp
Figure imgf000543_0001
yr ne (500 mg, 2.91 mmol), 4,4,5,5-tetramethyl-2- vinyl-1,3,2-dioxaborolane (537.19mg, 3.49 mmol, 591.62 uL), Pd2(dba)3 (133.08 mg, 145.33 umol), DIPEA (751.30 mg, 5.81 mmol) and tri-tert-butylphosphonium tetrafluoroborate (84.33 mg, 290.66 umol) in toluene (4 mL) was degassed and purged with N2 (3x) at 20°C, and then the mixture was stirred at 90°C for 12 hr under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent and the residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a 0-12% EtOAc/petroleum ether gradient eluent to afford the title compound (520 mg, 72%) as a yellow oil. MS-ESI (m/z) calc’d for C14H21BNO2 [M+H]+: 246.2. Found 164.3. Step 2: (E)-(2-(2-Methylpyridin-4-yl)vinyl)boronic acid To a solution of (E)-2-methyl-4-
Figure imgf000543_0002
( -( , ,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)vinyl)pyridine (400 mg, 1.63 mmol) in acetone (32 mL) and H2O (2 mL) were added a 1 M solution of NH4OAc (7.34 mL) and NaIO4 (1.05 g, 4.90 mmol) at 0 °C. The mixture was then stirred at 20 °C for 12 hrs. The residue was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (265 mg, 99%) as a yellow solid. MS-ESI (m/z) calc’d for C8H11BNO2 [M+H]+: 164.1. Found 164.3. Step 3: (E)-2-Cyano-3-isopropyl-N-(1-(2-(2-methylpyridin-4-yl)vinyl)-1H-indazol-6- yl)isonicotinamide To a solution of (E) onic acid (32.82 mg, 201.40
Figure imgf000544_0001
umol) in DCE (3 mL) were added 3-cyano-N-(1H-indazol-6-yl)-2-isopropylbenzamide (73.56 mg, 241.68 umol), Cu(OAc)2 (36.58 mg, 201.40 umol), 2-(2-pyridyl)pyridine (31.46 mg, 201.40 umol) and Na2CO3 (42.69 mg, 402.81 umol) at 20 °C. The mixture was stirred at 70 °C for 3 hrs under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by HPLC using Method KC to afford the title compounds (16.5 mg, 17%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.66 (s, 1H), 8.49 (d, J=14.01 Hz, 1H), 8.33-8.43 (m, 2H), 7.96 (d, J=7.25 Hz, 1H), 7.81 (d, J=8.63 Hz, 1H), 7.77 (d, J=7.25 Hz, 1H), 7.55 (br t, J=7.63 Hz, 2H), 7.49 (br d, J=4.63 Hz, 1H), 7.33 (d, J=8.50 Hz, 1H), 7.08 (d, J=14.01 Hz, 1H), 3.38-3.44 (m, 1H), 2.48 (br s, 3H), 1.45 (d, J=7.13 Hz, 6H). MS-ESI (m/z) calc’d for C26H24N5O [M+H]+: 422.2. Found 422.2. The following compounds were prepared according to the procedures described above. Example Structure Name
Figure imgf000544_0002
Figure imgf000545_0001
Figure imgf000546_0001
Figure imgf000547_0001
Figure imgf000548_0001
Figure imgf000549_0001
Figure imgf000550_0001
Figure imgf000551_0001
Figure imgf000552_0001
Example A. LRRK2 Kinase Activity
LRRK2 kinase activity was measured using a LanthaScreen™ Kinase Activity Assay from ThermoFisher Scientific. Recombinant wild type or G2019S-LRRK2 protein (Life Technologies, PR8604B or PV4881, respectively), was incubated with a fluorescein-labeled peptide substrate called LRRKtide that is based upon ezrin/radixin/moesin (ERM) (Life Technologies, PV4901) in the presence of ATP and serially diluted compound. After an incubation period of 1 hr, the phosphotransferase activity was stopped and a terbium-labelled anti-pERM antibody (Life Technologies, PV4899) was added to detect the phosphorylation of LRRKtide by measuring the time resolved-Forster resonant energy transfer (TR-FRET) signal from the terbium label on the antibody to the fluorescein tag on LRRKtide, expressed as the 520nm/495nm emission ratio. Compound-dependent inhibition of the TR-FRET signal was used to generate a concentration-response curve for IC50 determination.
The assay was carried out under the following protocol conditions: 1 mM compound in DMSO was serially diluted 1:3, 11 points in DMSO with a Biomek FX and 0.1 pL of the diluted compound was subsequently stamped into the assay plate (384-well format Lumitrac 200, Greiner, 781075) with an Echo Labcyte such that the final compound concentration in the assay was 10 pM to 169 pM. Subsequently, 5 pL of 2x kinase solution (2.9 nM final concentration) was added to the assay plate in assay buffer composed of 50 mM Tris pH 8.5 (Sigma, T6791), 5 mM MgCh (Fluka, 63020), 1 mM EGTA (Sigma, E3889), 0.01% BRIJ-35 (Sigma, Pl 254) and 2 mM DTT. The reaction was started by addition of 2x ATP/LRRKtide solution in assay buffer such that the final concentration was 400 nM LRRKtide and 25 pM ATP. After 60 min incubation at room temperature, the reaction was stopped by addition of 10 pL of 2x stop solution containing a final concentation of 2 nM anti-pERM antibody and 10 mM EDTA. After a 30 min incubation at RT, the TR-FRET signal was measured on a Wallac 2104 EnVision® multilabel reader at an excitation wavelength of 340 nm and reading emission at 520 nm and 495 nm. The ratio of the 520 nm and 495 nm emission was used to analyze the data.
The Results of the LRRK2 kinase activity assay are shown in Table A-l, Table A-2, and Table A-3. Data is displayed as follows: + is IC50 < 100 nM; ++ is 100 nM < IC50 < 1,000 nM; +++ is 1,000 nM < IC50 < 10,000 nM; and ++++ is IC50 > 10,000 nM.
Table A-l. LRRK2 Kinase Activity Assay
Figure imgf000553_0001
Figure imgf000554_0001
Table A-2. LRRK2 Kinase Activity Assay
Figure imgf000554_0002
Figure imgf000555_0001
Figure imgf000556_0001
Figure imgf000557_0001
Figure imgf000558_0001
Figure imgf000559_0001
Figure imgf000560_0001
Table A-2. LRRK2 Kinase Activity Assay
Figure imgf000560_0002
Figure imgf000561_0001
Figure imgf000562_0001
Figure imgf000563_0001
Figure imgf000564_0001
Figure imgf000565_0001
Figure imgf000566_0001
Figure imgf000567_0001
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:
1. A compound of Formula IA or IB’ :
Figure imgf000568_0001
or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1, Cy1-C1-4 alkyl-, Cy1-C2-4 alkenyl-, Cy1-C2-4 alkynyl-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, C(=NRe)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
L is -O- or -NH-;
Ring B is phenyl or 6-membered heteroaryl;
Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4; wherein not more than two of X2, X3, and X4 are simultaneously N;
Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, 0Ra, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(0)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 and R5 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R1 and R5 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl;
R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R2, R3 and R4 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, OR32, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, R32, Rb2, Rc2, Rd2 is independently selected from
H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, Ra2, Rb2, Rc2, and Rd2 is optionally substituted with
I, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or RC1 and Rdl together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalky 1, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; each Re, Rel, Re2, and Re3 is independently selected from H, C1-4 alkyl, and CN; n is 0, 1, 2, or 3; m is 0 or 1; and p is 0, 1, 2, or 3; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H.
2. A compound of Formula I A or IB:
Figure imgf000571_0001
IA
Figure imgf000571_0002
or a pharmaceutically acceptable salt thereof, wherein: A is Cy1, Cy1-C1-4 alkyl-, Cy1-C2-4 alkenyl-, Cy1-C2-4 alkynyl-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, C(=NRe)NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of A are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
L is -O- or -NH-;
Ring B is phenyl or 6-membered heteroaryl;
Ring C is phenyl or 6-membered heteroaryl, wherein Ring C is fused to Ring D; represents a single bond or a double bond;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4; wherein not more than two of X2, X3, and X4 are simultaneously N;
Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R1 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl;
R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of R2, R3 and R4 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, OR32, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, R32, Rb2, Rc2, Rd2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ral, Rbl, Rcl, Rdl, Ra2, Rb2, Rc2, and Rd2 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or RC1 and Rdl together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C 1-4 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, and S(O)2NRc3Rd3; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalky 1, and C1-6 haloalkoxy; each Re, Rel, Re2, and Re3 is independently selected fromH, C1-4 alkyl, and CN; n is 0, 1, 2, or 3; and m is 0 or 1; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having Formula I A:
Figure imgf000575_0001
4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having
Formula IB:
Figure imgf000575_0002
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X2 is CR2.
6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X2 is N.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein X3 is CR3.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X4 is CR4.
9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X4 is N.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, OR32, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4 are each independently selected from H, C1-6 alkyl, and halo.
12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4 are each independently selected from H, C1-6 alkyl, CN, OR32, and halo.
13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4 are each independently selected from H and halo.
14. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each H, and R4 is H, methyl, or Cl.
15. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each H, and R4 is H or Cl.
16. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4 are each H.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein A is Cy1, C1-6 alkyl, C1-6 haloalkyl, CN, C(O)NRcRd, C(O)ORa, S(O)2Rb, or S(O)2NRcRd, wherein said C1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, S(O)2Rb, and S(O)2NRcRd.
18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein A is Cy1.
19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein A is C2-4 alkenyl-, Cy1-C1-4 alkyl-, or Cy1-C2-4 alkenyl-.
20. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherien A is selected from prop-l-en-l-yl, 2-(pyridin-4-yl)vinyl, 2-(oxazol-4- yl)vinyl, 2-(l -methyl- lH-pyrazol-4-yl)vinyl, 2-(2,6-dimethylpyridin-4-yl)vinyl, 2-(2- methy lpyridin-4-y l)viny 1, 3 -(3-methoxy azetidin- 1 -y l)prop- 1 -en- 1 -y 1, 3 -(4-methy Ipiperazin- 1 - yl)prop- 1 -en- 1 -y 1, ( 1 -methylazeti din-3 -y l)methy 1, 3-(3,3 -difluoropy rrolidin- 1 -y l)prop- 1 -en- 1 - yl, 3-(pyrrolidin-l-yl)prop-l-en-l-yl, 3 -(4-methy Ipiperazin- 1 -yl)-3 -oxoprop- 1-en-l-yl, 2-(l- methyl-lH-pyrazol-3-yl)vinyl, and 2-(oxetan-3-yl)vinyl.
21. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein A is C1-6 alkyl.
22. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein A is methyl .
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Cy1 is C3-10 cycloalkyl or 5-14 membered heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4- 14 membered heterocycloalkyl, C6-10 ary 1-C 1-4 alkyl, C3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, wherein said substituents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 further substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd
24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Cy1 is C3-10 cycloalkyl or 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C3-10 cycloalkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, NRcRd, NRcC(O)Rb, S(O)2Rb, and S(O)2NRcRd
25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Cy1 is C3-6 cycloalkyl or 5-6 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C1-6 alkyl and C3-10 cycloalkyl.
26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from pyrazolyl, imidazolyl, thiazolyl, benzo[d]oxazolyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, triazolyl, cyclopropyl, and phenyl, wherein each Cy1 group is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.
27. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Cy1 is 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, or 1 -methyl- IH-pyrazol- 4-yl.
28. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, 1-methyl- IH-py razol-4-y 1, 1 -(bicy clo[ 1.1.1 ] pentan- 1 -y 1)- 177-py razol-4-y 1, 1 -(difluoromethyl)- 1H- pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1 -cyclopentyl- 17/-pyrazol-4-yl, benzo [r/]oxazol-2-yl, l-(2,2,2-trifluoroethyl)-17/-pyrazol-4-yl, 1 -(2-methoxy ethyl)- 1H- pyrazol-4-yl, 3-methoxy-l -methyl- IT/-pyrazol-4-yl. oxazol-2-yl, 4-phenyloxazol-2-yl, 4,5- dimethyloxazol-2-yl, 5-methyloxazol-2-yl, 4-methyloxazol-2-yl, 2-methylthiazol-5-yl, py rimi din-5 -yl, 2-methylpyrimidin-5-yl, 3-methylpyridin-4-yl, 1 -methyl- 17/-imidazol-4-yl, 1- pyrazin-2-yl, pyridazin-3-yl, 2-(pyrrolidin- l-yl)py rimi din-5 -yl, l-methyl-17/-l,2,3-triazol-4- yl, 4-methylpyrimidin-2-yl, 2-morpholinopyridin-4-yl, 2-(trifluoromethyl)pyrimidin-5-yl, 1- isopropyl-17/-pyrazol-4-yl, l,3-dimethyl-17/-pyrazol-4-yl, 1 -benzyl- l//-pyrazol-4-yl. 1- phenyl-17/-pyrazol-4-yl, 1 -(tert-butyl)- IT/-pyrazol-4-yl. 1,5 -dimethyl- 17/-pyrazol-4-yl, 1- (oxetan-3-yl)- IT/-pyrazol-4-yl. l-(pyridin-2-yl)-IT/-pyrazol-4-yl. l -(tetrahydro-27/-pyran-4- yl)-17/-pyrazol-4-yl, 1 -ethyl- l//-pyrazol-4-yl. 5-methylthiazol-2-yl, 1 -methyl- 17/-pyrazol-3- yl, 2-methyloxazol-5-yl, 4-methylthiazol-5-yl, pyrazolo[l,5-a]pyridin-3-yl, 2-methoxy-6- methylpyridin-4-yl, 3 -morpholinophenyl, and l -(pyrimidin-2-yl)-IT/-pyrazol-4-yl.
29. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from 1 -cyclopropyl- lH-pyrazol-4-yl, cyclopropyl, 1-methyl- IH-py razol-4-y 1, 1 -(bicy clo[ 1.1.1 ] pentan- 1 -y 1)- 177-py razol-4-y 1, 1 -(difluoromethyl)- 1H- pyrazol-4-yl, 2-methyl-17/-imidazol-5-yl, thiazol-5-yl, 1 -cyclopentyl- 17/-pyrazol-4-yl, benzo [r/]oxazol-2-yl, l-(2,2,2-trifluoroethyl)-17/-pyrazol-4-yl, 1 -(2-methoxy ethyl)- 1H- pyrazol-4-yl, 3-methoxy-l -methyl- l//-pyrazol-4-yl. oxazol-2-yl, 4-phenyloxazol-2-yl, 4,5- dimethyloxazol-2-yl, 5-methyloxazol-2-yl, 4-methyloxazol-2-yl, 2-methylthiazol-5-yl, py rimi din-5 -yl, 2-methylpyrimidin-5-yl, 3-methylpyridin-4-yl, 1 -methyl- 17/-imidazol-4-yl, 1- pyrazin-2-yl, pyridazin-3-yl, 2-(pyrrolidin- l-yl)py rimi din-5 -yl, l-methyl-17/-l,2,3-triazol-4- yl, 4-methylpyrimidin-2-yl, 2-morpholinopyridin-4-yl, 2-(trifluoromethyl)pyrimidin-5-yl, 1- isopropyl-17/-pyrazol-4-yl, l,3-dimethyl-17/-pyrazol-4-yl, 1 -benzyl- l//-pyrazol-4-yl. 1- phenyl-17/-pyrazol-4-yl, 1 -(tert-butyl)- IT/-pyrazol-4-yl. 1,5 -dimethyl- 17/-pyrazol-4-yl, 1- (oxetan-3-yl)- IT/-pyrazol-4-yl. l-(pyridin-2-yl)-IT/-pyrazol-4-yl. l -(tetrahydro-27/-pyran-4- yl)-17/-pyrazol-4-yl, 1 -ethyl- l//-pyrazol-4-yl. 5-methylthiazol-2-yl, 1 -methyl- 17/-pyrazol-3- yl, 2-methyloxazol-5-yl, 4-methylthiazol-5-yl, pyrazolo[l,5-a]pyridin-3-yl, 2-methoxy-6- methylpyridin-4-yl, 3 -morpholinophenyl, l-(py rimi din-2 -yl)- l//-pyrazol-4-yl. pyridazin-4-yl, 1 -(2-hy droxy-2-methylpropyl)- lH-pyrazol-4-yl, 2-(methoxymethyl)pyridin-4-yl, 1 -(1 , 1 - dioxidothietan-3-yl)-lH-pyrazol-4-yl, 2-chloropyridin-4-yl, 6-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)pyridin-3-yl, 2-(3-hydroxyazetidin-l-yl)pyridin-4-yl, 2-methylpyridin-4-yl, l-(oxetan-3- y Imethy 1)- lH-pyrazol-4-y 1, 2-(4-(dimethy Iphosphory l)piperidin- 1 -y l)pyridin-4-y 1, 2-((2-oxa- 6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl, 2-((2-oxa-6-azaspiro[3.3]heptan-6- yl)methyl)pyridin-4-yl, 2-(l-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl, 6- methylpyridazin-4-yl, 6-methoxypyridazin-4-yl, 2-methoxythiazol-5-yl, 4, 5,6,7- tetrahydropyrazolo[l,5-a]pyridin-3-yl, 2-isopropylthiazol-5-yl, 5-methyl-l,3,4-oxadiazol-2- yl, 2-methylthiazol-4-yl, pyrimidin-4-yl, l-(2-fluoroethyl)-lH-pyrazol-4-yl, 2- methoxypyrimidin-4-yl, l-methyl-6-oxo-l,6-dihydropyridin-3-yl, 3-fluoro-l-methyl-lH- pyrazol-4-yl, 5-fluoro-l-methyl-lH-pyrazol-4-yl, l-(2-cyanopropan-2-yl)-lH-pyrazol-4-yl, l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl, 2-(2-oxaspiro[3.3]heptan-6-yl)pyridin-4-yl, 2- (6-oxa-3-azabicyclo[3.1. l]heptan-3-yl)pyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl,
1-(2-morpholinoethyl)-lH-pyrazol-4-yl, l-((l-methylpiperidin-4-yl)methyl)-lH-pyrazol-4-yl,
2-(4-methylmorpholin-2-yl)pyridin-4-yl, 2-(4-methylmorpholin-3-yl)pyridin-4-yl, 6-(3-(2- hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl, 6-(3-(2-hydroxypropan-2-yl)pyrrolidin-
1-yl)pyrimidin-4-yl, 2-(pyridin-4-yl)cyclopropyl, 2-(2-methoxy ethoxy )-6-methylpyridin-4-yl,
2-(2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)pyridin-4-yl, 2,6-dimethoxypyridin-4-yl, 4- oxospiro[2.5]oct-5-en-6-yl, 6-(4-methylpiperazin-l-yl)pyridazin-4-yl, 3-oxocyclohex-l-en-l- yl, 2-(morpholinomethyl)pyridin-4-yl, l-((l-methylazetidin-3-yl)methyl)-lH-pyrazol-4-yl, T- methyl-r,2',3',6'-tetrahydro-[2,4'-bipyridin]-4-yl, and 3-oxocyclopent-l-en-l-yl.
30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein L is -O-.
31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.
32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl.
33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ring B is 6-membered heteroaryl.
34. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridinyl.
35. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl, pyrazinyl, or pyridinyl.
36. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl or pyridinyl.
37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein Ring C is phenyl.
38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein Ring C is 6-membered heteroaryl.
39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein Ring C is pyridinyl.
40. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein Ring C is phenyl or pyridinyl.
41. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein Ring C is phenyl, pyridinyl, pyrazinyl, or pyridazinyl.
42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein m is 0.
43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein m is 1.
44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl.
45. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl.
46. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C3-7 cycloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl, wherein said C1-6 alkyl and C2-6 alkenyl of R1 are each optionally substituted with a substituent selected from CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, and S(O)2NRclRdl.
47. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from halo and C1-6 alkyl.
48. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from methyl, isopropyl, and chloro.
49. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from methyl, isopropyl, ethyl, prop-l-en- 2-yl, chloro, fluoro, bromo, iodo, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, and trifluoromethoxy .
50. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from methyl, isopropyl, ethyl, prop-l-en- 2-yl, chloro, fluoro, bromo, iodo, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, trifluoromethoxy, CN, methoxymethyl, vinyl, but-2-en-2-yl, sec-butyl, 1,1,1-trifluoropropan- 2-yl, methylsulfonyl, and oxetan-3-yloxy.
51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein each R5 is selected from C1-6 alkyl and halo.
52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein n is 0.
53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.
54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein p is 0.
55. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein p is 1.
56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, having Formula Ila or lib:
Figure imgf000583_0001
Ila lib.
57. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, having Formula Illa or Illb:
Figure imgf000584_0001
Illa mb.
58. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, having Formula IIIc or Illd:
Figure imgf000584_0002
IIIc Illd.
59. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
A is Cy1 or C1-6 alkyl;
L is -O- or -NH-;
Ring B is phenyl, pyridinyl, or pyrazinyl;
Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D;
== represents a single bond or a double bond;
X2 is CR2 orN;
X3 is CR3; X4 is CR4 or N; Cy1 is selected from C3-10 cycloalkyl, C6-10 aryl, and 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4- 14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; each R1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and ORa1; each R5 is independently selected from C1-6 alkyl and halo; R2, R3, and R4 are each independently selected from H, C1-6 alkyl, and halo; n is 0, 1, 2, or 3; m is 0 or 1; and p is 0, 1, or 2; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H.
60. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: A is Cy1 or C1-6 alkyl; L is -O- or -NH-; Ring B is phenyl or pyridinyl; Ring C is phenyl or pyridinyl, wherein Ring C is fused to Ring D; represents a single bond or a double bond; X2 is CR2; X3 is CR3; X4 is CR4; Cy1 is selected from C3-10 cycloalkyl and 5-14 membered heteroaryl, each optionally substituted by 1 or 2 substituents independently selected from C1-6 alkyl and C3-10 cycloalkyl; each R1 is independently selected from halo and C1-6 alkyl; R2, R3, and R4 are each independently selected from H and halo; n is 0, 1, 2, or 3; and m is 0 or 1; wherein in Formula IA when ring B is phenyl, then: n is 1, 2, or 3 and R1 is a group other than H.
61. The compound of claim 1 or 2, which is selected from: 5-Cyano-N-(1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-3,4- dimethylpicolinamide; 5-((1-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile; N-(5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-5-cyano-3,4- dimethylpicolinamide; 5-((5-Chloro-1-(1-cyclopropyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile; 6-Chloro-5-cyano-3,4-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide; 6-Chloro-5-cyano-N-(1-cyclopropyl-1H-indazol-6-yl)-3,4-dimethylpicolinamide; 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile; 8-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydroquinoline-3-carbonitrile; 8-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline- 3-carbonitrile; 2-Chloro-8-((1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile; 6-Chloro-5-cyano-3,4-dimethyl-N-(1-methyl-1H-indazol-6-yl)picolinamide; 3-Cyano-2-isopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 7-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)oxy)-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carbonitrile; 7-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt of any of the aforementioned.
62. The compound of claim 1, wherein the compound is selected from: 4-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-3-(prop-1-en-2- yl)picolinamide; 3-Cyano-2-iodo-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 5-Cyano-6-(difluoromethyl)-3,4-dimethyl-N-(5-methyl-1-(1-methyl-1H-pyrazol-4- yl)-1H-indazol-6-yl)picolinamide; 5-Cyano-6-(difluoromethyl)-3,4-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H- indazol-6-yl)picolinamide; 5-Cyano-3,4-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-6-(prop-1- en-2-yl)picolinamide; 5-Cyano-6-isopropyl-3,4-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide; 5-Cyano-3,4-dimethyl-N-(5-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)- 6-(trifluoromethyl)picolinamide; 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-(prop-1-en-2- yl)benzamide; 5-Cyano-2-isopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 3-Cyano-2,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 3-Cyano-2-cyclopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide; 2-Chloro-4-cyano-6-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide; 5-Cyano-3,6-dimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide; 6-Cyano-2-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)nicotinamide; 2-Bromo-6-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)nicotinamide; 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)pyrazine-2-carboxamide; 5-Cyano-3-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)picolinamide; 6-Cyano-4-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)nicotinamide; 5-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)picolinamide; 4-Cyano-2-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 4-Cyano-2-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 3-Chloro-5-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)picolinamide; 2-Chloro-4-cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 5-Cyano-3,4,6-trimethyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)picolinamide; 5-Cyano-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)picolinamide; 4-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- (trifluoromethyl)benzamide;
6-Chloro-3-cyano-2-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
6-Cyano-3-methyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
5-Cyano-2-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
2-Chloro-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)ni cotinamide;
2-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)isoni cotinamide;
5-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)nicotinamide;
5-Cyano-6-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)nicotinamide;
2-Bromo-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2,6-difluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
2-Bromo-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-fluoro-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Bromo-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
4-Cyano-6-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
5-Cyano-2-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
2-Chloro-5-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-methoxy-/V-[l-(l-methylpyrazol-4-yl)indazol-6-yl]benzamide;
2-Chloro-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
5-Cyano-3,4-dimethyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6- (trifluoromethyl)picolinamide;
4-Cyano-3-methyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
6-Chloro-l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile;
5-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-pyrazolo [4, 3-6]pyridin-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(Bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; 8-((l-(l-(Bicyclo[l.l.l]pentan-l-yl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6- yl)oxy)-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-pyrazolo [3, 4-b]pyridin-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-pyrazolo [4, 3-c]pyridin-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(Difluoromethyl)-17/-pyrazol-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
7-Methyl-l-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile;
4-Methyl-8-((5-methyl-l-(l -methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
7 -Fluoro- 1 -((1 -( 1 -methyl- 17/-py razol -4-y 1)- 1 //-indazol -6-y I )oxy )-2.3 -dihydro- 1H- indene-5-carbonitrile;
2-Methyl-8-((5-methyl-l-(l -methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(l -(Difluoromethyl)- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Methyl-17/-imidazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(Thiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
4-Methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
1-Methyl-5-((l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
3-Methyl-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-Chloro-4-cyano-2,3-dimethyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
2-Chloro-7-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57/- cyclopenta[b]pyridine-3-carbonitrile; 5-((l-(l -Cy clopentyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(Benzo[r/|oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(l -(2,2, 2-Trifluoroethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(2-Methoxy ethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(3-Methoxy-l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Cyclopentyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
7-Methyl-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(Oxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(4-Phenyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(4,5-Dimethyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile;
5-((l-(5-Methyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(4-Methyloxazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(2-Methylthiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(Pyrimidin-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(2-Methylpyrimidin-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile;
5-((l-(3-Methylpyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(l -Methyl-17/-imidazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; 5-(( I -Pyrazin-2-yl)- 17/-indazol-6-yl)oxy )-5.6.7.8-tetrahy dronaphthalene-2- carbonitrile;
5-((l-(Pyridazin-3-yl)-177-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(2-(Pyrrolidin-l-yl)pyrimidin-5-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-Methyl-177-l,2,3-triazol-4-yl)-177-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(4-Methylpyrimi din-2 -yl)-17/-indazol-6-yl)oxy)-5, 6,7, 8-tetrahy dronaphthalene- 2-carbonitrile;
5-((l-(2-Morpholinopyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(Trifluoromethyl)pyrimidin-5-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Isopropyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l,3-Dimethyl-17/-pyrazol-4-yl)-77/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-Benzyl-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Phenyl- 177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(tert-Butyl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l,5-Dimethyl-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-(Oxetan-3-yl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(Pyri din-2-yl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(Tetr ahydro-2ff-pyran-4-yl)-177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -Ethyl- 177-pyrazol-4-yl)-177-indazol-6-yl)oxy)-5, 6, 7, 8-tetrahy dronaphthalene- 2-carbonitrile; 5-((l-(5-Methylthiazol-2-yl)-177-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(l -Methyl-17/-pyrazol-3-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Methyloxazol-5-yl)-177-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
3-Cyano-2-isopropyl-/V-(l-(l-(2-methoxyethyl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-/V-(l-(4,5-dimethyloxazol-2-yl)-17/-indazol-6-yl)-2-isopropylbenzamide;
3-Cyano-/V-(l-(l-cyclopentyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-JV-(l-(oxazol-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(4-phenyloxazol-2-yl)-17/-indazol-6-yl)benzamide;
7V-(l-(Benzo[<7]oxazol-2-yl)-177-indazol-6-yl)-3-cyano-2-isopropylbenzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methylthiazol-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(4-methylthiazol-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(pyrimidin-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-JV-(l-(2-methylpyrimidin-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(3-methylpyridin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(pyridazin-3-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-(pyrrolidin-l-yl)pyrimidin-5-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(pyrazolo[l,5-a]pyridin-3-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-isopropyl-7 /-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-7V-(l-(l,3-dimethyl-177-pyrazol-4-yl)-177-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-7V-(l-(l-phenyl-177-pyrazol-4-yl)-177-indazol-6-yl)benzamide;
7V-(l-(l-(/er/-Butyl)-177-pyrazol-4-yl)-177-indazol-6-yl)-3-cyano-2- isopropylbenzamide;
3-Cyano-2-isopropyl-7V-(l-(l-(oxetan-3-yl)-177-pyrazol-4-yl)-177-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-7V-(l-(l-methyl-177-pyrazol-3-yl)-177-indazol-6-yl)benzamide; methylpyridin-4-yl)-1H-indazol-6- yl)benzamide; 3-Cyano-2-isopropyl-N-(1-(3-morpholinophenyl)-1H-indazol-6-yl)benzamide; 3-Cyano-2-isopropyl-N-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)benzamide; 3-Cyano-2-isopropyl-N-(1-(pyrazin-2-yl)-1H-indazol-6-yl)benzamide; 3-Cyano-2-isopropyl-N-(1-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-6- yl)benzamide; 3-Cyano-2-isopropyl-N-(1-(1-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide; 3-Cyano-2-isopropyl-N-(1-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide; 3-Cyano-N-(1-(1-ethyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-isopropylbenzamide; 3-Cyano-N-(1-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- isopropylbenzamide; 3-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-(prop-1-en-2- yl)benzamide; 3-Cyano-2-fluoro-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide; 3-Cyano-2-methoxy-6-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide; 3-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- (trifluoromethoxy)benzamide; 3-Cyano-2-ethyl-6-fluoro-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6- yl)benzamide; 5-((1-(3-Morpholinophenyl)-1H-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile; 3-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2- (trifluoromethyl)benzamide; 5-((1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-1-carbonitrile; 4-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)benzamide; 4-Cyano-N-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)-2-(prop-1-en-2- yl)benzamide; 5-((l-(l-(Pyrimi din-2 -yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; and
8,8-Difluoro-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile, or pharmaceutically acceptable salts of any of the aforementioned.
63. The compound of claim 1, wherein the compound is selected from:
2-Methyl-8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
4-Methyl-8-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile; l-Methoxy-5-((l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Methoxy-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Chloro-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
6-Methyl-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; l-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/- indene-5-carbonitrile;
3-Fluoro-5-((l -(1 -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
3-Methoxy-5-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((4-Fluoro-l -(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroisoquinoline-3-carbonitrile; l-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-2,3-dihydro-17/-indene-5- carbonitrile; 5-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline- 2-carbonitrile;
4-Methy 1 - 8 - ((5 -methyl- 1 -(1 -methyl- 17/-py razol -4-y 1)- 17/-indazol-6-y l)amino)- 5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4- (trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile; l-Methoxy-5-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7-dihydro-57/- cyclopenta|6|pyrazme-2-carbonitrile;
1-Fluoro-5-((5-methyl-l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(Pyridazin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
4-(Difluoromethyl)-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(l -Methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl-3-d)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
2-(Difluoromethyl)-8-((l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
2-(Difluoromethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
6-((6-Cyano-l,2,3,4-tetrahydronaphthalen-l-yl)oxy)-l-(l-methyl-17/-pyrazol-4-yl)- 17/-indazole-5-carbonitrile;
8-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5-Methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Fluoro- 1 -(1 -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Fluoro- 1 -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-4-methyl-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
2-Chloro-8-((5-methyl-l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile; 4-(Difluoromethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
4-Methyl-7-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-6,7- dihydro-57/-cyclopenta[b]pyridine-3-carbonitrile;
8-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydrocinnoline- 3-carbonitrile;
5-((l-(l-(2-Hydroxy-2-methylpropyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(Methoxymethyl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l -(1,1-Dioxidothi etan-3 -yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((l-(2-Chloropyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3- carbonitrile;
8-((l -(6-(2-Oxa-6-azaspiro [3.3]heptan-6-yl)pyri din-3 -y 1)- 17/-indazol-6-yl)oxy )- 5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((l-(2-(3-Hy droxyazeti din-l-yl)pyri din-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(2-Methylpyridin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3- carbonitrile;
8-((l-(l -(Oxetan-3-ylmethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
4-Methoxy-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(4-(Dimethylphosphoryl)piperidin-l-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)- 5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((l-(2-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
8-((l-(2-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)methyl)pyridin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
4-(Methoxymethyl)-8-((5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(l-(Hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)-17/- indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile; 5-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6- (trifluoromethyl)picolinamide;
4-Cyano-3-isopropyl-/V-(l-(l-methyl-lH-pyrazol-4-yl)-17/-indazol-6-yl)picolinamide;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-vinylbenzamide;
3-Cyano-2-ethyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(pyridazin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(6-methylpyridazin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(6-methoxypyridazin-4-yl)-17/-indazol-6-yl)benzamide;
2-(But-2-en-2-yl)-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
2-(sec-Butyl)-3-cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
5-Cyano-4-isopropyl-N-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)ni cotinamide;
5-((l-(4-Methylthiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l -(2 -Methoxy thiazol-5-yl)- IT/-indazol-6-yl)oxy)-5.6,7, 8-tetrahydronaphthalene-2- carbonitrile;
5-((l -(4,5,6, 7-Tetrahydropyrazolo[l,5-a]pyridin-3-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Isopropylthiazol-5-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile;
5-((l-(Pyrazolo[l,5-a]pyridin-3-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(5-Methyl-l,3,4-oxadiazol-2-yl)-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-Methylthiazol-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
5-((l-(2-Morpholinopyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(Pyrimidin-4-yl)-17/-indazol-6-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2- carbonitrile;
3-Cyano-2-(prop-l-en-2-yl)-N-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-N-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methoxythiazol-5-yl)-17/-indazol-6-yl)benzamide; 3-Cyano-/V-(l-(l-(2-fluoroethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methoxypyrimidin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cy ano-2-isopropyl-/V-(l -(3-methoxy- 1 -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6- yl)benzamide;
3-Cyano-/V-(l-(l,5-dimethyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-/V-(l-(5-methyloxazol-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-morpholinopyridin-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-(2,2,2-trifluoroethyl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-JV-(l -(4,5,6, 7-tetrahy dropyrazolo[l, 5-a]pyridin-3-yl)-17/- indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-isopropylthiazol-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-(trifluoromethyl)pyrimidin-5-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-N-(l-(4-methyloxazol-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methylthiazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropenyl-6-methyl-JV-[l-(l-methylpyrazol-4-yl)indazol-6- yl]benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-(pyridin-4-yl)vinyl)-17/-indazol-6-yl)benzamide;
3-Cyano-/V-(l-(3-fluoro-l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
4-Cyano-2-isopropyl-JV-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-/V-(5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-(prop-l-en- 2-yl)benzamide;
3-Cyano-2-isopropyl-/V-(5-methyl-l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide; l-Methoxy-5-((l -(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; l-Isopropyl-5-((l-(l -methyl- 17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile; 5-((l -( 1 -Methyl- 17/-py razol-4-y 1)- 17/-indazol-6-yl)amino)- 1 -(trifluoromethy 1)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
3-Cyano-/V-(l-(5-fluoro-l-methyl-lH-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cy ano-6-fluoro-JV-( 1 -( 1 -methy 1- 17/-py razol-4-y 1)- I //-indazol -6-y l)-2-(prop- 1 -en-2- yl)benzamide;
3-Cyano-6-fluoro-2-isopropyl-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-/V-(l-(l-(2-cyanopropan-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2- isopropylbenzamide;
3-Cyano-2-isopropyl-JV-(l-(l-methyl-17/-imidazol-4-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-(tetrahydro-27/-pyran-4-yl)-17/-pyrazol-4-yl)-17/- indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-methyloxazol-5-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(4-methylpyrimidin-2-yl)-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(5-methyl-l,3,4-oxadiazol-2-yl)-17/-indazol-6- yl)benzamide;
JV-(l-(l-Benzyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-3-cyano-2 -isopropylbenzamide;
5-((l-(l-(2-Cyanopropan-2-yl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(5-Fluoro-l -methyl- 17/-pyrazol-4-yl)- 17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-Methyl-6-oxo-l,6-dihydropyridin-3-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(2-Oxaspiro[3.3]heptan-6-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
5-((l-(2-(6-Oxa-3-azabicyclo[3. 1. l]heptan-3-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
5-((l-(l-Methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)amino)-l-(prop-l-en-2-yl)-
5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
3-Cyano-2-isopropyl-/V-[l-[2-(4-methylpiperazin-l-yl)-4-pyridyl]indazol-6- yl]benzamide;
3-Cyano-2-isopropyl-JV-(l-methyl-17/-indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-(2-morpholinoethyl)-17/-pyrazol-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(l-((l-methylpiperidin-4-yl)methyl)-17/-pyrazol-4-yl)-17/- indazol-6-yl)benzamide;
3-Cyano-2-isopropyl-JV-(l-(2-(4-methylmorpholin-2-yl)pyridin-4-yl)-17/-indazol-6- yl)benzamide;
3-Cyano-2-isopropyl-/V-(l-(2-(4-methylmorpholin-3-yl)pyridin-4-yl)-17/-indazol-6- yl)benzamide;
Cyano-/V-(1 -(6-(3-(2-hy droxypropan-2-yl)pyrroli din-1 -yl)pyrimi din-4-yl)-17/- indazol-6-yl)-2-isopropylbenzamide;
3-Cyano-/V-(l-(l-methyl-17/-pyrazol-4-yl)-17/-indazol-6-yl)-2-(l,l,l-trifluoropropan- 2-yl)benzamide;
5-((l-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-l-carbonitrile;
5-((l-(6-((7?)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)amino)-5,6,7,8-tetrahydronaphthalene-l-carbonitrile;
3-Cyano-/V-(l-(l-(difluoromethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6-fluoro-2- (prop- 1 -en-2-y l)benzamide;
3-Cyano-JV-(l-(l-(difluoromethyl)-17/-pyrazol-4-yl)-17/-indazol-6-yl)-6-fluoro-2- isopropylbenzamide;
2-Cyano-JV-(l-(2-methoxy-6-methylpyridin-4-yl)-17/-indazol-6-yl)-3-(prop-l-en-2- yl)isonicotinamide;
2-Cyano-3-isopropyl-/V-(l-(2-methoxy-6-methylpyridin-4-yl)-17/-indazol-6- yl)isonicotinamide;
2-Cyano-3-(prop-l-en-2-yl)-JV-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)isonicotinamide;
2-Cyano-3-isopropyl-N-(l-(pyrimidin-4-yl)-17/-indazol-6-yl)isonicotinamide;
3-Cyano-2-isopropyl-/V-(l-(2-(pyridin-4-yl)cyclopropyl)-17/-indazol-6-yl)benzamide;
3-cyano-/V-(l-(2-(2,6-dimethylpyridin-4-yl)vinyl)-17/-indazol-6-yl)-2- isopropylbenzamide;
5-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-5,6,7,8- tetrahydronaphthalene- 1 -carbonitrile; l-((l-(2-Methoxy-6-methylpyridin-4-yl)-5-methyl-17/-indazol-6-yl)oxy)-2,3-dihydro- 17/-indene-5 -carbonitrile; 3-Cyano-2-isopropyl-/V-(l-(2-(2-methoxyethoxy)-6-methylpyridin-4-yl)-17/-indazol- 6-yl)benzamide;
2-Cyano-3-isopropyl-/V-(l-(2-(oxazol-4-yl)vinyl)-17/-indazol-6-yl)isonicotinamide;
2-Cyano-3-isopropyl-/V-(l-(2-(l-methyl-17/-pyrazol-4-yl)vinyl)-lH-indazol-6- yl)isonicotinamide;
5-((l-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile;
5-((l-(6-((7?)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile;
5-((l-(2-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)- 5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile;
5-((l-(6-(3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile; l-((l-(2-(3-(2-Hydroxypropan-2-yl)azetidin-l-yl)pyridin-4-yl)-17/-indazol-6-yl)oxy)- 2,3-dihydro-17/-indene-5-carbonitrile; l-((l-(6-((S)-3-(2-Hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile; l-((l-(6-((7?)-3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)-17/-indazol-6- yl)oxy)-2,3-dihydro-17/-indene-5-carbonitrile;
8-((l-(2-(2-Methylpyridin-4-yl)vinyl)-17/-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-[l-(2,6-Dimethoxy-4-pyridyl)indazol-6-yl]oxy-5,6,7,8-tetrahydroquinoline-3- carbonitrile;
8-((5-Methy 1- 1 -( 1 -methyl- 17/-pyrazol-4-y 1)- 17/-indazol-6-yl)oxy)-4- (trifhioromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
(£)-2-Cyano-3-isopropyl-/V-(l-(2-(2-methylpyridin-4-yl)vinyl)-17/-indazol-6- yl)isonicotinamide;
8-((5-Methyl-l -(2-(l-methyl-lH-pyrazol-4-yl)vinyl)-lH-indazol-6-yl)oxy )-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(3-(3-Methoxyazeti din-l-yl)prop-l -en-l-yl)-lH-indazol-6-yl)oxy )-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((l-(4-Oxospiro[2.5]oct-5-en-6-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile; 8-((5 -Methyl- 1 -(3-(4-methy Ipiperazin- 1 -y l)prop- 1 -en- 1 -y 1)- 1 H-indazol-6-y l)oxy )-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitrile;
8-((5-Methyl-l-(l-((l-methylazetidin-3-yl)methyl)-lH-pyrazol-4-yl)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
8-((5-Chloro-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(6-(4-Methylpiperazin-l-yl)pyridazin-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5 -Chloro- 1 -( 1 -methyl- 1 H-pyrazol-4-y 1)- lH-indazol-6-y l)oxy )-4-(trifluoromethy 1)-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitril e;
5-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-l- (methylsulfonyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
8-((l -(3-(3,3-Difluoropyrrolidin- 1 -yl)prop- 1 -en- 1 -yl)-5-methyl-lH-indazol-6-yl)oxy)-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitril e;
8-((l -(Prop-1 -en-l-yl)-lH-indazol-6-yl)oxy )-4-(trifluoromethyl)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
4-Methoxy-8-((5-methyl-l-(2-(l-methyl-lH-pyrazol-4-yl)vinyl)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile;
5-((5-Methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-l-(oxetan-3- yloxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
4-Ethyl-8-((5-methyl-l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(3-Oxocyclohex-l-en-l-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydronaphthalene-2-carbonitrile;
8-((5-Methyl-l-(3-(pyrrolidin-l-yl)prop-l-en-l-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
6-((6-Cy ano- 1 ,2,3,4-tetrahy dronaphthalen-1 -yl)oxy)-N-methyl- IH-indazole- 1 - carboxamide;
4-Methoxy-8-((5-methyl-l-(2-methylpyri din-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((5-Methyl-l-(3-(4-methylpiperazin-l-yl)-3-oxoprop-l-en-l-yl)-lH-indazol-6- yl)oxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile; 8-((l-(2-(4-Methylpiperazin-l-yl)pyridin-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(Morpholinomethyl)pyri din-4-yl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
8-((l-(2-(l-Methyl-lH-pyrazol-3-yl)vinyl)-lH-indazol-6-yl)oxy)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile;
5-((l-(l-((l-Methylazetidin-3-yl)methyl)-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
8-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-5,6,7,8-tetrahydroquinoline- 3, 4-di carbonitrile;
6-((6-Cyano-l,2,3,4-tetrahydronaphthalen-l-yl)oxy)-N-phenyl-lH-indazole-l- carboxamide;
8-((l-(r-Methyl-r,2',3',6'-tetrahydro-[2,4'-bipyridin]-4-yl)-lH-indazol-6-yl)oxy)-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitril e;
8-((l-(3-Oxocyclopent-l-en-l-yl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-5,6,7,8- tetrahydroquinoline-3-carbonitrile;
7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile;
8-((l-(2-(2-Methylpyridin-4-yl)vinyl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-
5 , 6, 7 , 8 -tetrahy droquinoline-3 -carbonitril e;
8-((l-(2-(Oxetan-3-yl)vinyl)-lH-indazol-6-yl)oxy)-4-(trifluoromethyl)-5, 6,7,8- tetrahydroquinoline-3-carbonitrile; and
7-((l-(l-Methyl-lH-pyrazol-4-yl)-lH-indazol-6-yl)amino)-4-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile, or pharmaceutically acceptable salts of any of the aforementioned.
64. A pharmaceutical composition comprising a compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
65. A method of inhibiting LRRK2 activity, said method comprising contacting a compound of any one of claims 1-63 or a pharmaceutically acceptable salt thereof with LRRK2.
66. The method of claim 65, wherein the LRRK2 is characterized by a G2019S mutation.
67. The method of claim 65, wherein the contacting comprises administering the compound to a patient.
68. A method of treating a disease or disorder associated with elevated expression or activity of LRRK2, or a functional variant thereof, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof.
69. The method of claim 68, wherein the LRRK2 is characterized by a G2019S mutation.
70. A method for treating a neurodegenerative disease in a patient, said method comprising: administering to the patient a therapeutically effective amount of the compound of any one of claims 1-63 or a pharmaceutically acceptable salt thereof.
71. The method of claim 70, wherein said neurodegenerative disease is selected from Parkinson's disease, Parkinson disease with dementia, Parkinson's associated risksyndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy -Drager syndrome.
72. The method of claim 70, wherein said neurodegenerative disease is Parkinson’s disease.
73. The method of claim 72, wherein the Parkinson’s disease is characterized by a G2019S mutation in LRRK2.
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CN115650909A (en) * 2022-10-19 2023-01-31 山西永津集团有限公司 Synthetic method of 3-amino isonicotinic nitrile

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