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WO2025038863A1 - Dérivés d'indole et de pyrroloypyridine utilisés en tant que modulateurs de gpr17 - Google Patents

Dérivés d'indole et de pyrroloypyridine utilisés en tant que modulateurs de gpr17 Download PDF

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WO2025038863A1
WO2025038863A1 PCT/US2024/042520 US2024042520W WO2025038863A1 WO 2025038863 A1 WO2025038863 A1 WO 2025038863A1 US 2024042520 W US2024042520 W US 2024042520W WO 2025038863 A1 WO2025038863 A1 WO 2025038863A1
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chloro
compound
pharmaceutically acceptable
independently selected
acceptable salt
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Andrew George CAPACCI
Ryan Evans
Thomas J. PURGETT
Zackary STEIN
Zain YOUSAF
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Biogen MA Inc
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Biogen MA Inc
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    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to new indole and pyrrolopyridine compounds and their use for treating GPR17 mediated disorders.
  • the present invention also relates to pharmaceutical compositions of the compounds and their use as a medicine, for example, for the treatment of GPR17 mediated disorders.
  • the invention also relates to processes for preparation of said compounds.
  • GPR17 is a member of a class of membrane receptors called G-protein coupled receptors (GPCRs). These receptors are characterized by a seven transmembrane domain structure with an intracellular region that couples through G proteins to numerous of intracellular signaling pathways. Many GPCRs have been used as targets for pharmaceutical drugs and diagnostics. Effective modulation of the GPR17 activity may have neuroprotective, anti- inflammatory, and anti- ischemic effects and may thus be useful for the treatment of cerebral, cardiac, and renal ischemia, and stroke, and/or for improving the recovery from these events. Pulmonary fibrosis may also be alleviated through suppressing GPR17-mediated inflammation.
  • GPR17 modulators are also thought to be involved in food uptake, insulin and leptin responses and are thus could have a role in obesity treatment. Moreover, there is strong evidence that GPR17 is involved in myelination processes. Myelin is an essential component of a healthy central nervous system (CNS). The failure to form myelin, damage to myelin and/or the failure to repair myelin may cause certain diseases and may also be a secondary consequence of certain diseases.
  • CNS central nervous system
  • the failure to form myelin, damage to myelin and/or the failure to repair myelin may cause certain diseases and may also be a secondary consequence of certain diseases.
  • One example of a disease that is primarily a result of damage to myelin is multiple sclerosis (MS). MS affects approximately 400,000 people in the United States and about 2.5 million people worldwide and is approximately three times more likely to occur in women than men.
  • MS is an inflammatory autoimmune disease that arises from an immune attack directed at oligodendrocytes which results in myelin damage and ultimately loss of neuronal axons.
  • the immediate consequence is a collection of acute symptoms that include difficulty in movement, speech, swallowing, dizziness, and fatigue. Symptoms may also include problems with vision, hearing, or balance.
  • the disease can take several forms. One form is associated with relapses and remissions where the acute symptoms resolve over time, and this form is termed relapsing remitting multiple sclerosis (RRMS).
  • RRMS relapsing remitting multiple sclerosis
  • Another form of the disease, primary progressive MS (PPMS) is characterized by a failure to resolve symptoms between attacks, and is considered a more severe form of the disease.
  • MS is a CNS disease
  • BBB blood brain barrier
  • many compounds targeting GPR17 have low brain penetration, low stability, and/or high efflux.
  • GPR17 mediated diseases such as myelination diseases (e.g., MS)
  • MS myelination diseases
  • the compounds should have excellent GPR17 potency and microsomal stability.
  • FIGURES Fig.1 A schematic of plasma and PBS buffer solution including volumes to RED plated and aliquoted to crash plates.
  • SUMMARY OF THE INVENTION Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions comprising the compounds or pharmaceutically acceptable salts thereof, which are useful for treating GPR17 mediated disorders.
  • the compounds of the present disclosure have improved potency, microsomal stability, and/or brain penetration in comparison to known GPR17 inhibitors.
  • X is N or CR x ;
  • R x is H, halo, OR x1 , SR x1 , C1-3alkyl, C1-3haloalkyl, NR x1 R x1 , C(O)R x1a , cyano, C 3-6 cycloalkyl, phenyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6-membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R x2 ;
  • R x1 is H, C1-3alkyl or C1-3haloalkyl;
  • R x1a is OR x1 , NR x1 R x1 , C
  • compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is for use in treating a disease or disorder mediated by GPR17.
  • Another aspect of the disclosure is a method of regulating GPR17 activities in a subject in need thereof. The method comprises administrating to the subject in need thereof an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • a compound of the disclosure for the manufacture of a medicament for regulating GPR17 activities in a subject in need thereof.
  • the disclosure also provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in regulating GPR17 activities in a subject in need thereof.
  • Another aspect of the disclosure is a method of treating a subject suffering from a disease or disorder mediated by GPR17. The method comprises administrating to the subject an effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • a compound of the disclosure for the manufacture of a medicament for treating a subject suffering from a disease or disorder mediated by GPR17.
  • the disclosure also provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a subject suffering from a disease or disorder mediated by GPR17.
  • Another aspect of the disclosure is a method of promoting myelination in a subject with a myelin-related disease. The method comprises administrating to the subject an effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • a compound of the disclosure for the manufacture of a medicament for promoting myelination in a subject with a myelin-related disease.
  • the disclosure also provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in promoting myelination in a subject with a myelin-related disease.
  • DETAILED DESCRIPTION OF THE INVENTION The compounds or pharmaceutically acceptable salts thereof, as described herein, can have activity as GPR17 modulators.
  • compounds or pharmaceutically acceptable salts thereof, as described herein can be GPR17 inhibitors.
  • the compounds of the disclosure are represented by Formula (I): or a pharmaceutical salt thereof, wherein: X is N or CR x ; R x is H, halo, OR x1 , SR x1 , C1-3alkyl, C 3-6 cycloalkyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6- membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R x1 is H, C1-3alkyl or C1-3haloalkyl; Ring A is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected form N, O and S, or a 9 to 10-membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R 1 , for each
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CR x ; R x is halo, OR x1 , SR x1 , C1-3alkyl, C1-3haloalkyl, NR x1 R x1 , C(O)R x1a , cyano, C3- 6 cycloalkyl, phenyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6-membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R x2 ; and R 2 is halo, C1-3alkyl, C1-3haloalkyl, C1-3alkyl
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, -CH3, -CH2CHF2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OH, -CH 2 C(O)OH, or -CH 2 C(O)NHCH 3 ; and the remainder of the variables are as described for Formula (I) above.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is H; and the remainder of the variables are as described for Formula (I) above.
  • the compounds of the disclosure are represented by Formula (I) or a pharmaceutical acceptable salt thereof, wherein X is CR x ; and R x is H, -Cl, or –OCH 3 ; and the remainder of the variables are as described for Formula (I) above.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (II), or a pharmaceutically acceptable salt thereof, wherein the variables are as described for Formula (I) above.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (IIIa), (IIIa); or a pharmaceutically acceptable salt thereof, wherein the variables are as described for Formula (I) above.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrazolyl, dihydropyrrolopyrazolyl, dihydropyrazolooxazolyl, dihydropyrazolooxazinyl, pyrazolopyrazinonyl, pyrazolopyridinyl, triazolyl, imidazolyl, imidazothiazolyl, imidazopyridinyl, triazolopyridinyl, isothiazolyl, thiazolyl, dihydrothiopyranothiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisox
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrazolyl, triazolyl, isothiazolyl, thiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl, each of which is optionally substituted with 1 or 2 R 1 ; and the remaining variables are as described in the first aspect or the first, second or third embodiment.
  • Ring A is selected from the group consisting of pyrazolyl, triazolyl, isothiazolyl, thiazolyl, thiadiazolyl, thiophenyl, isoxazolyl,
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula: each of which is optionally substituted with 1 to 3 R 1 ; and the remainder of the variables are as described in the first aspect or the first, second or third embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula: each of which is optionally substituted with 1 or 2 R 1 ; and the remainder of the variables are as described in the first aspect or the first, second or third embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula:
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein: R 1 , for each occurrence, is independently selected from halo, -CN, C 1-7 alkyl, –OR 1a , - C(O)NR 1b R 1b , C 3-6 cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl, wherein the C 1-7 alkyl is optionally substituted with 1 to 3 R 10 , and wherein the C 3-6 cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halo, C 1-3 alkyl, and C 1-3 haloalkyl; R 1a is H or C 1-4 alkyl optionally substituted with 1 to 3 halo; each R 1b is independently H or C1-3alkyl; R
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein: R 1 , for each occurrence, is independently selected from halo, -CN, C 1-7 alkyl, –OR 1a , C 3-6 cycloalkyl, and phenyl, wherein the C 1-7 alkyl is optionally substituted with 1 to 3 R 10 ; R 1a is C 1-4 alkyl optionally substituted with 1 to 3 halo; R 10 , for each occurrence, is independently selected from halo, -CN, -OR 1a , -SR 1a , C3- 6cycloalkyl, phenyl, and 4 to 6 membered saturated heterocyclyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, or sixth embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 1 , for each occurrence, is independently selected from -F, - Cl, -Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2C(CH3)3, - CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3 , -(CH 2 ) 6 CH 3 , -CH 2 CH 2 CH 2 CN, - CH 2 CH 2 CN, -CH 2 CN, -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CHF 2 , -CF 3 , - CH2CH2CF3, -CH2CF
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 1 , for each occurrence, is independently selected from –Cl, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - CH2CH2CH(CH3)2,-(CH2)6CH3, -CH2CH2CN, -CH2CN, -CHF2, -CF3, CH2CH2CF3, -CH2CF3, -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CH2Cl, -CH2CH2CHF2, -OCH3, -OCH2CH3, - CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CF 3 , -OCHF 2 , cycl
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1- 3haloalkoxy, -N(C1-3alkyl)2, phenyloxy, benzyloxy, -O-pyridinyl, -O-(methylpyrazolyl), -O- thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O-CH2-(methylpyrazolyl), -O-CH2-oxazolyl, or - O-CH 2 -thiazolyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, halo, C 1-3 alkoxy, C 1-3 haloalkyl, phenyloxy, benzyloxy, -O- pyridinyl, -O-(methylpyrazolyl), -O-thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O-CH2- (methylpyrazolyl), -O-CH2-oxazolyl, or -O-CH2-thiazolyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, halo, C 1-3 alkyl, C 1- 3alkoxy, C1-3haloalkyl, C1-3haloalkoxy-N(C1-3alkyl)2, or benzyloxy; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, Cl, Br, -OCH 3 , -CHF 2 , -CF 3 , the remainder of the variables are as described in the ninth embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -F, Cl, Br, -CH3, -CH2CH3, - CH2CH2CH3, -OCH3, -OCHF2, -OCF3, -OCH2CH3, -OCH2CH2CH3, -CHF2, -CF3, -N(CH3)2, the remainder of the variables are as described in the ninth embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein: X is CR x ; R x is H, halo, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, -N(C1-3alkyl)2, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 5 to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected form N, O, and S, wherein the phenyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 or 2 R x2 ; each R x2 is independently halo, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3- 4cycloalkyl, or two R x2 , together with the atom
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R x is phenyl, pyrrolidinyl, morpholinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, wherein the pyrazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl are each optionally substituted with 1 or 3 R x2 ; and the remainder of the variables are as described above.
  • R x is phenyl, pyrrolidinyl,
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein each R x2 is independently -CH 3 , -CHF 2 , -CH 2 CH 3 , -OCH 3 , - F,-Cl, -Br, -CN, or cyclopropyl; or two R x2 , together with the atoms to which they are attached, form cyclopentenyl or dihydrofuranyl; and the remainder of the variables are as described above.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein X is CR x and R x is H, -F, -Cl, -Br, -CH 3 , -CHF 2 , -CH 2 CH 3 , - the variables are as described above.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (IIIa), or a pharmaceutically acceptable salt thereof, wherein: R x is halo or 5-to 6-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O, and S, wherein the 5-to 6-membered monocyclic heteroaryl is optionally substituted with 1 to 2 R x2 ; each R x2 is independently halo, C1-3alkyl,or C3-4cycloalkyl, or two R x2 , together with the atoms to which they are attached, form C 3-6 carbocyclyl; R 2 is halo, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 haloalkyl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R 1 for each occurrence, is independently selected from halo, OR 1a , C 1-3 allkyl and C 1-
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III), or a pharmaceutically acceptable salt thereof, wherein: R x is halo or 5-to 6-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S, wherein the 5-to 6-membered monocyclic heteroaryl is optionally substituted with 1 to 2 R x2 ; each R x2 is independently halo, C1-3alkyl,or C3-4cycloalkyl, or two R x2 , together with the atoms to which they are attached, form C 3-6 carbocyclyl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R 1 for each occurrence, is independently selected from halo, OR 1a , C 1-3 allkyl and C 1- 3haloalkyl; R 1a is C1-3alkyl; and n is 1 or 2; and the remaining variables
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III), or a pharmaceutically acceptable salt thereof, wherein: R x is H or Cl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R 1 for each occurrence, is independently selected from halo, OR 1a , C 1-3 allkyl and C 1- 3haloalkyl; R 1a is C1-3alkyl; n is 1 or 2; and the remaining variables are as described for Formula (I) in the first aspect or the first embodiment.
  • R x is H or Cl
  • Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S
  • R 1 for each occurrence, is independently selected from halo, OR 1a , C 1-3 allkyl and C 1- 3haloalkyl
  • R 1a is C1-3alkyl
  • n is 1 or 2
  • the remaining variables are as described for Formula (I
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R x is pyrazolyl optionally substituted with halo; and the remainder of the variables are as described in the eleventh embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R x is H.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is isoxazolyl, pyrazolyl, or isothiazolyl, each of which is substituted with 1 or 2 R 1 ; and the remainder of the variables are as described in the eleventh embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula: and the remainder of the variables are as described in the eleventh embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 1 , for each occurrence, is independently selected from –Cl, - CH 2 CH 3 , -CHF 2 , -CF 3 , -CH 2 CH 2 Cl and -OCH 3 ; and the remainder of the variables are as described in the eleventh, twelfth, or thirteenth embodiment.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein ring A is represented by: wherein R 100 is C 1-3 haloalkyl and R 101 is halo; and the remainder of the variables are as described in the eleventh, twelfth, thirteenth, or fourteenth embodiment.
  • R x is H.
  • the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R 100 is -CHF2 or -CH2CH2Cl, and R 101 is Br; and the remainder of the variables are as described in the eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.
  • R 100 is -CHF2 or -CH2CH2Cl
  • R 101 is Br
  • the remainder of the variables are as described in the eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.
  • the compounds of the disclosure are shown below in Table 1 and in the Exemplification. Pharmaceutically acceptable salts thereof and the corresponding neutral form are included in the disclosure. Table 1:
  • the term “pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66:1-19.
  • Compounds of this disclosure with basic groups can form pharmaceutically acceptable salts with pharmaceuticallyacceptable acid(s).
  • Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids).
  • Compounds of this disclosure with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s).
  • Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • alkyl used alone or as part of a larger moiety, such as “alkoxy”, “alkylphenyl”, alkylspirocycloalkyl” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical.
  • an alkyl group typically has 1 to 10 carbon atoms (C 1-10 alkyl), 1 to 7 carbon atoms (C 1-7 alkyl), 1 to 6 carbon atoms (C1-6alkyl) (i.e., 1, 2, 3, 4, 5 or 6), alternatively, 1 to 4 carbon atoms (C1-4alkyl) (i.e., 1, 2, 3, or 4), alternatively, 1 to 3 carbon atoms (C1-3 alkyl) (i.e., 1, 2 or 3).
  • Examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and the like.
  • alkoxy used alone or as part of a larger moiety, such as haloalkoxy or alkylalkoxy, means a saturated aliphatic straight-chain or branched monovalent radical composed of an alkyl group bonded to oxygen. Unless otherwise specified, an alkoxy group typically has 1 to 6 carbon atoms and an oxygen atom (C1-6alkoxy), alternatively, 1 to 4 carbon atoms and an oxygen atom (C1-3 alkoxy). Examples of alkoxy include methoxy, ethoxy, and the like.
  • halogen or “halo” means fluorine or fluoro (F), chlorine or chloro (Cl) or bromine or bromo (Br).
  • haloalkyl used alone or as part of a large moiety, such as haloalkoxy or alkylhaloalkoxy, means an alkyl group wherein at least one hydrogen substituent is replaced by a halogen group. Unless otherwise specified, a haloalkyl group typically has 1 to 6 carbon atoms (C1-6haloalkyl), alternatively, 1 to 4 carbon atoms (C1-4haloalkyl). Examples include trifluoromethyl, trifluoroethyl, difluoroethyl, and the like.
  • haloalkoxy used alone or as part of a larger moiety, such as alkylhaloalkoxy, means an alkoxy group wherein at least one hydrogen substituent is replaced by a halogen. Unless otherwise specified, an haloalkoxy typically has 1 to 6 carbon atoms (C 1-6 haloalkoxy), alternatively 1 to 4 carbon atoms (C 1-4 haloalkoxy). Examples include difluoroethoxy and the like.
  • cycloalkyl used alone or as part of a larger moiety, such as alkylcycloalkyl, means a saturated aliphatic monocyclic hydrocarbon ring radical.
  • a cycloalkyl has 3 to 6 ring carbon atoms (C 3-6 cycloalkyl), alternatively, 3 to 5 ring carbon atoms (C3-5 cycloalkyl), alternatively, 3 to 4 carbon atoms (C3-4 cycloalkyl).
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, and the like.
  • the term “carbocyclyl”, used alone or as part of a larger moiety, means a fully or partially saturated monocyclic hydrocarbon ring radical.
  • a carbocyclyl has 3 to 6 ring carbon atoms (C 3 - 6 carbocyclyl), alternatively, 3 to 5 ring carbon atoms (C 3 - 5 carbocyclyl), alternatively, 3 to 4 carbon atoms (C 3-4 carbocyclyl).
  • carbocyclyl include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, and the like.
  • heterocyclyl refers to a non-aromatic, fully or partially saturated monocyclic or bicyclic (fused, bridged or spiro) ring radical having 1 to 4 ring heteroatoms independently selected from N, O, and S.
  • the heterocyclyl is a monocyclic ring radical, for example, a 4- to 8-membered monocyclic ring radical.
  • the heterocyclyl is a bicyclic ring radical, for example a 9- to 10-membered bicyclic ring radical.
  • Exemplary nitrogen containing heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.
  • Exemplary oxygen containing heterocycles include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
  • Exemplary heterocycles that contain both N and O include morpholinyl and the like.
  • a fused bicyclic ring is a ring system that has two rings each of which are independently selected from a carbocyclyl or a heterocyclyl, wherein the two ring structures share two adjacent ring atoms.
  • a fused ring may have from 9 to 12 ring members.
  • a bridged bicyclic ring is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably from one to three) atoms selected from C, N, O, or S.
  • a bridged ring may have from 6 to 8 ring members.
  • a spiro ring is a ring system that has two rings each of which are independently selected from a carbocyclyl or a heterocyclyl, wherein the two ring structures having one ring atom in common.
  • a spiro ring may have from 5 to 8 ring members.
  • Heteroaryl refers to an aromatic monocyclic or bicyclic ring radical having 1 to 4 ring heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone.
  • the heteroaryl is a monocyclic ring radical, such as 5- to 6-membered monocyclic ring.
  • the heteroaryl is a bicyclic ring radical, such as 9- to 10-membered bicyclic ring.
  • Examples of 5- to 6-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like.
  • 9- to 10-membered bicyclic heteroaryls include, but are not limited to, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl and the like.
  • substituted refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent.
  • a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group.
  • monofluoroalkyl is an alkyl substituted with a fluoro substituent
  • difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated). If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions.
  • Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both.
  • Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
  • Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.
  • the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds)
  • the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%.
  • “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.
  • “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.
  • a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center.
  • a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.
  • a racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer.
  • the present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.
  • a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”).
  • Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • the present disclosure provides methods of regulating or modulating GPR17 activity. In some embodiments, the present disclosure further provides methods of inhibiting GPR17 activity in a subject in need thereof by administering to the subject an effective amount of a compound of the disclosure. In some embodiments, the present disclosure relates to the use of the compound of present disclosure as a medicine, and preferably for use in the treatment of a GPR17 mediated disease or disorder.
  • the present disclosure provides methods of treating a subject suffering from a disease or disorder mediated by GPR17 by administering to the subject an effective amount of a compound of the disclosure
  • a “GPR17 mediated disease or disorder” or a “disease or disorder mediated by GPR17” can be defined as a disease or disorder which is associated with a dysfunction of the GPR17 singling system such as, for example, an overexpression and/or overactivity of GPR17 receptors.
  • the term of “myelination disease or disorder” or “myelin-related disease or disorder” includes demyelination, dysmyelination and hypomyelination disease or disorders.
  • the disclosure provides methods of treating a subject suffering from a demyelination disease or disorder.
  • a demyelination disease or disorder is a disease or disorder that causes damage to the protective covering (myelin sheath) that surrounds nerve fibers in the brain, the nerves leading to the eyes (optic nerves) and spinal cord.
  • the compounds described herein can be used for the treatment of various diseases of the CNS system, such as a CNS disorder associated with myelin loss and an inflammation disorder in CNS.
  • the compounds described herein have good brain penetration (i.e. are able to pass the blood-brain-barrier).
  • the compounds described herein have excellent microsomal stability.
  • the compounds described herein are potent GPR17 inbibitors.
  • the compounds of the present disclosure can be used in promoting, stimulating and/or accelerating remyelination or myelination in a subject in need thereof.
  • the compounds of the present disclosure can be used in treating a disease or disorder selected from multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
  • MS is a relapsing form of MS.
  • a “relapsing form of MS” includes clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease.
  • the compounds described herein can be used for treating MS selected from relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), non-relapsing SPMS, primary progressive MS (PPMS), clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS).
  • CIS is a first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system. The episode, which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS.
  • CIS When CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS.
  • CIS When CIS is not accompanied by MS-like lesions on a brain MRI, the person has a much lower likelihood of developing MS.
  • RRMS the most common disease course of MS, is characterized by clearly defined attacks of new or increasing neurologic symptoms. These attacks – also called relapses or exacerbations – are followed by periods of partial or complete recovery (remissions). During remissions, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission.
  • RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity over a specified period of time) or not active, as well as worsening (a confirmed increase in disability following a relapse) or not worsening.
  • SPMS follows an initial relapsing-remitting course. Some people who are diagnosed with RRMS will eventually transition to a secondary progressive course in which there is a progressive worsening of neurologic function (accumulation of disability) over time.
  • SPMS can be further characterized as either active (with relapses and/or evidence of new MRI activity during a specified period of time) or not active, as well as with progression (evidence of disability accumulation over time, with or without relapses or new MRI activity) or without progression.
  • PPMS is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions.
  • PPMS can be further characterized as either active (with an occasional relapse and/or evidence of new MRI activity over a specified period of time) or not active, as well as with progression (evidence of disability accumulation over time, with or without relapse or new MRI activity) or without progression.
  • Patients diagnosed with RIS do not present any overt symptoms of MS, but exhibit brain abnormality (e.g., observed by magnetic resonance imaging (MRI)) that are similar to what is seen in patients with MS.
  • MRI magnetic resonance imaging
  • RIS Although there is a strong association between RIS and MS (RIS often indicates the earliest detectable preclinical phase of the disease), patients with RIS may not go on to develop MS.
  • Compounds of the present disclosure can also be useful in the treatment of a disorder or syndrome associated with brain tissue damage, a cerebrovascular disorder, and certain neurodegenerative diseases. Neurodegenerative disorders have been recently associated strongly with a loss of myelination. Accordingly, it is believed that preserved oligodendroglial and myelin functionality is a crucial prerequisite for the prevention of axonal and neuronal degeneration.
  • the compounds of the present disclosure can used in treating a neurodegenerative disease associated with demyelination and/or impacted myelination, such as amyotropic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, Huntington Disease or Parkinson's Disease.
  • a neurodegenerative disease associated with demyelination and/or impacted myelination such as amyotropic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, Huntington Disease or Parkinson's Disease.
  • ALS amyotropic lateral sclerosis
  • MSA multiple system atrophy
  • Alzheimer's disease Huntington Disease or Parkinson's Disease.
  • the compounds of the disclosure or pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way for use in human or veterinary medicine.
  • the disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.
  • 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.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such
  • the amount of compound of the disclosure or pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure or pharmaceutically acceptable salts thereof include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the compounds of the disclosure or pharmaceutically acceptable salts thereof are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.
  • an effective amount means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.
  • an effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day).
  • the precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general the route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • administer refers to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like.
  • a ”treating” or “treatment” of any disease or disorder includes, in one embodiment, to improve the disease or disorder (i.e., arresting or reducing the development of the disease or at least reducing one of the clinical symptoms of the disease).
  • treating refers to improve at least one physical parameter, which may or may not be discernible by the subject, in particular a human subject, but which is based on or associated with the disease or disorder to be treated
  • “treating” or treatment” refers to modulating the disease or disorder, either physically (e.g. stabilization of discernible on non-discernible symptom), physiologically (e.g. stabilization of a physiological parameter), or both.
  • “treating” or treatment” refers to delaying the onset or delaying, inhibiting or decreaseing the likelihood of the progression of the disease or disorder. Accordingly, “treating” or treatment” includes any causal treatment of the underlying disease or disorder (i.e.
  • Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.
  • a “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • veterinary treatment e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the patient is a human.
  • the patient is an adult human.
  • silica gel chromatography was performed using 20 ⁇ 40 ⁇ M (particle size), 250 ⁇ 400 mesh, or 400 ⁇ 632 mesh silica gel using either a Teledyne ISCO Combiflash RF or a Grace Reveleris X2 with ELSD purification systems or using pressurized nitrogen ( ⁇ 10-15 psi) to drive solvent through the column (“flash chromatography”). Wherein an SCX column has been used, the eluant conditions are MeOH followed by methanolic ammonia. Except where otherwise noted, reactions were run under an atmosphere of nitrogen.
  • the disclosure further includes any variant of the present processes, in which the reaction components are used in the form of their salts or optically pure material.
  • Compounds of the disclosure and intermediates can also be converted into each other according to methods generally known to those skilled in the art.
  • SFC analytical separation Instrument Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150 ⁇ 4.6mm I.D., 3 ⁇ m. Mobile phase: A for CO2 and B for Ethanol (0.05%DEA). Gradient: B 40%. Flow rate: 2.5 mL/min. Back pressure: 100 bar. Column temperature: 35° C. Wavelength: 220nm.
  • Detectors Gilson UV/VIS-156 with UV detection at 220/254 nm, Gilson 281 automatic collection, utilizing acidic, basic and neutral methods. For mass-directed peak collection, an ACQUITY QDa Mass Detector (Waters Corporation) was employed.
  • Preparative SFC purification Instrument MG III preparative SFC (SFC-1). Column: ChiralCel OJ, 250 ⁇ 30mm I.D., 5 ⁇ m. Mobile phase: A for CO2 and B for Ethanol (0.1%NH3H2O). Gradient: B 50%. Flow rate: 40 mL /min. Back pressure: 100 bar. Column temperature: 38° C. Wavelength: 220nm. Cycle time: ⁇ 8min.
  • the 1H NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance III 400 MHz, Varian-400 VNMRS, or Varian-400 MR.
  • Characteristic chemical shifts ( ⁇ ) are given in parts-per-million downfield from tetramethylsilane (for 1 H-NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad.
  • Step b To a solution of methyl 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-carboxylate (160.00 mg, 684.91 ⁇ mol, 1.0 eq.) and CaCl2 (76.01 mg, 684.91 ⁇ mol, 1.0 eq.) in EtOH (2.0 mL) was added NaBH 4 (51.82 mg, 1.37 mmol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with water (20 mL) and extracted with EA (15 mL x 3). The combined organic layers was washed with brine (20 mL), dried over Na2SO4.
  • Step c To a solution of (1-(2-chloroethyl)-4-nitro-1H-pyrazol-5-yl)methanol (86.00 mg, 418.29 ⁇ mol, 1.0 eq.) in DCM (10.0 mL) was added MnO 2 (727.30 mg, 8.37 mmol, 20.0 eq.) at 25 °C. The mixture was stirred at 40 °C for 3 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5- carbaldehyde (60.00 mg, 70.46% yield).
  • Step e To a solution of 1-(2-chloroethyl)-5-(difluoromethyl)-4-nitro-1H-pyrazole (35.00 mg, 155.16 ⁇ mol, 1.0 eq.) in MeOH (5.0 mL) was added Pd/C (16.51 mg, 15.52 ⁇ mol, 10% purity, 0.1 eq.) at 25 °C under H2 (30 Psi). The reaction was stirred at 25 °C for 2 hours. The mixture was filtrated and concentrated in vacuum to give 1-(2-chloroethyl)-5- (difluoromethyl)-1H-pyrazol-4-amine (44.00 mg, crude).
  • Step b To a solution of 1-heptyl-4-nitro-1H-pyrazole-5-carbonitrile (50 mg, 211.62 ⁇ mol, 1.0 eq.) in EtOH (5 mL) was added Fe (59.10 mg, 1.06 mmol, 7.52 ⁇ L, 5.0 eq.) and NH 4 Cl (56.60 mg, 1.06 mmol, 5.0 eq.) at 25 °C. The mixture was stirred at 80 °C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 4-amino-1- heptyl-1H-pyrazole-5-carbonitrile (40 mg, 79.07% yield, 86.3% purity).
  • Step b To a solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1.0 eq.) and K 2 CO 3 (1.83 g, 13.27 mmol, 3.0 eq.) in MeCN (10 mL) was added 2,2-difluoropropyl trifluoromethanesulfonate (1.01 g, 4.42 mmol, 1.0 eq.) at 25 °C.
  • Step c To a solution of 1-(2,2-difluoropropyl)-4-nitro-1H-pyrazole (500 mg, 2.62 mmol, 1.0 eq.), NH 4 Cl (699.66 mg, 13.08 mmol, 5.0 eq.) in EtOH (6 mL) and water (2 mL) at 25 °C was added Fe (730.50 mg, 13.08 mmol, 5.0 eq.). The reaction mixture was stirred at 80 °C for 1 hours. The mixture was filtered through a celite pad, and the filtrate was concentrated to give 1-(2,2-difluoropropyl)-1H-pyrazol-4-amine (400 mg, crude).
  • Step d To a solution of 1-(2,2-difluoropropyl)-1H-pyrazol-4-amine (400 mg, 2.48 mmol, 1.0 eq.) in DCM (3 mL) was added TEA (753.50 mg, 7.45 mmol, 1.04 mL, 3.0 eq.) and Boc2O (541.72 mg, 2.48 mmol, 570.23 ⁇ L, 1.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • TEA 753.50 mg, 7.45 mmol, 1.04 mL, 3.0 eq.
  • Boc2O 541.72 mg, 2.48 mmol, 570.23 ⁇ L, 1.0 eq.
  • Step e To a solution of tert-butyl (1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)carbamate (150 mg, 574.12 ⁇ mol, 1.0 eq.) and NCS (114.99 mg, 861.19 ⁇ mol, 1.5 eq.) in DCM (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step f Tert-butyl (5-chloro-1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)carbamate (100 mg, 338.17 ⁇ mol, 1.0 eq.) was dissolved in HCl (2 M, 169.08 ⁇ L, EtOAc) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min. The mixture was concentrated to give the compound 5-chloro-1-(2,2-difluoropropyl)-1H-pyrazol-4-amine (60 mg, crude) as a white solid.
  • Step b To a solution of compound (1-methyl-4-nitro-1H-pyrazol-5-yl)methanol (130.00 mg, 827.36 ⁇ mol, 1.0 eq.) in DCM (10 mL) was added MnO 2 (1.44 g, 16.55 mmol, 20.0 eq.) at 25 °C. The mixture was stirred at 40 °C for 3 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give compound 1-methyl-4-nitro-1H-pyrazole-5-carbaldehyde (120.00 mg, 93.51% yield).
  • Step c To a solution compound 1-methyl-4-nitro-1H-pyrazole-5-carbaldehyde (120.00 mg, 773.64 ⁇ mol, 1.0 eq.) in DCM (5 mL) was added DAST (249.40 mg, 1.55 mmol, 2.0 eq.) dropwise at 0 °C. The mixture was stirred at 20°C for 2 hours. The mixture was quenched with NaHCO3.aq (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4.
  • Step d To a solution of compound 5-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole (45.00 mg, 254.08 ⁇ mol, 1.0 eq.) in MeOH (3.0 mL) was added Pd/C (27.04 mg, 25.41 ⁇ mol, 10% purity, 0.1 eq.) at 25 °C under H 2 (15 Psi). The reaction was stirred at 25 °C for 2 hours. The mixture was filtrated and concentrated in vacuum to give compound 5-(difluoromethyl)-1- methyl-1H-pyrazol-4-amine (30.00 mg, crude).
  • Step c To a solution of 5-chloro-1-cyclobutyl-4-nitro-1H-pyrazole (180 mg, 0.89 mmol) and ammonium hydrochloride (239 mg, 4.46 mmol) in EtOH (5.4 mL) and water (3.6 mL) was added iron powder (499 mg, 8.93 mmol) and the resulting solution was heated to 70 °C for 2 hours. The solution was then cooled to room temperature, and concentrated.
  • Preparation 21 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile 4-amino-1-(oxetan-3-ylmethyl)-1H-pyrazole-5-carbonitrile was obtained (80 mg, 20.6% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 3-(bromomethyl)oxetane following a similar procedure to that described in Preparation 3.
  • Step b To a solution of 6,7-dichloro-1H-indole (4.98 g, 26.8 mmol) in MeCN (100 mL) was added sulfurochloridic acid (15.60 g, 133.8 mmol, 8.90 mL) slowly at 0 °C and the mixture was stirred at 20 °C for 2 h under N2 atmosphere. The reaction mixture was added to ice water dropwise and stirred at 20 °C for 0.5 h.
  • Step a To a 30-mL scintillation vial containing a solution of 7-bromo-6-chloro-1H-indole (1.50 g, 6.51 mmol) in acetonitrile (13.0 mL) at 0 °C was added sulfurochloridic acid (2.73 g, 23.4 mmol, 1.56 mL) dropwise. The solution was kept in the ice bath for 1 h, removed, and then stirred at 20 °C for 2 days. The reaction mixture was then poured into ice water and extracted three times with EtOAc.
  • Step c To a solution of 1-(2,3-difluoropropyl)-4-nitro-1H-pyrazole (100 mg, 523.2 ⁇ mol, 1.0 eq.) in EtOH (3 mL) and H2O (1 mL) at 25 ° was added NH4Cl (139.9 mg, 2.6 mmol, 5.0 eq.) and Fe (146.1 mg, 2.62 mmol, 5.0 eq.). The reaction mixture was stirred at 80 °C for 1 hour. The mixture was filtered through a celite pad, and the filtrate was concentrated to give 1-(2,3- difluoropropyl)-1H-pyrazol-4-amine (80 mg, crude).
  • reaction mixture was stirred at 40 °C for 1 hour.
  • the reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • the residue was purified by column chromatography to yield tert-butyl (5-chloro-1-(2,3-difluoropropyl)-1H-pyrazol-4- yl)carbamate (35 mg, 59.5% yield, 96.2% purity).
  • Step b To a mixture of 6-chloro-7-(difluoromethoxy)-1H-indole (20 mg, 91.91 ⁇ mol, 1.0 eq.) in MeCN (1 mL) was added sulfurochloridic acid (182.07 mg, 1.56 mmol, 103.86 ⁇ L, 17.0 eq.) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • Preparation 38 7-chloro-6-(dimethylamino)-1H-indole-3-sulfonyl chloride
  • Step a To a solution of N,N-dimethyl-3-nitroaniline (2.00 g, 12.04 mmol, 1.0 eq.) in DMF (20.0 mL) at 20 °C, a solution of NCS (1.61 g, 12.04 mmol, 1.0 eq.) in DMF (5.0 mL) was added at 20 °C. The mixture was stirred at 75 °C for 3 hours. The mixture was quenched via addition of water (30 mL) and extracted with EtOAc (30 mL x 3).
  • Step b To a solution of 2-chloro-N,N-dimethyl-3-nitroaniline (500.00 mg, 2.49 mmol, 1.0 eq.) in THF (50.0 mL) was added vinylmagnesium bromide (1 M, 9.97 mmol, 4.0 eq.) at -78 °C dropwise under N2. The mixture was stirred at -78 °C for 3 hours. The mixture was quenched with addition of saturated aq. NH 4 Cl (20 mL) and then extracted with EA (20 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 then filtered.
  • Step c To a solution 7-chloro-N,N-dimethyl-1H-indol-6-amine (40.00 mg, 205.49 ⁇ mol, 1.0 eq.) in DCM (5.0 mL) was treated with SO3.DMF (141.62 mg, 924.69 ⁇ mol, 4.5 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 hours.
  • Step b To a solution of 3-nitro-5-propyl-1H-pyrazole (60 mg, 386.7 ⁇ mol, 1.0 eq.) in MeCN (8 mL) was added sodium 2-chloro-2,2-difluoroacetate (176.9 mg, 1.16 mmol, 3.0 eq.) and K 2 CO 3 (160.3 mg, 1.16 mmol, 3.0 eq.) at 20 °C. The reaction mixture was stirred at 80 °C for 12 hours.
  • Preparation 42 5-chloro-1-(difluoromethyl)-1H-pyrazol-3-amine
  • Step a To a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (70.00 mg, 382.08 ⁇ mol, 1.0 eq.) in MeCN (5.0 mL) was added Cs2CO3 (248.98 mg, 764.16 ⁇ mol, 3.0 eq.) and 1-(2- bromoethyl)-1-(trifluoromethyl)cyclopropane (82.92 mg, 382.08 ⁇ mol, 1.0 eq.) at 20 °C. The mixture was stirred at 55 °C for 16 hours.
  • Step b To a solution of tert-butyl (1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazol-4- yl)carbamate (70.00 mg, 219.21 ⁇ mol, 1.0 eq.) in MeCN (2.0 mL) was added NCS (58.54 mg, 438.43 ⁇ mol, 2.0 eq.) at 20 °C. The mixture was stirred at 50 °C for 10 hours. The mixture was quenched with saturated aq. Na 2 SO 3 (20 mL). The mixture was extracted with EtOAc (20 mL x 3).
  • Step c To a solution of tert-butyl (5-chloro-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H- pyrazol-4-yl)carbamate (20.00 mg, 56.53 ⁇ mol, 1.0 eq.) in HFIP (2.0 mL) was added TFA (32.23 mg, 282.67 ⁇ mol, 5.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 hours. Solvent was evaporated under vacuum to give 5-chloro-1-(2-(1- (trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazol-4-amine (13.00 mg, 90.66% yield).
  • Step b To a solution of 7-chloro-6-methyl-1H-indole (200 mg, 1.21 mmol, 1.0 eq.) in MeCN (8.0 mL) was dropwise added HSO3Cl (1.41 g, 12.08 mmol, 802.70 ⁇ L, 10.0 eq.) at 0 °C. The reaction was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Preparation 48 7-chloro-6-fluoro-1H-indole-3-sulfonyl chloride 7-chloro-6-fluoro-1H-indole-3-sulfonyl chloride was obtained (40 mg, yield 32% over two steps), from 2-chloro-1-fluoro-3-nitrobenzene following a similar procedure to that described in Preparation 45.
  • 1 H NMR (400MHz, CDCl3) ⁇ : 9.07 (s, 1H), 8.05 (d, J 3.2 Hz, 1H), 7.94- 7.89 (m, 1H), 7.31-7.28 (m, 1H).
  • Step a To a solution of 1-chloro-2-fluoro-3-nitrobenzene (1 g, 5.70 mmol, 1.0 eq.) in DCM (20 mL) was added dimethylamine hydrochloride (929.04 mg, 11.39 mmol, 2.0 eq.) and TEA (1.73 g, 17.09 mmol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 3 hours. The reaction was filtered and the filtrate was evaporated under vacuum.
  • Step c To a stirred solution of 6-chloro-N,N-dimethyl-1H-indol-7-amine (100 mg, 513.72 ⁇ mol, 1.0 eq.) in MeCN (4 mL) was added HSO 3 Cl (718.30 g, 6.16 mmol, 0.4 mL, 12.0 eq.) at 0 °C.
  • Step a To a solution of methyl 3-(4-nitro-1H-pyrazol-1-yl)propanoate (1.0 g, 5.02 mmol, 1.0 eq.) and CaCl 2 (557.23 mg, 5.02 mmol, 1.0 eq.) in EtOH (10 mL) was added NaBH 4 (379.91 mg, 10.04 mmol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3).
  • Step b To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (2.05 g, 11.98 mmol, 1.0 eq.) in DCM (20 mL) was added Dess-Martin periodinane (7.62 g, 17.97 mmol, 1.5 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 .
  • Step c To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propanal (760 mg, 4.49 mmol, 1.0 eq.) in DCM (10 mL) was added DAST (1.45 g, 8.99 mmol, 1.19 mL, 2.0 eq.) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4.
  • Step d To a solution of 1-(4,4-difluorobutyl)-4-nitro-1H-pyrazole (360 mg, 1.88 mmol, 1.0 eq.) in MeOH (5 mL) was added Pd/C (20.04 mg, 188.35 ⁇ mol, 0.1 eq.) at 25 °C. The mixture was stirred at 25 °C under H 2 (15 Psi) for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (286 mg, 94.23% yield).
  • Step e To a solution of 1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (286 mg, 1.77 mmol, 1.0 eq.) in DCM (5 mL) was added TEA (359.17 mg, 3.55 mmol, 494.72 ⁇ L, 2.0 eq.) and Boc2O (464.79 mg, 2.13 mmol, 489.25 ⁇ L, 1.2 eq.) at 25 °C. The mixture was stirred at 25 °C for 12 hours.
  • Step f To a solution of tert-butyl (1-(4,4-difluorobutyl)-1H-pyrazol-4-yl)carbamate (150 mg, 574.12 ⁇ mol, 1.0 eq.) in MeCN (5 mL) was added NCS (229.99 mg, 1.72 mmol, 3.0 eq.) at 25 °C. The mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step g To a solution of tert-butyl (5-chloro-1-(4,4-difluorobutyl)-1H-pyrazol-4-yl)carbamate (50 mg, 169.08 ⁇ mol, 1.0 eq.) in HFIP (2 mL) was added TFA (19.28 mg, 169.08 ⁇ mol, 12.95 ⁇ L, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuum to give 5-chloro-1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (33 mg, 99.78% yield), which was used without further purification.
  • the reaction was stirred at 0 °C for 30 min. To the reaction was then added benzenesulfonyl chloride (669.21 mg, 3.79 mmol, 483.53 ⁇ L, 1.1 eq.) at 0 °C. The reaction was stirred at 20 °C for 14 hours. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (30 mL x 3). The combined organic layer was dried over Na 2 SO 4 ; filtered and the filtrate was evaporated under vacuum.
  • Step b To a solution of 1-(phenylsulfonyl)-1H-indole-6-carbaldehyde (550 mg, 1.93 mmol, 1.0 eq.) in DCM (10 mL) was added DAST (1.55 g, 9.64 mmol, 1.27 mL, 5.0 eq.) at 0 °C. The reaction was stirred at 20 °C for 14 hours. The reaction was quenched with saturated NaHCO3 till pH > 7, extracted with DCM (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered; evaporated under vacuum.
  • Step c To a solution of 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole (100 mg, 325.40 ⁇ mol, 1.0 eq.) in MeCN (1 mL) was slowly added sulfurochloridic acid (189.58 mg, 1.63 mmol, 108.14 ⁇ L, 5.0 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 14 hours. It was then slowly poured with stirring into ice-water (5 mL). The reaction was extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum.
  • Preparation 54 7-chloro-6-methoxy-1H-indole-3-sulfonyl chloride 7-chloro-6-methoxy-1H-indole-3-sulfonyl chloride was obtained (70 mg, yield 14% over two steps), from 2-chloro-1-methoxy-3-nitrobenzene following a similar procedure to that described in Preparation 45.
  • Prep-HPLC-A Welch Xtimate C18150 x 25 mm, 5 ⁇ m; 30-72% MeCN/H2O (10 mm NH4HCO3); Prep-HPLC-B: Phenomenex Luna C18150 x 25 mm, 10 ⁇ m; 54-84% MeCN/H2O (0.05%(NH4HCO3)-ACN); Prep-HPLC-C: Waters Sunfire OBD 100 x 50 mm, 5 mm; 5-75% MeCN/H2O (+ 0.1% TFA).
  • Prep-HPLC-D Phenomenex Synergi C18150 x 30 mm, 4 mm; 49-69% MeCN/H 2 O (0.05%(NH 4 HCO 3 )-ACN);
  • Prep-HPLC-E Waters Oxbridge C18 150 x 25 mm, 10 um; 25-60% MeCN/H 2 O (0.05%(NH 4 HCO 3 )-ACN);
  • Prep-HPLC-F Boston Prime C18150 x 30 mm, 15mm; 10-40% MeCN/H2O ((NH3H2O+NH4HCO3)-ACN);
  • Prep-HPLC-G Boston Green ODS 150 x 30 mm, 5um; 30-60% MeCN/H2O (0.05%(NH 4 HCO 3 )-ACN);
  • Prep-HPLC-H Phenomenex Gemini-NX 150 x 30 mm, 5um; 25- 55% MeCN/H2O (0.05%(NH4HCO3)-ACN);
  • Prep-HPLC-J YMC-Triart Prep C18150 x 40 mm, 7 ⁇ M; 40-60% MeCN/ H2O.
  • Prep-HPLC-K Waters XSelect CSH C18 30 x 100 mm, 5 uM; 5-30% MeCN/H2O (0.05%(NH4HCO3)-ACN).
  • Step b To a solution of tert-butyl (5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)carbamate (100 mg, 320.40 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added TFA (595.60 mg, 5.22 mmol, 16.3 eq.) at 20 °C. The reaction was stirred at 20 °C for 3 hours. TLC showed the reaction was complete. The mixture was concentrated under vacuum to afford 5-bromo-1- (difluoromethyl)-1H-pyrazol-4-amine. The material was used without further purification assuming quantitative yield.
  • Step b To a solution of 4-(6-chloro-1H-indol-7-yl)thiazole (50 mg, 213.03 ⁇ mol, 1.0 eq.) in MeCN (2 mL) was added dropwise sulfurochloridic acid (124.12 mg, 1.07 mmol, 70.80 ⁇ L, 5.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC showed the reactant was consumed completely. Then the mixture was added POCl3 (163.32 mg, 1.07 mmol, 99.29 ⁇ L, 5.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour.
  • Step b To a solution of 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole (100 mg, 457.37 ⁇ mol, 1.0 eq.) in MeCN (3 mL) was added sulfurochloridic acid (133.24 mg, 1.14 mmol, 76.00 ⁇ L, 2.5 eq.) at 0 °C.
  • Step b To a solution of 1-(2-chloro-6-nitrophenyl)-1H-pyrazole (250 mg, 1.12 mmol, 1.0 eq.) in THF (10 mL) was added bromo(vinyl)magnesium (1 M, 4.47 mmol, 4.47 mL, 4.0 eq.) at -78 °C under N 2 . The mixture was stirred at -78 °C for 2 hours. LCMS showed desired product was obtained. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step c To a solution of 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole (50.00 mg, 229.72 ⁇ mol, 1.0 eq.) in MeCN (10 mL) was added HSO3Cl (267.68 mg, 2.30 mmol, 152.70 ⁇ L, 10.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed desired product was obtained. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step b To a solution of 4-chloro-1-(2-chloro-6-nitrophenyl)-1H-pyrazole (1 g, 3.88 mmol, 1.0 eq.) in THF (60 mL) was added bromo(vinyl)magnesium (1 M, 15.50 mmol, 15.50 mL, 4.0 eq.) at -78 °C under N 2 . The reaction was stirred at -78 °C for 2 hours. TLC showed a new main spot was observed. The reaction was slowly quenched with saturate aq.NH4Cl (40 mL) at 0 °C about 10 min. The reaction was extracted with EtOAc (20 mL x 3).
  • Step c To a solution of 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole (50 mg, 198.33 ⁇ mol, 1.0 eq.) in MeCN (3 mL) was added sulfurochloridic acid (57.78 mg, 495.84 ⁇ mol, 32.96 ⁇ L, 2.5 eq.) at 0 °C. The reaction was stirred at 0 °C for 2 hours. LCMS showed the reaction was complete. To the reaction was added POCl3 (121.64 mg, 793.34 ⁇ mol, 73.95 ⁇ L, 4.0 eq.) at 0 °C. The reaction was stirred at 60 °C for 14 hours.
  • Preparation 62 7-(4-bromo-1H-pyrazol-1-yl)-6-chloro-1H-indole-3-sulfonyl chloride 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride was obtained (100 mg, yield 16.9% yield over three steps), from 1-chloro-2-fluoro-3-nitrobenzene and 4-bromo-1H- pyrazole following a similar procedure to that described in Preparation 60.
  • Step b To a mixture of 1-(2-chloro-6-nitrophenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole and 2-(2-chloro-6-nitrophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole as a mixture (800.00 mg, 3.04 mmol, 1.0 eq.) in THF (10 mL) was carefully added bromo(vinyl)magnesium (1 M, 12.14 mmol, 12.14 mL, 4.0 eq.) at -60 °C under N2. Then the mixture was stirred at -60 °C for 3 hours. LCMS showed that the reaction was complete. The mixture was quenched with saturated aq.
  • Example 95 N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6-(difluoromethyl)-1H-indole-3- sulfonamide
  • Step a To a solution of 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile (33.55 mg, 246.41 ⁇ mol, 1.0 eq.) in pyridine (8 mL) was added 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3- sulfonyl chloride (Preparation 53) (100 mg, 246.41 ⁇ mol, 1.0 eq.). The reaction was stirred at 50 °C for 14 hours.
  • Step b To a solution of N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6-(difluoromethyl)-1- (phenylsulfonyl)-1H-indole-3-sulfonamide (70 mg, 138.47 ⁇ mol, 1.0 eq.) in THF (5 mL) was added TBAF (1 M, 415.42 ⁇ L, 3.0 eq.) at 20 °C. The reaction was stirred at 60 °C for 14 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (10 mL x 3).
  • Example 96 N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(difluoromethyl)-1H- indole-3-slfonamide
  • Step a To solution of 6-(difluoromethyl)-1H-indole-3-sulfonyl chloride (Preparation 53) (50 mg, 123.21 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(trifluoromethyl)-1H- pyrazol-4-amine (Preparation 2) (22.86 mg, 123.21 ⁇ mol, 1.0 eq.), pyridine (29.24 mg, 369.62 ⁇ mol, 3.0 eq.) at 25 °C.
  • Step b To a solution of N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6- (difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (40 mg, 72.09 ⁇ mol, 1.0 eq.) in THF (2 mL) was added TBAF (1 M, 360.43 ⁇ mol, 360.43 ⁇ L, 5.0 eq.) at 25 °C. The reaction was stirred at 60 °C for 12 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (5 mL x 3).
  • Example 97 N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-1H-indole-3- sulfonamide
  • Step a To a solution of 6-(trifluoromethyl)-1H-indole (200 mg, 1.08 mmol, 1.0 eq.) in DCM (8 mL) was added NaOH (133.94 mg, 3.35 mmol, 3.1 eq.) and tetrabutylammonium hydrogensulfate (110.03 mg, 324.07 ⁇ mol, 0.3 eq.) at 0 °C.
  • Step b To a solution of 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (100 mg, 307.40 ⁇ mol, 1.0 eq.) in MeCN (1 mL) was slowly added sulfurochloridic acid (179.10 mg, 1.54 mmol, 102.17 ⁇ L, 5.0 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 14 hours. The reaction was slowly added into ice-water (10 mL). The reaction was extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na 2 SO 4 ; filtered and evaporated under vacuum.
  • Step c To a solution of 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile (93.38 mg, 220.34 ⁇ mol, 1.0 eq.) in pyridine (5 mL) was added 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3- sulfonyl chloride (30 mg, 220.34 ⁇ mol, 1.0 eq.). The reaction was stirred at 50 °C for 14 hours. Solvent was evaporated under vacuum.
  • Example 98 6-chloro-N-(4-ethyl-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of tert-butyl (5-methylisoxazol-3-yl)carbamate (800 mg, 4.04 mmol, 1.0 eq.) in THF (20.0 mL) was added n-BuLi (2.5 M, 3.55 mL, 2.2 eq.) dropwise at -78 °C under N 2, the mixture was stirred -78 °C for 1 hour. Iodoethane (944.20 mg, 6.05 mmol, 1.5 eq.) was added to the mixture.
  • Step b To a solution of tert-butyl (4-ethyl-5-methylisoxazol-3-yl)carbamate (70 mg, 309.36 ⁇ mol, 1.0 eq.) in HFIP (2 mL) was added TFA (70.55 mg, 618.73 ⁇ mol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours.
  • Step c To a solution of 4-ethyl-5-methylisoxazol-3-amine (20 mg, 158.53 ⁇ mol, 1.0 eq.) in THF (2.0 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (39.65 mg, 158.53 ⁇ mol, 1.0 eq.) at 20 °C.
  • Example 99 6-chloro-N-(4-chloro-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide
  • 6-chloro-1H-indole-3-sulfonyl chloride 50 mg, 199.92 ⁇ mol, 1.0 eq.
  • 4-chloro-5-methylisoxazol-3-amine 26.5 mg, 199.92 ⁇ mol, 1.0 eq.
  • Example 100 6-chloro-N-(5-(1,1-difluoroethyl)isoxazol-3-yl)-1H-indole-3-sulfonamide
  • 6-chloro-1H-indole-3-sulfonyl chloride 50 mg, 199.92 ⁇ mol, 1.0 eq.
  • pyridine 1.0 mL
  • 5-(1,1-difluoroethyl)isoxazol-3-amine 29.6 mg, 199.92 ⁇ mol, 1.0 eq.
  • Example 101 6-chloro-N-(4-chloro-5-ethylisoxazol-3-yl)-1H-indole-3-sulfonamide
  • 4-chloro-5-ethylisoxazol-3-amine Preparation 43
  • 6-chloro-1H-indole-3-sulfonyl chloride 25.6 mg, 102.34 ⁇ mol, 1.0 eq.
  • CH2Cl2 2.0 mL
  • pyridine 24.28 mg, 307.01 ⁇ mol, 3.0 eq.
  • Example 137 6-chloro-N-(5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide
  • Step a To a solution of 1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-amine (100.0 mg, 558.2 ⁇ mol, 1.0 eq.) in DCM (4.0 mL) was added TEA (169.5 mg, 1.6 mmol, 3.0 eq.) and (Boc) 2 O (182.7 mg, 837.3 ⁇ mol, 1.5 eq.) at 20 °C.
  • Step b To a solution of tert-butyl (1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)carbamate 2 (50.0 mg, 179.1 ⁇ mol, 1.0 eq.) in MeCN (2 mL) was added NCS (23.9 mg, 179.1 ⁇ mol, 1.0 eq.) 25 °C. The mixture was stirred at 60 °C for 16 hours.
  • Step c To a solution of tert-butyl (5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4- yl)carbamate (50.0 mg, 159.39 ⁇ mol, 1.0 eq.) was added a solution of HCl in dioxane (4 M, 796.9 ⁇ L, 3.19 mmol, 20.0 eq.), at 20 °C. The mixture was stirred at 20 °C for 2 hours. Solvent was evaporated under vacuum to give 5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol- 4-amine (30.0 mg, 88.1% yield) which was used without further purification.
  • Step d To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (35.13 mg, 140.5 ⁇ mol, 1.0 eq.) and 5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-amine (30.00 mg, 140.5 ⁇ mol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (33.33 mg, 421.4 ⁇ mol, 3.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 hours.
  • Example 138 N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-indole-3- sulfonamide
  • Step a To solution of 6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (50 mg, 129.59 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4- amine (23.33 mg, 129.59 ⁇ mol, 1.0 eq.), Pyridine (30.75 mg, 388.76 ⁇ mol, 3.0 eq.) at 25 °C.
  • Step b To a solution of N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-6-methoxy-1- (phenylsulfonyl)-1H-indole-3-sulfonamide (30 mg, 56.67 ⁇ mol, 1.0 eq.) in MeOH (2 mL) was added K2CO3 (31.33 mg, 226.66 ⁇ mol, 4.0 eq.) at 25°C. The reaction was stirred at 60 °C for 12 hours. The reaction was evaporated under vacuum.
  • Example 139 N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-indole-3- sulfonamide
  • Step a To solution of 6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (100 mg, 259.17 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(trifluoromethyl)-1H-pyrazol-4- amine (48.09 mg, 259.17 ⁇ mol, 1.0 eq.), Pyridine (61.50 mg, 777.52 ⁇ mol, 3.0 eq.) at 25 °C.
  • Step b To a solution of N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-methoxy-1- (phenylsulfonyl)-1H-indole-3-sulfonamide (20.00 mg, 37.39 ⁇ mol, 1.0 eq.) in THF (3 mL) was added TBAF (1 M, 186.95 ⁇ mol, 5.0 eq., 186.95 uL) at 25°C. The reaction was stirred at 60 °C for 12 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (5 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum.
  • Example 140 6-chloro-N-(5-chloro-1-phenyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol, 1.0 eq.) and iodobenzene (3.61 g, 17.69 mmol, 1.98 mL, 2.0 eq.) in DMF (20 mL) was added CuI (168.43 mg, 884.37 ⁇ mol, 0.1 eq.) and K 2 CO 3 (2.44 g, 17.69 mmol, 2.0 eq.) at 20 °C under N2. The reaction mixture was stirred at 110 °C for 14 hours.
  • Step b To a solution of 4-nitro-1-phenyl-1H-pyrazole (300 mg, 1.59 mmol, 1.0 eq.) in EtOH (3 mL) and water (1 mL) was added Fe (442.85 mg, 7.93 mmol, 56.34 ⁇ L, 5.0 eq.) and NH 4 Cl (424.15 mg, 7.93 mmol, 5.0 eq.) at 20 °C. The reaction mixture was stirred at 70 °C for 2 hours. LCMS showed material was consumed completely and one main peak was detected. The mixture was filtered and concentrated. The residue was purified by column chromatography to give 1-phenyl-1H-pyrazol-4-amine (100 mg, 39.61% yield).
  • Step c To a stirred solution of 1-phenyl-1H-pyrazol-4-amine (190 mg, 1.19 mmol, 1.0 eq.) in DCM (3 mL) was added Boc2O (1.30 g, 5.97 mmol, 1.37 mL, 5.0 eq.) and TEA (603.88 mg, 5.97 mmol, 831.79 ⁇ L, 5.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. LCMS showed material was consumed completely and one main peak was detected. The mixture was filtered and concentrated to give a residue.
  • Step d To a stirred solution of tert-butyl (1-phenyl-1H-pyrazol-4-yl)carbamate (50 mg, 192.82 ⁇ mol, 1.0 eq.) in MeCN (1 mL) was added NCS (38.62 mg, 289.24 ⁇ mol, 1.5 eq.) at 20 °C. The reaction mixture was stirred at 40 °C for 2 hours. LCMS showed material was consumed completely and one main peak was detected.
  • Step f To a solution of 5-chloro-1-phenyl-1H-pyrazol-4-amine (30 mg, 154.93 ⁇ mol, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (20.00 mg, 79.97 ⁇ mol, 5.16e-1 eq.) in DCM (3 mL) was added Pyridine (12.26 mg, 154.93 ⁇ mol, 12.53 ⁇ L, 1.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Example 141 6-chloro-N-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indole- 3-sulfonamide
  • Step a To a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol, 1.0 eq.) and K2CO3 (3.67 g, 26.53 mmol, 3.0 eq.) in DMF (20 mL) was added compound 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.05 g, 8.84 mmol, 1.27 mL, 1.0 eq.) at 25 °C.
  • the reaction mixture was stirred at 70 °C for 2 hours.
  • the reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by column chromatography to yield the 4-nitro-1-(2,2,2- trifluoroethyl)-1H-pyrazole (1.7 g, 96.55% yield).
  • Step b To a solution of 4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (200 mg, 1.03 mmol, 1.0 eq.), NH4Cl (274.18 mg, 5.13 mmol, 5.0 eq.) and Fe (286.26 mg, 5.13 mmol, 5.0 eq.) in EtOH (3 mL) and H2O (1 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 1 hour.
  • Step c To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (150 mg, 908.45 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added TEA (275.78 mg, 2.73 mmol, 379.86 ⁇ L, 3.0 eq.) and Boc 2 O (237.92 mg, 1.09 mmol, 250.44 uL, 1.2 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours.
  • Step d To a solution of tert-butyl (1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)carbamate (200 mg, 754.06 ⁇ mol, 1.0 eq.) and NCS (151.03 mg, 1.13 mmol, 1.5 eq.) in MeCN (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step e To a solution of tert-butyl (5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)carbamate (50 mg, 157.84 ⁇ mol, 1.0 eq.) in HCl/EtOAc (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give the 5-chloro-1- (2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (30 mg, crude).
  • Example 142 6-chloro-N-(4,5-dimethylisothiazol-3-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 5-methylisothiazol-3-amine (40.00 mg, 265.55 ⁇ mol, 1.0 eq.) in MeCN (2.0 mL) was added N-iodosuccinamide (59.74 mg, 265.55 ⁇ mol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was quenched with saturated Na2SO3(aq). The mixture was extracted with EtOAc (50 mL x 3).
  • Step b To a solution of 4-iodo-5-methylisothiazol-3-amine (27.00 mg, 112.47 ⁇ mol, 1.0 eq.) in dioxane (2 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (56.48 mg, 224.94 ⁇ mol, 2.0 eq.), K2CO3 (46.63 mg, 337.41 ⁇ mol, 3.0 eq.), Pd(dppf)Cl2 (8.23 mg, 11.25 ⁇ mol, 0.1 eq.) and water (0.4 mL) at 25 °C under N2. The mixture was stirred at 90 °C for 16 hours.
  • Step c To a solution of 4,5-dimethylisothiazol-3-amine (13.00 mg, 101.41 ⁇ mol, 1.0 eq.) in THF (2.0 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (25.36 mg, 101.41 ⁇ mol, 1.0 eq.) at 20 °C.
  • Example 143 6-chloro-N-(4-chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide
  • 4-chloro-5-methylisothiazol-3-amine Preparation 52
  • THF 2.0 mL
  • 6-chloro-1H-indole-3-sulfonyl chloride 25.36 mg, 101.41 ⁇ mol, 1.0 eq.
  • t-BuOK (1 M, 223.10 ⁇ L, 2.2 eq.
  • Example 144 6-chloro-N-(3-methoxyisothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3- sulfonamide
  • Step a A mixture of 6-chloro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.31 mmol, 1.0 eq.) in sulfurochloridic acid (3.51 g, 30.09 mmol, 2 mL) was stirred at 20 °C. The reaction was stirred at 90 °C for 14 hours. The reaction was quenched with ice-water (60 mL), filtered and washed with water (60 mL).
  • Step b To solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (50 mg, 199.13 ⁇ mol, 1.0 eq.) in DCM (2 mL) was added 3-methoxyisothiazol-4-amine (33.18 mg, 199.13 ⁇ mol, 1.0 eq.HCl), Pyridine (47.25 mg, 597.40 ⁇ mol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 12 hours.
  • Example 145 6-chloro-N-(3-ethoxyisothiazol-4-yl)-1H-indole-3-sulfonamide Step a: To a solution of isothiazol-3-ol (500.00 mg, 4.94 mmol, 1.0 eq.) in DMF (10.0 mL), was added iodoethane (925.36 mg, 3.91 mmol, 1.2 eq.) and Cs2CO3 (3.22 g, 9.89 mmol, 2.0 eq.) at 25 °C and stirred at 25 °C for 16 hours. The mixture was added water (30 mL) and extracted with EA (30 mL x 3).
  • Step c To a solution of 3-ethoxy-4-nitroisothiazole (20.00 mg, 114.83 ⁇ mol, 1.0 eq.) in EtOH (3.0 mL) and water (1 mL) was added Fe (64.13 mg, 1.15 mmol, 10.0 eq.) and NH 4 Cl (30.71 mg, 574.13 ⁇ mol, 5.0 eq.) at 25 °C under N2. The mixture was stirred at 70 °C for 2 hours. The mixture was filtered and concentrated in vacuum. Then the residue was dissolved in water (20 mL) and extracted with EA (20 mL x 3).
  • Example 146 6-chloro-N-(5-chloro-3-methoxyisothiazol-4-yl)-1H-indole-3-sulfonamide Step a: To a solution of 3-methoxyisothiazol-4-amine (15 mg, 115.24 ⁇ mol, 1.0 eq.) in MeCN (2 mL) was added NCS (15.39 mg, 115.24 ⁇ mol, 1.0 eq.) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with saturated Na2SO3 (20 mL).
  • Step b To solution of 5-chloro-3-methoxyisothiazol-4-amine (28 mg, 111.95 ⁇ mol, 1.0 eq.) in DCM (2 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (18.43 mg, 111.95 ⁇ mol, 1.0 eq.), Pyridine (26.57 mg, 335.86 ⁇ mol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours.
  • Example 147 6-chloro-N-(3-chloroisothiazol-4-yl)-1H-indole-3-sulfonamide
  • Step b To a solution of 3-chloro-4-nitroisothiazole (90.00 mg, 546.88 ⁇ mol, 1.0 eq.) in EtOH (3 mL) and water (1 mL) was added Fe (305.40 mg, 5.47 mmol, 10.0 eq.) and NH 4 Cl (146.27 mg, 2.73 mmol, 5.0 eq.) at 25 °C under N2. The mixture was stirred at 70 °C for 2 hours. The mixture was filtered and concentrated in vacuum. Then the residue was dissolved in water (20mL) and extracted with EA (20mL x 3).
  • Step c To a solution of 3-chloroisothiazol-4-amine (20.00 mg, 148.60 ⁇ mol, 1.0 eq.) and 6- chloro-1H-indole-3-sulfonyl chloride (37.17 mg, 148.60 ⁇ mol 1.0 eq.) in DCM (2.0 mL) was added pyridine (35.26 mg, 445.81 ⁇ mol, 3.0 eq.) at 25 °C and stirred at 20 °C for 16 hours.
  • Example 148 6-chloro-N-(4-chlorothiazol-5-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of tert-butyl thiazol-5-ylcarbamate (150 mg, 749.04 ⁇ mol, 1.0 eq.) and NCS (150.03 mg, 1.12 mmol, 1.5 eq.) in MeCN (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step b To a solution of tert-butyl (4-chlorothiazol-5-yl)carbamate (100 mg, 426.07 ⁇ mol, 1.0 eq.) in HFIP (3 mL) was added TFA (48.58 mg, 426.07 ⁇ mol, 32.63 ⁇ L, 1.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give a residue.
  • the residue was purified by prep-HPLC (Welch Xtimate C18150 x 25mm x 10um, water (NH 3 H 2 O)-ACN as a mobile phase, from 5% to 35%, Gradient Time (min): 10, Flow Rate (ml/min): 30) to give the 4-chlorothiazol-5-amine (12 mg, 13.39% yield, 64% purity).
  • Step c A solution of 4-chlorothiazol-5-amine (12 mg, 89.16 ⁇ mol, 1.0 eq.) and 6-chloro-1H- indole-3-sulfonyl chloride (22.30 mg, 89.16 ⁇ mol, 1.0 eq.) in DCM (2 mL) was added Pyridine (28.21 mg, 356.65 ⁇ mol, 28.85 ⁇ L, 3.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. Solvent was evaporated under vacuum.
  • the residue was purified by prep-HPLC (Welch Xtimate C18150 x 25mm x 5um, water (NH3H2O)-ACN as a mobile phase, from 1% to 30%, Gradient Time (min): 10, Flow Rate (ml/min): 30) to give the 6- chloro-N-(4-chlorothiazol-5-yl)-1H-indole-3-sulfonamide (9.6 mg, 30.60% yield).
  • Example 149 6-chloro-7-methoxy-N-(3-methoxyisothiazol-4-yl)-1H-indole-3- sulfonamide
  • Step a To a solution of 1-chloro-2-methoxy-3-nitrobenzene (500 mg, 2.67 mmol, 1.0 eq.) in THF (20.0 mL) was dropwise added vinyl magnesium bromide (1 M, 10.66 mL, 4.0 eq.) at - 78 °C under N2. The reaction was stirred at -78 °C for 3 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl.
  • Step b To a solution of 6-chloro-7-methoxy-1H-indole (80 mg, 440.48 ⁇ mol, 1.0 eq.) in MeCN (3.0 mL) was dropwise added HSO3Cl (513.27 mg, 4.40 mmol, 292.79 ⁇ L, 10.0 eq.) at 0 °C. The reaction was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • HSO3Cl 513.27 mg, 4.40 mmol, 292.79 ⁇ L, 10.0 eq.
  • Step c To a solution of 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride (30.00 mg, 107.09 ⁇ mol, 1.0 eq.) and 3-methoxyisothiazol-4-amine (13.94 mg, 107.09 ⁇ mol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (25.41 mg, 321.28 ⁇ mol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 16 hours.
  • Example 150 6-chloro-N-(4-methoxyisothiazol-3-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 4-hydroxyisothiazole-3-carboxylic acid (100 mg, 689.01 ⁇ mol, 1.0 eq.) in MeOH (5.00 mL) and THF (5.00 mL) was added diazomethyl(trimethyl)silane (2 M, 1.38 mmol, 689.01 ⁇ L, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was evaporated under vacuum. The mixture was diluted with AcOH and extracted with EtOAc (50 mL x 3).
  • Step c To a mixture of methyl 4-methoxyisothiazole-3-carboxylate (30 mg, 173.22 ⁇ mol, 1.0 eq.) in MeOH (2 mL) and water (2 mL) was added lithium hydroxide (14.55 mg, 346.44 ⁇ mol, 2.0 eq.) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours.
  • Step d To a solution of 4-methoxyisothiazole-3-carboxylic acid (27 mg, 169.64 ⁇ mol, 1.0 eq.) in t-BuOH (2 mL) was added TEA (51.50 mg, 508.91 ⁇ mol, 3.0 eq.) and diphenyl phosphorazidate (70.03 mg, 254.46 ⁇ mol, 1.5 eq.) at 20 °C. The mixture was warmed and stirred at 90 °C for 16 hours. The mixture was concentrated in vacuo to give the residue, which was purified by column chromatography to give tert-butyl (4-methoxyisothiazol-3- yl)carbamate (10 mg, 25.60% yield).
  • Step f To solution of 6-chloro-1H-indole-3-sulfonyl chloride (20 mg, 79.97 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added 4-methoxyisothiazol-3-amine (10.41 mg, 79.97 ⁇ mol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours.
  • Example 151 6-chloro-N-(5-chloro-1-(3,3-difluoropropyl)-1H-pyrazol-4-yl)-1H-indole- 3-sulfonamide
  • Step h To a solution of 5-chloro-1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (Preparation 51) (33 mg, 168.71 ⁇ mol, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (42.20 mg, 168.71 ⁇ mol, 1.0 eq.) in DCM (2 mL) was added pyridine (40.04 mg, 506.14 ⁇ mol, 40.94 ⁇ L, 3.0 eq.) at 25 °C.
  • Example 152 6-chloro-N-(5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide
  • Step a To a solution of 4-nitro-1H-pyrazole (1.0 g, 8.84 mmol, 1.0 eq.) and 2-bromoethan-1- ol (1.22 g, 9.73 mmol, 689.54 ⁇ L, 1.1 eq.) in DMF (15 mL) was added K 2 CO 3 (3.67 g, 26.53 mmol, 3.0 eq.). The mixture was stirred at 70 °C for 12 hours.
  • Step b To a solution of yield 2-(4-nitro-1H-pyrazol-1-yl)ethan-1-ol (500 mg, 3.18 mmol, 1.0 eq.) and CuI (303.02 mg, 1.59 mmol, 0.5 eq.) in MeCN (10 mL) was added a solution of 2,2- difluoro-2-(fluorosulfonyl)acetic acid (850.05 mg, 4.77 mmol, 493.35 ⁇ L, 1.5 eq.) in MeCN (10 mL) dropwise at 55 °C over a period of 30 min under N 2 . The reaction mixture was stirred at 55 °C for another 2 hours.
  • Step c To a solution of 1-(2-(difluoromethoxy)ethyl)-4-nitro-1H-pyrazole (120 mg, 579.33 ⁇ mol, 1.0 eq.) in EtOH (3 mL) and water (1 mL) was added Fe (161.78 mg, 2.90 mmol, 20.58 ⁇ L, 5.0 eq.) and NH4Cl (154.95 mg, 2.90 mmol, 5.0 eq.) at 20 °C. The reaction mixture was stirred at 80 °C for 2 hours.
  • Step e To a solution of tert-butyl (1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-yl)carbamate (100 mg, 360.66 ⁇ mol, 1.0 eq.) in MeCN (5 mL) was added NCS (96.32 mg, 721.33 ⁇ mol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Example 153 6-chloro-N-(5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)- 1H-indole-3-sulfonamide
  • Step a To a solution of 4-nitro-1H-pyrazole (500.00 mg, 4.42 mmol, 1.0 eq.), 2-(2,2,2- trifluoroethoxy)ethan-1-ol (637.15 mg, 4.42 mmol, 1.0 eq.) and PPh3 (1.16 g, 4.42 mmol, 1.0 eq.) in THF (20 mL) was added DIAD (894.13 mg, 4.42 mmol, 1.0 eq.) slowly at 20 °C.
  • Step c To a solution of 1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-amine (40.00 mg, 191.23 ⁇ mol, 1.0 eq.) in DCM (4 mL) was added TEA (58.05mg, 573.30 ⁇ mol, 3.0 eq.) and (Boc) 2 O (83.47 mg, 382.47 ⁇ mol, 2.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was added to water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered.
  • TEA 58.05mg, 573.30 ⁇ mol, 3.0 eq.
  • Boc 2 O 83.47 mg, 382.47 ⁇ mol, 2.0 eq.
  • Step f To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (7.19 mg, 28.73 ⁇ mol, 1.0 eq.) in DCM (2.0 mL) was added crude 5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H- pyrazol-4-amine (7.00 mg, 28.73 ⁇ mol, 1.0 eq.) and pyridine (22.73 mg, 287.34 ⁇ mol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 16 hours.
  • Example 154 6-chloro-N-(5-chloro-1-isopentyl-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide
  • N-(5-chloro-1-isopentyl-1H-pyrazol-4-yl) prepared by a solution of 5-chloro-1-isopentyl-1H-pyrazol-4-amine (Preparation 35) (30 mg, 159.86 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added Pyridine (37.93 mg, 479.57 ⁇ mol, 38.9 ⁇ L, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (15.00 mg, 59.98 ⁇ mol, 0.38 eq.) at 25 °C.
  • Example 155 7-bromo-6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide
  • a solution of 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-amine (Preparation 10) (36.01 mg, 0.20 mmol) in pyridine (1.00 mL, 0.2 M) was added 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride (Preparation 29; 65.8 mg, 0.20 mmol) and a crystal of DMAP (cat.).
  • Example 156 7-bromo-6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide
  • a scintillation vial containing 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 18) (713.7 mg, 4.26 mmol, 2 eq.) was added 7-bromo-6-chloro-1H-indole-3- sulfonyl chloride (Preparation 29) (700.0 mg, 2.13 mmol, 1 eq) and a crystal of DMAP (cat.).
  • Example 157 6-chloro-N-(5-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide
  • 6-chloro-1H-indole-3-sulfonyl chloride (40.00 mg, 220.30 ⁇ mol, 1.0 eq.) in Pyridine (2 mL) was added 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine (Preparation 6) (27.55 mg, 110.15 ⁇ mol, 0.5 eq.) at 25 °C.
  • the reaction was stirred at 60 °C for 1 hour.
  • Example 158 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide
  • a scintillation vial containing tert-butyl (5-chloro-1-(difluoromethyl)-1H-pyrazol-4- yl)carbamate (864.9 mg, 3.23 mmol, 2.0 eq.) was added HFIP (16.2 mL, 0.1 M) followed by TFA (0.25 mL, 3.23 mmol, 2.0 eq.).
  • the reaction mixture was stirred at rt for 2 h, changing from bright yellow to orange as the reaction progressed.
  • reaction mixture was then directly concentrated under reduced pressure to provide 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine as a thick red oil, which was used without purification assuming quantitative yield.
  • 6-chloro-1H-indole-3-sulfonyl chloride 404.0 mg, 1.62 mmol.1.0 eq.
  • the reactants were dissolved in pyridine (8.0 mL) and DMAP (19.7 mg, 0.162 mmol, 0.10 eq.) was then added.
  • the reaction mixture was stirred at 75 °C for approximately 18 h, after which time it was diluted with water and extracted twice with DCM and then once with EtOAc.
  • Example 159 6-chloro-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide 6-Chloro-1H-indole-3-sulfonyl chloride (39 mg, 1.0 equiv.) was added to the solution of 1- methyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride (35 mg, 1.1 eq) in dry Pyridine (1 mL). The reaction mixture was stirred at 60 °C for 24 h. Then the solvent was evaporated in vacuo and the residue was dissolved in DMSO (0.5 mL) and subjected to prep.
  • DMSO 0.5 mL
  • Example 160 6-chloro-N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide
  • 6-chloro-1H-indole-3-sulfonyl chloride 90 mg, 359.85 ⁇ mol, 1.0 eq.
  • DCM 3 mL
  • 5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-amine Preparation 2 (66.77 mg, 359.85 ⁇ mol, 1.0 eq.)
  • Pyridine 85.39 mg, 1.08 mmol, 3.0 eq.
  • Example 161 6,7-dichloro-N-(3-methoxyisothiazol-4-yl)-1H-indole-3-sulfonamide
  • a solution of 6,7-dichloro-1H-indole-3-sulfonyl chloride (Preperation 28) (15.00 mg, 52.72 ⁇ mol, 1.0 eq.) and 3-methoxyisothiazol-4-amine (6.86 mg, 52.72 ⁇ mol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (12.51 mg, 158.15 ⁇ mol, 3.0 eq.) at 20 °C.
  • the reaction was stirred at 20 °C for 4 hours.
  • Example 162 6-chloro-N-(5-propylthiazol-2-yl)-1H-indole-3-sulfonamide
  • 5-propylthiazol-2-amine 34.1 mg, 240.0 ⁇ mol, 1.2 eq.
  • 6-chloro-1H-indole-3-sulfonyl chloride 50.0 mg, 200.0 ⁇ mol, 1.0 eq.
  • DMAP cat.
  • the contents were dissolved in pyridine (2.0 mL, 0.1 M) and stirred at 50 °C for approximately 72 h. After this time, the reaction mixture was quenched with water and extracted with EtOAc.
  • the organics were dried over sodium sulfate and concentrated under vacuum to provide the crude product as a brown oil.
  • the crude product was purified by prep- HPLC (Column: Waters XSelect CSH Prep C185um OBD 30 x 100 mm); Mobile Phase: from 5% to 55% of water (NH 4 HCO 3 )-MeCN; Flow Rate (ml/min): 50) to provide 6-chloro- N-(5-propylthiazol-2-yl)-1H-indole-3-sulfonamide (16.0 mg, 22.5% yield) as a white solid.
  • Example 163 6-chloro-N-(5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)- 1H-indole-3-sulfonamide
  • Step a To a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (200 mg, 1.09 mmol, 1.0 eq.) in MeCN (3 mL) was added cesium carbonate (711 mg, 2.18 mmol, 2 eq.) at 25 °C.
  • Step b To a solution of tert-butyl (1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4- yl)carbamate (85 mg, 275.1 ⁇ mol, 1.0 eq.) in MeCN (2 mL) was added N-chlorosuccinimide (36 mg, 206.4 ⁇ mol, 1.0 eq.) at 25 °C. The mixture was allowed to stir at 70 °C for 8 hours. The mixture was concentrated to a residue which was redissolved in dichloromethane, washed with 10mL NaOH (1 M), 10mL water, then 10mL brine. The organics were then dried with sodium sulfate, filtered, and concentrated to a residue.
  • Step c To a solution of tert-butyl (5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4- yl)carbamate (84 mg, 275.1 ⁇ mol, 1.0 eq.) in HFIP (3 mL) was added TFA (69.11 mg, 606.06 ⁇ mol, 46.41 ⁇ L, 3.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours. The mixture was concentrated to give a residue. The residue was redissolved in ethyl acetate and washed with 10mL saturated sodium bicarbonate solution, 10mL of water, and then 10mL of brine.
  • Example 164 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(pyridazin-3- yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 7-bromo-6-chloro-1H-indole (93.66 mg, 406.36 ⁇ mol, 1.5 eq.) in toluene (5 mL) was added 3-(tributylstannyl)pyridazine (100.00 mg, 270.91 ⁇ mol, 1.0 eq.), cateCXium A-Pd-G2 (18.11 mg, 27.09 ⁇ mol, 0.1 eq.) and KF (47.22 mg, 812.72 ⁇ mol, 3.0 eq.) at 20 °C under N 2 .
  • Example 165 N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-1H-indole-3- sulfonamide
  • pyridine 22.39 mg, 283.03 ⁇ mol, 22.89 ⁇ L, 2.0 eq.
  • 6-chloro-1H-indole-3-sulfonyl chloride 35.39 mg, 141.51 ⁇ mol, 1.0 eq.
  • Example 166 N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(thiazol-4- yl)-1H-indole-3-sulfonamide
  • pyridine 22.39 mg, 283.03 ⁇ mol, 22.89 ⁇ L, 2.0 eq.
  • 6-chloro-7-(thiazol-4-yl)-1H-indole-3-sulfonyl chloride Preparation 56) (50 mg, 150.05 ⁇ mol, 1.0 eq.) at 20 °C.
  • Example 167 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(thiazol-4-yl)- 1H-indole-3-sulfonamide
  • 6-chloro-7-(thiazol-4-yl)-1H-indole-3-sulfonyl chloride (Preparation 56) (60.00 mg, 180.06 ⁇ mol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (30.17 mg, 180.06 ⁇ mol, 1.0 eq.) in DCM (3.0 mL) was added pyridine (42.73 mg, 540.19 ⁇ mol, 3.0 eq.) at 25 °C.
  • Example 168 N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(2H-1,2,3- triazol-2-yl)-1H-indole-3-sulfonamide
  • pyridine 24.94 mg, 315.31 ⁇ mol, 25.50 ⁇ L, 2.0 eq.
  • 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine Preparation 55) (33.42mg, 157.65 ⁇ mol, 1.0 eq.) at 20 °C.
  • Example 169 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(2H-1,2,3- triazol-2-yl)-1H-indole-3-sulfonamide
  • 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 57) (60.00 mg, 189.18 ⁇ mol, 1.0 eq.) and 5-chloro-1-(2-chloroethyl)-1H- pyrazol-4-amine (34.06 mg, 189.18 ⁇ mol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (44.89 mg, 567.55 ⁇ mol, 3.0 eq.) at 25 °C.
  • Example 170 N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(pyridin-2- yl)-1H-indole-3-sulfonamide
  • pyridine ((24.18 mg, 305.64 ⁇ mol, 24.72 ⁇ L, 2.0 eq.)
  • 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine Preparation 55) (32.40 mg, 152.82 ⁇ mol, 1.0 eq.) at 20 °C.
  • Example 171 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(pyridin-2- yl)-1H-indole-3-sulfonamide
  • 6-chloro-7-(pyridin-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 58) (40 mg, 122.25 ⁇ mol, 1.0 eq.) in DCM (4 mL) was added 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine (20.48 mg, 122.25 ⁇ mol, 1.0 eq.) and pyridine (29.01 mg, 366.76 ⁇ mol, 3.0 eq.) at 25 °C.
  • Example 172 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(pyridin-2- yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 7-bromo-6-chloro-1H-indole (150 mg, 650.79 ⁇ mol, 1.0 eq.) and 5- methyl-2-(tributylstannyl)pyridine (248.71 mg, 650.79 ⁇ mol, 1.0 eq.) in dioxane (3 mL) was added PdCl2(PPh3)2 (45.68 mg, 65.08 ⁇ mol, 0.1 eq.).
  • Step c To a solution of 6-chloro-7-(5-methylpyridin-2-yl)-1H-indole-3-sulfonyl (50 mg, 146.54 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(difluoromethyl)-1H-pyrazol-4- amine (24.55 mg, 146.54 ⁇ mol, 1.0 eq.) and pyridine (34.77 mg, 439.61 ⁇ mol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete.
  • Example 173 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol- 1-yl)-1H-indole-3-sulfonamide
  • 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (50 mg, 158.15 ⁇ mol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (39.74 mg, 237.22 ⁇ mol, 1.5 eq.) in DCM (2 mL) was added pyridine (37.53 mg, 474.44 ⁇ mol, 38.37 ⁇ L, 3.0 eq.) at 20 °C.
  • Example 174 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-1- yl)-1H-indole-3-sulfonamide
  • 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (50 mg, 158.15 ⁇ mol, 1.0 eq.) in DCM (2 mL) was added pyridine (25.02 mg, 316.29 ⁇ mol, 25.58 ⁇ L, 2.0 eq.) and 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-amine (28.47 mg, 158.15 ⁇ mol, 1.0 eq.) at 20 °C.
  • Example 175 N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(1H-pyrazol- 1-yl)-1H-indole-3-sulfonamide
  • pyridine 22.39 mg, 283.03 ⁇ mol, 22.89 ⁇ L, 2.0 eq.
  • 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride Preparation 59) (44.74 mg, 141.51 ⁇ mol, 1.85 eq.) at 20 °C.
  • Example 176 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- methoxypyridin-2-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 7-bromo-6-chloro-1H-indole (130.25 mg, 565.0 ⁇ mol, 1.5 eq.) in toluene (5 mL) was added 4-methoxy-2-(tributylstannyl)pyridine (150.00 mg, 376.72 ⁇ mol, 1.0 eq.), cataCXium A-Pd-G2 (25.19 mg, 37.67 ⁇ mol, 0.1 eq.) and KF (65.66 mg, 1.13 mmol, 3.0 eq.) at 25 °C under N 2 .
  • Example 177 N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(4-chloro- 1H-pyrazol-1-yl)-1H-indole-3-sulfonamide
  • pyridine 18.05 mg, 228.18 ⁇ mol, 18.45 ⁇ L, 2.0 eq.
  • 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride Preparation 60) (24.19 mg, 114.09 ⁇ mol, 1.0 eq.) at 25 °C.
  • Example 178 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4-chloro-1H- pyrazol-1-yl)-1H-indole-3-sulfonamide
  • 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (30 mg, 179.06 ⁇ mol, 1.57 eq.
  • 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 60) (40 mg, 114.09 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added pyridine (27.07 mg, 342.26 ⁇ mol, 27.68 ⁇ L, 3.0 eq.) at 25 °C.
  • Example 179 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- (difluoromethyl)-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 1H-pyrazole-4-carbaldehyde (200 mg, 2.08 mmol, 1.0 eq.) in DCM (5 mL) was added TEA (631.86 mg, 6.24 mmol, 870.34 ⁇ L, 3.0 eq.), Boc2O (263.25 mg, 1.38 mmol, 1.5 eq.) and DMAP (22.49 mg, 184.11 ⁇ mol, 0.2 eq.) at 20 °C.
  • Step b To a solution of butyl 4-formyl-1H-pyrazole-1-carboxylate (130 mg, 662.58 ⁇ mol, 1.0 eq.) in DCM (3 mL) was added DAST (427.20 mg, 2.65 mmol, 350.17 ⁇ L, 4.0 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. The reaction mixture was quenched with saturated aq.NaHCO3 (20 mL) and extracted with DCM (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step d A solution of 1-chloro-2-fluoro-3-nitrobenzene (500 mg, 2.85 mmol, 1.0 eq.), 4- (difluoromethyl)-1H-pyrazole (403.61 mg, 3.42 mmol, 1.2 eq.) and Cs2CO3 (2.78 g, 8.54 mmol, 3.0 eq.) in DMF (2 mL) was stirred at 25 °C for 12 hours.
  • Step f To a solution of 6-chloro-7-(4-(difluoromethyl)-1H-pyrazol-1-yl)-1H-indole (100 mg, 373.61 ⁇ mol, 1.0 eq.) in MeCN (4 mL) was added HSO3Cl (108.84 mg, 934.02 ⁇ mol, 62.09 ⁇ L, 2.5 eq.) at 0 °C. The mixture was stirred at 0 °C for 2 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. Then POCl 3 (229.14 mg, 1.49 mmol, 139.30 ⁇ L, 4.0 eq.) was added and stirred at 70 °C for 12 hours.
  • Step g To a solution of 6-chloro-7-(4-(difluoromethyl)-1H-pyrazol-1-yl)-1H-indole-3- sulfonyl chloride (40.00 mg, 109.24 ⁇ mol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine (18.30 mg, 109.24 ⁇ mol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (25.92 mg, 327.72 ⁇ mol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed.
  • the mixture was concentrated to give a residue.
  • the residue was purified by prep-HPLC (Welch Ultimate C18150*25mm*7um, water (FA)- ACN as a mobile phase, from 35% to 65%, Gradient Time (min): 10, Flow Rate (ml/min): 25) to afford 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- (difluoromethyl)-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (18.96 mg, 34.90% yield).
  • Example 180 6-chloro-N-(3-methoxyisothiazol-4-yl)-7-(1H-pyrazol-1-yl)-1H-indole-3- sulfonamide
  • 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (40.00 mg, 126.52 ⁇ mol, 1.0 eq.) and 3-methoxyisothiazol-4-amine (21.08 mg, 126.52 ⁇ mol 1.06 eq.) in DCM (2 mL) was added pyridine (30.02 mg, 379.55 ⁇ mol, 3.0 eq.) at 25 °C.
  • Example 181 N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(4-ethyl-1H- pyrazol-1-yl)-1H-indole-3-sulfonamide
  • 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 61) (70 mg, 203.36 ⁇ mol, 1.0 eq.) in DCM (4 mL) was added 5-bromo-1- (difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (43.11 mg, 203.36 ⁇ mol, 1.0 eq.) and pyridine (48.26 mg, 610.08 ⁇ mol, 3.0 eq.) at 25 °C.
  • Example 182 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4-ethyl-1H- pyrazol-1-yl)-1H-indole-3-sulfonamide
  • 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 61) (40 mg, 116.21 ⁇ mol, 1.0 eq.) in DCM (4 mL) was added 5-chloro-1- (difluoromethyl)-1H-pyrazol-4-amine (19.47 mg, 116.21 ⁇ mol, 1.0 eq.) and pyridine (27.58 mg, 348.62 ⁇ mol, 3.0 eq.) at 25 °C.
  • Example 183 7-(4-bromo-1H-pyrazol-1-yl)-6-chloro-N-(5-chloro-1-(difluoromethyl)- 1H-pyrazol-4-yl)-1H-indole-3-sulfonamide
  • 7-(4-bromo-1H-pyrazol-1-yl)-6-chloro-1H-indole-3-sulfonyl chloride (Preparation 62) (100.00 mg, 253.13 ⁇ mol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine (45.00 mg, 268.59 ⁇ mol 1.06 eq.) in DCM (2.0 mL) was added pyridine (60.07 mg, 759.38 ⁇ mol, 3.0 eq.) at 25 °C.
  • Example 184 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- cyclopropyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 1-chloro-2-fluoro-3-nitrobenzene (400.00 mg, 2.28 mmol, 1.0 eq.) in MeCN (10 mL) was added K2CO3 (944.75 mg, 6.84 mmol, 3.0 eq.) and 4-cyclopropyl-1H- pyrazole (295.69 mg, 2.73 mmol, 1.2 eq.) at 25 °C.
  • Step b To a solution of 1-(2-chloro-6-nitrophenyl)-4-cyclopropyl-1H-pyrazole (270.00 mg, 1.02 mmol, 1.0 eq.) in THF (40 mL) was added bromo(vinyl)magnesium (1 M, 5.12 mmol, 5.0 eq.) at -78 °C under N2. The mixture was stirred at -78 °C for 3 h. TLC showed the starting material was consumed completely and a new spot was observed. The reaction mixture was quenched with saturated aq.NH4Cl (50 mL) and extracted with EtOAc (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the crude was purified by column chromatography to give the crude product, which was purified by prep-HPLC (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 60% to 90%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to 3-(benzylthio)-6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole (120.00 mg, 88.60% yield).
  • Step f To a solution of 6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, 112.29 ⁇ mol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4- amine (18.81 mg, 112.29 ⁇ mol 1.06 eq.) in DCM (2 mL) was added pyridine (26.65 mg, 336.86 ⁇ mol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and the desired Mass was observed.
  • Example 185 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(5,6- dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole (Preparation 63) (50.00 mg, 194.01 ⁇ mol, 1.0 eq.) in MeCN (2 mL) was added dropwise sulfurochloridic acid (226.07 mg, 1.94 mmol, 128.96 ⁇ L, 10.0 eq.) at 0 °C.
  • Step b To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole-3- sulfonyl chloride (50 mg, 140.36 ⁇ mol, 1.0 eq.) in DCM (2 mL) was added pyridine (22.20 mg, 280.72 ⁇ mol, 22.70 ⁇ L, 2.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (23.52 mg, 140.36 ⁇ mol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed that the desired product was detected.
  • Example 186 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(5,6- dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole-3-sulfonamide
  • Step a To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-1H-indole (Preparation 63) (50.00 mg, 194.01 ⁇ mol, 1.0 eq.) in MeCN (2 mL) was added dropwise sulfurochloridic acid (113.03 mg, 970.05 ⁇ mol, 64.48 ⁇ L, 5.0 eq.) at 0 °C.
  • Step b To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-1H-indole-3- sulfonyl chloride (50 mg, 140.36 ⁇ mol, 1.0 eq.) in DCM (2 mL) was added pyridine (22.20 mg, 280.72 ⁇ mol, 22.70 ⁇ L, 2.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (23.52 mg, 140.36 ⁇ mol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the desired product was detected.
  • GPR17 cAMP HTRF assay A stably expressing GPR17-1321N1 clonal cell line was generated using lentivirus to introduce full length GPR17 expression and evaluate cAMP activity using a cAMP HTRF assay.
  • GPR17-1321N1 and wt-1321N1 cells were cultured in DMEM with 10% FBS, 1% glutamax and 1% Penicillin-Streptomycin, supplemented with 5 ⁇ g/ml of puromycin for the GPR17-1321N1 line.
  • MDR1-MDCK assay procedure Human MDR1 transfected MDCK cells (NIH cell line in-licensed from Absorption Systems) were used in the assay. ⁇ The compounds were tested at 1 ⁇ M concentration prepared in transport buffer (Hank’s balanced salt solution with HEPES) ⁇ MDR1-MDCK cell were cultured for 7 days in 96 well transwell insert plates (Corning).
  • Insert plates were washed before the assay and TEER (Trans epithelial electric resistance) was measured. ⁇ These plates were loaded with test compound solution 85 ⁇ L for A-B transport and 260 ⁇ L for B-A transport in the respective donor compartment.
  • the volume of receiver buffer (Transport buffer supplemented with 1% BSA) in the respective receiver compartment was 250 and 75 ⁇ L.
  • Assay plates were incubated for 120 minutes.
  • Kp brain-to-plasma partition coefficient
  • Bioanalysis Tissue samples were typically homogenized in phosphate buffer saline (PBS) using a bead ruptor.
  • CSF samples were typically diluted with 8% BSA in PBS to prevent from non-specific binding.
  • Artificial CSF (aCSF) is used as the surrogate matrix. Dosing solutions were spiked into plasma for analysis when needed.
  • Calibration curves were prepared by spiking the analyte(s) into blank matrices, which were processed together with plasma, tissue homogenate and/or CSF samples by protein precipitation using a proper organic solvent (e.g. acetonitrile and methanol) containing generic analogue internal standards (e.g. verapamil, chrysin and glyburide). Matrix matching was used when analyzing multiple matrices in the same run. Samples above the upper limit of quantitation (ULOQ) needed to be diluted into the calibration range using either a pre- extraction or post-extraction dilution approach.
  • UAOQ upper limit of quantitation
  • PK Plasma concentrations were analyzed by non-compartmental analysis (NCA) using a “Linear up log down” fitting to generate basic PK parameters that include but are not limited to volume of distribution (Vd), maximal concentration (Cmax), time to reach maximal concentration (Tmax), area under the curve (AUC), half-life (t1/2), clearance (CL) and bioavailability (F).
  • Vd volume of distribution
  • Cmax maximal concentration
  • Tmax time to reach maximal concentration
  • AUC area under the curve
  • t1/2 half-life
  • clearance CL
  • bioavailability F
  • Unbound drug partition coefficient (Kpuu), defined as the ratio of unbound drug partition across the blood-brain barrier, was calculated using the equation below: Cb: measured total drug concentration in brain Fub: unbound drug fraction in brain C p : measured total drug concentration in plasma F up : unbound drug fraction in plasma Compound- or study-specific PK analysis that deviates from the typical procedure might be used when necessary, which will be documented in a study specific protocol included in the data upload. Determination of Fraction Unbound (Fu): The unbound fraction of the test compound was determined based on the protocols described below.
  • D Final calculation using dilution factor (D) This dilution factor formula is used only if tissue or plasma is diluted.

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Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Les variables dans la formule (I) sont définies dans la description. Les composés de formule (I) sont utiles pour réguler l'activité de GPR17 et pour traiter des troubles et des maladies médiés par GPR17 chez l'homme ou les animaux.
PCT/US2024/042520 2023-08-15 2024-08-15 Dérivés d'indole et de pyrroloypyridine utilisés en tant que modulateurs de gpr17 Pending WO2025038863A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018122232A1 (fr) * 2016-12-28 2018-07-05 Ucb Pharma Gmbh (aza)indole, benzothiophène et benzofuran-3-sulfonamides
WO2020254289A1 (fr) * 2019-06-17 2020-12-24 Ucb Pharma Gmbh Dérivés de n-(phényl)-indole-3-sulfonamide et composés apparentés en tant que modulateurs de gpr17 pour le traitement de troubles du système nerveux central tels que la sclérose en plaques
WO2024017855A1 (fr) * 2022-07-20 2024-01-25 F. Hoffmann-La Roche Ag Nouveaux composés isothiazol-3-yl et isoxazol-3-yl sulfonamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018122232A1 (fr) * 2016-12-28 2018-07-05 Ucb Pharma Gmbh (aza)indole, benzothiophène et benzofuran-3-sulfonamides
WO2020254289A1 (fr) * 2019-06-17 2020-12-24 Ucb Pharma Gmbh Dérivés de n-(phényl)-indole-3-sulfonamide et composés apparentés en tant que modulateurs de gpr17 pour le traitement de troubles du système nerveux central tels que la sclérose en plaques
WO2024017855A1 (fr) * 2022-07-20 2024-01-25 F. Hoffmann-La Roche Ag Nouveaux composés isothiazol-3-yl et isoxazol-3-yl sulfonamide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GOODMANGILMAN: "The Pharmacological Basis of Therapeutics", MACK PUBLISHING CO.
S. M. BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19

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