US20160221945A1 - Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators - Google Patents

Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators Download PDF

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US20160221945A1
US20160221945A1 US15/095,467 US201615095467A US2016221945A1 US 20160221945 A1 US20160221945 A1 US 20160221945A1 US 201615095467 A US201615095467 A US 201615095467A US 2016221945 A1 US2016221945 A1 US 2016221945A1
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alkyl
haloalkyl
halogen
independently selected
compound
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Inventor
Huifen Chen
Yanyan Chu
Steven Do
Anthony Estrada
Baihua Hu
Aleksandr Kolesnikov
Xingyu Lin
Joseph P. Lyssikatos
Daniel Shore
Vishal Verma
Lan Wang
Guosheng Wu
Po-Wai Yuen
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Genentech Inc
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Genentech Inc
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Priority to US15/095,467 priority Critical patent/US20160221945A1/en
Publication of US20160221945A1 publication Critical patent/US20160221945A1/en
Priority to US15/851,322 priority patent/US20180118680A1/en
Priority to US16/001,770 priority patent/US20180282272A1/en
Abandoned legal-status Critical Current

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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Definitions

  • the present invention relates to substituted sulfonamide compounds, their manufacture, pharmaceutical compositions containing them and their use as Transient Receptor Potential (TRP) channel antagonists.
  • TRP Transient Receptor Potential
  • TRP channels are a class of ion channels found on the plasma membrane of a variety of human (and other animal) cell types. There are at least 28 known human TRP channels which are broken into a number of families or groups based upon sequence homology and function.
  • TRPA1 is a non-selective cation conducting channel that modulates membrane potential via flux of sodium, potassium and calcium. TRPA1 has been shown to be highly expressed in the human dorsal root ganglion neurons and peripheral sensory nerves. In humans, TRPA1 is activated by a number of reactive compounds such as acrolein, allylisothiocyanate, ozone as well as unreactive compounds such as nicotine and menthol and is thus thought to act as a ‘chemosensor.’
  • TRPA1 agonists are irritants that cause pain, irritation and neurogenic inflammation in humans and other animals. Therefore, it would be expected that TRPA1 antagonists or agents that block the biological effect of TRPA1 channel activators would be useful in the treatment of diseases such as asthma and its exacerbations, chronic cough and related maladies as well as being useful for the treatment of acute and chronic pain. Recently, it has also been shown that products of tissue damage and oxidative stress, e.g. 4-hydroxynonenal and related compounds, activate the TRPA1 channel.
  • the invention provides a compound of the invention which is a compound of Formula I:
  • B is B 1 and R 5 is R 5a ;
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 4 and R 5 is R 5a ;
  • B is B 1 and R 5 is R 5a ;
  • B is B 1 , B 2 , B 3 or B 4 ;
  • B 1 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl, and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula I at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 4 is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 2 is halogen, (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • each R 3a is independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3b group is halogen or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H and (C 1 -C 6 )alkyl;
  • one R 3b′ group is halogen or (C 1 -C 6 )alkyl and the remaining R 3b′ groups are independently selected from H and (C 1 -C 6 )alkyl;
  • R 3c groups attached to different non-adjacent carbon atoms are combined to form a (C 2 -C 4 )alkyl linker, wherein the (C 2 -C 4 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3c groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3d group is halogen, (C 1 -C 6 )alkyl or CN and the remaining R 3d groups are independently selected from H, halogen and (C 1 -C 6 )alkyl, wherein any (C 1 -C 6 )alkyl of R 3d is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5 is R 5a or R 5b ;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 7 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 7 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl; and
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6 or 7-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl, and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • the invention also provides a compound of the invention which is a compound of formula II:
  • B is B 1 and R 5 is R 5a ;
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 4 and R 5 is R 5a ;
  • B is B 1 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 1 , B 2 , B 3 , B 4 , or B 5 ;
  • B 1 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 4 is a 5-membered heteroaryl, 6-membered heteroaryl, or phenyl, wherein any 5-membered heteroaryl, 6-membered heteroaryl, or phenyl of B 4 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 2 is halogen, (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • each R 3a is independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3b group is halogen, —CN, or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 3b′ group is halogen, (C 1 -C 6 )alkyl, —CN, or (C 1 -C 6 )haloalkyl and the remaining R 3b′ groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 3c groups attached to different non-adjacent carbon atoms or adjacent carbon atoms are combined to form a (C 1 -C 4 )alkyl linker or a (C 1 -C 2 )alkyl-O—(C 1 -C 2 )alkyl linker, wherein the (C 1 -C 4 )alkyl linker or (C 1 -C 2 )alkyl-O—(C 1 -C 2 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3c groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • each R 3d group is independently selected from H, halogen, (C 1 -C 6 )alkyl, and —CN, wherein any (C 1 -C 6 )alkyl of R 3d is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • one R 3e group is halogen, —CN or (C 1 -C 6 )alkyl and the remaining R 3e groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 3f groups attached to the same carbon atom are combined to form a (C 2 -C 4 )alkyl linker, wherein the (C 2 -C 4 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3f groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5 is R 5a or R 5b ;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6, 7 or 8-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more
  • each R 6 is independently H or (C 1 -C 6 )alkyl
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the invention also provides a compound of the invention or a pharmaceutically acceptable salt thereof for use in medical therapy.
  • the invention also provides for a compound of the invention or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a respiratory disorder.
  • the invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a respiratory disorder.
  • the invention also provides for a method for treating a respiratory disorder in a mammal (e.g., a human) comprising, administering a compound of the invention or a pharmaceutically acceptable salt thereof to the mammal.
  • a mammal e.g., a human
  • the invention also provides for a compound of the invention or a pharmaceutically acceptable salt thereof for modulating TRPA1 activity.
  • the invention provides for a method for modulating TRPA1 activity, comprising contacting TRPA1 with a compound of the invention or a salt thereof.
  • the invention provides for a compound of the invention or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a disease or condition mediated by TRPA1 activity.
  • the disease or condition is pain, itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
  • the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
  • the invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TRPA1 activity.
  • the disease or condition is pain, itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
  • the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
  • the invention provides for a method for treating a disease or condition mediated by TRPA1 activity in a mammal (e.g., a human), comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof to the mammal.
  • a mammal e.g., a human
  • the disease or condition is pain, itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
  • the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
  • the invention also provides a compound of formula I or formula II or a salt thereof.
  • the invention also provides a compound of formula I or formula II or a pharmaceutically acceptable salt thereof.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or formula II or a salt thereof.
  • the invention also provides an invention as described herein.
  • moiety refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule.
  • variables R 1 to R 5 of formula I or II refer to moieties that are attached to the core structure of formula I or II by a covalent bond.
  • substituted refers to the fact that at least one of the hydrogen atoms of that moiety is replaced by another substituent or moiety.
  • lower alkyl substituted by halogen refers to the fact that one or more hydrogen atoms of a lower alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).
  • alkyl refers to an aliphatic straight-chain or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms. In particular embodiments the alkyl has 1 to 10 carbon atoms. In particular embodiments the alkyl has 1 to 6 carbon atoms.
  • alkoxy denotes a group of the formula —O—R′, wherein R′ is an alkyl group.
  • alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.
  • Aryl means a cyclic aromatic hydrocarbon moiety having a mono-, bi- or tricyclic aromatic ring of 6 to 16 carbon ring atoms.
  • the aryl group can be optionally substituted as defined herein.
  • Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like,
  • aryl also includes partially hydrogenated derivatives of the cyclic aromatic hydrocarbon moiety provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each being optionally substituted.
  • the aryl has 6 to 14 carbon ring atoms (i.e., (C 6 -C 14 )aryl). In another embodiment the aryl has 6 to 10 carbon ring atoms (i.e., (C 6 -C 10 )aryl)
  • heteroaryl denotes an aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or
  • halo refers to a substituent fluoro, chloro, bromo, or iodo.
  • haloalkyl denotes an alkyl group wherein one or more of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms, particularly fluoro atoms.
  • haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.
  • Cycloalkyl means a saturated or partially unsaturated carbocyclic moiety having mono- or bicyclic (including bridged bicyclic) rings and 3 to 10 carbon atoms in the ring.
  • the cycloalkyl moiety can optionally be substituted with one or more substituents.
  • cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C 3 -C 8 )cycloalkyl).
  • cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C 3 -C 6 )cycloalkyl).
  • cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl).
  • the cycloalkyl moiety can be attached in a “spirocycloakyl” fashion such as “spirocyclopropyl”:
  • Heterocycle refers to a 4, 5, 6 and 7-membered monocyclic or 7, 8, 9 and 10-membered bicyclic (including bridged bicyclic) heterocyclic moiety that is saturated or partially unsaturated, and has one or more (e.g., 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon.
  • a nitrogen or sulfur may also be in an oxidized form, and a nitrogen may be substituted with one or more (C 1 -C 6 )alkyl or groups.
  • the heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocycles include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.
  • hydro refers to the moiety of a hydrogen atom (—H) and not H 2 .
  • a compound of the formula or “a compound of formula” or “compounds of the formula” or “compounds of formula” refers to any compound selected from the genus of compounds as defined by the formula (including any pharmaceutically acceptable salt or ester of any such compound if not otherwise noted).
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, N-acetylcystein and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid
  • salts may be prepared by the addition of an inorganic base or an organic base to the free acid.
  • Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like.
  • the compounds of the present invention can be present in the form of pharmaceutically acceptable salts.
  • Another embodiment provides non-pharmaceutically acceptable salts of a compound of formula I or II, which can be useful as an intermediate for isolating or purifying a compound of Formula I or II.
  • the compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of Formula I or II to be used as prodrugs).
  • the compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be effected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of Formula I or II.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compound is enriched by at least about 90% by weight with a single diastereomer or enantiomer.
  • the compound is enriched by at least about 95%, 98%, or 99% by weight with a single diastereomer or enantiomer.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.
  • a therapeutically effective amount of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated.
  • a daily dosage of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded when indicated.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
  • pharmaceutically acceptable carrier is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • Useful pharmaceutical carriers for the preparation of the compositions hereof can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like.
  • the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile.
  • Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • the compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
  • Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
  • an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt or ester thereof is administered via any of the usual and acceptable methods known in the art, either singly or in combination.
  • the compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions.
  • buccal cavity e.g., buccal cavity
  • parenterally e.g., intramuscularly, intravenously, or subcutaneously
  • rectally e.g., by suppositories or washings
  • transdermally e.g., skin electroporation
  • the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.
  • the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.
  • the present invention provides for compounds of formula I as described herein below as a first embodiment of the invention (embodiment “E1”):
  • B is B 1 and R 5 is R 5a ;
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 4 and R 5 is R 5a ;
  • B is B 1 and R 5 is R 5a ;
  • B is B 1 , B 2 , B 3 or B 4 ;
  • B 1 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B′ is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl, and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula I at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 4 is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 2 is halogen, (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • each R 3a is independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3b group is halogen or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H and (C 1 -C 6 )alkyl;
  • one R 3b′ group is halogen or (C 1 -C 6 )alkyl and the remaining R 3b′ groups are independently selected from H and (C 1 -C 6 )alkyl;
  • R 3c groups attached to different non-adjacent carbon atoms are combined to form a (C 2 -C 4 )alkyl linker, wherein the (C 2 -C 4 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3c groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3d group is halogen, (C 1 -C 6 )alkyl or CN and the remaining R 3d groups are independently selected from H, halogen and (C 1 -C 6 )alkyl, wherein any (C 1 -C 6 )alkyl of R 3d is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5 is R 5a or R 5b ;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 7 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 7 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl; and
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6 or 7-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl, and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • B is B 1 and R 5 is R 5a ;
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R.
  • B is B 4 and R 5 is R 5a ;
  • B is B 1 and R 5 is R 5a ;
  • B is B 1 , B 2 , B 3 or B 4 ;
  • B 1 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl, and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula I at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 4 is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 2 is halogen, (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • each R 3a is independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3b group is halogen or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H and (C 1 -C 6 )alkyl;
  • one R 3b′ group is halogen or (C 1 -C 6 )alkyl and the remaining R 3b′ groups are independently selected from H and (C 1 -C 6 )alkyl;
  • R 3c groups attached to different non-adjacent carbon atoms are combined to form a (C 2 -C 4 )alkyl linker, wherein the (C 2 -C 4 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3c groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3d group is halogen, (C 1 -C 6 )alkyl or CN and the remaining R 3d groups are independently selected from H, halogen and (C 1 -C 6 )alkyl, wherein any (C 1 -C 6 )alkyl of R 3d is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5 is R 5a or R 5b ;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 7 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 7 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl; and
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6 or 7-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl, and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • E3 The compound according to E1 or E2, wherein each R 3a is independently H or F.
  • E4 The compound according to E1 or E2, wherein one R 3a is F and the remaining R 3a groups are H.
  • E5 The compound according to E1 or E2, wherein each R 3a is H.
  • E6 The compound according to any one of E1-E5, wherein R 2 is (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl.
  • E7 The compound according to any one of E1-E5, wherein R 2 is —CH 3 , —CH 2 OH, —CHF 2 , —CH 2 OCH 3 or CN.
  • E8 The compound according to any one of E1-E5, wherein R 2 is —CH 3 .
  • E9 The compound according to any one of E1-E8, wherein B 1 is a pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl, triazolyl, pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E10 The compound according to any one of E1-E8, wherein B 1 is a pyridinyl or pyrimidinyl, wherein any pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E11 The compound according to any one of E1-E8, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E12 The compound according to any one of E1-E8, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E13 The compound according to any one of E1-E8, wherein B 1 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E14 The compound according to any one of E1-E8, wherein B 1 is a pyrazolyl, wherein any pyrazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E15 The compound according to any one of E1-E8, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E16 The compound according to any one of E1-E15, wherein one R 3b group is F, one R 3b′ group is F and the remaining R 3b groups and R 3b′ groups are H.
  • E17 The compound according to any one of E1-E15, wherein
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a .
  • E18 The compound according to any one of E1-E15, wherein B 2 is pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E19 The compound according to any one of E1-E15, wherein B 2 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E20 The compound according to any one of E1-E19, wherein B 3 is pyrazolyl, triazolyl or pyrimidinyl, wherein any pyrazolyl, triazolyl or pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E21 The compound according to any one of E1-E19, wherein B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E22 The compound according to any one of E1-E19, wherein B 3 is:
  • each R Z1 is independently selected from hydrogen halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E23 The compound according to any one of E1-E19, wherein B 3 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E24 The compound according to any one of E1-E19, wherein B 3 is a pyrazolyl, wherein any pyrazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E25 The compound according to any one of E1-E19, wherein B 3 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E26 The compound according to any one of E1-E25, wherein one two R 3c groups attached to different non-adjacent carbon atoms are combined to form a —CH 2 CH 2 — linker and the remaining R 3c groups are each H.
  • E27 The compound according to any one of E1-E25, wherein the
  • B is B 4 and R 5 is R 5a .
  • E28 The compound according to any one of E1-E27, wherein B 4 is a pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl, triazolyl, pyridinyl or pyrimidinyl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E29 The compound according to any one of E1-E27, wherein B 4 is a pyrimidinyl, wherein any pyrimidinyl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E30 The compound according to any one of E1-E27, wherein B 4 is:
  • each R Z1 is independently selected from hydrogen halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E31 The compound according to any one of E1-E30, wherein one R 3d group is halogen or (C 1 -C 6 )alkyl and the remaining R 3d groups are H.
  • E32 The compound according to any one of E1-E30, wherein one R 3d group is methyl and the remaining R 3d groups are H.
  • E33 The compound according to any one of E1-E30, wherein the
  • B is B 1 and R 5 is R 5a .
  • E34 The compound of any one of E11, E12, E15, E19, E22, E25 or E30, wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, and (C 3 -C 7 )cycloalkyl.
  • E35 The compound of any one of E11, E12, E15, E19, E22, E25 or E30, wherein each R Z1 is independently selected from H, fluoro, chloro, methyl and cyclopropyl.
  • E36 The compound of any one of 12, 22 or 30, wherein each R Z1 is H.
  • E37 The compound according to any one of E1-E36, wherein R 4 is H.
  • E38 The compound according to any one of E1-E37, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • E39 The compound according to any one of E1-E37, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen and —CN.
  • E40 The compound according to any one of E1-E37, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
  • E41 The compound according to any one of E1-E37, wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
  • E42 The compound according to any one of E1-E41, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl; and R 5b is phenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl,
  • E43 The compound according to any one of E1-E41, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl; and R 5b is phenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl, 6-membered heteroaryl or 6-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7
  • E44 The compound according to any one of E1-E41, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl; and R 5b is phenyl, pyridinyl or piperidinyl, wherein any phenyl, pyridinyl or piperidinyl of R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3
  • E45 The compound according to any one of E1-E41, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl; and R 5b is phenyl, pyridinyl or piperidinyl, wherein any phenyl, pyridinyl or piperidinyl of R 5b is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E46 The compound according to any one of E1-E41, wherein R 5a or R 5b is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a or R 5b is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from halogen, (C
  • E47 The compound according to any one of E1-E41, wherein R 5a or R 5b is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E48 The compound according to any one of E1-E41, wherein R 5a or R 5b is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E49 The compound according to any one of E1-E41, wherein R 5a is
  • E50 The compound according to any one of E1-E41, wherein R 5b is
  • E1A The compound according to E1, wherein
  • B is B 1 and R 5 is R 5a .
  • E2A The compound according to E1, wherein
  • B is B 1 and R 5 is R 5a .
  • E3A The compound according to E1 which is a compound of formula Ia:
  • E4A The compound according to E1 which is a compound of formula Ia′:
  • E5A The compound according to any one of E1A-E4A, wherein one R 3a is F and the remaining R 3a groups are H.
  • E6A The compound according to any one of E1A-E4A, wherein each R 3a is H.
  • E7A The compound according to any one of E1A-E6A, wherein R 2 is (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl.
  • E8A The compound according to any one of E1A-E6A, wherein R 2 is —CH 3 , —CH 2 OH, —CHF 2 , —CH 2 OCH 3 or CN.
  • E9A The compound according to any one of E1A-E6A, wherein R 2 is —CH 3 .
  • E10A The compound according to any one of E1A-E9A, wherein B 1 is a pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl, triazolyl, pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E11A The compound according to any one of E1A-E9A, wherein B 1 is a pyridinyl or pyrimidinyl, wherein any pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E12A The compound according to any one of E1A-E9A, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E13A The compound according to any one of E1A-E9A, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E14A The compound according to any one of E1A-E9A, wherein B 1 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E15A The compound according to any one of E1A-E9A, wherein B 1 is a pyrazolyl, wherein any pyrazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E16A The compound according to any one of E1A-E9A, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E17A The compound according to any one E12A, E13A or E14A, wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, and (C 3 -C 7 )cycloalkyl.
  • E18A The compound according to any one E12A, E1A or E14A, wherein each R Z1 is independently selected from H, fluoro, chloro, methyl and cyclopropyl.
  • E19A The compound according to E12A or E13A, wherein each R Z1 is H.
  • E20A The compound according to any one of E1A-E19A, wherein R 4 is H.
  • E21A The compound according to any one of E1A-E20A, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • E22A The compound according to any one of E1A-E20A, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen and —CN.
  • E23A The compound according to any one of E1A-E20A, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
  • E24A The compound according to any one of E1A-E20A, wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
  • E25A The compound according to any one of E1A-E24A, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6
  • E26A The compound according to any one of E1A-E24A, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E27A The compound according to any one of E1A-E24A, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, pyridinyl, piperidiny
  • E28A The compound according to any one of E1A-E24A, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E29A The compound according to any one of E1A-E24A, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E30A The compound according to any one of E1A-E24A, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl or pyridinyl
  • any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • E31A The compound according to any one of E1A-E24A, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E32A The compound according to any one of E1A-E24A, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E33A The compound according to any one of E1A-E24A, wherein R 5a is
  • E1B The compound of E1 wherein:
  • B is B 2 and R 5 is R 5b .
  • E2B The compound of E1 wherein:
  • B is B 2 and R 5 is R 5b .
  • E3B The compound according to E1 which is a compound of formula Ib:
  • E4B The compound according to E1 which is a compound of formula Ib′:
  • E5B The compound according to any one of E1B-E4B, wherein one R 3b group is F and the remaining R 3b groups are H.
  • E6B The compound according to E2B or E4B, wherein
  • E7B The compound according to any one of E1B-E7B, wherein B 2 is pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E8B The compound according to any one of E1B-E7B, wherein B 2 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E9B The compound according to E8B, wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E10B The compound according to EBB, wherein each R Z1 is H.
  • E11B The compound according to any one of E1B-E10B, wherein R 4 is H.
  • E12B The compound according to any one of E1B-E11B, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • E13B The compound according to any one of E1B-E11B, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen and —CN.
  • E14B The compound according to any one of E1B-E11B, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
  • E15B The compound according to any one of E1B-E11B, wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
  • E16B The compound according to any one of E1B-E15B, wherein R 5b is phenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl, 6-membered heteroaryl or 6-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5b is phenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl, 6-membered heteroaryl or 6-membered heterocycle of R 5b
  • E17B The compound according to any one of E1B-E15B, wherein R 5b is phenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl, 6-membered heteroaryl or 6-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E18B The compound according to any one of E1B-E15B, wherein R 5b is phenyl, pyridinyl, or piperidinyl, wherein any phenyl, pyridinyl or piperidinyl of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5b is phenyl, pyridinyl, or piperidinyl, wherein any phenyl, pyridinyl or piperidinyl of R 5b is optionally substituted with
  • E19B The compound according to any one of E1B-E15B, wherein R 5b is phenyl, pyridinyl, or piperidinyl, wherein any phenyl, pyridinyl or piperidinyl of R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E20B The compound according to any one of E1B-E15B, wherein R 5b is phenyl, pyridinyl, or piperidinyl, wherein any phenyl, pyridinyl or piperidinyl of R 5b is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E21B The compound according to any one of E1B-E15B, wherein R 5b is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5b is phenyl or pyridinyl
  • any phenyl or pyridinyl of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • E22B The compound according to any one of EIB-E15B, wherein R 5b is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E23B The compound according to any one of EIB-E15B, wherein R 5b is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5b is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E24B The compound according to any one of EIB-E15B, wherein R 5b is
  • E1C The compound of E1 wherein:
  • B is B 3 and R 5 is R 5a .
  • E2C The compound of E1 wherein:
  • B is B 3 and R 5 is R 5a .
  • E3C The compound according to E1 which is a compound of formula Ic:
  • E4C The compound according to E1 which is a compound of formula Ic′:
  • E5C The compound according to any one of E1C-E4C, wherein one R 3b′ group is F and the remaining R 3b′ groups are H.
  • E6C The compound according to E2C or E4C, wherein
  • E7C The compound according to any one of E1C-E6C, wherein B 3 is pyrazolyl, triazolyl or pyrimidinyl, wherein any pyrazolyl, triazolyl or pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E8C The compound according to any one of E1C-E6C, wherein B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E9C The compound according to any one of E1C-E6C, wherein B 3 is:
  • each R Z1 is independently selected from hydrogen halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E10C The compound according to any one of E1C-E6C, wherein B 3 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E11C The compound according to any one of E1C-E6C, wherein B 3 is a pyrazolyl, wherein any pyrazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E12C The compound according to any one of E1C-E6C, wherein B 3 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E13C The compound according to E9C or E12C, wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, and (C 3 -C 7 )cycloalkyl.
  • E14C The compound according to E9C or E12C, wherein each R Z1 is independently selected from H, fluoro, chloro, methyl and cyclopropyl.
  • E15C The compound according to E9C, wherein each R Z1 is H.
  • E16C The compound according to any one of E1C-E15C, wherein R 4 is H.
  • E17C The compound according to any one of E1C-E16C, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • E18C The compound according to any one of E1C-E16C, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen and —CN.
  • E19C The compound according to any one of E1C-E16C, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
  • E20C The compound according to any one of E1C-E16C, wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
  • E21C The compound according to any one of E1C-E20C, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6
  • E22C The compound according to any one of E1C-E20C, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E23C The compound according to any one of E1C-E20C, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, pyridinyl, piperidiny
  • E24C The compound according to any one of E1C-E20C, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E25C The compound according to any one of E1C-E20C, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E26C The compound according to any one of E1C-E20C, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl or pyridinyl
  • any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • E27C The compound according to any one of E1C-E20C, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E28C The compound according to any one of E1C-E20C, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E29C The compound according to any one of E1C-E20C, wherein R 5a is
  • E1D The compound of E1 wherein:
  • B is B 4 and R 5 is R 5a .
  • E2D The compound of E1 wherein:
  • B is B 4 and R 5 is R 5a .
  • E3D The compound according to E1 which is a compound of formula Id:
  • E4D The compound according to E1 which is a compound of formula Id′:
  • E5D The compound according to any one of E1D-E4D, wherein two R 3c groups attached to different non-adjacent carbon atoms are combined to form a —CH 2 CH 2 — linker and the remaining R 3c groups are each H.
  • E6D The compound according to E2D or E4D, wherein the
  • E7D The compound according to any one of E1D-E6D, wherein B 4 is a pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl, triazolyl, pyridinyl or pyrimidinyl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E8D The compound according to any one of E1D-E6D, wherein B 4 is a pyrimidinyl, wherein any pyrimidinyl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E9D The compound according to any one of E1D-E6D, wherein B 4 is:
  • each R Z1 is independently selected from hydrogen halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E10D The compound according to E9D, wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, and (C 3 -C 7 )cycloalkyl.
  • E11D The compound according to E9D, wherein each R Z1 is independently selected from H, fluoro, chloro, methyl and cyclopropyl.
  • E12D The compound according to E9D, wherein each R Z1 is H.
  • E13D The compound according to any one of E1D-E12D, wherein R 4 is H.
  • E14D The compound according to any one of E1D-E13D, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • E15D The compound according to any one of E1D-E13D, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen and —CN.
  • E16D The compound according to any one of E1D-E13D, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
  • E17D The compound according to any one of E1D-E13D, wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
  • E18D The compound according to any one of E1D-E17D, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6
  • E19D The compound according to any one of E1D-E17D, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E20D The compound according to any one of E1D-E17D, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, pyridinyl, piperidiny
  • E21D The compound according to any one of E1D-E17D, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E22D The compound according to any one of E1D-E17D, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E23D The compound according to any one of E1D-E17D, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl or pyridinyl
  • any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • E24D The compound according to any one of E1D-E17D, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E25D The compound according to any one of E1D-E17D, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E26D The compound according to any one of E1D-E17D, wherein R 5a is
  • E1E The compound according to E1, wherein
  • B is B 1 and R 5 is R 5a .
  • E2E The compound according to E1, wherein
  • B is B 1 and R 5 is R 5a .
  • E3E The compound according to E1 which is a compound of formula Ie:
  • E4E The compound according to E1 which is a compound of formula Ie′:
  • E5E The compound according to any one of E1E-E5E, wherein one R 3d group is halogen or (C 1 -C 6 )alkyl and the remaining R 3d groups are H.
  • E6E The compound according to any one of E1E-E5E, wherein one R 3d group is halogen and the remaining R 3d groups are H.
  • E7E The compound according to any one of E1E-E5E, wherein one R 3d (C 1 -C 6 )alkyl and the remaining R 3d groups are H.
  • E8E The compound according to any one of E1E-E5E, wherein one R 3d group is methyl and the remaining R 3d groups are H.
  • E9E The compound according to E2E or E4E, wherein the
  • E10E The compound according to any one of E1E-E9E, wherein B 1 is a pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl, triazolyl, pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E11E The compound according to any one of E1E-E9E, wherein B 1 is a pyridinyl or pyrimidinyl, wherein any pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E12E The compound according to any one of E1E-E9E, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E13E The compound according to any one of E1E-E9E, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E14E The compound according to any one of E1E-E9E, wherein B 1 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E15E The compound according to any one of E1E-E9E, wherein B 1 is a pyrazolyl, wherein any pyrazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E16E The compound according to any one of E1E-E9E, wherein B 1 is:
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • E17E The compound according to E12E, E13E or E16E, wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, and (C 3 -C 7 )cycloalkyl.
  • E18E The compound according to E12E, E13E or E16E, wherein each R Z1 is independently selected from H, fluoro, chloro, methyl and cyclopropyl.
  • E19E The compound according to E12E or E13E, wherein each R Z1 is H.
  • E20E The compound according to any one of E1E-E19E, wherein R 4 is H.
  • E21E The compound according to any one of E1E-E20E, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • E22E The compound according to any one of E1E-E20E, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen and —CN.
  • E23E The compound according to any one of E1E-E20E, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
  • E24E The compound according to any one of E1E-E20E, wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
  • E25E The compound according to any one of E1E-E24E, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6
  • E26E The compound according to any one of E1E-E24E, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E27E The compound according to any one of E1E-E24E, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl, pyridinyl, piperidiny
  • E28E The compound according to any one of E1E-E24E, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E29E The compound according to any one of E1E-E24E, wherein R 5a is phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, wherein any phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E30E The compound according to any one of E1E-E24E, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a is phenyl or pyridinyl
  • any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1
  • E31E The compound according to any one of E1E-E24E, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • E32E The compound according to any one of E1E-E24E, wherein R 5a is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R 5a is optionally substituted with one or more groups independently selected from —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
  • E33E The compound according to any one of E1E-E24E, wherein R 5a is
  • compounds of formula I or formula II are selected from the compound in the Table 1 below or a salt or a pharmaceutically acceptable salt thereof.
  • the present invention provides for compounds of formula II as described herein below as a second embodiment of the invention (embodiment “EE1”):
  • B is B 1 and R 5 is R 5a ;
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 4 and R 5 is R 5a ;
  • B is B 1 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 1 , B 2 , B 3 , B 4 , or B 5 ;
  • B 1 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of Formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 4 is a 5-membered heteroaryl, 6-membered heteroaryl, or phenyl, wherein any 5-membered heteroaryl, 6-membered heteroaryl, or phenyl of B 4 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 2 is halogen, (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • each R 3a is independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • one R 3b group is halogen, —CN, or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 3b′ group is halogen, (C 1 -C 6 )alkyl, —CN, or (C 1 -C 6 )haloalkyl and the remaining R 3b′ groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 3c groups attached to different non-adjacent carbon atoms or adjacent carbon atoms are combined to form a (C 1 -C 4 )alkyl linker or a (C 1 -C 2 )alkyl-O—(C 1 -C 2 )alkyl linker, wherein the (C 1 -C 4 )alkyl linker or (C 1 -C 2 )alkyl-O—(C 1 -C 2 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3c groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • each R 3d group is independently selected from H, halogen, (C 1 -C 6 )alkyl, and —CN, wherein any (C 1 -C 6 )alkyl of R 3d is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
  • one R 3e group is halogen, —CN or (C 1 -C 6 )alkyl and the remaining R 3e groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 3f groups attached to the same carbon atom are combined to form a (C 2 -C 4 )alkyl linker, wherein the (C 2 -C 4 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3f groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5 is R 5a or R 5b ;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6, 7 or 8-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7 or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more
  • each R 6 is independently H or (C 1 -C 6 )alkyl
  • B is B 1 and R 5 is R 5a ;
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a or
  • B is B 4 and R 5 is R 5a ;
  • B is B 1 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B is B 3 and R 5 is R.
  • EE6 The compound of any one of embodiments EE1-EE5, wherein R 2 is (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl.
  • B 1 is a pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl, triazolyl, pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • B 1 is a pyridinyl or pyrimidinyl wherein any pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • EE13 The compound of any one of embodiments EE1-EE8, wherein B 1 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • EE14 The compound of any one of embodiments EE1-EE8, wherein B 1 is a pyrazolyl, wherein any pyrazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • EE16 The compound of any one of embodiments EE1-EE15, wherein one R 3b group is F and the remaining R 3b groups are H, and one R 3b′ group is F and the remaining R 3b′ groups are H.
  • EE16a The compound of any one of embodiments EE1-EE15, wherein one R 3b group is halogen, —CN, or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl, and one R 3b′ group is halogen, (C 1 -C 6 )alkyl, —CN, or (C 1 -C 6 )haloalkyl and the remaining R 3b′ groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • EE16b The compound of any one of embodiments EE1-EE15, wherein one R 3b group is halogen or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H and (C 1 -C 6 )alkyl, and one R 3b′ group is halogen, (C 1 -C 6 )alkyl, —CN, or (C 1 -C 6 )haloalkyl and the remaining R 3b′ groups are independently selected from H and (C 1 -C 6 )alkyl.
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R.
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a .
  • EE18 The compound of any one of embodiments EE1-EE17, wherein B 2 is pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • EE18a The compound of any one of embodiments EE1-EE17, wherein B 2 is pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • EE20 The compound of any one of embodiments EE1-EE19, wherein B 3 is pyrazolyl, triazolyl or pyrimidinyl, wherein any pyrazolyl, triazolyl or pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 .
  • EE21 The compound of any one of embodiments EE1-EE19, wherein B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 .
  • each R Z1 is independently selected from hydrogen, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 .
  • EE23 The compound of any one of embodiments EE1-EE19, wherein B 3 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • EE24 The compound of any one of embodiments EE1-EE19, wherein B 3 is a pyrazolyl, wherein any pyrazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • EE26 The compound of any one of embodiments EE1-EE25, wherein two R 3c groups attached to different non-adjacent carbon atoms or different adjacent carbon atoms are combined to form a —CH 2 , —CH 2 CH 2 — or a CH 2 OCH 2 — linker, wherein the —CH 2 —, —CH 2 CH 2 — or a —CH 2 OCH 2 — linker is optionally substituted with one or more independent halogen groups and the remaining R 3c groups are each H.
  • B is B 4 and R 5 is R 5a .
  • B is B 4 and R 5 is R 5a .
  • EE28 The compound of any one of embodiments EE1-EE27, wherein B 4 is a pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or phenyl wherein any pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or phenyl of B 4 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • EE29 The compound of any one of embodiments EE1-EE27, wherein B 4 is a pyrimidinyl, wherein any pyrimidinyl of B 4 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • each R Z1 is independently selected from hydrogen, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • each R Z1 is independently selected from hydrogen, halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
  • B is B 1 and R 5 is R 5a .
  • B is B 1 and R 5 is R 5a .
  • each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, and (C 3 -C 7 )cycloalkyl.
  • each R Z1 is independently selected from H, fluoro, chloro, methyl, O(CH 3 ), —CN, 2-(trifluoromethyl)pyrimidin-5-yl, —NH(CH 3 ), 2-methoxyethoxy, and cyclopropyl.
  • each R Z1 is independently selected from H, fluoro, chloro, methyl, trifluoromethyl, —O(CH 3 ), —CN, 2-(trifluoromethyl)pyrimidin-5-yl, 2-(trifluoromethyl)pyrinin-5-yl, —NH(CH 3 ), 2-methoxyethoxy, and cyclopropyl.
  • EE36 The compound of any one of embodiments EE12, EE22 or EE30, wherein each R Z1 is H.
  • EE38 The compound of any one of embodiments EE1-EE37, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • EE40 The compound of any one of embodiments EE1-EE37, wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
  • EE41 The compound of any one of embodiments EE1-EE37, wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
  • R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(
  • EE42a The compound of any one of embodiments EE1-EE41, wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl
  • R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7
  • R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7
  • R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from —F, —CHF 2 , —CF 3 , —SCF 3 , —OCHF 2 , —OCF 3 , oxo,
  • R 5a or R 5b is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl wherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
  • R 5a or R 5b is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl wherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
  • EE48 The compound of any one of embodiments EE1-EE41, wherein R 5a or R 5b is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl wherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from —F, —CF 3 , —OCF 3 or cyclopropyl.
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B is B 2 , B 3 , or B 5 ;
  • a group is:
  • B is B 2 and R 5 is R 5b ;
  • B is B 3 and R 5 is R 5a ;
  • B is B 5 and R 5 is R 5a ;
  • B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups
  • R 6 is H or (C 1 -C 6 )alkyl
  • B 2 is pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 ;
  • B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
  • R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )al
  • R 5b is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl, wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )al
  • R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN; and
  • R 4 is H.
  • B is B 3 ;
  • B is B 3 and R 5 is R 5a ;
  • B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
  • R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
  • R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl
  • R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —
  • B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 ; and
  • R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )al
  • EE68 The compound of any one of embodiments EE1-EE30 wherein one R 3e group is halogen, —CN or (C 1 -C 6 )alkyl and the remaining R 3e groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
  • the compounds of Formula I or II are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number.
  • isotopically-labeled (i.e., radiolabelled) compounds of Formula I or II are considered to be within the scope of this invention.
  • isotopes that can be incorporated into the compounds of Formula I or II include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 F, 32 F, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • isotopically-labeled compounds would be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action on the ion channels, or binding affinity to pharmacologically important site of action on the ion channels, particularly TRPA1.
  • Certain isotopically-labeled compounds of Formula I or II are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • a compound of Formula I or II can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Isotopically-labeled compounds of Formula I or II can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the invention provides for a pharmaceutical composition, comprising a therapeutically effective amount of a compound according to Formula I or II and a pharmaceutically acceptable carrier.
  • the present invention provides compounds which are in a prodrug form.
  • prodrug refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.
  • prodrugs are also encompassed.
  • a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester.
  • compounds of this invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem., (1996), 39:10.
  • More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C 1-6 )alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N—(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkanoyl, alpha-amino(C 1-4 )alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , —P(O)(O(C 1-6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of
  • prodrug derivatives see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.
  • a “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • Metabolite products typically are identified by preparing a radiolabelled (e.g., 14 C or 3 H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • metabolites In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art.
  • the metabolite products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • compositions and medicaments comprising a compound of Formula I or II or and embodiment thereof and at least one pharmaceutically acceptable carrier.
  • the compositions of the invention can be used to selectively inhibit TRPA1 in patients (e.g., humans).
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the invention provides for pharmaceutical compositions or medicaments comprising a compound of Formula I or II or an embodiment thereof, and its stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides for preparing compositions (or medicaments) comprising compounds of the invention.
  • the invention provides for administering compounds of Formula I or II or its embodiments and compositions comprising compounds of Formula I or II or an embodiment thereof to a patient (e.g., a human patient) in need thereof.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit TRPA1 activity as required to prevent or treat the undesired disease or disorder, such as for example, pain. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • the daily does is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional or subcutaneous administration.
  • compositions comprising compounds of Formula I or II or an embodiment thereof are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • a typical formulation is prepared by mixing a compound of the present invention and a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine,
  • a active pharmaceutical ingredient of the invention can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.
  • Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include
  • Sustained-release preparations of a compound of the invention can be prepared.
  • suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula I or II or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No.
  • Sustained release compositions also include liposomally entrapped compounds, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).
  • the liposomes are of the small (about 200-800 Angstroms) unilamelar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal therapy.
  • compounds of Formula I or II or an embodiment thereof may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of Formula I or II (or an embodiment thereof) is formulated in an acetate buffer, at pH 5.
  • the compounds of Formula I or II or an embodiment thereof are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • Formulations of a compound of the invention e.g., compound of Formula I or II or an embodiment thereof
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use.
  • Formulations of a compound of the invention (e.g., compound of Formula I or II or an embodiment thereof) intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as starch, ge
  • An example of a suitable oral administration form is a tablet containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • a suitable buffer solution e.g. a phosphate buffer
  • a tonicifier e.g. a salt such sodium chloride
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w.
  • the active ingredient can be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients can be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations can desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • a pharmaceutical composition according to the invention for topical formulations, it is desired to administer an effective amount of a pharmaceutical composition according to the invention to target area, e.g., skin surfaces, mucous membranes, and the like, which are adjacent to peripheral neurons which are to be treated.
  • This amount will generally range from about 0.0001 mg to about 1 g of a compound of the invention per application, depending upon the area to be treated, whether the use is diagnostic, prophylactic or therapeutic, the severity of the symptoms, and the nature of the topical vehicle employed.
  • a preferred topical preparation is an ointment, wherein about 0.001 to about 50 mg of active ingredient is used per cc of ointment base.
  • the pharmaceutical composition can be formulated as transdermal compositions or transdermal delivery devices (“patches”). Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive. Such transdermal patches may be used to provide continuous pulsatile, or on demand delivery of the compounds of the present invention as desired.
  • the formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • certain embodiments of the invention provide for a compound of Formula I or II (or an embodiment thereof) to traverse the blood-brain barrier.
  • Certain neurodegenerative diseases are associated with an increase in permeability of the blood-brain barrier, such that a compound of Formula I or II (or an embodiment thereof) can be readily introduced to the brain.
  • the blood-brain barrier remains intact, several art-known approaches exist for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods.
  • Physical methods of transporting a compound of Formula I or II (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, circumventing the blood-brain barrier entirely, or by creating openings in the blood-brain barrier.
  • Circumvention methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion/convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080, 1994), and implanting a delivery device in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel WafersTM, Guildford.
  • direct injection into the brain see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002
  • interstitial infusion/convection-enhanced delivery see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-20
  • Methods of creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002/0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).
  • ultrasound see, e.g., U.S. Patent Publication No. 2002/0038086
  • osmotic pressure e.g., by administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press,
  • Lipid-based methods of transporting a compound of Formula I or II (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating the a compound of Formula I or II (or an embodiment thereof) in liposomes that are coupled to antibody binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Application Publication No. 2002/0025313), and coating a compound of Formula I or II (or an embodiment thereof) in low-density lipoprotein particles (see, e.g., U.S. Patent Application Publication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S. Patent Application Publication No. 2004/0131692).
  • Receptor and channel-based methods of transporting a compound of Formula I or II (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase permeability of the blood-brain barrier (see, e.g., U.S. Patent Application Publication Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. Patent Application Publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Application Publication No.
  • the compounds can be administered continuously by infusion into the fluid reservoirs of the CNS, although bolus injection may be acceptable.
  • the inhibitors can be administered into the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration can be performed by use of an indwelling catheter and a continuous administration means such as a pump, or it can be administered by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitors can be injected through chronically implanted cannulas or chronically infused with the help of osmotic minipumps. Subcutaneous pumps are available that deliver proteins through a small tubing to the cerebral ventricles.
  • Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set without surgical intervention.
  • suitable administration protocols and delivery systems involving a subcutaneous pump device or continuous intracerebroventricular infusion through a totally implanted drug delivery system are those used for the administration of dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models for Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143, 1987.
  • Representative compounds of the invention have been shown to modulate TRPA lactivity. Accordingly, the compounds of the invention are useful for treating diseases and conditions mediated by TRPA1 activity. Such diseases and conditions include but are not limited to: pain (acute, chronic, inflammatory, or neuropathic pain); itch or various inflammatory disorders; inner ear disorders; fever or other disorders of thermoregulation; tracheobronchial or diaphragmatic dysfunction; gastrointestinal or urinary tract disorders; chronic obstructive pulmonary disease; incontinence; and disorders associated with reduced blood flow to the CNS or CNS hypoxia.
  • pain acute, chronic, inflammatory, or neuropathic pain
  • itch or various inflammatory disorders include inner ear disorders; fever or other disorders of thermoregulation; tracheobronchial or diaphragmatic dysfunction; gastrointestinal or urinary tract disorders; chronic obstructive pulmonary disease; incontinence; and disorders associated with reduced blood flow to the CNS or CNS hypoxia.
  • compounds of the invention can be administered to treat pain, including but not limited to neuropathic and inflammatory pain, among others.
  • pain may be considered a disease or disorder, while other types may be considered symptoms of various diseases or disorders, and pain may include various etiologies.
  • Exemplary types of pain treatable with a TRPA1-modulating agent according to the invention include pain associated with, arising from, or caused by: osteoarthritis, rotator cuff disorders, arthritis (e.g., rheumatoid arthritis or inflammatory arthritis; see, Barton et al. Exp. Mol. Pathol. 2006, 81(2), 166-170), fibromyalgia, migraine and headache (e.g.
  • herpes simplex pleurisy
  • pericarditis non-cardiac chest pain, contusions, abrasions, skin incision (Honore, P. et al., J Pharmacal Exp Ther., 2005, 314, 410-21)
  • postoperative pain peripheral neuropathy, central neuropathy, diabetic neuropathy, acute herpetic neuralgia, post-herpetic neuralgia, trigeminal neuralgia, glossopharyngeal neuralgia, atypical facial pain, gradiculopathy, HIV associated neuropathy, physical nerve damage, causalgia, reflex sympathetic dystrophy, sciatica, cervical, thoracic or lumbar radiculopathy, brachial plexopathy, lumbar plexopathy, neurodegenerative disorders, occipital neuralgia, intercostal neuralgia, supraorbital neuralgia, inguinal neuralgia, meralgia paresthetica, genitofemoral neuralgia, carpal tunnel
  • thalamic pain e.g. pain caused by cancer, including osteolytic sarcoma, by treatment of cancer by radiation or chemotherapy, or by nerve or bone lesions associated with cancer (see, Menendez, L. et al., Neurosci. Lett. 2005, 393 (1), 70-73; Asai, H. et al., Pain 2005, 117, 19-29), or bone destruction pain (see, Ghilardi, J. R. et al., J. Neurosci.
  • the compounds may be used to treat pain indications such as visceral pain, ocular pain, thermal pain, dental pain, capsaicin-induced pain (as well as other symptomatic conditions induced by capsaicin such as cough, lachrymation, and bronchospasm).
  • pain indications such as visceral pain, ocular pain, thermal pain, dental pain, capsaicin-induced pain (as well as other symptomatic conditions induced by capsaicin such as cough, lachrymation, and bronchospasm).
  • compounds of the invention can be administered to treat itch, which may arise from various sources, such as dermatological or inflammatory disorders.
  • compounds of the invention can be administered to treat inflammatory disorders, including disorders selected from the group consisting of: renal or hepatobiliary disorders, immunological disorders, medication reactions and unknown/idiopathic conditions.
  • Inflammatory disorders treatable with an inventive agent include, for example, inflammatory bowel disease (IBO), Crohn's disease, and ulcerative colitis (Geppetti, P. et al., Br. J. Pharmacal. 2004, 141, 1313-20; Yiangou, Y. et al., Lancet 2001, 357, 1338-39; Kimball, E. S. et al., Neurogastroenterol. Motif., 2004, 16, 811), osteoarthritis (Szabo, A. et al., J.
  • compounds of the invention can be administered to treat inner ear disorders.
  • disorders include, for example, hyperacusis, tinnitus, vestibular hypersensitivity, and episodic vertigo.
  • compounds of the invention can be administered to treat tracheobronchial and diaphragmatic dysfunctions including, for example, asthma and allergy-related immune responses (Agopyan, N. et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2004, 286, L563-72; Agopyan, N. et al., Toxicol. Appl. Pharmacal. 2003, 192, 21-35), cough (e.g., acute or chronic cough, or cough caused by irritation from gastroesophageal reflux disease; see, Lalloo, U. G. et al., J. Appl. Physiol. 1995, 79(4), 1082-7), bronchospasm, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and hiccups (hiccoughs, singultus).
  • asthma and allergy-related immune responses Agopyan, N. et al., Am. J. Physiol
  • compounds of the invention can be administered to treat gastrointestinal and urinary tract disorders such as, bladder overactivity, inflammatory hyperalgesia, visceral hyperreflexia of the urinary bladder, hemorrhagic cystitis (Dinis, P. et al., J Neurosci., 2004, 24, 11253-11263), interstitial cystitis (Sculptoreanu, A. et al., Neurosci Lett., 2005, 381, 42-46), inflammatory prostate disease, prostatitis (Sanchez, M. et al., Eur J Pharmacal., 2005, 515, 20-27), nausea, vomiting, intestinal cramping, intestinal bloating, bladder spasms, urinary urgency, defecation urgency and urge incontinence.
  • gastrointestinal and urinary tract disorders such as, bladder overactivity, inflammatory hyperalgesia, visceral hyperreflexia of the urinary bladder, hemorrhagic cystitis (Dinis, P. et al., J Neuro
  • compounds of the invention can be administered to treat disorders associated with reduced blood flow to the CNS or CNS hypoxia.
  • disorders include, for example, head trauma, spinal injury, thromboembolic or hemorrhagic stroke, transient ischaemic attacks, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, Alzheimer's disease, and Huntington's Disease.
  • compounds of the invention can be administered to treat other diseases, disorders, or conditions mediated through TRPA1 activity, such as: anxiety; learning or memory disorders; eye-related disorders (such as glaucoma, vision loss, increased intraocular pressure, and conjunctivitis); baldness (e.g., by stimulating hair growth); diabetes (including insulin-resistant diabetes or diabetic conditions mediated by insulin sensitivity or secretion); obesity (e.g., through appetite suppression); dyspepsia; biliary colic; renal colic; painful bladder syndrome; inflamed esophagus; upper airway disease; urinary incontinence; acute cystitis; and envenomations (such as marine, snake, or insect stings or bites, including jellyfish, spider, or stingray envenomations).
  • TRPA1 activity such as: anxiety; learning or memory disorders; eye-related disorders (such as glaucoma, vision loss, increased intraocular pressure, and conjunctivitis); baldness (e.g.,
  • compounds of the invention are administered to treat pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, or inflammatory bowel disease.
  • pain including but not limited to acute, chronic, neuropathic and inflammatory pain
  • arthritis including but not limited to acute, chronic, neuropathic and inflammatory pain
  • itch including but not limited to itch, cough, asthma, or inflammatory bowel disease.
  • the invention provides for a method for treating neuropathic pain or inflammatory pain, comprising the step of administering a therapeutically effective amount of a compound according to Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) to a subject in need thereof.
  • a compound according to Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • the invention provides for a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceutically acceptable salt thereof for modulating TRPA1 activity.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • a pharmaceutically acceptable salt thereof for modulating TRPA1 activity e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D,
  • the invention provides for a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above), or a pharmaceutically acceptable salt thereof for use in medical therapy.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • a pharmaceutically acceptable salt thereof for use in medical therapy.
  • the invention provides for a method for treating a respiratory disorder selected from chronic obstructive pulmonary disorder (COPD), asthma, allergic rhinitis and bronchospasm, comprising the step of administering a therapeutically effective amount of a compound according to Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) to a subject in need thereof.
  • COPD chronic obstructive pulmonary disorder
  • asthma chronic obstructive pulmonary disorder
  • bronchospasm comprising the step of administering a therapeutically effective amount of a compound according to Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-
  • the invention provides for a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a respiratory disorder.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a respiratory disorder.
  • the invention provides for the use of a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a respiratory disorder.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a respiratory disorder.
  • the invention provides for a method for treating a respiratory disorder in a mammal (e.g., a human) comprising administering a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceutically acceptable salt thereof to the mammal.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • the invention provides for a method for modulating TRPA1 activity, comprising contacting TRPA1 with a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a salt thereof.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • the invention provides for a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a disease or condition mediated by TRPA1 activity.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a disease or condition mediated by TRPA1 activity.
  • the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
  • the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
  • the invention provides for the use of a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TRPA1 activity.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TRPA1 activity.
  • the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
  • the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
  • the invention provides for a method for treating a disease or condition mediated by TRPA1 activity in a mammal (e.g., a human), comprising administering a compound of Formula I or II (e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceutically acceptable salt thereof to the mammal.
  • a compound of Formula I or II e.g., a compound as described in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above
  • the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
  • the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
  • compounds of the invention demonstrate surprisingly superior stability in in vivo rat pharmacokinetic (PK) studies over related compounds.
  • a monofluorinated compound at the proline 3-position (2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide, possess the highest stability (slowest clearance) over related difluorinated, non-fluorinated, and 3-fluorinated compounds as shown below:
  • the compounds of the invention may be usefully combined with one or more other compounds of the invention or one or more other therapeutic agent or as any combination thereof, in the treatment of ion channel-mediated diseases and conditions.
  • a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including, but not limited to:
  • opiates analgesics e.g., morphine, heroin, cocaine, oxymorphine, levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;
  • morphine heroin, cocaine, oxymorphine, levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine
  • non-opiate analgesics e.g., acetomeniphen, salicylates (e.g., aspirin);
  • nonsteroidal antiinflammatory drugs e.g., ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac;
  • NSAIDs nonsteroidal antiinflammatory drugs
  • anticonvulsants e.g., carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin and pregabalin;
  • antidepressants such as tricyclic antidepressants, e.g., amitriptyline, clomipramine, despramine, imipramine and nortriptyline;
  • COX-2 selective inhibitors e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;
  • alpha-adrenergics e.g., doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methane sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
  • barbiturate sedatives e.g., amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal and thiopental;
  • tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g., ( ⁇ R,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phen
  • coal-tar analgesics in particular paracetamol
  • serotonin reuptake inhibitors e.g., paroxetine, sertraline, norfluoxetine (fluoxetine desmethyl metabolite), metabolite demethylsertraline, ′3 fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and fluoxetine;
  • noradrenaline (norepinephrine) reuptake inhibitors e.g., maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®)
  • a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine, and venlafaxine duloxetine neuroleptics sedative/anxiolytics;
  • dual serotonin-noradrenaline reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • acetylcholinesterase inhibitors such as donepezil
  • 5-HT3 antagonists such as ondansetron
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