Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
  • C07D487/10—Spiro-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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• UDP Glycosyltransferase 8 is an enzyme within the UDP-glycosyltransferase enzyme family.
• UGT8 catalyzes the transfer of galactose to ceramide, a key enzymatic step in the biosynthesis of galactoyslceramides.
• These molecules are abundant sphingolipids of the myelin membrane of the central and peripheral nervous systems.
• Galactocerebrosides also serve as precursors in the glycosphingolipid biosynthetic pathway and are further modified by cerebroside sulfotransferase, an enzyme which converts Galactocerebrosides to sulfatides.
• Sulfatides are also important components of the central nervous system (CNS) and peripheral nervous system (PNS) as a component of myelin, which is a crucial insulator sheath that surrounds axons as a bilayer membrane.
• CNS central nervous system
• PNS peripheral nervous system
• Krabbe’s disease is a lysosomal storage disorder in which galactosylceramide (a specific galactocerebroside) and psychosine cannot be adequately degraded because of a deficiency in the galactosylceramidase enzyme.
• galactosylceramide a specific galactocerebroside
• psychosine cannot be adequately degraded because of a deficiency in the galactosylceramidase enzyme.
• Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA), a lysosomal sulfatase that hydrolyzes the 3-0 ester bond from sulfatides including 3-O-sulfogalactosylceramide and 3-0- sulfolactosylceramide.
• ASA arylsulfatase A
• MLD lysosomal sulfatase that hydrolyzes the 3-0 ester bond from sulfatides including 3-O-sulfogalactosylceramide and 3-0- sulfolactosylceramide.
• the deficiency expressed in MLD causes a buildup of sulfatides within the CNS and PNS.
• a therapeutic approach similar to Krabbe’s via the inhibition of UGT8 (and the resulting production of sulfatides)
• the present application is directed to a compound of Formula (I):
• X 2 is CR 2 or N;
• X 6 is CR 1 or N;
• Y is -CN, Ci- 4 alkyl, -C(0)NR a R b , -NR a -C(0)-R b , -C(0)0R a , -C(0)R a , heteroaryl or -S(0) 2 NR a R b , wherein the C M alkyl or heteroaryl may be substituted with 0-3 occurrences of R z ;
• each R a is independently H, Ci- 4 alkyl, Ci- 4 haloalkyl, Ci- 4 alkyl-C 3 -9 cycloalkyl or C3-9 cycloalkyl;
• each R b is independently Ci- 4 alkyl, Ci- 4 alkoxy, C3-9 cycloalkyl or Ci- 4 alkyl-Ci- 4 alkoxy; or
• R a and R b can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring substituted with 0-3 occurrences of R x ;
• R 7 is hydrogen, Ci- 4 alkyl, C 1 -4 alkoxy, -S(0) 2 -NR a R b - or heteroaryl;
• R 1 is hydrogen, halo, -OH, Ci- 4 alkyl, Ci- 4 alkoxy, Ci- 4 haloalkyl, Ci- 4 haloalkoxy, - NH 3, -NH(C I-4 alkyl) or -N(C I-4 alkyl) 2 , C 3-9 cycloalkyl or heterocycloalkyl, wherein each -NH(C I -4 alkyl), cycloalkyl or heterocycloalkyl is substituted with 0-5 occurrences of R x ;
• R 2 is hydrogen, halo, -OH, C M alkyl, C M alkoxy or C 3-9 cycloalkyl;
• a 1 is a bond, C 1-4 alkylene, -0-, -O-C 1-4 alkylene, -C 2-4 alkenylene, -C 2-4
• alkynylene -NR a , -NR a -Ci_ 4 alkylene-, -S-, -S(O)-, -S(0) 2 -, -C(O)-, -C(0)-0- or -O- C(O)-;
• (k) L is aryl, heteroaryl, C3-12 cycloalkyl, a 3-12 membered heterocycloalkyl or a 3-12 membered heterocycloalkenyl each of which may be substituted with 0-3 occurrences of R x ;
• (l) A 2 is a bond, -0-, -NR a -, -Ci_ 4 -alkyl-NR a -, -C(O)-, -CM alkyl-C(O)-, -O-C(O)-, -CM alkyl-O-C(O)-, -C(0)-0-, -CM alkyl-C(0)-0-, -0-C(0)-0-, -S(0) 2 -, -NR a -S(0)-, -Ci- 4-alkyl-NR a -S(0)-, -NR a -S(0) 2 -, -Ci- 4 -alkyl-NR a -S(0) 2 -, -C(0)-NR a -, -CM alkyl- C(0)-NR a -, -NR a -C(0)-, -Ci- 4 -alkyl-NR a -C(0)-, -0-C(0)-NR
• (m)R 4 is hydrogen, -OH, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-9 cycloalkyl,
• heterocycloalkyl aryl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R 4 is substituted with 0-5 occurrences of R 5 ;
• R 5 is OH, halo, CO2H, CM alkyl, C2-6 alkynyl, CM alkoxy, CM haloalkyl, -O-C1-4 haloalkyl, -CM alkyl-O-Ci-4 alkyl, -S-CM alkyl, -S(0) 2 -CM alkyl, -S(0)-CM alkyl, - N(R a ) 2 , -CH 2 N(R a ) 2 , -N(R a )-S(0)-Ci- 4 alkyl, -A-(R a )-S(0) 2 -Ci- 4 alkyl, -NO2, -CN, - CH2CN, C3-9 cycloalkyl, -O-C3-9 cycloalkyl, -CM alkyl-C3-9 cycloalkyl, -O-C1-4 alkyl- C3-9 cycloalkyl, -NO2,
• each R w is independently halo, -OH, CM alkyl, CM haloalkyl or -CM alkoxy;
• each R x is independently halo, -OH, CM alkyl, -CM alkoxy, -CM alkyl-O-Ci- 4 alkyl, - C(0)-N(R a ) 2 , -0-C(0)-N(R a ) 2 , -N(R a ) 2 , -CH 2 N(R a ) 2 , heterocycloalkyl, -O- heterocycloalkyl, -O-aryl or -O-heteroaryl; and (q) each R z is independently hydrogen, halo, -OH, C M alkyl, C 1-4 alkoxy or C 3-9 cycloalkyl.
• the compound of Formula I may be a compound of Formula la, as shown below:
• the compound of Formula I may be a compound of Formula lb, as shown below:
• the compound of Formula I may be a compound of Formula Ic, as shown below:
• the compound of Formula I may be a compound of Formula Id, as shown below:
• the compound of Formula I may be a compound of Formula Ie, as shown below:
• the compound of Formula I may be a compound of Formula If, as shown below:
• the compound of Formula I may be a compound of Formula II, Ila, lib, or lie, as shown below:
• the compound of Formula I may be a compound of Formula III, Ilia, Illb, or IIIc, as shown below:
• the present application is directed to a compound (Compound 1) of Formula (I):
• X 2 is CR 2 or N;
• X 6 is CR 1 or N;
• Y is -CN, Ci- 4 alkyl, -C(0)NR a R b , -NR a -C(0)-R b , -C(0)OR a , -C(0)R a , heteroaryl or -S(0) 2 NR a R b , wherein the C M alkyl or heteroaryl may be substituted with 0-3 occurrences of R z ;
• each R a is independently H, Ci- 4 alkyl, Ci- 4 haloalkyl, -Ci- 4 alkyl-C 3 -9 cycloalkyl or C 3- 9 cycloalkyl;
• Each R b is independently C1-4 alkyl, CM alkoxy, C3-9 cycloalkyl or -Ci- 4 alkyl-Ci- 4 alkoxy; or when Y is -C(0)NR a R b , R a and R b can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring substituted with 0-3 occurrences of R x ;
• R 7 is hydrogen, Ci- 4 alkyl, C alkoxy, -S(0) 2 -NR a R b - or heteroaryl;
• R 1 is hydrogen, halo, -OH, C M alkyl, Ci- 4 alkoxy, Ci- 4 haloalkyl, Ci- 4 haloalkoxy, - NH 3, -NH(C I-4 alkyl) or -N(C I-4 alkyl) 2 , C3-9 cycloalkyl or heterocycloalkyl, wherein each -NH(C I-4 alkyl), cycloalkyl or heterocycloalkyl is substituted with 0-5
• R 2 is hydrogen, halo, -OH, Ci- 4 alkyl, Ci- 4 alkoxy or C3-9 cycloalkyl;
• a 1 is a bond, Ci- 4 alkylene, -0-, -0-Ci- 4 alkylene, -C2-4 alkenylene, -C2-4
• alkynylene -NR a , -NR a -Ci_ 4 alkylene-, -S-, -S(O)-, -S(0) 2 -, -C(O)-, -C(0)-0- or -O- C(O)-;
• (k) L is aryl, heteroaryl, C 3-i2 cycloalkyl, a 3-12 membered heterocycloalkyl or a 3-12 membered heterocycloalkenyl each of which may be substituted with 0-3 occurrences of R x ;
• (l) A 2 is a bond, -0-, -NR a -, -Ci_ 4 -alkyl-NR a -, -C(O)-, -CM alkyl-C(O)-, -O-C(O)-, -C M alkyl-O-C(O)-, -C(0)-0-, -C M alkyl-C(0)-0-, -0-C(0)-0-, -S(0) 2 -, -NR a -S(0)-, -Ci- 4-alkyl-NR a -S(0)-, -NR a -S(0) 2 -, -Ci_ 4 -alkyl-NR a -S(0) 2 -, -C(0)-NR a -, -C M alkyl- C(0)-NR a -, -NR a -C(0)-, -Ci_ 4 -alkyl-NR a -C(0) 2 -, -C
• (m)R 4 is hydrogen, -OH, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-9 cycloalkyl,
• heterocycloalkyl aryl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R 4 is substituted with 0-5 occurrences of R 5 ;
• R 5 is OH, halo, C0 2 H, CM alkyl, C 2-6 alkynyl, Ci -4 alkoxy, CM haloalkyl, -0-Ci- 4 haloalkyl, -CM alkyl-0-Ci_ 4 alkyl, -S-CM alkyl, -S(0) 2 -CM alkyl, -S(0)-CM alkyl, - N(R a ) 2 , -CH 2 N(R a ) 2 , -N(R a )-S(0)-Ci- 4 alkyl, -A-(R a )-S(0) 2 -Ci_ 4 alkyl, -N0 2 , -CN, - CH 2 CN, C3-9 cycloalkyl, -O-C3-9 cycloalkyl, -CM alkyl-C3-9 cycloalkyl, -0-Ci- 4 alkyl- C 3-9
• each R w is independently halo, -OH, CM alkyl, C1-4 haloalkyl or -Ci- 4 alkoxy;
• each R x is independently halo, -OH, Ci- 4 alkyl, -Ci- 4 alkoxy, -Ci- 4 alkyl-0-Ci- 4 alkyl, - C(0)-N(R a ) 2 , -0-C(0)-N(R a ) 2 , -N(R a ) 2 , -CH 2 N(R a ) 2 , heterocycloalkyl, -O- heterocycloalkyl, -O-aryl or -O-heteroaryl; and
• each R z is independently hydrogen, halo, -OH, Ci- 4 alkyl, Ci- 4 alkoxy or C3-9
• the present application further provides:
• halo e.g., fluoro, chloro or bromo
• Y is oxazolyl (e.g., 2-oxazolyl) substituted with 1 occurrence of R 2 , optionally wherein Y is 4-methyl-2-oxazolyl or 5-methyl-2- oxazolyl.
• R a is C1-4 alkyl (e.g., methyl or /-butyl), optionally wherein Y is -C(0)OMe.
• R x is -O-heteroaryl (e.g., -O-2-pyridyl).
• R a is hydrogen and R b is Ci- 4 alkyl (e.g., methyl, ethyl, propyl, isopropyl or n-butyl), optionally wherein R a is hydrogen and R b is ethyl, or R a is hydrogen and R b is isopropyl, or R a is hydrogen and R b is «-butyl, or R a is hydrogen and R b is methyl.
• Ci- 4 alkyl e.g., methyl, ethyl, propyl, isopropyl or n-butyl
• R 1 is hydrogen, halo, (e.g., chloro), Ci-4 haloalkyl (e.g., difluoromethyl or trifluoromethyl).
• R 1 is C3-9 cycloalkyl substituted with 0 occurrences of R x .
• R 1 is heterocycloalkyl (e.g., azetidinyl) substituted with 0-3 occurrences of R x .
• each R x is independently halo (e.g., fluoro), for example, wherein R 1 is 2,2-difluoroazetidinyl.
• R 1 is C M alkyl (e.g., methyl, isopropyl or /-butyl), optionally wherein R 1 is methyl, or R 1 is isopropyl, or R 1 is t- butyl.
• R 1 is 2,2,2-trifluoroethoxy. Any of Compound 1, or 1.1 et seq., wherein R 1 is C M haloalkyl, optionally wherein R 1 is trifluoromethyl or difluoromethyl or l,l-difluoroethyl.
• a 1 is -0-, Ci- 4 alkylene, -O-Ci-4 alkylene, a bond, -O-C(O)-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, C2-4 alkynylene, -NR a - or -NR a -Ci-4 alkylene.
• a 1 is C1-4 alkylene, optionally wherein A 1 is -CH 2 - or - CH(CH 3 )-.
• heterocycloalkyl or a 3-12 membered heterocycloalkenyl, optionally substituted with 0-3 occurrences of R x .
• a 2 is a bond, -C(0)-0-, -OC(0)-NR a -, -OC(O)-, -0-, -C(O)-, -NR a -C(0)-0-, -NR a -C(0)-NR a -, -C(0)-NR a -, -CM alkyl- C(0)-NR a -, -C1-4 alkyl-0-C(0)-NR a -, -0-C(0)-0-, -NR a -C(0)-, -NR a -, -S(0) 2 -, - CM alkyl-C(O)-, -CM alkyl-NR a -, -CM alkyl-NR a -S(0)- or -CM alkyl-C(0)-0-.
• a 2 is a bond, -C(0)-0-, -0C(0)-NR a -, -OC(O)-, -0-, - NR a -C(0)-0-, -CM alkyl-C(0)-NR a -, -CM alkyl-0-C(0)-NR a - or -NR a -.
• a 2 is -C(0)-NR a -, optionally wherein R a is H, or optionally wherein R a is C M alkyl (e.g., methyl or ethyl).
• R a is CM alkyl, optionally wherein R a is methyl, for example, wherein A 2 is -C M alkyl-N(Me)-, e.g., A 2 is -CH 2 -N(Me)-.
• a 2 is -C M alkyl-NR a -S(0)-, optionally wherein R a is H, for example, wherein A 2 is -CH 2 -NH-S(0)-.
• Compound 1.113 wherein A 2 is -C M alkyl-C(0)-0-, optionally wherein A 2 is - CH 2 -C(0)-0- or -CH(CH 3 )-C(0)-0-.
• a 2 is -C M alkyl-0-C(0)-NR a -, optionally wherein R a is H, for example, wherein A 2 is -CH 2 -0-C(0)-NH-.
• R a is H, for example, wherein A 2 is -CH 2 -C(0)-NH- or A 2 is -CH(CH 3 )-C(0)-NH- or A 2 is -C(CH ) 2 -C(0)-NH- or A 2 is -CH(CH 2 CH )- C(0)-NH-.
• R a is C M alkyl (e.g., methyl), for example, wherein A 2 is -CH 2 -C(0)-N(Me)-,
• Compound 1.113 wherein A 2 is -0-.
• a 2 is -0-C(0)-NR a -, optionally wherein R a is H, or wherein R a is Ci- 4 alkyl (e.g., methyl, ethyl or isopropyl), for example, wherein A 2 is -0-C(0)-N(Me)-, or A 2 is -0-C(0)-N(Et)-, or A 2 is -0-C(0)-N(zPr)-.
• R a is H
• R a is Ci- 4 alkyl (e.g., methyl, ethyl or isopropyl)
• R 4 is Ci- 6 alkyl, C 2-6 alkynyl, heterocycloalkyl, C3-9 cycloalkyl or heteroaryl, each optionally substituted with 0-5 occurrences of R 5 , optionally wherein any one or more of the R 5 are the same or different.
• Compound 1.142 or 1.143 wherein the C1-6 alkyl of R 4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, 3,3-dimethylbutyl or 4-methylpentan-2-yl.
• Compound 1.142 or 1.143 wherein the C1-6 alkyl of R 4 is neopentyl.
• Compound 1.142 or 1.143, wherein the Ci -6 alkyl of R 4 is 4-methylpentan-2-yl.
• Compound 1.142 or 1.143, wherein the Ci -6 alkyl of R 4 is 3,3-dimethylbutyl.
• R 4 is C2-6 alkynyl substituted with 0 occurrences of R 5 , or with 1 occurrence of R 5 , or with 2 occurrences of R 5 , or with 3 occurrences of R 5 , or with 4 occurrences of R 5 , or with 5 occurrences of R 5 .
• R 4 is C3-9 cycloalkyl substituted with 0 occurrences of R 5 , or with 1 occurrence of R 5 , or with 2 occurrences of R 5 , or with 3 occurrences of R 5 , or with 4 occurrences of R 5 , or with 5 occurrences of R 5 .
• Compound 1.174 or 1.175 wherein the C3-9 cycloalkyl of R 4 is selected from cyclopropyl, cyclobutyl and cyclohexyl.
• R 4 is aryl substituted with 0 occurrences of R 5 , or with 1 occurrence of R 5 , or with 2 occurrences of R 5 , or with 3 occurrences of R 5 , or with 4 occurrences of R 5 , or with 5 occurrences of R 5 .
• R 4 is heterocycloalkyl substituted with 0 occurrences of R 5 , or with 1 occurrence of R 5 , or with 2 occurrences of R 5 , or with 3 occurrences of R 5 , or with 4 occurrences of R 5 , or with 5 occurrences of R 5 .
• heterocycloalkyl of R 4 is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, azaspiro[2.3]hexanyl, diazaspiro[3.3]heptanyl, oxaazaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, oxaazaspiro[3.4]octanyl, dioxaazaspiro[3.4]octanyl, oxaazaspiro[3.5]nonanyl, diazabicyclo[4.1.0]heptanyl, 3-(tetrahydrothiophene- 1 , l-dioxide), 2- (octahydropyrrolo
• Compound 1.203 or 1.204, wherein the heterocycloalkyl of R 4 is azetidinyl, e.g., 2- azetidinyl or 3 -azetidinyl.
• Compound 1.203 or 1.204, wherein the heterocycloalkyl of R 4 is oxetanyl, e.g., 2- oxetanyl or 3-oxetanyl.
• Compound 1.203 or 1.204, wherein the heterocycloalkyl of R 4 is piperidinyl, e.g., 3-piperidinyl or 4-piperidinyl.
• tetrahydrofuranyl e.g., 2-tetrahydrofuranyl or 3-tetrahydrofuranyl.
• azaspiro[2.3]hexanyl e.g., 5-(5-azaspiro[2.3]hexanyl).
• diazaspiro[3.3]heptanyl e.g., 6-(l,6-diazaspiro[3.3]heptanyl), or l-(l,6- diazaspiro[3.3]heptanyl), or 2-(2,6-diazaspiro[3.3]heptanyl).
• oxaazaspiro[3.3]heptanyl e.g., 6-(l-oxa-6-azaspiro[3.3]heptanyl), or l-(6-oxa-l- azaspiro[3.3]heptanyl), or 6-(2-oxa-6-azaspiro[3.3]heptanyl).
• diazabicyclo[4.1.0]heptanyl e.g., 2-(2,5-diazabicyclo[4.1.0]heptanyl).
• oxaazaspiro [3.4] octanyl e.g . , 2-(5-oxa-2-azaspiro [3.4] octanyl) .
• dioxaazaspiro[3.4]octanyl e.g., 2-(5,8-dioxa-2-azaspiro[3.4]octanyl).
• oxaazaspiro[3.5]nonanyl e.g., 7-(l-oxa-7-azaspiro[3.5]nonanyl).
• Compound 1.203 or 1.204, wherein the heterocycloalkyl of R 4 is thiomorpholinyl, e.g., thiomorpholinyl- 1 -oxide or thiomorpholinyl- l,l-dioxide.
• each R 5 is independently selected from OH, halo, C0 2 H, C M alkyl, Ci- 4 alkoxy, C M haloalkyl, -0-Ci- 4 haloalkyl, - CM alkyl-O-CM alkyl, -S-CM alkyl, -S(0) 2 -CM alkyl, -S(0)-CM alkyl, -N(R a ) 2 , - CH 2 N(R a ) 2 , -N(R a )-S(0)-Ci- 4 alkyl, -N0 2 , -CN, -CH 2 CN, C3-9 cycloalkyl, -C M alkyl-C 3 -9 cycloalkyl, -O-CM alkyl-C 3 -9 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-heteroary
• R 5 is halo, Ci- 4 alkyl, C M alkoxy, Ci- 4 haloalkyl, 0-Ci- 4 haloalkyl, -CN, C3-9 cycloalkyl, Ci- 4 alkyl-C 3-9 cycloalkyl, -0-Ci- 4 alkyl-C 3-9 cycloalkyl, -Ci- 4 alkyl-0-Ci- 4 haloalkyl, or heterocycloalkyl, and wherein each of said cycloalkyl, aryl, heteroaryl or heterocycloalkyl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from halo, C M alkyl, CM alkoxy, CM haloalkyl, -0-C M haloalkyl, N(R a ) 2 , -N(R a )-S(0)-Ci- 4 alkyl, -CN, C 3 -9 cycloalkyl, -CM alkyl-C 3 -9 cycloalkyl, -0-Ci- 4 alkyl-C 3 -9 cycloalkyl, and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or
• heterocycloalkyl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from halo, OH, CM alkoxy, -0-Ci- 4 haloalkyl, N(R a ) 2 , -CH 2 -N(R a ) 2 , -CN, C 3 -9 cycloalkyl, -CM alkyl- C 3- 9 cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each alkyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from OH, C0 2 H, C M alkoxy, C M haloalkyl, -0-Ci- 4 haloalkyl, -S(0) 2 -Ci- 4 alkyl, -N(R a ) 2 , C 3 -9 cycloalkyl, heterocycloalkyl, heteroaryl, wherein each alkyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R w .
• R 5 is independently selected from OH, halo, -CN, C M alkoxy, S-CM alkyl, -S(0) 2 -CM alkyl, -S(0)-CM alkyl, C 3 -9 cycloalkyl, heterocycloalkyl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from halo, OH, CM alkoxy, -O-CM haloalkyl, N(R a ) 2 , -S(0) 2 -CM alkyl, -CN, and O-aralkyl, wherein each alkyl or aryl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from OH, halo, C M alkyl, C M alkoxy, C M haloalkyl, N(R a ) 2 , and O-heterocycloalkyl, wherein each alkyl or heterocycloalkyl is substituted with 0-3 occurrences of R w .
• R 5 is independently selected from C M alkyl, C M haloalkyl, S-CM alkyl, -S(0) 2 -CM alkyl, -S(0)-CM alkyl, C 3 -9 cycloalkyl, and heteroaryl, wherein each alkyl, cycloalkyl or heteroaryl is substituted with 0-3 occurrences of R w .
• R 5 is independently selected from C M alkyl, Ci- 4 alkoxy, -CH 2 CN, and -S(0) 2 -Ci- 4 alkyl, wherein each alkyl, cycloalkyl or heteroaryl is substituted with 0-3 occurrences of R w .
• R 5 is independently selected from OH, halo, Ci- 4 alkyl, -CN, -CH 2 CN, and heteroaryl, wherein each alkyl or heteroaryl is substituted with 0-3 occurrences of R w .
• R 5 is independently selected from Ci- 4 alkyl, Ci- 4 haloalkyl, and C3-9 cycloalkyl, wherein each alkyl or cycloalkyl is substituted with 0-3 occurrences of R w .
• R 5 is independently selected from Ci- 4 haloalkyl, C3-9 cycloalkyl, aryl, heteroaryl and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of
• R 5 is independently selected from C3-9 cycloalkyl, aryl, heteroaryl and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from halo, Ci- 4 alkoxy, and -0-Ci- 4 haloalkyl, wherein each alkyl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from OH, Ci- 4 alkyl, and C3-9 cycloalkyl, wherein each alkyl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from Ci- 4 haloalkyl and -0-Ci- 4 alkoxy, wherein each alkyl is substituted with 0-3 occurrences of R w .
• R 5 is independently selected from C3-9 cycloalkyl and heteroaryl, wherein each cycloalkyl or heteroaryl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from OH and Ci- 4 alkyl, wherein each alkyl is substituted with 0-3 occurrences of R w .
• each R 5 is independently selected from C M alkyl, C 3-9 cycloalkyl, and C1-4 alkyl-C 3-9 cycloalkyl, wherein each alkyl is substituted with 0- 3 occurrences of R w .
• each R 5 is independently selected from C1-4 alkyl and C1-4 alkyl-O-Ci-4 alkyl, wherein each alkyl is substituted with 0-3 occurrences of
• R 5 is independently C1-4 alkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said C1-4 alkyl is selected from methyl, ethyl, and isopropyl.
• R 5 is independently C1-4 alkoxy substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said C1-4 alkoxy is selected from methoxy, ethoxy, isopropoxy and i-butoxy.
• R 5 is independently C1-4 haloalkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said C1-4 haloalkyl is selected from trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2,- trifluoroethyl, 3-fluoropropyl, l,l,l-trifluoroisopropyl, and l,3-difluoroisopropyl.
• R 5 is independently -O-C1-4 haloalkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said -O-C1-4 haloalkyl is selected from fluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
• R 5 is independently -C1-4 alkyl-O-Ci-4 alkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said -C1-4 alkyl-O-Ci-4 alkyl is CH2-O-CH3.
• R 5 is independently -S(0) 2 -Ci- 4 alkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said -S(0) 2 -Ci- 4 alkyl is -S(0) 2 -
• each R a is independently H, Ci-4alkyl, or C 3 -9 cycloalkyl, optionally wherein said R a is methyl or cyclopropyl, and further optionally wherein each R a is the same or each R a is different.
• each R a is independently H, Ci-4alkyl, or C 3 -9 cycloalkyl, optionally wherein said R a is methyl or cyclopropyl, and further optionally wherein each R a is the same or each R a is different.
• R 5 is independently -N(R a )-S(0)-Ci- 4 alkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said -N(R a )-S(0)-Ci- 4 alkyl is -N (R a )-S (O)-t-butyl.
• R w 1, 2 or 3 occurrences of R w , optionally wherein said C 3 -9 cycloalkyl is selected from cyclopropyl, cyclobutyl, and cyclohexyl.
• R 5 is independently -Ci-4 alkyl-C 3 -9 cycloalkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said -Ci-4 alkyl - C 3 -9 cycloalkyl is methylcyclopropyl.
• R 5 is independently -O-Ci-4 alkyl-C 3 -9 cycloalkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said -O-Ci-4 alkyl-C 3 -9 cycloalkyl is O-methyl-cyclopropyl.
• R 5 is independently heterocycloalkyl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said heterocycloalkyl is selected from azetidinyl (e.g., 2-azetidinyl or 3-azetidinyl), oxetanyl (e.g., 2-oxetanyl or 3- oxetanyl), tetrahydrofuranyl (e.g., 2-tetrahydrofuranyl), pyrrolidinyl, dioxanyl (e.g., l,4-dioxanyl), morpholinyl (e.g., 2-morpholinyl), piperidinyl, and
• dihydrooxazolyl e.g., 2-(4,5-dihydrooxazolyl).
• R 5 is independently aryl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said aryl is phenyl.
• R 5 is independently heteroaryl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said heteroaryl is selected from imidazolyl (e.g., 2-imidazolyl), oxazolyl (e.g., 2-oxazolyl, or 4-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl), thiazolyl (e.g., 2-thiazolyl or 4-thiazolyl), pyrazolyl (e.g., l-pyrazolyl, 2-pyrazolyl), triazolyl (e.g., l,2,3-triazolyl or l,2,4-triazolyl), thiophenyl (e.g., 2-thiophenyl), oxadiazolyl (e.g., 2-(l,3,4-oxadiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyr
• R 5 is independently -O-heteroaryl substituted with 0, 1, 2 or 3 occurrences of R w , optionally wherein said O-heteroaryl is O-pyridiyl (e.g., 0-3 -pyridyl).
• each R w is independently halo, optionally selected from fluoro, chloro and bromo.
• each R w is independently C M alkyl, optionally selected from methyl, ethyl, and isopropyl.
• each R w is independently Ci- 4 alkoxy, optionally selected from methoxy and isopropoxy.
• each R w is independently Ci- 4 haloalkyl, optionally selected from trifluoromethyl and 2,2-difluoroethyl.
• X 2 is CR 2 and R 2 is hydrogen, halo (e.g., fluoro) or Ci- 4 alkyl (e.g., methyl);
• X 5 is CR 7 and R 7 is hydrogen;
• X 6 is CR 1 and R 1 is Ci- 4 haloalkyl (e.g., trifluoromethyl);
• Y is -C(0)NR a R b , and R a is H, and R b is Ci- 4 alkyl (e.g., methyl), or R a and R b are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring substituted with 0 occurrences of R x (e.g., R a and R b form l-azetidinyl);
• a 1 is a bond, Ci- 4 alkyene (e.g., CH 2 ) or -0-;
• L is a 3-12 membered heterocyclo
• heterocycloalkyl e.g., azetidinyl
• heteroaryl e.g., 2-pyridyl
• each R 5 is independently selected from halo (e.g., fluoro), C1-4 alkyl (e.g., methyl or isopropyl), C1-4 alkoxy (e.g., methoxy), Ci- 4haloalkyl (e.g., trifluoromethyl), -OCi-4haloalkyl (e.g., trifluoromethoxy), CN, C3-9 cycloalkyl (e.g., cyclopropyl), heteroaryl (e.g., 2-thiazolyl), or
• heterocycloalkyl e.g., l-pyrrolidinyl
• said heteroaryl or heterocycloalkyl is substituted with 0, 1, or 2 halo (e.g., fluoro) or C1-4 alkyl (e.g., isopropyl).
• L is selected from one of the following moieties, each substituted with 0, 1 or 2 occurrences of R x , and wherein R x is halo (e.g., fluoro) or C1-4 alkyl (e.g., methyl):
• R 4 is Ci alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), C3-9 cycloalkyl (e.g., cyclopropyl or cyclohexyl), each substituted with 0 or 1 occurrences of R 5 , and each R 5 is independently selected from halo (e.g., fluoro), C M alkyl (e.g., methyl or isopropyl), C1-4 alkoxy (e.g., methoxy), Ci- 4 haloalkyl (e.g., trifluoromethyl), -OCi- 4 haloalkyl (e.g., trifluoromethoxy), and C3-9 cycloalkyl (e.g., cyclopropyl).
• R 4 is Ci alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), C3-9 cycloal
• the present application provides Compound 1 or any of Compounds 1.1 to 1.300, wherein the compound is selected from one or more of the following compounds represented in Table 1 below:
• the present application provides Compound 1 or any of Compounds 1.1 to 1.300, wherein the compound is selected from one or more of the following compounds represented in Table 2 below:
• the present application provides Compound 1 or any of Compounds 1.1 to 1.300, wherein the compound is selected from the following named compounds below:
• (+/-)-/ e/ - B utyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]pyridin-5- yljpiperazin- l-yl)propanoate;
• Oxetan-3-yl (c/5-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyridin-5- yl)oxy)cyclobutyl)carbamate;
• Neopentyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)piperidin-4- yl)carbamate;
• Neopentyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)azetidin-3- yl)carbamate;
• (+/-)-trans 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyridin-5- yl)piperidin-4-yl 3-methoxyazetidine- 1 -carboxylate;
• (+/-)-trans 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyridin-5- yl)piperidin-4-yl cyclopropylcarbamate;
• (+/-)-trans 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyridin-5- yl)piperidin-4-yl 4-methylpiperazine- 1 -carboxylate;
• (+/-)-trans 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyridin-5- yl)piperidin-4-yl cyclopropylcarbamate;
• (+/-)-trans 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyridin-5- yl)piperidin-4-yl (2-(trifluoromethoxy)ethyl)carbamate;

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