WO2019014352A1 - CARBOXAMIDES AS INHIBITORS OF SODIUM CHANNELS - Google Patents

CARBOXAMIDES AS INHIBITORS OF SODIUM CHANNELS Download PDF

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Publication number
WO2019014352A1
WO2019014352A1 PCT/US2018/041649 US2018041649W WO2019014352A1 WO 2019014352 A1 WO2019014352 A1 WO 2019014352A1 US 2018041649 W US2018041649 W US 2018041649W WO 2019014352 A1 WO2019014352 A1 WO 2019014352A1
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WIPO (PCT)
Prior art keywords
halo
alkyl
alkoxy
haloalkyl
haloalkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2018/041649
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English (en)
French (fr)
Inventor
Nadia AHMAD
Corey Anderson
Vijayalaksmi Arumugam
Iuliana Luci ASGIAN
Joanne Louise CAMP
Lev Tyler Dewey Fanning
Sara Sabina HADIDA RUAH
Dennis Hurley
Yvonne Schmidt
David Shaw
Urvi Jagdishbhai Sheth
Stephen Andrew Thomson
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Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
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Publication date
Priority to CN201880058540.1A priority Critical patent/CN111065383A/zh
Priority to CA3069720A priority patent/CA3069720A1/en
Priority to ES18746526T priority patent/ES3008911T3/es
Priority to CR20200064A priority patent/CR20200064A/es
Priority to KR1020207003933A priority patent/KR20200026987A/ko
Priority to EA202090268A priority patent/EA202090268A1/ru
Priority to JOP/2020/0001A priority patent/JOP20200001A1/ar
Priority to EP18746526.5A priority patent/EP3651752B1/en
Priority to TNP/2020/000001A priority patent/TN2020000001A1/en
Priority to BR112020000553-3A priority patent/BR112020000553A2/pt
Priority to AU2018300150A priority patent/AU2018300150A1/en
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Priority to JP2020501369A priority patent/JP7277431B2/ja
Priority to PE2020000022A priority patent/PE20201164A1/es
Priority to SG11202000230VA priority patent/SG11202000230VA/en
Publication of WO2019014352A1 publication Critical patent/WO2019014352A1/en
Priority to DO2020000004A priority patent/DOP2020000004A/es
Priority to CONC2020/0000145A priority patent/CO2020000145A2/es
Priority to PH12020500066A priority patent/PH12020500066A1/en
Priority to IL271948A priority patent/IL271948A/en
Anticipated expiration legal-status Critical
Priority to ECSENADI20203147A priority patent/ECSP20003147A/es
Ceased legal-status Critical Current

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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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Definitions

  • Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain.
  • Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8).
  • Neuropathic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury.
  • the metabolic neuropathies include post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy.
  • Discrete nerve injury indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.
  • Nav's Voltage-gated sodium channels
  • excitable cell types e.g. neurons, skeletal myocytes, cardiac myocytes.
  • the evidence for the role of these channels in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents all point to the central role of Nav's in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Nayl.8 Sodium Channels. Mol.
  • analgesics have been identified as inhibitors of Nay channels.
  • the local anesthetic drugs such as lidocaine block pain by inhibiting Nay channels
  • other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na + currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).
  • the Nay's form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated Nayl .1 - Nayl .9.
  • the tissue localizations of the nine isoforms vary.
  • Nayl .4 is the primary sodium channel of skeletal muscle
  • Nayl .5 is primary sodium channel of cardiac myocytes.
  • Nay's 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Nay's 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems.
  • the functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of
  • Nayl.8 has been shown to be a carrier of the sodium current that maintains action potential firing in small DRG neurons (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277- 90).
  • Nay 1.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C, et al., The tetrodotoxin-resistant Na + channel Nayl .8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, a potent and selective Nayl .8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p.
  • Nayl .8 mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Nayl .8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between Nayl .7 and Nayl.8 sodium channels: a computer simulation study. J. Neurophysiol . 106(6): p. 3173-84; Renganathan, M., T.R. Cummins, and S.G.
  • Nayl .8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of NaVl .7, Nayl .8 and Nayl .9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J.
  • the invention relates to a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
  • the invention relates to a method of inhibiting a voltage gated sodium channel in a subject by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.
  • the invention relates to a method of treating or lessening the severity in a subject of a variety of diseases, disorders, or conditions, including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia, by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.
  • diseases, disorders, or conditions including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, and cardiac arrhythmia,
  • the invention relates to a compound of formula (I-A) l-A
  • L is O, C(R)2, or a single bond
  • X 5 is N or CR 5 ;
  • X 7 is N or CR 7 ;
  • X 9 is N or CR 9 ;
  • Xn is N or CRn
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • Ria is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • R5, R5, and R7 are defined as follows:
  • R5, R5, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ; and R5 and R7, together with the carbon atoms to which they are attached, form a ring of formula:
  • R7 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w :
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ; or R12 and R13, together with the carbon atoms to which they are attached, form a ring of formula:
  • Yi, Y2, Zi, and Z2 are each independently O or C(Ri4)2;
  • each Ri 4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1 ;
  • L is O, C(R)2, or a single bond
  • X 2a is N, N + -0 , or CR 2a ;
  • X 5 is N or CR 5 ;
  • X 6 is N or CRe
  • X 7 is N or CR 7 ;
  • X 9 is N or CR 9 ;
  • Xn is N or CRn
  • each R is independently H or Ci-Ce alkyl
  • R 2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are defined as follows:
  • R5, Re, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ; and R5 and R7, together with the carbon atoms to which they are attached, form a ring of formula:
  • R7 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w :
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R 12 and Rn are each independently H, halo, CN, OH, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W-(CH 2 ) deliberately-R W ; or R 12 and R 1 3, together with the carbon atoms to which they are attached, form a ring of formula:
  • Yi, Y2, Zi, and Z2 are each independently O or C(Ri4)2;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1 ;
  • Xi a , X2a, X3a, and X4a is N or N + -0 " ;
  • L is O, C(R)2, or a single bond
  • X 5 is N or CR 5 ;
  • X 6 is N or CRe
  • X 7 is N or CR 7 ;
  • X 9 is N or CR 9 ;
  • Xn is N or CRn
  • each R is independently H or Ci-Ce alkyl
  • Rib is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R2b is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3b is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rib is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are defined as follows:
  • R5, Re, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ; and R5 and R7, together with the carbon atoms to which they are attached, form a ring of formula:
  • R7 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w :
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R 12 and Rn are each independently H, halo, CN, OH, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W-(CH 2 ) deliberately-R W ; or R 12 and R 1 3, together with the carbon atoms to which they are attached, form a ring of formula:
  • Yi, Y2, Zi, and Z2 are each independently O or C(Ri4)2;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1
  • the term "compounds of the invention” refers to the compounds of formulas (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-8), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5), (I-B-6), (I-B-7), (I-B-8), (I-B-9), (I-B-10), (II), (II-A-1), (II-A-2), (II-B-1), (II-B-2), (II- B-3), (II-B-4), and (II-B-5), and all of the embodiments thereof, as described herein, and to the compounds identified in Tables 1, 1A, IB, and 1C.
  • the compounds of the invention comprise multiple variable groups (e.g., L, R, X2a, R5, etc.).
  • combinations of groups envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • substituted refers to a group in which one or more hydrogen radicals has been replaced with a specified substituent. Unless otherwise indicated, a substituted group can have a substituent at any substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. As one of ordinary skill in the art will recognize, substituted groups envisioned by this invention are those that result in the formation of stable or chemically feasible compounds.
  • halo means F, CI, Br or I.
  • alkyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond.
  • a "C1-C6 alkyl” group is an alkyl group having between one and six carbon atoms.
  • haloalkyl refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.
  • a "Ci-Ce haloalkyl” group is an alkyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.
  • alkoxy refers to a radical of the formula -OR a where R a is an alkyl group having the specified number of carbon atoms.
  • R a is an alkyl group having the specified number of carbon atoms.
  • a "Ci-Ce alkoxy” group is a radical of the formula -ORa where Ra is an alkyl group having the between one and six carbon atoms.
  • haloalkoxy refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.
  • cycloalkyl refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and which is attached to the rest of the molecule by a single bond.
  • heteroaryl refers to a stable, aromatic, mono- or bicyclic ring radical having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • "*5,” “*6,” “*7,” “* 12,” and “* 13” in the following structures designate the carbon atom in formula (I-A), (I-A-l), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-8), (I-B), (I-B- l), (I-B-2), (I-B-3), (I-B-4), (I-B-5), (I-B-6), (I-B-7), (I-B-8), (I-B-9), (I-B-10), (II), (II-A-1), (II-A- 2), (II-B-1), (II-B-2), (II-B-3), (II-B-4), or (II-B-5) to which the corresponding R group is attached.
  • "*5" designates the carbon atom to which R5 is attached.
  • the compounds of the invention include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers, of the compounds identified by the chemical names and chemical structures provided herein.
  • stereoisomers e.g., enantiomers and diastereomers
  • double bond isomers e.g., (Z) and (E)
  • conformational isomers e.g., and tautomers
  • single stereoisomers, double bond isomers, conformation isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformation isomers, and tautomers are within the scope of the invention.
  • a bold or hashed straight bond attached to a stereocenter of a compound
  • the term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules.
  • the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co- crystal.
  • any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element.
  • an atom is not specifically designated as a particular isotope in any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.
  • stable when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay.
  • Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & CM. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).
  • ⁇ refers to hydrogen and includes any stable isotope of hydrogen, namely l and D.
  • H an atom is designated as "H”
  • protium As used herein, "3 ⁇ 4" refers to protium. Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as protium, protium is present at the specified position at at least the natural abundance concentration of protium.
  • the compounds of the invention, and pharmaceutically acceptable salts thereof include each constituent atom at approximately the natural abundance isotopic composition of the specified element.
  • the compounds of the invention, and pharmaceutically acceptable salts thereof include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element ("isotope-labelled" compounds and salts).
  • isotope-labelled compounds and salts include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example 2 H, 13 C, 15 N, 18 0, 17 0, and 31 P, respectively.
  • the isotope-labelled compounds and salts can be used in a number of beneficial ways, including as medicaments.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled.
  • Deuterium ( 2 H)-labelled compounds and salts are therapeutically useful with potential therapeutic advantages over the non- 2 H-labelled compounds.
  • deuterium ( 2 H)- labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention.
  • the isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes, the examples and the related description, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • the deuterium ( 2 H)-labelled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction.
  • Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially.
  • the concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope-labelled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.
  • the isotopic enrichment factor is at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium
  • the invention rmula (I-A)
  • L is O, C(R)2, or a single bond
  • X 5 is N or CR 5 ;
  • X 6 is N or CR ⁇ ,
  • X 7 is N or CR 7 ;
  • X 9 is N or CR 9 ;
  • Xn is N or CRn
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy
  • R4a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are defined as follows:
  • R5, Re, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ; and R5 and R7, together with the carbon atoms to which they are attached, form a ring of formula:
  • R7 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) Struktur-R W :
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ; or R12 and R13, together with the carbon atoms to which they are attached, form a ring of formula:
  • Yi, Y2, Zi, and Z2 are each independently O or C(Ri4)2;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1 ;
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L is O or a single bond. In other embodiments, L is O. In other embodiments, L is a single bond.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X5 is N. In other embodiments, X5 is CR5.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Xe is N. In other embodiments, Xe is CR5.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X7 is N. In other embodiments, X7 is CR7.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X9 is N. In other embodiments, X9 is CR9.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X10 is N. In other embodiments, X10 is CR10.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Xn is N. In other embodiments, Xn is CRn.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct3 ⁇ 4.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2a is H, halo, OH, C 1 -C6 alkyl, or C 1 -C6 alkoxy.
  • R 2a is halo, OH, C 1 -C6 alkyl, or C 1 -C6 alkoxy.
  • R 2a is H, OH, C 1 -C6 alkyl, or C 1 -C6 alkoxy.
  • R 2a is H, halo, C 1 -C6 alkyl, or C 1 -C6 alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, R2 a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2a is halo. In other embodiments, R2a is Ci-Ce alkyl. In other embodiments, R2a is Ci-Ce alkoxy. In other embodiments, R2 a is H, F, CI, OH, Ct1 ⁇ 4, or OCH3. In other embodiments, R2a is H. In other embodiments, R2 a is F. In other embodiments, R2a is CI. In other embodiments, R2a is OH. In other embodiments, R2a is CH3. In other embodiments, R2a is OCH3.
  • the invention relates to a compound of formula (I-A), or a
  • R3 a is H or halo. In other embodiments, R3a is halo. In other embodiments, R3a is H or F. In other embodiments, R3a is H. In other embodiments, R3a is F.
  • the invention relates to a compound of formula (I-A), or a
  • Rt a is H or Ci-Ce alkyl. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rta is H or CH3. In other embodiments, Rta is H. In other embodiments, Rta is 3 ⁇ 4. In other embodiments, Rta is D. In other embodiments, Rta is CH3.
  • the invention relates to a compound of formula (I-A), or a
  • R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce haloalkyl. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl.
  • R5 is Ci-Ce alkoxy. In other embodiments, R5 is H, F, CF3, or OCH3. In other embodiments, R5 is H. In other embodiments, R5 is F. In other embodiments, R5 is CF3. In other embodiments, R5 is OCH3.
  • the invention relates to a compound of formula (I-A), or a
  • R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W-(CH 2 ) deliberately-R W .
  • R5 is H, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W- (CH 2 ) deliberately-R W .
  • R5 is H, halo, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W- (CH 2 ) wherever-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W- (CH2) juxtapos-R W .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R5 is halo.
  • R5 is Ci-Ce alkyl.
  • R5 is Ci-Ce haloalkyl.
  • R5 is Ci-Ce alkoxy.
  • Re is Ci-Ce haloalkoxy.
  • R5 is -W-(CH2) n -R w . In other embodiments, R5 is -W- (CH2)n-R w , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl. In other embodiments, R5 is H, F, CI, CHF2, CF3, CF2CF3, OCF3, or cyclopropyl. In other embodiments, R5 is H. In other embodiments, R5 is F. In other embodiments, R5 is CI. In other embodiments, R5 is CHF2. In other embodiments, R5 is CF3. In other embodiments, R5 is CF2CF3. In other embodiments, R5 is OCF3. In other embodiments, R5 is cyclopropyl.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R5 and R5, together with the carbon atoms to which they are attached, form a ring of formula:
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, C 1 -C6 alkylamino, or -W-(CH 2 ) resort-R W .
  • R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) deliberately-R W .
  • R7 is halo, Ci- C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) utilizat-R W .
  • R7 is H, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) admir-R W .
  • R7 is H, halo, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) deliberately-R W .
  • R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W- (CH2) cramp-R W .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R7 is halo.
  • R7 is Ci-Ce alkyl.
  • R7 is Ci-Ce haloalkyl.
  • R7 is Ci-Ce alkoxy. In other embodiments, R7 is -W-(CH2) n -R w . In other embodiments, R7 is -W-(CH2)n-R w , wherein W is O, n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R 7 is H, F, CI, CH(CH 3 ) 2 , C(CH 3 ) 3 , CF(CH 3 ) 2 , CF 3 , OCH 3 , OCH 2 Ph, cyclopropyl, 1- methylcylopropyl, 2-methylcyclopropyl, or 2,2-difluorocyclopropyl.
  • R7 is H.
  • R7 is F.
  • R7 is CI.
  • R7 is CH(CH 3 )2.
  • R7 is C(CH 3 ) 3 .
  • R7 is CF(CH 3 )2.
  • R7 is CF 3 .
  • R7 is OCH 3 . In other embodiments, R7 is OCH2PI1. In other embodiments, R7 is cyclopropyl. In other embodiments, R7 is 1 -methylcylopropyl. In other embodiments, R7 is 2- methylcyclopropyl. In other embodiments, R7 is 2,2-difluorocyclopropyl.
  • the invention relates to a compound of formula (I-A), or a
  • the invention relates to a compound of formula (I-A), or a
  • R3 ⁇ 4 is -0-(CH2) n -R w .
  • Rs is -O- (CH2)n-R w , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • Rs is H or OCttPh.
  • 3 ⁇ 4 is H.
  • Rs is OCH2PI1.
  • the invention relates to a compound of formula (I-A), or a
  • R9 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) juxtapos-R W .
  • R9 is H, halo, OH, C1-C6 alkyl, C1-C6 alkoxy, or -W-(CH2) strictly-R W .
  • R9 is halo, OH, C1-C6 alkyl, C1-C6 alkoxy, or -W- (CH2) strictly-R W .
  • R9 is H, OH, C1-C6 alkyl, C1-C6 alkoxy, or -W-(CH2) strictly-R W . In other embodiments, R9 is H, halo, C1-C6 alkyl, C1-C6 alkoxy, or -W-(CH2) strictly-R W . In other embodiments, R9 is H, halo, OH, C1-C6 alkoxy, or -W-(CH2) justify-R W . In other embodiments, R9 is H, halo, OH, C1-C6 alkyl, or -W- (CH2)n-R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other
  • R9 is halo. In other embodiments, R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is -W-(CH2) n -R w . In other embodiments, R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R is H, F, CI, OH, CH3, OCH3, or 1- methylpyrazol-5-yl.
  • R9 is H. In other embodiments, R9 is 3 ⁇ 4. In other embodiments, R9 is D. In other embodiments, R9 is F. In other embodiments, R9 is CI. In other embodiments, R9 is OH. In other embodiments, R9 is CH3. In other embodiments, R9 is OCH3. In other embodiments, R9 is OC( 1 H)3. In other embodiments, R9 is OCD3. In other embodiments, R9 is 1- methylpyrazol-5 -yl .
  • the invention relates to a compound of formula (I-A), or a
  • Rio is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Rio is H, halo, OH, or Ci-Ce alkoxy.
  • Rio is halo, OH, or Ci-Ce alkoxy.
  • Rio is H, OH, or Ci-Ce alkoxy.
  • Rio is H, halo, or Ci-Ce alkoxy.
  • Rio is H, halo, or OH.
  • Rio is halo. In other embodiments, Rio is Ci-Ce alkoxy. In other embodiments, Rio is H, F, CI, OH, or OCH3. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D. In other embodiments, Rio is F. In other embodiments, Rio is CI. In other embodiments, Rio is OH. In other embodiments, Rio is OCH3.
  • the invention relates to a compound of formula (I-A), or a
  • Rn is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Rn is H, halo, Ci-Ce alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is halo, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is H, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is H, halo, or Ci- Ce haloalkoxy. In other embodiments, Rn is H, halo, or C 1 -C6 alkoxy. In other embodiments, Rn is halo. In other embodiments, Rn is C 1 -C6 alkoxy. In other embodiments, Rn is C 1 -C6 haloalkoxy. In other embodiments, Rn is H, F, CI, OCH3, or OCF3. In other embodiments, Rn is H. In other embodiments, Rn is l . In other embodiments, Rn is D. In other embodiments, Rn is F. In other embodiments, Rn is CI. In other embodiments, Rn is OCH3. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A), or a
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 3 is H. In other embodiments, R 1 3 is 3 ⁇ 4. In other embodiments, R13 is D.
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 12 and R 1 3, together with the carbon atoms to which they are attached, form a ring of formula:
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Yi is O, and Y2 is C(Ri4)2. In other embodiments, Yi is C(Ri4)2, and Y2 is O. In other embodiments, Yi is O, and Y2 is O. In other embodiments, Yi is C(Ri4)2,
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Zi is O, and Z2 is C(Ri4)2. In other embodiments, Zi is C(Ri4)2, and Z2 is O. In other embodiments, Zi is O, and Z2 is O. In other embodiments, Zi is C(Ri4)2,
  • the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R14 is independently H or F.
  • each R14 is independently H or F.
  • each R14 is H. In other embodiments, R14 is l . In other embodiments, R14 is D.
  • each R14 is F.
  • the invention relates to a compound of formula (I-A), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-A-l)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • R5, Re, R7, and Rs is not H
  • R7 is Ci-Ce alkyl, then R2 a is not H;
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein L is O or a single bond. In other embodiments, L is O. In other embodiments, L is a single bond.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein R2 a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2 a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2 a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, R2 a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2a is halo. In other embodiments, R2a is Ci-Ce alkyl. In other embodiments, R2a is Ci-Ce alkoxy. In other embodiments, R2a is H, F, CI, OH, or G3 ⁇ 4. In other embodiments, R2a is H. In other embodiments, R2a is F. In other embodiments, R2a is CI. In other embodiments, R2a is OH. In other embodiments, R2a is C3 ⁇ 4.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3a is halo. In other embodiments, R3a is H or F. In other embodiments, R3a is H. In other embodiments, R3a is F.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein Rt a is H or Ci-Ce alkyl. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rta is H or C3 ⁇ 4. In other embodiments, Rta is H. In other embodiments, Rta is 3 ⁇ 4. In other embodiments, Rta is D. In other embodiments, Rta is Q3 ⁇ 4.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce haloalkyl. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is H, F, CF3, or OCH3. In other embodiments, R5 is H. In other embodiments, R5 is F. In other embodiments, R5 is CF3. In other embodiments, R5 is OCH3.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein 5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R ⁇ 5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R ⁇ 5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R ⁇ 5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R ⁇ 5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R ⁇ 5 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R5 is halo.
  • R ⁇ 5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R ⁇ 5 is Ci-Ce alkoxy. In other embodiments, R ⁇ 5 is Ci-Ce haloalkoxy. In other embodiments, R5 is -W-(CH2) n - R w . In other embodiments, R ⁇ 5 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is
  • R ⁇ 5 is H, F, CI, CHF 2 , CF3, CF 2 CF3, OCF 3 , or cyclopropyl.
  • R ⁇ 5 is H.
  • 5 is F.
  • R ⁇ 5 is CI.
  • R ⁇ 5 is CHF 2 .
  • R ⁇ 5 is CF3.
  • R ⁇ 5 is CF 2 CF3.
  • R ⁇ 5 is OCF3.
  • R ⁇ 5 is cyclopropyl.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) utilizat-R W .
  • R7 is halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH2) strictly-R W .
  • R7 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w . In other embodiments, R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R7 is halo.
  • R7 is Ci-Ce alkyl.
  • R7 is Ci-Ce haloalkyl.
  • R7 is Ci-Ce alkoxy.
  • R7 is -W-(CH2) n -R w .
  • R7 is -W-(CH2) n -R w , wherein W is O, n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is H, F, CF3, OCH3, or OCH2PI1.
  • R7 is H.
  • R7 is F.
  • R7 is CF3.
  • R7 is OCH3.
  • R7 is OCH 2 Ph.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is -0-(CH2) n -R w .
  • R3 ⁇ 4 is -0-(CH2) n -R w .
  • Rs is -O- (CH2)n-R w , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • Rs is H or OCttPh.
  • Rs is H.
  • Rs is OCFhPh.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, C 1 -C6 alkyl, or C 1 -C6 alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is C 1 -C6 alkyl. In other embodiments, R9 is C 1 -C6 alkoxy. In other embodiments, R9
  • R9 is -W-(CH 2 ) complicat-R W .
  • R9 is -W-(CH 2 ) admir-R W .
  • R9 is -W-(CH 2 ) friendship-R W , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R9 is H, F, CI, OH, CH3, OCH3, or l-methylpyrazol-5- yl.
  • R9 is H.
  • R9 is 3 ⁇ 4.
  • R9 is D. In other embodiments, R9 is F. In other embodiments, R9 is CI. In other embodiments, R9 is OH. In other embodiments, R9 is CH3. In other embodiments, R9 is OCH3. In other embodiments, R9 is OC ⁇ H . In other embodiments, R9 is OCD3. In other embodiments, R9 is l-methylpyrazol-5-yl.
  • the invention relates to a compound of formula (I-A- l), or a pharmaceutically acceptable salt thereof, wherein Rio is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or OH. In other embodiments, Rio is halo. In other embodiments, Rio is Ci-Ce alkoxy. In other embodiments, Rio is H, F, CI, OH, or OCH3.
  • Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D. In other embodiments, Rio is F. In other embodiments, Rio is CI. In other embodiments, Rio is OH. In other embodiments, Rio is OCH3.
  • the invention relates to a compound of formula (I-A- 1), or a pharmaceutically acceptable salt thereof, wherein Ru is H, halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Ru is H, Ci- Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy. In other embodiments, Rn is Ci-Ce haloalkoxy. In other embodiments, Rn is F, OCH3, or OCF3. In other embodiments, Rn is H. In other embodiments, Rn is l . In other
  • Rn is D. In other embodiments, Rn is F. In other embodiments, Rn is OCH3. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A- 1), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-A- 1), or a pharmaceutically acceptable salt thereof, wherein R13 is H. In other embodiments, R13 is l . In other embodiments, R13 is D.
  • the invention relates to a compound of formula (I-A- 1), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-A-2)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5 and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • R5, R7, and Rs is not H
  • R7 is Ci-Ce alkyl, then R2 a is not H;
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein L is O or a single bond. In other embodiments, L is O. In other embodiments, L is a single bond.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R2 a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2 a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2 a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2a is H, halo, OH, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2a is halo. In other embodiments, R2a is Ci-Ce alkyl. In other embodiments, R2a is Ci-Ce alkoxy. In other embodiments, R2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2a is H, F, G3 ⁇ 4, or OCH3. In other embodiments, R2a is H. In other embodiments, R2a is F. In other embodiments, R2a is CH3. In other embodiments, R2a is OCH3.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3a is halo. In other embodiments, R3a is H.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein Rt a is H or Ci-Ce alkyl. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rta is H.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce haloalkyl. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is H.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R7 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2)n-R w .
  • R7 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w . In other embodiments, R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R7 is halo.
  • R7 is Ci-Ce alkyl.
  • R7 is Ci-Ce haloalkyl.
  • R7 is Ci-Ce alkoxy.
  • R7 is -W-(CH2) n -R w .
  • R7 is -W-(CH2) n -R w , wherein W is O, n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C6 alkyl, and C 1 -C6 haloalkyl.
  • R7 is CH(CI3 ⁇ 4) 2 , C(CI3 ⁇ 4)3, CF(CI3 ⁇ 4) 2 , CF3, cyclopropyl, 1-methylcylopropyl, 2- methylcyclopropyl, or 2,2-difluorocyclopropyl.
  • R7 is CH(CI3 ⁇ 4) 2 .
  • R7 is C(CI3 ⁇ 4)3.
  • R7 is CF(CH3) 2 .
  • R7 is CF3.
  • R7 is cyclopropyl.
  • R7 is 1-methylcylopropyl.
  • R7 is 2-methylcyclopropyl.
  • R7 is 2,2-difluorocyclopropyl.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein Rg is -0-(CH 2 ) contend-R w .
  • Rs is -O- (CH2)n-R w , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • Rs is H.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo.
  • R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R is -W-(CH2) n -R w . In other embodiments, R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl. In other embodiments, R9 is H or Ci-Ce alkoxy.
  • R9 is H or OCH3. In other embodiments, R9 is H. In other embodiments, R9 is 3 ⁇ 4. In other embodiments, R9 is D. In other embodiments, R9 is OCH3. In other embodiments, R9 is OC ⁇ H . In other embodiments, R9
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein Rio is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or OH. In other embodiments, Rio is halo. In other embodiments, Rio is Ci-Ce alkoxy. In other embodiments, Rio is H or halo. In other embodiments, Rio is H, F or CI. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D. In other embodiments, Rio is F. In other embodiments, Rio is CI.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein Rn is H, halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, Ci- Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or C 1 -C6 alkoxy. In other embodiments, Rn is halo.
  • Rn is C 1 -C6 alkoxy. In other embodiments, Rn is C 1 -C6 haloalkoxy. In other embodiments, Rn is halo or C 1 -C6 haloalkoxy. In other embodiments, Rn is F or OCF 3 . In other embodiments, Rn is H. In other embodiments, Rn is 3 ⁇ 4. In other embodiments, Rn is D. In other embodiments, Rn is F. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R 12 is H.
  • the invention relates to a compound of formula (I-A-2), or a pharmaceutically acceptable salt thereof, wherein R 1 3 is H.
  • the invention relates to a compound of formula (I-A-2), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-A-3)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Re and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • R5, R7, and Rs is not H
  • R7 is Ci-Ce alkyl, then R2 a is not H;
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct3 ⁇ 4.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein R 2a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2 a is halo. In other embodiments, R2 a is Ci-Ce alkyl. In other embodiments, R2 a is Ci-Ce alkoxy. In other embodiments, R2 a is H or halo. In other embodiments, R2 a is H or F. In other embodiments, R 2a is H. In other embodiments, R 2a is F.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3 a is halo. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein R4 a is H or Ci-Ce alkyl. In other embodiments, R/t a is Ci-Ce alkyl. In other embodiments, R/t a is H.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein Re is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Re is halo.
  • Re is Ci-Ce alkyl. In other embodiments, Re is Ci-Ce haloalkyl. In other embodiments, Re is Ci-Ce alkoxy. In other embodiments, Re is Ci-Ce haloalkoxy. In other embodiments, Re is -W-(CH2) n - R w . In other embodiments, Re is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl. In other embodiments, Re is H.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2) n -R w .
  • R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2)n-R w .
  • R7 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W- (CH2)n-R w . In other embodiments, R7 is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, C1-C6 alkyl, C1-C6 alkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -W-(CH2) n -R w .
  • R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy.
  • R7 is halo.
  • R7 is C1-C6 alkyl.
  • R7 is C1-C6 haloalkyl.
  • R7 is C1-C6 alkoxy.
  • R7 is -W-(CH2) n -R w .
  • R7 is -W-(CH2) n -R w , wherein W is O, n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl.
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C6 alkyl, and C 1 -C6 haloalkyl.
  • R7 is CF3.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein Rs is -0-(CH 2 ) compassion-R w .
  • Rs is -O- (CH 2 ) friendship-R W , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C6 alkyl, and C 1 -C6 haloalkyl.
  • Rs is H.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W- (CH 2 ) resort-R W .
  • R9 is halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) resort-R W .
  • R9 is H, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) contend-R W .
  • R9 is H, halo, C1-C6 alkyl, C1-C6 alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, C1-C6 alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, C1-C6 alkyl, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, C1-C6 alkyl, or C1-C6 alkoxy. In other embodiments, R9 is halo.
  • R9 is C1-C6 alkyl. In other embodiments, R9 is C1-C6 alkoxy. In other embodiments, R is -W-(CH2) n -R w . In other embodiments, R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein Rio is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or OH. In other embodiments, Rio is halo. In other embodiments, Rio is Ci-Ce alkoxy. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein Rn is H, halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, Ci- Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy. In other embodiments, Rn is Ci-Ce haloalkoxy. In other embodiments, Rn is H. In other embodiments, Rio is l . In other embodiments, Rn is D. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-A-3), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-A-3), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-A-4)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5 and R5 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • R5, Re, and Rs is not H
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein L is O or a single bond. In other embodiments, L is O. In other embodiments, L is a single bond.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein R2 a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2 a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2 a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R2a is H, halo, OH, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2a is halo. In other embodiments, R2a is Ci-Ce alkyl. In other embodiments, R2a is Ci-Ce alkoxy. In other embodiments, R2a is F.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3a is halo. In other embodiments, R3a is H.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein Rt a is H or Ci-Ce alkyl. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rta is H.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce haloalkyl. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is H, halo, or Ci-Ce alkoxy. In other embodiments, R5 is H, F, or OCH3. In other embodiments, R5 is H. In other embodiments, R5 is F. In other embodiments, R5 is OCH3.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • 5 is halo.
  • Re is C1-C6 alkyl. In other embodiments, Re is C1-C6 haloalkyl. In other embodiments, Re is C1-C6 alkoxy. In other embodiments, Re is C1-C6 haloalkoxy. In other embodiments, Re is -W-(CH2) n - R w . In other embodiments, Re is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is
  • Re is H, C1-C6 alkyl, C1-C6 haloalkyl, or - W-(CH 2 ) deliberately-R W .
  • Re is H, CF3, or cyclopropyl.
  • Re is H.
  • Re is CF3.
  • Re is cyclopropyl.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein Rg is -0-(CH 2 ) folk-R w .
  • R3 ⁇ 4 is -O- (CH 2 ) friendship-R W , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C6 alkyl, and C 1 -C6 haloalkyl.
  • R 3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W- (CH 2 ) resort-R W .
  • R9 is halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) resort-R W .
  • R9 is H, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) contend-R W .
  • R9 is H, halo, C1-C6 alkyl, C1-C6 alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, C1-C6 alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, C1-C6 alkyl, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, C1-C6 alkyl, or C1-C6 alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is C1-C6 alkyl. In other embodiments, R9 is C1-C6 alkoxy. In other embodiments, R9
  • R9 is -W-(CH2) n -R w .
  • R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R9 is H or Ci-Ce alkoxy.
  • R9 is H or OCH3.
  • R9 is H.
  • R9 is 3 ⁇ 4.
  • R9 is D.
  • R9 is OCH3.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein Rio is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or OH. In other embodiments, Rio is halo. In other embodiments, Rio is Ci-Ce alkoxy. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein Ru is H, halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Ru is H, Ci- Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy. In other embodiments, Rn is Ci-Ce haloalkoxy. In other embodiments, Rn is halo or Ci-Ce haloalkoxy. In other embodiments, Rn is F or OCF3. In other embodiments, Rn is H. In other embodiments, Rn is 3 ⁇ 4. In other embodiments, Rn is D. In other embodiments, Rn is F. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-A-4), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-A-4), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-A-5)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Ru are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • R5, Re, R7, and Rs is not H
  • R7 is Ci-Ce alkyl, then R2 a is not H;
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct3 ⁇ 4.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R 2a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2 a is halo. In other embodiments, R2 a is Ci-Ce alkyl. In other embodiments, R2 a is Ci-Ce alkoxy. In other embodiments, R2 a is F.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3 a is halo. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein Ri a is H or Ci-Ce alkyl. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rt a is H.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce haloalkyl. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is H or halo. In other embodiments, R5 is H or F. In other embodiments, R5 is H. In other embodiments, R5 is F.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • Re is halo.
  • Re is C1-C6 alkyl. In other embodiments, Re is C1-C6 haloalkyl. In other embodiments, Re is C1-C6 alkoxy. In other embodiments, Re is C1-C6 haloalkoxy. In other embodiments, Re is -W-(CH2) n - R w . In other embodiments, Re is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl. In other embodiments, Re is halo, C1-C6 alkyl, or C1-C6 haloalkyl. In other embodiments, Re is CI or CF3. In other embodiments, Re is CI. In other embodiments,
  • Re is CF3.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2) n -R w .
  • R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH 2 ) deliberately-R W .
  • R7 is H, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W- (CH 2 ) lake-R W . In other embodiments, R7 is H, halo, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) admir-R W . In other embodiments, R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) deliberately-R W .
  • R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, or -W-(CH 2 ) deliberately-R W .
  • R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, or C 1 -C6 alkoxy.
  • R7 is halo.
  • R7 is C1-C6 alkyl.
  • R7 is C1-C6 haloalkyl.
  • R7 is C1-C6 alkoxy.
  • R7 is -W-(CH2) n -R w .
  • R7 is -W-(CH2) n -R w , wherein W is O, n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and Ci-Ce haloalkyl.
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R7 is H or halo.
  • R7 is H or CI. In other embodiments, R7 is H. In other embodiments, R7 is CI. [00140] In some embodiments, the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein 3 ⁇ 4 is -0-(CH 2 ) contend-R w . In other embodiments, Rs is -O- (CH2)n-R w , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl. In other embodiments, Rs is H.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo.
  • R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is -W-(CH2) n -R w . In other embodiments, R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl. In other embodiments, R9 is H or Ci-Ce alkoxy. In other embodiments, R9 is H or OCH3. In other embodiments, R9 is H. In other embodiments, R9 is 3 ⁇ 4. In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein Rn is H, halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, Ci- alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is H, halo, or C 1 -C6 haloalkoxy.
  • Rn is H, halo, or C 1 -C6 alkoxy.
  • Rn is halo.
  • Rn is C 1 -C6 alkoxy. In other embodiments, Rn is C 1 -C6 haloalkoxy. In other embodiments, Rn is H, CI, OCH 3 , or OCF 3 . In other embodiments, Rn is H. In other embodiments, Rn is 3 ⁇ 4. In other
  • Rn is D. In other embodiments, Rn is CI. In other embodiments, Rn is OCH 3 . In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R 12 is H. [00144] In some embodiments, the invention relates to a compound of formula (I-A-5), or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
  • the invention relates to a compound of formula (I-A-5), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-A-6)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • R3a is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • Ria is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • R5, R5, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1; wherein at least one of R5, Re, R7, and Rs is not H;
  • R7 is Ci-Ce alkyl, then R2 a is not H;
  • Rt a is halo, then R2 a is not H.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct1 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein R2 a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is H, halo, OH, or Ci-Ce alkoxy.
  • R2a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2a is halo. In other embodiments, R2a is Ci-Ce alkyl. In other embodiments, R2a is Ci-Ce alkoxy. In other embodiments, R2a is F.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3a is halo. In other embodiments, R3a is H.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein Rta is H or Ci-Ce alkyl. In other embodiments, Rta is Ci-Ce alkyl. In other embodiments, Rta is H.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce haloalkyl. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is F.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, Ci- Ce alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2) n -R w .
  • Re is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • Re is halo.
  • Re is C1-C6 alkyl. In other embodiments, Re is C1-C6 haloalkyl. In other embodiments, Re is C1-C6 alkoxy. In other embodiments, Re is C1-C6 haloalkoxy. In other embodiments, Re is -W-(CH2) n - R w . In other embodiments, Re is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is
  • Re is CF3.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2) n -R w .
  • R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH 2 ) deliberately-R W .
  • R7 is H, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W- (CH 2 ) lake-R W . In other embodiments, R7 is H, halo, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) admir-R W . In other embodiments, R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) deliberately-R W .
  • R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, or -W-(CH 2 ) deliberately-R W .
  • R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, or C 1 -C6 alkoxy.
  • R7 is halo.
  • R7 is Ci-Ce alkyl.
  • R7 is Ci-Ce haloalkyl.
  • R7 is Ci-Ce alkoxy.
  • R7 is -W-(CH2) n -R w .
  • R7 is -W-(CH2) n -R w , wherein W is O, n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is H.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is -0-(CH2) n -R w .
  • R3 ⁇ 4 is -0-(CH2) n -R w .
  • Rs is -O- (CH2)n-R w , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • 3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo.
  • R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is -W-(CH2) n -R w . In other embodiments, R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein Rio is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or OH. In other embodiments, Rio is halo. In other embodiments, Rio is C 1 -C6 alkoxy. In other embodiments, Rio is H. In other embodiments, Rio is 3 ⁇ 4. In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein Rn is H, halo, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is halo, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is H, Ci- Ce alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is H, halo, or C 1 -C6 haloalkoxy.
  • Rn is H, halo, or C 1 -C6 alkoxy.
  • Rn is halo. In other embodiments, Rn is C 1 -C6 alkoxy. In other embodiments, Rn is C 1 -C6 haloalkoxy. In other embodiments, Rn is H. In other embodiments, Rn is l . In other embodiments, Rn is D.
  • the invention relates to a compound of formula (I-A-6), or a pharmaceutically acceptable salt thereof, wherein each R14 is H. [00160] In some embodiments, the invention relates to a compound of formula (I-A-6), i compound in non-salt form.
  • the invention relates to a compound of formula (I-A-7)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Ria is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5 IS H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1 ; wherein when R4 a is halo, then R2 a is not H.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein R 2a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R 2a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2 a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkoxy.
  • R2 a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2 a is halo. In other embodiments, R2 a is Ci-Ce alkyl. In other embodiments, R2 a is Ci-Ce alkoxy. In other embodiments, R2 a is F.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3 a is halo. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein Ri a is H or Ci-Ce alkyl. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rt a is H.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R5 is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R5 is H, halo, Ci-Ce alkyl, or Ci-Ce haloalkyl. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is H.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is -0-(CH2) n -R w .
  • R3 ⁇ 4 is -0-(CH2) n -R w .
  • Rs is -O- (CH2)n-R w , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • 3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or -W-(CH2) n -R w . In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo.
  • R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is -W-(CH2) n -R w . In other embodiments, R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein Rio is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or OH. In other embodiments, Rio is halo. In other embodiments, Rio is C 1 -C6 alkoxy. In other embodiments, Rio is H. In other embodiments, Rio is 3 ⁇ 4. In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein Rn is H, halo, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is halo, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is H, Ci- Ce alkoxy, or C 1 -C6 haloalkoxy.
  • Rn is H, halo, or C 1 -C6 haloalkoxy.
  • Rn is H, halo, or C 1 -C6 alkoxy.
  • Rn is halo. In other embodiments, Rn is C 1 -C6 alkoxy. In other embodiments, Rn is C 1 -C6 haloalkoxy. In other embodiments, Rn is H. In other embodiments, Rio is l . In other embodiments, Rn is D. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A-7), or a pharmaceutically acceptable salt thereof, wherein each R 4 is F.
  • the invention relates to a compound of formula (I-A-7), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-A-8)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • Ria is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • R7 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Ri3 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • n 0 or 1
  • R7 is Ci-Ce alkyl, then R2 a is not H;
  • Rt a is halo, then R2 a is not H.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct1 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein R2 a is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is H, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is H, halo, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R2a is H, halo, OH, or Ci-Ce alkoxy.
  • R2a is H, halo, OH, or Ci-Ce alkyl. In other embodiments, R2a is halo. In other embodiments, R2a is Ci-Ce alkyl. In other embodiments, R2a is Ci-Ce alkoxy. In other embodiments, R2a is F.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or halo. In other embodiments, R3a is halo. In other embodiments, R3a is H.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein Rta is H or Ci-Ce alkyl. In other embodiments, Rta is Ci-Ce alkyl. In other embodiments, Rta is H.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R7 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2)n-R w .
  • R7 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w . In other embodiments, R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.
  • R7 is halo.
  • R7 is Ci-Ce alkyl.
  • R7 is Ci-Ce haloalkyl.
  • R7 is Ci-Ce alkoxy.
  • R7 is -W-(CH2) n -R w .
  • R7 is -W-(CH2) n -R w , wherein W is O, n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is H.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is -0-(CH2) n -R w .
  • R3 ⁇ 4 is -0-(CH2) n -R w .
  • Rs is -O- (CH2)n-R w , wherein n is 1, and R w is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • Rs is H.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w .
  • R9 is H, halo, C 1 -C6 alkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) hurry-R W . In other embodiments, R9 is H, halo, OH, C 1 -C6 alkoxy, or -W-(CH 2 ) admir-R W . In other embodiments, R9 is H, halo, OH, C 1 -C6 alkyl, or -W-(CH 2 ) complicat-R W . In other embodiments, R9 is H, halo, OH, C 1 -C6 alkyl, or C 1 -C6 alkoxy. In other embodiments, R9 is halo.
  • R9 is C 1 -C6 alkyl. In other embodiments, R9 is C 1 -C6 alkoxy. In other embodiments, R9 is -W-(CH2) n -R w . In other embodiments, R9 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein Rio is H, halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is halo, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, OH, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or Ci-Ce alkoxy. In other embodiments, Rio is H, halo, or OH. In other embodiments, Rio is halo. In other embodiments, Rio is Ci-Ce alkoxy. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein Ru is H, halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Ru is H, Ci- Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce haloalkoxy.
  • Rn is H, halo, or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy. In other embodiments, Rn is Ci-Ce haloalkoxy. In other embodiments, Rn is H. In other embodiments, Rn is l . In other embodiments, Rn is D. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-A-8), or a pharmaceutically acceptable salt thereof, wherein each R14 is independently H or F.
  • the invention relates to a compound of formula (I-A-8), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B)
  • L is O, C(R)2, or a single bond
  • X 2a is N, N + -0 , or CR 2a ;
  • X 5 is N or CR 5 ;
  • X 7 is N or CR 7 ;
  • X 9 is N or CR 9 ;
  • Xn is N or CRn
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, R5, and R7 are defined as follows:
  • R5, R5, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or -W-(CH2) shadow-R W ;
  • R5 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or -W-(CH2) n -R w ; and R5 and R7, together with the carbon atoms to which they are attached, form a ring of formula:
  • R7 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w :
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • Ri2 and R13 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ; or R12 and R13, together with the carbon atoms to which they are attached, form a ring of formula:
  • Yi, Y2, Zi, and Z2 are each independently O or C(Ri4)2;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1
  • Xi a , X2a, X3a, and X4 a is N or N + -0 " ;
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X la is N. In other embodiments, Xi a is CH.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2 a is N or N + -0 " . In other embodiments, X2 a is N. In other embodiments, X2 a is N + -0 " . In other embodiments, X2 a is CR2 a .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X3 a is N. In other embodiments, X3 a is CR3 a .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X4 a is N. In other embodiments, X4 a is CRt a .
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X5 is N. In other embodiments, X5 is CR5. [00198] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Xe is N. In other embodiments, Xe is CR6.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X7 is N. In other embodiments, X7 is CR7.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X is N.
  • X9 is CR9.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X10 is N. In other embodiments, X10 is CR10.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Xn is N. In other embodiments, Xn is CRn.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct1 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R2 a is H or halo. In other embodiments, R2 a is halo. In other embodiments, R2a is H or F. In other embodiments, R2a is H. In other embodiments, R2a is F.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3a is Ci-Ce alkyl. In other embodiments, R3a is H or CH3. In other embodiments, R3a is H. In other embodiments, R3a is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Rt a is H, halo, or Ci-Ce alkyl. In other embodiments, Rta is halo or Ci-Ce alkyl. In other embodiments, Rta is H or Ci-Ce alkyl. In other embodiments, Rta is H or halo. In other embodiments, Rta is halo. In other embodiments, Rta is Ci-Ce alkyl. In other embodiments, Rta is H, F, CI, or Ct1 ⁇ 4. In other embodiments, Rta is H. In other embodiments, Rta is F. In other embodiments, Rta is CI. In other embodiments, Rta is CH3.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or C 1 -C6 alkylamino.
  • R5 is halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or C 1 -C6 alkylamino.
  • R5 is H, C 1 -C6 alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy.
  • R5 is Ci-Ce alkylamino. In other embodiments, R5 is H, F, CI, NHCH3, CF3, OCH3, or OCH2CH3. In other embodiments, R5 is H. In other embodiments, R5 is F. In other embodiments, R5 is CI. In other embodiments, R5 is NHCH3. In other embodiments, R5 is CF3. In other embodiments, R5 is OCH3. In other embodiments, R5 is
  • the invention relates to a compound of formula (I-B), or a
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W- (CH 2 ) deliberately-R W .
  • R5 is H, halo, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W- (CH 2 ) complicat-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W- (CH 2 ) deliberately-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 haloalkoxy, or -W- (CH 2 ) favor-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, Re is Ci-Ce haloalkoxy. In other embodiments, R5 is -W-(CH2) n -R w . In other embodiments, R5 is -W- (CH2)n-R w , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl.
  • R5 is H, F, CI, CH3, CHF2, CF3, CF2CF3, OCHF2, OCF3, or cyclopropyl.
  • R5 is H.
  • R5 is F.
  • R5 is CI.
  • R5 is CH3.
  • R5 is C ⁇ Ff .
  • R5 is CD3.
  • R5 is CHF2.
  • R5 is CF3.
  • R5 is CF2CF3.
  • R5 is OCHF2.
  • R5 is OCF3.
  • R5 is cyclopropyl.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5 and R5, together with the carbon atoms to which they are attached, form a ring of formula:
  • the invention relates to a compound of formula (I-B), or a
  • R7 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W- (CH2)n-R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R7 is halo. In other embodiments, R7 is Ci-Ce alkyl. In other embodiments, R7 is C 1 -C6 haloalkyl. In other embodiments, R7 is C 1 -C6 alkoxy. In other embodiments, R7 is C 1 -C6 haloalkoxy. In other embodiments, R7 is -W-(CH 2 ) deliberately-R W .
  • R7 is -W- (CH 2 ) compassion-R W , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C6 alkyl, and C 1 -C6 haloalkyl.
  • R7 is H, CI, C(CI3 ⁇ 4)3, CF(CI3 ⁇ 4)2, CF3, OCHF2, OCF3, cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, 2,2- difluorocyclopropyl, or 1-trifluoromethylcyclopropyl.
  • R7 is H.
  • R7 is CI.
  • R7 is C(CH3)3.
  • R7 is CF(CH3)2.
  • R7 is CF3.
  • R7 is OCHF2.
  • R7 is OCF3.
  • R7 is cyclopropyl.
  • R7 is 1-methylcyclopropyl. In other embodiments, R7 is 2-methylcyclopropyl. In other embodiments, R7 is 2,2-difluorocyclopropyl. In other embodiments, R7 is 1-trifluoromethylcyclopropyl. [00211] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein 5 and R7, together with the carbon atoms to which they are attached, form a ring of formula:
  • the invention relates to a compound of formula (I-B), or a
  • the invention relates to a compound of formula (I-B), or a
  • R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy.
  • R9 is H, F, CI, OH, CH3, OCH3, OCHF2, or OCF3. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D. In other embodiments, R9 is F. In other embodiments, R9 is CI. In other embodiments, R9 is OH. In other embodiments, R9 is CH3. In other embodiments, R9 is C ⁇ H . In other embodiments, R9 is CD3. In other embodiments, R9 is OCH3. In other embodiments, R9 is OC ⁇ H . In other embodiments, R9 is OCD3. In other embodiments, R9 is OCHF2. In other embodiments, R9 is
  • the invention relates to a compound of formula (I-B), or a
  • Rio is H or halo.
  • Rio is halo.
  • Rio is H, F, or CI.
  • Rio is H.
  • Rio is l .
  • Rio is D.
  • Rio is F.
  • Rio is CI.
  • the invention relates to a compound of formula (I-B), or a
  • Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is C 1 -C6 alkoxy or C 1 -C6 haloalkoxy.
  • Rn is halo or C 1 -C6 haloalkoxy.
  • Rn is halo or C 1 -C6 alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is F, OCH3, OCHF2, or OCF3.
  • Rn is H.
  • Rn is l . In other embodiments, Rn is D. In other embodiments, Rn is F. In other embodiments, Rn is OCH3. In other embodiments, Rn is OCHF2. In other embodiments, Rn is OCF3.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R12 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R12 is H.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R13 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R13 is H.
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Yi is O, and Y2 is C(Ri4)2. In other embodiments, Yi is C(Ri4)2, and Y2 is O. In other embodiments, Yi is O, and Y2 is O. In other embodiments, Yi is C(Ri4)2,
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Zi is O, and Z2 is C(Ri4)2. In other embodiments, Zi is C(Ri4)2, and Z2 is O. In other embodiments, Zi is O, and Z2 is O. In other embodiments, Zi is C(Ri4)2,
  • the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R14 is independently H or F.
  • each R14 is independently H or F.
  • each R14 is H. In other embodiments, each R14 is F.
  • the invention relates to a compound of formula (I-B), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-l)
  • L is O, C(R) 2 , or a single bond
  • X 2a is N or N + -0 " ;
  • each R is independently H or Ci-Ce alkyl
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C6 alkyl, and C 1 -C6 haloalkyl; and
  • n 0 or 1
  • R5, Re, R7, and Rs is not H.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein X 2a is N. In other embodiments, Xia is N + -0 " .
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct3 ⁇ 4.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3 a is Ci-Ce alkyl. In other embodiments, R 3a is H or CH 3 . In other embodiments, R 3a is H. In other embodiments, R3 a is CH3.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein R( a is H, halo, or C 1 -C6 alkyl. In other embodiments, Rta is halo or C 1 -C6 alkyl. In other embodiments, Ri a is H or C 1 -C6 alkyl. In other embodiments, Ri a is H or halo. In other embodiments, Rt a is halo. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rt a is H, F, CI, or CH3. In other embodiments, Rt a is H. In other embodiments, Rt a is F. In other embodiments, Rt a is CI. In other embodiments, Rt a is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo.
  • R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, F, CI, NHCH3, CF3, or OCH3. In other embodiments, R5 is H. In other embodiments, R5 is F. In other embodiments, R5 is CI. In other embodiments, R5 is NHCH3. In other embodiments, R5 is CF3. In other embodiments, R5 is OCH3.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • Re is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • Re is halo.
  • Re is C 1 -C6 alkyl.
  • Re is C1-C6 haloalkyl.
  • Re is C1-C6 alkoxy.
  • Re is C1-C6 haloalkoxy.
  • Re is -W-(CH2) n -R w .
  • Re is -W- (CH 2 ) regularly-R W , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl.
  • Re is H, F, CI, CH3, CHF 2 , CF3, CF 2 CF3, OCHF 2 , OCF3, or cyclopropyl.
  • Re is H.
  • Re is F.
  • Re is CI.
  • Re is CH 3 .
  • Re is C ⁇ Ff . In other embodiments, Re is CD 3 . In other embodiments, Re is CHF2. In other embodiments, Re is CF3. In other embodiments, Re is CF2CF3. In other embodiments, Re is OCHF2. In other embodiments, Re is OCF3. In other embodiments, Re is cyclopropyl.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2)n-R w .
  • R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2)n-R w .
  • R7 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2)n-R w . In other embodiments, R7 is H, halo, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2)n-R w . In other embodiments, R7 is H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2)n-R w .
  • R7 is H, halo, Ci- C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -W-(CH2)n-R w . In other embodiments, R7 is H, halo, Ci- C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -W-(CH2)n-R w . In other embodiments, R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. In other embodiments, R7 is halo.
  • R7 is C1-C6 alkyl. In other embodiments, R7 is C1-C6 haloalkyl. In other embodiments, R7 is C1-C6 alkoxy. In other embodiments, R7 is C1-C6 haloalkoxy. In other embodiments, R7 is R w .
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is halo, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, CI, CF3, OCHF2, OCF3, or cyclopropyl. In other embodiments, R7 is H. In other embodiments, R7 is CI. In other embodiments, R7 is CF3. In other embodiments, R7 is OCHF2. In other embodiments, R7 is OCF3. In other embodiments, R7 is cyclopropyl.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is Ci-Ce alkyl.
  • R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H, F, CI, OH, CH3, OCH3, OCHF2, or OCF3. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R 9 is D. In other embodiments, R 9 is F. In other embodiments, R 9 is CI. In other embodiments, R 9 is OH. In other embodiments, R 9 is C3 ⁇ 4. In other embodiments, R 9 is C ⁇ H ⁇ . In other embodiments, R 9 is CD 3 . In other embodiments, R 9 is OCH 3 . In other embodiments, R 9 is OC ⁇ Hb. In other embodiments, R9 is OCD3. In other embodiments, R9 is OCHF 2 . In other embodiments, R9 is
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H, F, or CI. In other embodiments, Rio is H. In other embodiments, Rio is 3 ⁇ 4. In other embodiments, Rio is D. In other embodiments, Rio is F. In other embodiments, Rio is CI.
  • the invention relates to a compound of formula (I-B-l), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce alkoxy.
  • Ru is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is F, OCH3, OCHF2, or OCF3.
  • Rn is H.
  • Rn is l .
  • Rn is D.
  • Rn is F.
  • Rn is OCH3.
  • Rn is OCHF2.
  • Rn is OCF3.
  • the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-1), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-1), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-2)
  • L is O, C(R) 2 , or a single bond
  • each R is independently H or C 1 -C6 alkyl
  • R3a is H, halo, OH, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5 and R5 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ; or
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • Ri2 and R13 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct1 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3 a is Ci-Ce alkyl. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein Rt a is H, halo, or Ci-Ce alkyl. In other embodiments, Rt a is halo or Ci-Ce alkyl. In other embodiments, Rt a is H or Ci-Ce alkyl. In other embodiments, Rt a is H or halo. In other embodiments, Rt a is halo. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rt a is H or Ct1 ⁇ 4. In other embodiments, Rt a is H. In other embodiments, Rt a is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy. In other embodiments, R5 is halo.
  • R5 is C1-C6 alkyl. In other embodiments, R5 is C1-C6 haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R5 is halo or Ci-Ce alkoxy. In other embodiments, R5 is F, OCH3, or OCH2CH3. In other embodiments, R5 is F. In other embodiments, R5 is OCH3. In other embodiments, R5 is OCH2CH3.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w . In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W- (CH2)n-R w . In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is C 1 -C6 haloalkyl. In other embodiments, R5 is C 1 -C6 alkoxy. In other embodiments, R5 is C 1 -C6 haloalkoxy. In other embodiments, R5 is -W-(CH 2 ) deliberately-R W .
  • R5 is -W- (CH 2 ) regularly-R W , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl.
  • R5 is H or C 1 -C6 haloalkyl.
  • R5 is H or CF3.
  • R5 is H.
  • R5 is CF3.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein Rg is H.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R9 is halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R9 is H, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R9 is H, halo, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other
  • R9 is halo. In other embodiments, R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H or Ci-Ce alkoxy. In other embodiments, R is H or OCH3. In other embodiments, R9 is H. In other embodiments, R9 is 3 ⁇ 4. In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein Ru is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is H.
  • Rn is l .
  • Rn is D.
  • Rn is OCF3.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-2), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-2), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-3)
  • L is O, C(R) 2 , or a single bond
  • each R is independently H or C 1 -C6 alkyl
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy
  • R4a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5 and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • R5, R7, and Rs is not H.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or C3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is C3 ⁇ 4.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or C1-C6 alkyl. In other embodiments, R3 a is C1-C6 alkyl. In other embodiments, R3 a is H or CH3. In other embodiments, R3 a is H. In other embodiments, R3 a is Q3 ⁇ 4.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein Rt a is H, halo, or C1-C6 alkyl.
  • Ria is halo or C1-C6 alkyl.
  • Rta is H or C1-C6 alkyl.
  • Rta is H or halo.
  • Rta is halo.
  • Rta is C1-C6 alkyl.
  • Rta is H.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or Ci-Ce alkylamino.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo.
  • R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R 5 is H.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci- Ce alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W-(CH 2 ) deliberately-R W . In other embodiments, R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R7 is halo. In other embodiments, R7 is C 1 -C6 alkyl. In other embodiments, R7 is C 1 -C6 haloalkyl. In other embodiments, R7 is C 1 -C6 alkoxy. In other embodiments, R7 is C 1 -C6 haloalkoxy. In other embodiments, R7 is - ⁇ -(03 ⁇ 4) justify- R w .
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is Ci-Ce alkyl, Ci-Ce haloalkyl, or -W-(CH2) n -R w .
  • R7 is C(Ct1 ⁇ 4)3, CF(Ct1 ⁇ 4)2, CF3, cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, or 1- trifluoromethylcyclopropyl. In other embodiments, R7 is C(CH3)3. In other embodiments, R7 is
  • R7 is CF(CH3)2. In other embodiments, R7 is CF3. In other embodiments, R7 is cyclopropyl. In other embodiments, R7 is 1-methylcyclopropyl. In other embodiments, R7 is 2-methylcyclopropyl. In other embodiments, R7 is 2,2-difluorocyclopropyl. In other embodiments, R7 is 1-trifluoromethylcyclopropyl.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is Ci-Ce alkyl.
  • R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is H.
  • Rn is l .
  • Rn is D.
  • Rn is OCF3.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-3), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-3), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-4)
  • L is O, C(R) 2 , or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1
  • R5, R5, R7, and Rs is not H.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein R 2a is H.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein R
  • Ri a is halo or Ci-Ce alkyl.
  • Rt a is H or Ci-Ce alkyl.
  • Rt a is H or halo.
  • Rt a is halo.
  • Rt a is Ci-Ce alkyl.
  • Rta is H.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or Ci-Ce alkylamino.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo.
  • R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R 5 is F.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein 5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH 2 ) utilizat-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 haloalkoxy, or -W- (CH 2 ) admir-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, Re is halo. In other embodiments, Re is Ci-Ce alkyl. In other embodiments, Re is C1-C6 haloalkyl. In other embodiments, Re is C1-C6 alkoxy. In other embodiments, Re is C1-C6 haloalkoxy. In other embodiments, Re is -W-(CH2) n -R w .
  • Re is -W- (CH2)n-R w , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl. In other embodiments, Re is CF3.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) n -R w .
  • R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, C1-C6 haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy. In other embodiments, R7 is halo.
  • R7 is C 1 -C6 alkyl. In other embodiments, R7 is C 1 -C6 haloalkyl. In other embodiments, R7 is C 1 -C6 alkoxy. In other embodiments, R7 is C 1 -C6 haloalkoxy. In other embodiments, R7 is - ⁇ -(03 ⁇ 4) impart- R w .
  • R7 is -W-(CH 2 ) compassion-R W , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is H.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Rg is H.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R9 is halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R is halo. In other embodiments, R9 is Ci-Ce alkyl.
  • R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is OCF3.
  • Rn is H.
  • Rn is l .
  • Rn is D.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-4), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-4), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-5)
  • L is O, C(R)2, or a single bond; each R is independently H or Ci-Ce alkyl;
  • R2a is H, halo, OH, or Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, or Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5, Re, and R7 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • R5, Re, R7, and Rs is not H.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or C3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is C3 ⁇ 4.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R2 a is H.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3 a is C1-C6 alkyl. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C1-C6 alkylamino.
  • R5 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkylamino.
  • R5 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo.
  • R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R 5 is F.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein 5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH 2 ) utilizat-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 haloalkoxy, or -W- (CH 2 ) admir-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or -W- (CH 2 ) contend-R W .
  • R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy. In other embodiments, R5 is halo. In other embodiments, R5 is C 1 -C6 alkyl. In other embodiments, R5 is C 1 -C6 haloalkyl. In other embodiments, R5 is C 1 -C6 alkoxy. In other embodiments, Re is Ci-Ce haloalkoxy. In other embodiments, R5 is -W-(CH2) n -R w .
  • R5 is -W- (CH2)n-R w , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl. In other embodiments, R5 is CF3.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R7 is halo.
  • R7 is Ci-Ce alkyl. In other embodiments, R7 is Ci-Ce haloalkyl. In other embodiments, R7 is Ci-Ce alkoxy. In other embodiments, R7 is Ci-Ce haloalkoxy. In other embodiments, R7 is -W-(CH2) n - R w .
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is H.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is Ci-Ce alkyl.
  • R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H. In other embodiments, R9 is 3 ⁇ 4. In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is 3 ⁇ 4. In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or C 1 -C6 alkoxy.
  • Rn is halo.
  • Rn is C 1 -C6 alkoxy.
  • Rn is C 1 -C6 haloalkoxy.
  • Rn is H. In other embodiments, Rn is 3 ⁇ 4. In other embodiments, Rn is D. In other embodiments, Rn is OCF3. [00293] In some embodiments, the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-5), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-5), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-6)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • Ria is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • R5 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or -W-(CH2) shadow-R W ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Ri3 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • n 0 or 1.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct1 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3 a is Ci-Ce alkyl. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein Rt a is H, halo, or Ci-Ce alkyl. In other embodiments, Rt a is halo or Ci-Ce alkyl. In other embodiments, Rt a is H or Ci-Ce alkyl. In other embodiments, Rt a is H or halo. In other embodiments, Rt a is halo. In other embodiments, Rt a is Ci-Ce alkyl. In other embodiments, Rt a is H.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo.
  • R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R 5 is H.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R9 is halo. In other embodiments, R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is H.
  • Rn is l .
  • Rn is D.
  • Rn is OCF3.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-6), or a pharmaceutically acceptable salt thereof, wherein each R14 is F.
  • the invention relates to a compound of formula (I-B-6), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-7)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Rta is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R5 and R5 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl; and
  • n 0 or 1
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R 2a is F.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3 a is Ci-Ce alkyl. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R( a is H, halo, or Ci-Ce alkyl.
  • R t a is halo or Ci-Ce alkyl.
  • Ri a is H or Ci-Ce alkyl.
  • Ri a is H or halo.
  • Ri a is halo.
  • Ri a is Ci-Ce alkyl.
  • Rt a is H.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or C 1 -C6 alkylamino.
  • R5 is halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, or Ci-Ce alkylamino.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R 5 is F.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein 5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • Re is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, Re is Ci-Ce haloalkoxy. In other embodiments, R5 is -W-(CH2) n -R w .
  • R5 is -W- (CH2)n-R w , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl. In other embodiments, R5 is H.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R9 is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is Ci-Ce alkyl.
  • R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H. In other embodiments, R9 is 3 ⁇ 4. In other embodiments, R9 is D. In other embodiments, R9 is OCH3.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is 3 ⁇ 4. In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is C 1 -C6 alkoxy or C 1 -C6 haloalkoxy.
  • Rn is halo or C 1 -C6 haloalkoxy.
  • Rn is halo or C 1 -C6 alkoxy.
  • Rn is halo.
  • Rn is C 1 -C6 alkoxy.
  • Rn is C 1 -C6 haloalkoxy. In other embodiments, Rn is H. In other embodiments, Rn is 3 ⁇ 4. In other embodiments, Rn is D. In other embodiments, Rn is OCF3. [00322] In some embodiments, the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-7), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-7), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-8)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R2a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R3a is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • Ria is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
  • R5, R5, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or -W-(CH2) shadow-R W ;
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Ri3 are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • n 0 or 1 ;
  • R5, Re, R7, and Rs is not H.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct1 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct1 ⁇ 4.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R2 a is F.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3 a is Ci-Ce alkyl. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein Ri a is H, halo, or Ci-Ce alkyl.
  • Rt a is halo or Ci-Ce alkyl.
  • Rt a is H or Ci-Ce alkyl.
  • Rt a is H or halo.
  • Rt a is halo.
  • Rt a is Ci-Ce alkyl.
  • Rt a is H.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino.
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkylamino. In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In other embodiments, R5 is halo.
  • R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is Ci-Ce alkylamino. In other embodiments, R 5 is F.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R5 is H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylamino, or -W-(CH2) n -R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R5 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W- (CH2)n-R w . In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W- (CH2)n-R w . In other embodiments, R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W- (CH2)n-R w .
  • R5 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R5 is halo. In other embodiments, R5 is Ci-Ce alkyl. In other embodiments, R5 is Ci-Ce haloalkyl. In other embodiments, R5 is Ci-Ce alkoxy. In other embodiments, R5 is C1-C6 haloalkoxy. In other embodiments, R5 is -W-(CH2) justify-R W .
  • R5 is -W- (CH2) strictly-R W , wherein W is a single bond, n is 0, and R w is unsubstituted 3-6 membered cycloalkyl. In other embodiments, R5 is CF3.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) wherever-R W .
  • R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) strictly-R W .
  • R7 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-(CH2) directly-R W .
  • R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R7 is halo.
  • R7 is Ci-Ce alkyl. In other embodiments, R7 is Ci-Ce haloalkyl. In other embodiments, R7 is Ci-Ce alkoxy. In other embodiments, R7 is Ci-Ce haloalkoxy. In other embodiments, R7 is -W-(CH2) n - R w .
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is H.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein 3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is halo. In other embodiments, R9 is Ci-Ce alkyl.
  • R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H. In other embodiments, R9 is 3 ⁇ 4. In other embodiments, R9 is D. In other embodiments, R9 is OCH3. In other embodiments, R9 is OC ⁇ H . In other embodiments, R9 is OCD3.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is H.
  • Rn is l .
  • Rn is D.
  • Rn is OCF3.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-8), or a pharmaceutically acceptable salt thereof, wherein R13 is H. [00340] In some embodiments, the invention relates to a compound of formula (I-B-8), i compound in non-salt form.
  • the invention relates to a compound of formula (I-B-9)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • Ria is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;
  • R7 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -W-
  • R9, Rio, and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • R12 and Rn are each independently H, halo, CN, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w ;
  • each Ri4 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
  • each W is independently O or a single bond
  • each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl; and
  • n 0 or 1.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein L is O.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein each R is independently H or Ct3 ⁇ 4. In other embodiments, each R is H. In other embodiments, each R is Ct3 ⁇ 4.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein R3 a is H or Ci-Ce alkyl. In other embodiments, R3 a is Ci-Ce alkyl. In other embodiments, R3 a is H.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein R( a is H, halo, or Ci-Ce alkyl.
  • Rta is halo or Ci-Ce alkyl.
  • Ri a is H or Ci-Ce alkyl.
  • Ri a is H or halo.
  • Ri a is halo.
  • Ri a is Ci-Ce alkyl.
  • Rt a is H.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein R7 is H, halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or -W-(CH 2 ) deliberately-R W .
  • R7 is halo, C 1 -C6 alkyl, C 1 -C6 haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or -W-(CH2) n -R w .
  • R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci- Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -W-(CH2) n -R w . In other embodiments, R7 is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R7 is halo.
  • R7 is Ci-Ce alkyl. In other embodiments, R7 is Ci-Ce haloalkyl. In other embodiments, R7 is Ci-Ce alkoxy. In other embodiments, R7 is Ci-Ce haloalkoxy. In other embodiments, R7 is -W-(CH2) n - R w .
  • R7 is -W-(CH2) n -R w , wherein W is a single bond, n is 0, and R w is 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl.
  • R7 is H.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein R3 ⁇ 4 is H.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein R is H, halo, OH, C 1 -C6 alkyl, C 1 -C6 alkoxy, or C 1 -C6 haloalkoxy.
  • R9 is halo, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • R9 is H, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkoxy, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce haloalkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In other embodiments, R9 is H, halo, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.
  • R9 is halo. In other embodiments, R9 is Ci-Ce alkyl. In other embodiments, R9 is Ci-Ce alkoxy. In other embodiments, R9 is Ci-Ce haloalkoxy. In other embodiments, R9 is H. In other embodiments, R9 is l . In other embodiments, R9 is D.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein Rio is H or halo. In other embodiments, Rio is halo. In other embodiments, Rio is H. In other embodiments, Rio is l . In other embodiments, Rio is D.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein Rn is halo, Ci-Ce alkoxy, or Ci-Ce haloalkoxy.
  • Rn is Ci-Ce alkoxy or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce haloalkoxy.
  • Rn is halo or Ci-Ce alkoxy.
  • Rn is halo.
  • Rn is Ci-Ce alkoxy.
  • Rn is Ci-Ce haloalkoxy.
  • Rn is H.
  • Rn is l .
  • Rn is D.
  • Rn is OCF3.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein R12 is H.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein R13 is H.
  • the invention relates to a compound of formula (I-B-9), or a pharmaceutically acceptable salt thereof, wherein each R14 is independently H or F.
  • the invention relates to a compound of formula (I-B-9), i.e., the compound in non-salt form.
  • the invention relates to a compound of formula (I-B-10)
  • L is O, C(R)2, or a single bond
  • each R is independently H or Ci-Ce alkyl
  • R3a is H, halo, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110937994A (zh) * 2019-12-10 2020-03-31 浙江大洋生物科技集团股份有限公司 二步氯化法合成2,4-二氯-6-氟苯甲酰氯的方法
WO2020146682A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
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WO2020176763A1 (en) 2019-02-27 2020-09-03 Vertex Pharmaceuticals Incorporated Dosage form comprising prodrug of na 1.8 sodium channel inhibitor
WO2020219867A1 (en) 2019-04-25 2020-10-29 Vertex Pharmaceuticals Incorporated Pyridone amide co-crystal compositions for the treatment of pain
WO2021032074A1 (zh) * 2019-08-19 2021-02-25 江苏恒瑞医药股份有限公司 苯甲酰胺稠芳环类衍生物、其制备方法及其在医药上的应用
CN112479996A (zh) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
CN112689633A (zh) * 2018-07-09 2021-04-20 利伯研究所公司 用于抑制Nav1.8的吡啶甲酰胺化合物
WO2021113627A1 (en) 2019-12-06 2021-06-10 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
CN112996774A (zh) * 2019-01-25 2021-06-18 江苏恒瑞医药股份有限公司 2-氧代-1,2-二氢吡啶类衍生物、其制备方法及其在医药上的应用
WO2021224220A1 (en) 2020-05-06 2021-11-11 Bayer Aktiengesellschaft Pyridine (thio)amides as fungicidal compounds
WO2021228734A1 (en) 2020-05-12 2021-11-18 Bayer Aktiengesellschaft Triazine and pyrimidine (thio)amides as fungicidal compounds
WO2021257490A1 (en) 2020-06-17 2021-12-23 Merck Sharp & Dohme Corp. 2-oxoimidazolidine-4-carboxamides as nav1.8 inhibitors
JP2022506146A (ja) * 2018-11-02 2022-01-17 メルク・シャープ・アンド・ドーム・コーポレーション Ｎａｖ１．８阻害薬としての２－アミノ－Ｎ－ヘテロアリール－ニコチンアミド類
WO2022188872A1 (zh) 2021-03-11 2022-09-15 上海济煜医药科技有限公司 吡啶氮氧化合物晶型及其应用
WO2022216573A1 (en) 2021-04-05 2022-10-13 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds for the treatment of cancer
WO2022235859A1 (en) 2021-05-07 2022-11-10 Merck Sharp & Dohme Llc Cycloalkyl 3-oxopiperazine carboxamides and cycloheteroalkyl 3-oxopiperazine carboxamides as nav1.8 inhibitors
WO2022256660A1 (en) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Process for the synthesis of substituted tetrahydrofuran modulators of sodium channels
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WO2022256702A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran-2-carboxamides as modulators of sodium channels
WO2022256842A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Hydroxy and (halo)alkoxy substituted tetrahydrofurans as modulators of sodium channels
WO2022256676A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran analogs as modulators of sodium channels
WO2023010191A1 (pt) 2021-08-02 2023-02-09 Eurofarma Laboratórios S.A. Compostos n-acilidrazônicos inibidores de nav 1.7 e/ou nav 1.8, seus processos de obtenção, composições, usos, métodos de tratamento destes e kits
WO2023010192A1 (pt) 2021-08-02 2023-02-09 Eurofarma Laboratórios S.A. Compostos n-acilidrazônicos inibidores de nav 1.7 e/ou nav 1.8, seus processos de obtenção, composições, usos, métodos de tratamento destes e kits
JP2023529643A (ja) * 2020-06-04 2023-07-11 バイエル、アクチエンゲゼルシャフト 新規殺真菌剤としてのヘテロシクリルピリジン
WO2023138599A1 (zh) 2022-01-18 2023-07-27 成都康弘药业集团股份有限公司 芳香并环类Nav1.8抑制剂及其用途
WO2023205463A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205465A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205468A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205778A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023211990A1 (en) 2022-04-25 2023-11-02 Siteone Therapeutics, Inc. Bicyclic heterocyclic amide inhibitors of na v1.8 for the treatment of pain
US11866450B2 (en) 2018-02-15 2024-01-09 Vertex Pharmaceuticals Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulators
US11873300B2 (en) 2019-08-14 2024-01-16 Vertex Pharmaceuticals Incorporated Crystalline forms of CFTR modulators
US11993581B2 (en) 2018-07-09 2024-05-28 Lieber Institue, Inc Pyridazine compounds for inhibiting Nav1.8
WO2024123815A1 (en) 2022-12-06 2024-06-13 Vertex Pharmaceuticals Incorporated Process for the synthesis of substituted tetrahydrofuran modulators of sodium channels
WO2024153856A1 (en) * 2023-01-18 2024-07-25 Orion Corporation Process for the preparation of 3-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridine 1-oxide
EP4405344A2 (en) * 2021-09-24 2024-07-31 Xenon Pharmaceuticals Inc. Pyridinyl derivatives as sodium channel activators
US12122788B2 (en) 2019-08-14 2024-10-22 Vertex Pharmaceuticals Incorporated Process of making CFTR modulators
WO2024217344A1 (zh) * 2023-04-19 2024-10-24 中国科学院上海药物研究所 Nav1.8抑制剂及其制备方法和用途
WO2024255834A1 (zh) * 2023-06-14 2024-12-19 上海济煜医药科技有限公司 吡啶氮氧化合物的盐型、共晶及其制备方法和应用
US12186306B2 (en) 2020-12-10 2025-01-07 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US12269831B2 (en) 2020-08-07 2025-04-08 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US12281057B2 (en) 2017-07-11 2025-04-22 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
WO2025090511A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Methods of preparing modulators of sodium channels and solid forms of the same for treating pain
WO2025090516A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Methods of preparing compounds for treating pain and solid forms thereof
WO2025090480A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2025090465A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
US12324802B2 (en) 2020-11-18 2025-06-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2025122953A1 (en) 2023-12-07 2025-06-12 Vertex Pharmaceuticals Incorporated Dosing regimens and formulations of suzetrigine for use in the treatment of acute and chronic pain
WO2025160286A1 (en) 2024-01-24 2025-07-31 Siteone Therapeutics, Inc. 2-aryl cycloalkyl and heterocycloalkyl inhibitors of nav1.8 for the treatment of pain
US12421251B2 (en) 2019-04-03 2025-09-23 Vertex Pharmaceuticals Incorporated Cystic fibrosis transmembrane conductance regulator modulating agents
EP4660184A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting hydroxamates, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660185A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting amides, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660182A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting aryl pyridine compounds, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660181A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting hydrazides, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660183A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting phenolic compounds, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105026373B (zh) 2013-01-31 2018-03-30 沃泰克斯药物股份有限公司 作为钠通道调节剂的吡啶酮酰胺
RU2680401C2 (ru) 2013-07-19 2019-02-21 Вертекс Фармасьютикалз Инкорпорейтед Сульфонамиды в качестве модуляторов натриевых каналов
LT3080134T (lt) 2013-12-13 2018-11-12 Vertex Pharmaceuticals Incorporated Piridono amidų provaistai, naudotini kaip natrio kanalų moduliatoriai
US11358977B2 (en) 2017-05-16 2022-06-14 Vertex Pharmaceuticals Incorporated Deuterated pyridone amides and prodrugs thereof as modulators of sodium channels
US20190343817A1 (en) 2018-02-12 2019-11-14 Vertex Pharmaceuticals Incorporated Method of treating pain
CN110950797A (zh) * 2019-12-06 2020-04-03 丽水绿氟科技有限公司 一种2-三氟甲基-3-氟-4-吡啶甲酸及其衍生物的制备方法
CN114437062B (zh) * 2020-04-30 2024-05-17 成都海博为药业有限公司 一种可作为钠通道调节剂的化合物及其用途
CN113880771B (zh) * 2020-07-03 2023-09-19 福建盛迪医药有限公司 一种选择性Nav抑制剂的结晶形式及其制备方法
CN111920796A (zh) * 2020-08-28 2020-11-13 南京医科大学 化合物在制备治疗癫痫药物中的应用
CN111808019B (zh) * 2020-09-08 2020-11-27 上海济煜医药科技有限公司 一种并环化合物及其应用
CN114031518B (zh) * 2020-12-08 2023-08-18 成都海博为药业有限公司 一种苄胺或苄醇衍生物及其用途
CN114288289A (zh) * 2022-02-17 2022-04-08 昆山彭济凯丰生物科技有限公司 具有镇痛和/或止痒功能的药物组合物及其应用
WO2023186102A1 (zh) * 2022-04-02 2023-10-05 武汉人福创新药物研发中心有限公司 Nav1.8抑制剂及其用途
CN116947713A (zh) * 2022-04-25 2023-10-27 中国科学院上海药物研究所 并环类化合物及其应用
EP4545517A1 (en) * 2022-06-22 2025-04-30 Wuhan Humanwell Innovative Drug Research and Development Center Limited Company Nav1.8 inhibitor
EP4578852A1 (en) * 2022-08-24 2025-07-02 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Heterocyclic compound, method for preparing same, and pharmaceutical use thereof
WO2024046253A1 (zh) * 2022-08-28 2024-03-07 上海汇伦医药股份有限公司 一种钠通道调节剂及其应用
WO2024046409A1 (zh) * 2022-08-31 2024-03-07 江苏恒瑞医药股份有限公司 杂环类化合物、其制备方法及其在医药上的应用
CA3264861A1 (en) * 2022-09-09 2024-03-14 Latigo Biotherapeutics Inc SODIUM CHANNEL BLOCKING COMPOUNDS, THEIR DERIVATIVES AND THEIR METHODS OF USE
AU2024206785A1 (en) * 2023-01-06 2025-07-24 Haisco Pharmaceutical Group Co., Ltd. Tetrahydrothiophene derivative and use thereof in medicine
WO2025124502A1 (zh) * 2023-12-13 2025-06-19 武汉人福创新药物研发中心有限公司 一种Nav1.8抑制剂化合物及其盐、多晶型和用途
WO2025131100A1 (zh) * 2023-12-21 2025-06-26 武汉熙瑞医药科技有限公司 一种含苯环的多环化合物、其药物组合物及其应用
CN118772124A (zh) * 2024-07-01 2024-10-15 山东福长药业有限公司 一种Suzetrigine的制备方法

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
WO2006011050A2 (en) 2004-07-23 2006-02-02 Pfizer Limited Pyridine derivatives
WO2008135826A2 (en) 2007-05-03 2008-11-13 Pfizer Limited 2 -pyridine carboxamide derivatives as sodium channel modulators
WO2009049183A1 (en) * 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Aryl amides useful as inhibitors of voltage-gated sodium channels
WO2009049181A1 (en) * 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Amides useful as inhibitors of voltage-gated sodium channels
WO2011026240A1 (en) 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Oxopiperazine derivatives for the treatment of pain and epilepsy
WO2011140425A1 (en) 2010-05-06 2011-11-10 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
US20120196869A1 (en) 2011-02-02 2012-08-02 Sara Sabina Hadida Ruah Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
WO2012112743A1 (en) 2011-02-18 2012-08-23 Vertex Pharmaceuticals Incorporated Chroman - spirocyclic piperidine amides as modulators of ion channels
WO2012116440A1 (en) 2011-03-03 2012-09-07 Zalicus Pharmaceuticals Ltd. Benzimidazole inhibitors of the sodium channel
WO2012125613A1 (en) 2011-03-14 2012-09-20 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
WO2013061205A2 (en) 2011-10-26 2013-05-02 Pfizer Limited Chemical compounds
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
WO2013109521A1 (en) 2012-01-16 2013-07-25 Vertex Pharmaceuticals Incorporated Pyran-spirocyclic piperidine amides as modulators of ion channels
WO2013114250A1 (en) 2012-02-03 2013-08-08 Pfizer Inc. Benziimidazole and imidazopyridine derivatives as sodium channel modulators
WO2013131018A1 (en) 2012-03-02 2013-09-06 Zalicus Pharmaceuticals Ltd. Biaryl inhibitors of the sodium channel
US20130303535A1 (en) 2008-12-26 2013-11-14 Dainippon Sumitomo Pharma Co., Ltd. Novel bicyclic heterocyclic compound
US20140213616A1 (en) 2013-01-31 2014-07-31 Vertex Pharmaceuticals Incorporated Pyridone amides as modulators of sodium channels
US20140221435A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Amides as modulators of sodium channels
WO2014120815A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Quinoline and quinazoline amides as modulators of sodium channels
US8883840B2 (en) 2009-06-29 2014-11-11 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
WO2015010065A1 (en) 2013-07-19 2015-01-22 Vertex Pharmaceuticals Incorporated Sulfonamides as modulators of sodium channels
US20150166589A1 (en) 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels

Family Cites Families (224)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1025305A (en) 1910-07-29 1912-05-07 Andrew Rasmussen Feeding means for power hacksaw-machines.
US1008714A (en) 1910-12-27 1911-11-14 Henry M Hammer Delinting-machine.
US2511231A (en) 1949-03-26 1950-06-13 Eastman Kodak Co 1-cyanophenyl-3-acylamino-5-pyrazolone couplers for color photography
US2688617A (en) 1951-07-17 1954-09-07 American Cyanamid Co Sulfonated dihalogeno diaminostilbenes
US2657134A (en) 1951-12-05 1953-10-27 Eastman Kodak Co Photographic emulsion with colored couplers containing isophthalic ester groups
BE516025A (enExample) 1951-12-05
US2725292A (en) 1952-05-15 1955-11-29 Eastman Kodak Co Colored couplers containing solubilizing groups
US2710802A (en) 1953-03-16 1955-06-14 Eastman Kodak Co Dialkyl-5-(oxanilamido) isophthalate couplers for color photography
US2710803A (en) 1953-03-26 1955-06-14 Eastman Kodak Co Color couplers containing hydroxyalkyl groups
BE528163A (enExample) 1953-04-17
BE531589A (enExample) 1953-09-02
US4218765A (en) 1974-10-03 1980-08-19 Standard Oil Company (Indiana) Two-dimensional frequency domain filtering
DE2623228C3 (de) 1976-05-24 1981-09-10 Ludwig Merckle Kg Chem. Pharm. Fabrik, 7902 Blaubeuren N-Acyl-substituierte Benzamide, Verfahren zu ihrer Herstellung und Arzneimittel, enthaltend solche Benzamide
US4639273A (en) 1983-05-06 1987-01-27 Morton Thiokol, Inc. Asphalt-adhesion improving additives prepared by formaldehyde condensation with polyamines
JPS63182182A (ja) 1987-01-23 1988-07-27 Fuji Photo Film Co Ltd 感熱記録材料
FR2628864B1 (fr) 1988-03-21 1990-06-15 France Etat Procede de segmentation d'un champ de vecteurs vitesse, notamment de vitesses de deplacement de points d'une image dans une sequence d'images
WO1991000858A1 (en) 1989-07-07 1991-01-24 Schering Corporation Pharmaceutically active compounds
JP2766323B2 (ja) 1989-07-19 1998-06-18 株式会社東芝 表示調整装置
DE4019307A1 (de) 1990-06-16 1991-12-19 Bayer Ag 2-methoximinocarbonsaeureester
US5258407A (en) 1991-12-31 1993-11-02 Sterling Winthrop Inc. 3,4-disubstituted phenols-immunomodulating agents
US5449691A (en) 1991-12-31 1995-09-12 Sterling Winthrop Inc. 3,4-disubstituted anilines-immunomodulating agents
FR2687932A1 (fr) 1992-02-27 1993-09-03 Oreal Dispersion huile-dans-l'eau susceptible de former des films composites.
JPH05313169A (ja) 1992-05-08 1993-11-26 Fuji Photo Film Co Ltd 液晶配向膜
HUT63941A (en) 1992-05-15 1993-11-29 Hoechst Ag Process for producing 4-alkyl-substituted pyrimidine-5-carboxanilide derivatives, and fungicidal compositions comprising same
GB9408185D0 (en) * 1994-04-25 1994-06-15 Fujisawa Pharmaceutical Co New benzamide derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same
DE69512777T2 (de) 1994-05-31 2000-04-27 Teijin Ltd., Osaka Naphthalinderivate
AR002459A1 (es) 1995-01-17 1998-03-25 American Cyanamid Co Antagonistas de vasopresina de benzacepina triciclicos, una composicion farmaceutica que los contiene, un metodo para tratar enfermedades y unprocedimiento para su preparacion.
US5532235A (en) 1995-01-17 1996-07-02 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5536718A (en) 1995-01-17 1996-07-16 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5753648A (en) 1995-01-17 1998-05-19 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
DE19523640A1 (de) 1995-06-29 1997-01-02 Bayer Ag Substituierte Carbonylaminophenyluracile
DE19621522A1 (de) 1996-05-29 1997-12-04 Hoechst Schering Agrevo Gmbh Neue N-Acylsulfonamide, neue Mischungen aus Herbiziden und Antidots und deren Verwendung
JP3731963B2 (ja) 1997-01-14 2006-01-05 株式会社シマノ 釣り竿用口栓
JPH10213820A (ja) 1997-01-31 1998-08-11 Canon Inc 液晶素子及び液晶装置
RU2197482C2 (ru) 1997-04-22 2003-01-27 НьюроСёрч А/С Замещенные фенильные производные, способ их получения, содержащая их фармацевтическая композиция и способ лечения (варианты)
WO1999047529A1 (en) 1998-03-18 1999-09-23 Ariad Pharmaceuticals, Inc. Heterocyclic signal transduction inhibitors, compositions containing them
EP1076641A1 (en) 1998-04-29 2001-02-21 Vertex Pharmaceuticals Incorporated Inhibitors of impdh enzyme
JP2002179651A (ja) 1998-06-19 2002-06-26 Wakamoto Pharmaceut Co Ltd ベンズアニリド誘導体及び医薬組成物
EE04849B1 (et) 1998-10-22 2007-06-15 Neurosearch A/S Asendatud fenüülderivaadid, nende valmistamine jakasutamine
IL145923A0 (en) 1999-04-28 2002-07-25 Aventis Pharma Gmbh Tri-aryl acid derivatives as ppar receptor ligands
WO2001007028A2 (en) 1999-07-23 2001-02-01 Allergan Sales, Inc. The use of retinoid receptor antagonists in the treatment of prostate carcinoma
EP1216228B1 (en) 1999-09-17 2008-10-29 Millennium Pharmaceuticals, Inc. BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa
US6531291B1 (en) 1999-11-10 2003-03-11 The Trustees Of Columbia University In The City Of New York Antimicrobial activity of gemfibrozil and related compounds and derivatives and metabolites thereof
US20030114482A1 (en) 1999-12-15 2003-06-19 Maurizio Pacifici Use of retinoid receptor antagonists or agonists in the treatment of cartilage and bone pathologies
US6313168B1 (en) 1999-12-15 2001-11-06 Allergan Sales, Inc. Use of retinoid receptor antagonists in the treatment of cartilage and bone pathologies
AU2001234689A1 (en) 2000-02-01 2001-08-14 Cor Therapeutics, Inc. Bivalent phenylene inhibitors of factor xa
AU2001245353A1 (en) 2000-02-29 2001-09-12 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor xa
IL151517A0 (en) 2000-03-09 2003-04-10 Aventis Pharma Gmbh Therapeutic uses of ppar mediators
MY138097A (en) 2000-03-22 2009-04-30 Du Pont Insecticidal anthranilamides
US20020032238A1 (en) * 2000-07-08 2002-03-14 Henning Priepke Biphenylcarboxylic acid amides, the preparation thereof and the use thereof as medicaments
DE10033337A1 (de) * 2000-07-08 2002-01-17 Boehringer Ingelheim Pharma Biphenylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
KR20030067675A (ko) 2000-10-05 2003-08-14 후지사와 야꾸힝 고교 가부시키가이샤 벤자미드 화합물
NZ526003A (en) 2000-10-20 2005-09-30 Biocryst Pharm Inc Biaryl compounds as serine protease inhibitors
US6642252B2 (en) 2000-11-07 2003-11-04 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
EP1338597A4 (en) 2000-11-28 2008-06-18 Astellas Pharma Inc DERIVATIVES OF 1,4,5,6-TETRAHYDROIMIDAZO 4,5-D DIAZEPINE OR SALTS THEREOF
RU2003120070A (ru) 2000-12-06 2004-12-27 Авентис Фармаа Дойчланд Гмбх (De) Производные гуанидина и амидина в качестве ингибиторов фактора ха
CA2432713C (en) 2000-12-22 2009-10-27 Ishihara Sangyo Kaisha, Ltd. Aniline derivatives or salts thereof and cytokine production inhibitors containing the same
EP1217000A1 (en) 2000-12-23 2002-06-26 Aventis Pharma Deutschland GmbH Inhibitors of factor Xa and factor VIIa
WO2002054077A2 (en) 2000-12-29 2002-07-11 7Tm Pharma A/S Validating biological molecules as drug targets by metal-ion chelates in animal test models
CA2437840A1 (en) 2001-03-05 2002-09-12 E.I. Du Pont De Nemours Heterocyclic diamide invertebrate pest control agents
ES2332090T3 (es) 2001-04-06 2010-01-26 Biocryst Pharmaceuticals, Inc. Compuestos biarilicos como inhibidores de serina proteasa.
EP1383760A1 (en) 2001-04-30 2004-01-28 Fujisawa Pharmaceutical Co., Ltd. Biarylcarboxamide compounds as apolipoprotein b inhibitors
WO2002098839A1 (en) 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Biphenylcarboxamides and process for preparation thereof
WO2002101007A2 (en) 2001-06-13 2002-12-19 Genesoft Pharmaceuticals, Inc Antipathogenic benzamide compounds
WO2003003009A1 (en) 2001-06-29 2003-01-09 7Tm Pharma A/S Use of metal-ion chelates in validating biological molecules as drug targets in test animal models
WO2003003008A1 (en) 2001-06-29 2003-01-09 7Tm Pharma A/S Chemical libraries useful for drug discovery processes
DE10132686A1 (de) 2001-07-05 2003-01-16 Boehringer Ingelheim Pharma Heteroarylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2003007955A2 (en) 2001-07-20 2003-01-30 Cancer Research Technology Limited Biphenyl apurinic/apyrimidinic site endonuclease inhibitors to treat cancer
US20030130343A1 (en) 2001-08-10 2003-07-10 Adipogenix, Inc. Fat accumulation-modulating compounds
AUPR738301A0 (en) 2001-08-30 2001-09-20 Starpharma Limited Chemotherapeutic agents
US20050038035A1 (en) 2001-11-28 2005-02-17 Hisashi Takasugi Heterocyclic amide compounds as apolipoprotein b inhibitors
WO2003055477A1 (en) 2001-12-21 2003-07-10 7Tm Pharma A/S Method for the treatment of mc receptor related disorders with a chelate and/or a chelator
JP2005525309A (ja) 2002-01-10 2005-08-25 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 医薬品としての使用のためのＭＴＰインヒビター又はａｐｏＢ分泌インヒビターとフィブレートの組み合わせ
CN1620449A (zh) 2002-01-22 2005-05-25 纳幕尔杜邦公司 二酰胺化合物无脊椎害虫防治剂
SG165154A1 (en) 2002-02-28 2010-10-28 Japan Tobacco Inc Ester compound and medical use thereof
NZ535614A (en) 2002-03-11 2006-10-27 Tibotec Pharm Ltd Small molecule entry inhibitors
US6875780B2 (en) 2002-04-05 2005-04-05 Warner-Lambert Company Compounds that modulate PPAR activity and methods for their preparation
JP2004043456A (ja) 2002-05-24 2004-02-12 Yamanouchi Pharmaceut Co Ltd ベンゾアゼピン誘導体又はその塩を有効成分とする医薬
JP2003342175A (ja) 2002-05-24 2003-12-03 Yamanouchi Pharmaceut Co Ltd 新規なベンゾアゼピン誘導体又はその塩を有効成分とするメニエール病治療剤
AU2003245669A1 (en) 2002-06-21 2004-01-06 Cellular Genomics, Inc. Certain aromatic monocycles as kinase modulators
WO2004014844A2 (en) 2002-08-09 2004-02-19 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
US20040110802A1 (en) 2002-08-23 2004-06-10 Atli Thorarensen Antibacterial benzoic acid derivatives
JP2004175739A (ja) 2002-11-28 2004-06-24 Tanabe Seiyaku Co Ltd 医薬組成物
AU2003298343B2 (en) 2002-12-12 2010-02-25 Basf Se Amino substituted hydroxyphenyl benzophenone derivatives
BR0317323A (pt) * 2002-12-20 2005-11-16 Pfizer Prod Inc Inibidores de proteìna de transferência de triglicerìdeos microssomal
AU2004204760C1 (en) 2003-01-08 2010-08-19 Novartis Vaccines And Diagnostics, Inc. Antibacterial agents
TW200505902A (en) 2003-03-20 2005-02-16 Schering Corp Cannabinoid receptor ligands
JP2004315395A (ja) 2003-04-14 2004-11-11 Yamanouchi Pharmaceut Co Ltd 新規な安息香酸誘導体又はその塩
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
CN102060806A (zh) 2003-09-11 2011-05-18 iTherX药品公司 细胞因子抑制剂
EP1669348A4 (en) 2003-09-30 2009-03-11 Eisai R&D Man Co Ltd NEW ANTIPILIC AGENT CONTAINING A HETEROCYCLIC COMPOUND
JPWO2005040135A1 (ja) 2003-10-24 2007-03-08 小野薬品工業株式会社 抗ストレス薬およびその医薬用途
WO2005073165A1 (ja) 2004-01-28 2005-08-11 Mitsui Chemicals, Inc. アミド誘導体及びその製造方法ならびにその殺虫剤としての使用方法
DE102004009238A1 (de) 2004-02-26 2005-09-08 Merck Patent Gmbh Arylamid-Derivate
US7427390B2 (en) 2004-03-10 2008-09-23 Schering Ag Radiohalogenated benzamide derivatives and their use in tumor diagnosis and tumor therapy
WO2006007864A1 (en) 2004-07-17 2006-01-26 Max Planck Geselllschaft Zur Förderung Der Wissenschaft Treating neurodegenerative conditions
DE102004050196A1 (de) 2004-10-15 2006-04-20 Sanofi-Aventis Deutschland Gmbh Substituierte 2-Pyridon-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Medikament
US20080125432A1 (en) 2004-12-01 2008-05-29 Devgen Nv 5-Carboxamido Substituted Thiazole Derivatives that Interact With Ion Channels, In Particular With Ion Channels From the Kv Family
WO2006067445A2 (en) 2004-12-22 2006-06-29 Astrazeneca Ab Csf-1r kinase inhibitors
WO2006068199A1 (ja) 2004-12-22 2006-06-29 Mochida Pharmaceutical Co., Ltd. 代謝的に安定な３－オキシ－１，２，４－トリアゾール誘導体
CA2612976C (en) 2005-06-21 2012-04-10 Mitsui Chemicals, Inc. Amide derivative and insecticide containing the same
JP5193861B2 (ja) 2005-07-07 2013-05-08 アボット・ラボラトリーズ アポトーシス促進剤
JP4580836B2 (ja) 2005-07-25 2010-11-17 三井化学アグロ株式会社 殺虫殺菌組成物
AU2006287521A1 (en) 2005-09-07 2007-03-15 Plexxikon, Inc. PPARactive compounds
WO2007056143A2 (en) 2005-11-02 2007-05-18 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
WO2007052843A1 (ja) 2005-11-04 2007-05-10 Takeda Pharmaceutical Company Limited 複素環アミド化合物およびその用途
EP1966184B1 (en) 2005-12-20 2010-08-25 NeuroSearch A/S Pyridinyl-quinazoline derivatives and their medical use
UY30117A1 (es) 2006-01-31 2007-06-29 Tanabe Seiyaku Co Compuesto amina trisustituido
US7351434B2 (en) 2006-04-07 2008-04-01 Academia Sinica Therapeutic Gastrodia extracts
CN101466665B (zh) 2006-04-11 2013-12-04 沃泰克斯药物股份有限公司 适用作电压-门控钠通道抑制剂的组合物
WO2008044767A1 (en) 2006-10-13 2008-04-17 Takeda Pharmaceutical Company Limited Aromatic amine derivative and use thereof
JP2008106017A (ja) 2006-10-27 2008-05-08 Tokyo Univ Of Science Ｏａｔｐ選択的阻害性を有する化合物、及び該化合物を含むｏａｔｐの選択的阻害剤
CA2913963A1 (en) 2006-12-08 2008-06-19 Millenium Pharmaceuticals, Inc. Unit dose formulations and methods of treating thrombosis with an oral factor xa inhibitor
GB0625659D0 (en) 2006-12-21 2007-01-31 Cancer Rec Tech Ltd Therapeutic compounds and their use
JP4325681B2 (ja) 2007-02-13 2009-09-02 ソニー株式会社 固体撮像装置、撮像装置
JP5491871B2 (ja) 2007-02-28 2014-05-14 アドビナス セラピュティックス プライベート リミテッド グルコキナーゼ活性化因子としての２，２，２−三置換アセトアミド誘導体、その方法及び薬学的応用
WO2008140810A1 (en) 2007-05-11 2008-11-20 Cytokinetics, Incorporated Certain chemical entities, compositions, and methods
AU2008266856A1 (en) 2007-06-18 2008-12-24 University Of Louisville Research Foundation, Inc. Family of PFKFB3 inhibitors with anti-neoplastic activities
CN101687815A (zh) 2007-06-26 2010-03-31 塞诺菲-安万特股份有限公司 苯并咪唑和氮杂苯并咪唑的区域选择性铜催化合成
US20090012091A1 (en) 2007-07-02 2009-01-08 Kinagen, Inc. Oximide derivatives and their therapeutical application
WO2009047151A1 (en) 2007-10-10 2009-04-16 Basf Se Sulphonium salt initiators
EP2197869B1 (en) 2007-10-10 2013-04-24 Basf Se Sulphonium salt initiators
AU2008310660A1 (en) 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Heteroaryl amides useful as inhibitors of voltage-gated sodium channels
JP2009108152A (ja) 2007-10-29 2009-05-21 Sumitomo Chemical Co Ltd 重合性化合物および光学フィルム
WO2009070533A1 (en) 2007-11-29 2009-06-04 Complegen, Inc. Methods of inhibiting steroyl coa desaturase
JP2009149754A (ja) 2007-12-20 2009-07-09 Sumitomo Chemical Co Ltd 重合性化合物および該重合性化合物を重合してなる光学フィルム
AU2008345225A1 (en) 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
JP2009209090A (ja) 2008-03-04 2009-09-17 Mitsui Chemicals Inc 殺虫剤及び該殺虫剤に含まれる化合物、並びに該化合物の使用方法
US20100009970A1 (en) 2008-03-19 2010-01-14 Combinatorx (Singapore) Pte. Ltd. Compositions and methods for treatment of viral diseases
JP5219583B2 (ja) 2008-03-31 2013-06-26 住友化学株式会社 組成物、光学フィルムとその製造方法、光学部材及び表示装置
JP2010001284A (ja) 2008-05-20 2010-01-07 Sumitomo Chemical Co Ltd 化合物及び光学フィルム
DK2959900T3 (en) 2008-06-16 2017-06-26 Univ Tennessee Res Found CONNECTION TO TREATMENT OF CANCER
EP2328871B1 (en) 2008-08-25 2020-04-01 Novartis AG Hedgehog pathway modulators
JP5443720B2 (ja) 2008-09-05 2014-03-19 住友化学株式会社 組成物、光学フィルム及びその製造方法、光学部材ならびに表示装置
JP2010066630A (ja) 2008-09-12 2010-03-25 Sumitomo Chemical Co Ltd 光学フィルムの製造方法及び光学フィルム
KR101380013B1 (ko) 2008-09-18 2014-04-10 에프. 호프만-라 로슈 아게 치환 피롤리딘-2-카르복사미드
US8354444B2 (en) 2008-09-18 2013-01-15 Hoffmann-La Roche Inc. Substituted pyrrolidine-2-carboxamides
WO2010048149A2 (en) 2008-10-20 2010-04-29 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
JP5649779B2 (ja) 2008-11-28 2015-01-07 住友化学株式会社 液晶性組成物及び光学フィルム
KR101641385B1 (ko) 2009-03-16 2016-07-20 스미또모 가가꾸 가부시끼가이샤 화합물, 광학 필름 및 광학 필름의 제조 방법
JP5899607B2 (ja) 2009-03-16 2016-04-06 住友化学株式会社 化合物、光学フィルム及び光学フィルムの製造方法
KR20120058468A (ko) 2009-05-18 2012-06-07 오리온 코포레이션 프로테아제 억제제
EP2253617A1 (de) 2009-05-20 2010-11-24 Bayer CropScience AG Halogen-substituierte Verbindungen als Pestizide
WO2010138901A1 (en) 2009-05-29 2010-12-02 Biogen Idec Ma Inc Carboxylic acid-containing compounds, derivatives thereof, and related methods of use
JP2011006360A (ja) 2009-06-26 2011-01-13 Sumitomo Chemical Co Ltd 化合物、光学フィルム及び光学フィルムの製造方法
KR101256018B1 (ko) 2009-08-20 2013-04-18 한국과학기술연구원 단백질 키나아제 저해활성을 갖는 1,3,6-치환된 인돌 화합물
EP2477625A4 (en) 2009-09-14 2012-10-24 Phusis Therapeutics Inc PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS COMPRISING PLECKSTRINE HOMOLOGY DOMAIN INHIBITORS AND METHODS OF USE
US8420647B2 (en) 2010-01-21 2013-04-16 Hoffmann-La Roche Inc. 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds
JP5375644B2 (ja) 2010-02-10 2013-12-25 住友化学株式会社 組成物及び光学フィルム
CN102883607B (zh) 2010-03-01 2015-07-22 Gtx公司 用于治疗癌的化合物
JP2013525368A (ja) 2010-04-23 2013-06-20 キネタ・インコーポレイテツド 抗ウイルス性化合物
CA2797533A1 (en) 2010-04-27 2011-11-10 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2012016133A2 (en) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
WO2012027392A2 (en) 2010-08-24 2012-03-01 Brigham Young University Antimetastatic compounds
WO2012026931A1 (en) 2010-08-25 2012-03-01 Synta Pharmaceuticals Corp. Method of synthesizing substituted 2-alkyl phenols
JP5937102B2 (ja) 2010-12-14 2016-06-22 エレクトロフォレティクス リミテッド カゼインキナーゼ１デルタ（ｃｋ１デルタ）阻害剤
US9464065B2 (en) 2011-03-24 2016-10-11 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
EP2713722B1 (en) 2011-05-31 2017-03-15 Receptos, LLC Novel glp-1 receptor stabilizers and modulators
JP2014520151A (ja) 2011-06-20 2014-08-21 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 蠕虫感染を処置するためのヘテロ環式化合物
CA2839451A1 (en) 2011-06-27 2013-01-03 The Jackson Laboratory Methods and compositions for treatment of cancer and autoimmune disease
PL2573073T3 (pl) 2011-09-26 2015-04-30 Sanofi Sa Pochodne pirazolochinolinonu, ich wytwarzanie i ich zastosowanie terapeutyczne
CN103012397B (zh) 2011-09-26 2017-03-01 赛诺菲 吡唑并喹啉酮衍生物、其制备方法及其治疗用途
US9169246B2 (en) 2011-09-26 2015-10-27 Sanofi Pyrazoloquinolinone derivatives, preparation thereof and therapeutic use thereof
GB201119799D0 (en) 2011-11-16 2011-12-28 Sentinel Oncology Ltd Pharmaceutical compounds
EP2788332A1 (en) 2011-12-07 2014-10-15 Amgen, Inc. Bicyclic aryl and heteroaryl sodium channel inhibitors
EP2606726A1 (de) 2011-12-21 2013-06-26 Bayer CropScience AG N-Arylamidine-substituierte trifluoroethylsulfid-Derivate als Akarizide und Insektizide
JP2015503519A (ja) 2011-12-23 2015-02-02 ノバルティス アーゲー Ｂｃｌ２と結合相手の相互作用を阻害するための化合物
US8980823B2 (en) 2012-03-07 2015-03-17 Shaker A. Mousa Formulations of Factor VIIa inhibitors and utility
US8481479B1 (en) 2012-03-07 2013-07-09 Shaker A. Mousa Formulations of factor VIIa inhibitors and utility
US20150210717A1 (en) 2012-09-13 2015-07-30 Baden-Württemberg Stiftung Gmbh Specific inhibitors of protein p21 as therapeutic agents
WO2014055644A2 (en) 2012-10-02 2014-04-10 New York University Pharmaceutical compositions and treatment of genetic diseases associated with nonsense mediated rna decay
WO2014055634A1 (en) 2012-10-02 2014-04-10 Yale University Identification of small molecule inhibitors of jumonji at-rich interactive domain 1a (jarid1a) and 1b (jarid1b) histone demethylase
US20140200215A1 (en) 2013-01-15 2014-07-17 Intermune, Inc. Lysophosphatidic acid receptor antagonists
CN103961348B (zh) 2013-02-05 2016-08-17 上海交通大学医学院 Senp1小分子抑制剂及其应用
WO2014134127A1 (en) 2013-02-26 2014-09-04 Northeastern University Cannabinergic nitrate esters and related analogs
WO2014149207A2 (en) 2013-03-15 2014-09-25 Dow Agrosciences Llc Benzimidazole-based insecticidal compositions and related methods
JP5902641B2 (ja) 2013-03-27 2016-04-13 富士フイルム株式会社 光干渉顔料およびその製造方法
JP2014232188A (ja) 2013-05-29 2014-12-11 コニカミノルタ株式会社 セルロースアシレートフィルム、円偏光板及び画像表示装置
WO2014192681A1 (ja) 2013-05-31 2014-12-04 コニカミノルタ株式会社 樹脂組成物、光学部材、光学フィルム、偏光板、円偏光板及び画像表示装置
WO2015030898A2 (en) 2013-06-07 2015-03-05 The Regents Of The University Of California Micromechanical resonant switches and charge pumps
EP3010512B1 (en) 2013-06-18 2017-12-27 Merck Sharp & Dohme Corp. Cyclic phosphonate substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
CN105793424B (zh) 2013-07-12 2021-02-19 亥姆霍兹感染研究中心有限公司 孢囊菌酰胺
US20160250221A1 (en) 2013-07-25 2016-09-01 Fondazione Telethon Inhibitors of fapp2 and uses thereof
WO2015014900A1 (en) 2013-07-31 2015-02-05 Minoryx Therapeutics S.L. Di(hetero)arylamides and sulfonamides, methods for their preparation and therapeutic uses thereof
KR101628288B1 (ko) 2013-09-30 2016-06-08 주식회사 엘지화학 음성 광학 분산도를 갖는 광학 소자 제조용 조성물 및 이로부터 제조된 광학 이방체
WO2015085238A1 (en) 2013-12-05 2015-06-11 The Regents Of The University Of California, A California Corporation Inhibitors of lpxc
US9204150B2 (en) 2014-02-26 2015-12-01 Intel Corporation Techniques for evaluating compressed motion video quality
WO2015196072A2 (en) 2014-06-19 2015-12-23 Whitehead Institute For Biomedical Research Uses of kinase inhibitors for inducing and maintaining pluripotency
WO2016022626A1 (en) 2014-08-06 2016-02-11 Merck Sharp & Dohme Corp. Heterocyclic cgrp receptor antagonists
WO2016040449A1 (en) 2014-09-10 2016-03-17 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
EP2997966A1 (en) 2014-09-16 2016-03-23 Sanofi Naphthyl Sulfonamide Pyrrolidine Derivatives as KEAP-1 Modulators for the Treatment of Diabetes, Obesity, Dyslipidemia and Related Disorders
CN106317027A (zh) 2015-06-15 2017-01-11 山东轩竹医药科技有限公司 杂芳基酰胺类衍生物及其作为tgr5激动剂的应用
EP3350181B1 (en) 2015-09-02 2023-11-01 The Regents of The University of California Her3 ligands and uses thereof
WO2017062751A1 (en) 2015-10-08 2017-04-13 The Regents Of The University Of California Compounds and methods for promoting stress resistance
CA3001857A1 (en) 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Compounds, compositions and methods of use against stress granules
SG11201807982UA (en) 2016-03-16 2018-10-30 Kura Oncology Inc Substituted inhibitors of menin-mll and methods of use
JP7179735B2 (ja) 2016-09-28 2022-11-29 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング 重合性液晶材料および重合された液晶膜
KR20190063473A (ko) 2016-09-28 2019-06-07 블레이드 테라퓨틱스, 인크. 칼페인 조정자 및 그 치료학적 용도
WO2018161033A1 (en) 2017-03-02 2018-09-07 Wright, Adrian Small molecule ire1-alpha inhibitors
AU2018255413A1 (en) 2017-04-20 2019-12-05 Leidos Biomedical Research, Inc. K-Ras modulators
WO2018202681A1 (en) 2017-05-04 2018-11-08 Bayer Cropscience Aktiengesellschaft Use of disubstituted benzenes to control insecticide-resistant pests
JP2019015998A (ja) 2017-07-03 2019-01-31 東芝テック株式会社 情報処理装置およびプログラム
ES3008911T3 (en) 2017-07-11 2025-03-25 Vertex Pharma Carboxamides as modulators of sodium channels
WO2019018119A1 (en) 2017-07-18 2019-01-24 Pairnomix, Llc METHODS FOR TREATING EPILEPSY AND DISORDERS ASSOCIATED WITH KCNTI
CA3073051A1 (en) 2017-08-17 2019-02-21 Ikena Oncology, Inc. Ahr inhibitors and uses thereof
CA3090764A1 (en) 2018-01-30 2019-08-08 Pi Industries Ltd Novel anthranilamides, their use as insecticide and processes for preparing the same
US20190343817A1 (en) 2018-02-12 2019-11-14 Vertex Pharmaceuticals Incorporated Method of treating pain
CN112041413A (zh) 2018-04-27 2020-12-04 默克专利股份有限公司 可聚合的液晶材料和聚合的液晶膜
TWI871280B (zh) 2018-04-27 2025-02-01 德商馬克專利公司 可聚合的液晶材料及經聚合的液晶膜
WO2019241787A1 (en) 2018-06-15 2019-12-19 The Regents Of The University Of Colorado A Body Corporate Novel cyclic gmp-amp synthase (cgas) inhibitors and their method of use
WO2020051207A2 (en) 2018-09-04 2020-03-12 Magenta Therapeutics Inc. Aryl hydrocarbon receptor antagonists and methods of use
WO2020081572A1 (en) 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Transcriptional enhanced associate domain (tead) transcription factor inhibitors and uses thereof
WO2020123675A1 (en) 2018-12-11 2020-06-18 Duke University Compositions and methods for the treatment of cancer
CA3124970A1 (en) 2018-12-28 2020-07-02 Cedars-Sinai Medical Center Methods of treating inflammatory bowel diseases that target ripk2
WO2020146612A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
WO2020146682A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
JP7534306B2 (ja) 2019-01-22 2024-08-14 メルク・パテント・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング 液晶ポリマーフィルムの製造方法
CA3127590A1 (en) 2019-01-28 2020-08-06 Mitochondria Emotion, Inc. Mitofusin activators and methods of use thereof
WO2020176763A1 (en) 2019-02-27 2020-09-03 Vertex Pharmaceuticals Incorporated Dosage form comprising prodrug of na 1.8 sodium channel inhibitor
EP3937943A4 (en) 2019-03-15 2022-12-07 The General Hospital Corporation NEW SMALL MOLECULE INHIBITORS OF TEAD TRANSCRIPTION FACTORS
WO2020198712A1 (en) 2019-03-28 2020-10-01 Essa Pharma, Inc. Pharmaceutical compositions and combinations comprising inhibitors of the androgen receptor and uses thereof
WO2020219867A1 (en) 2019-04-25 2020-10-29 Vertex Pharmaceuticals Incorporated Pyridone amide co-crystal compositions for the treatment of pain
EP3963026A1 (en) 2019-04-30 2022-03-09 Merck Patent GmbH Reactive mesogens
US20220324880A1 (en) 2019-06-10 2022-10-13 Kymara Therapeutics, Inc. Smarca inhibitors and uses thereof

Patent Citations (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
WO2006011050A2 (en) 2004-07-23 2006-02-02 Pfizer Limited Pyridine derivatives
US20080312235A1 (en) 2004-07-23 2008-12-18 Charlotte Alice Louise Lane Pyridine Derivatives
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
WO2008135826A2 (en) 2007-05-03 2008-11-13 Pfizer Limited 2 -pyridine carboxamide derivatives as sodium channel modulators
US20090048306A1 (en) 2007-05-03 2009-02-19 Pfizer, Inc. Pyridine derivatives
WO2009049181A1 (en) * 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Amides useful as inhibitors of voltage-gated sodium channels
WO2009049183A1 (en) * 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Aryl amides useful as inhibitors of voltage-gated sodium channels
US20130303535A1 (en) 2008-12-26 2013-11-14 Dainippon Sumitomo Pharma Co., Ltd. Novel bicyclic heterocyclic compound
US8883840B2 (en) 2009-06-29 2014-11-11 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
WO2011026240A1 (en) 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Oxopiperazine derivatives for the treatment of pain and epilepsy
US20120220605A1 (en) 2009-09-04 2012-08-30 Zalicus Pharmaceuticals Ltd. Oxopiperazine derivatives for the treatment of pain and epilepsy
WO2011140425A1 (en) 2010-05-06 2011-11-10 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
US20110306607A1 (en) 2010-05-06 2011-12-15 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
US20120196869A1 (en) 2011-02-02 2012-08-02 Sara Sabina Hadida Ruah Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
WO2012106499A1 (en) 2011-02-02 2012-08-09 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
US20120245136A1 (en) 2011-02-18 2012-09-27 Sara Sabina Hadida-Ruah Chroman-spirocyclic piperidine amides as modulators of ion channels
WO2012112743A1 (en) 2011-02-18 2012-08-23 Vertex Pharmaceuticals Incorporated Chroman - spirocyclic piperidine amides as modulators of ion channels
WO2012116440A1 (en) 2011-03-03 2012-09-07 Zalicus Pharmaceuticals Ltd. Benzimidazole inhibitors of the sodium channel
US20140187533A1 (en) 2011-03-03 2014-07-03 Zalicus Pharmaceuticals Ltd. Benzimidazole inhibitors of the sodium channel
WO2012125613A1 (en) 2011-03-14 2012-09-20 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US20120264749A1 (en) 2011-03-14 2012-10-18 Sara Sabina Hadida-Ruah Morpholine-spirocyclic piperidine amides as modulators of ion channels
WO2013061205A2 (en) 2011-10-26 2013-05-02 Pfizer Limited Chemical compounds
US20140296313A1 (en) 2011-10-26 2014-10-02 Pfizer Limited (4-Phenylimidazol-2-yl) Ethylamine Derivatives Useful As Sodium Channel Modulators
US20150005304A1 (en) 2012-01-16 2015-01-01 Vertex Pharmaceuticals Incorporated Pyran-Spirocyclic Piperidine Amides as Modulators of Ion Channels
WO2013109521A1 (en) 2012-01-16 2013-07-25 Vertex Pharmaceuticals Incorporated Pyran-spirocyclic piperidine amides as modulators of ion channels
US20130274243A1 (en) 2012-02-03 2013-10-17 Pfizer Limited Chemical Compounds
WO2013114250A1 (en) 2012-02-03 2013-08-08 Pfizer Inc. Benziimidazole and imidazopyridine derivatives as sodium channel modulators
WO2013131018A1 (en) 2012-03-02 2013-09-06 Zalicus Pharmaceuticals Ltd. Biaryl inhibitors of the sodium channel
US20140228371A1 (en) 2013-01-31 2014-08-14 Vertex Pharmaceuticals Incorporated Quinoline and quinazoline amides as modulators of sodium channels
WO2014120815A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Quinoline and quinazoline amides as modulators of sodium channels
WO2014120808A1 (en) 2013-01-31 2014-08-07 Vertex Parmaceuticals Incorporated Pyridone amides as modulators of sodium channels
WO2014120820A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Amides as modulators of sodium channels
US20140221435A1 (en) 2013-01-31 2014-08-07 Vertex Pharmaceuticals Incorporated Amides as modulators of sodium channels
US20140213616A1 (en) 2013-01-31 2014-07-31 Vertex Pharmaceuticals Incorporated Pyridone amides as modulators of sodium channels
WO2014120808A9 (en) 2013-01-31 2015-05-14 Vertex Parmaceuticals Incorporated Pyridone amides as modulators of sodium channels
WO2015010065A1 (en) 2013-07-19 2015-01-22 Vertex Pharmaceuticals Incorporated Sulfonamides as modulators of sodium channels
US20160152561A1 (en) 2013-07-19 2016-06-02 Vertex Pharmaceuticals Incorporated Sulfonamides as modulators of sodium channels
US20150166589A1 (en) 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
WO2015089361A1 (en) 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences, Sixteenth Edition,", 1980, MACK PUBLISHING CO.
.: "Handbook of Chemistry and Physics, 75th Ed.", .
AKOPIAN, A.N.; L. SIVILOTTI; J.N. WOOD: "A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons", NATURE, vol. 379, no. 6562, 1996, pages 257 - 62, XP000605462, DOI: doi:10.1038/379257a0
BLACK, J.A. ET AL.: "Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas", ANN. NEUROL., vol. 64, no. 6, 2008, pages 644 - 53, XP009143330, DOI: doi:10.1002/ana.21527
BLAIR, N.T.; B.P. BEAN: "Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons", J. NEUROSCI., vol. 22, no. 23, 2002, pages 10277 - 90
CATTERALL, W. A.; GOLDIN, A. L.; WAXMAN, S. G.: "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels", PHARMACOL. REV., vol. 57, no. 4, 2005, pages 397, XP055146853, DOI: doi:10.1124/pr.57.4.4
CHAHINE, M.; CHATELIER, A.; BABICH, O.; KRUPP, J. J.: "Voltage-gated sodium channels in neurological disorders", CNS NEUROL. DISORD. DRUG TARGETS, vol. 7, no. 2, 2008, pages 144 - 58
CHOI, J.S.; S.G. WAXMAN: "Physiological interactions between Na l.7 and Na l.8 sodium channels: a computer simulation study", J. NEUROPHYSIOL., vol. 106, no. 6, pages 3173 - 84
COWARD, K. ET AL.: "Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states", PAIN, vol. 85, no. 1-2, 2000, pages 41 - 50
DIELEMAN, J.P. ET AL.: "Incidence rates and treatment of neuropathic pain conditions in the general population", PAIN, vol. 137, no. 3, 2008, pages 681 - 8, XP022853979, DOI: doi:10.1016/j.pain.2008.03.002
DONG, X.W. ET AL.: "Small interfering RNA-mediated selective knockdown of Na(v)1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats", NEUROSCIENCE, vol. 146, no. 2, 2007, pages 812 - 21, XP022061734, DOI: doi:10.1016/j.neuroscience.2007.01.054
EXPERT OPIN. INVESTIG. DRUGS, vol. 17, no. 12, 2008, pages 1849 - 64
FOOD AND DRUG
HILLE; BERTIL: "Ion Channels of Excitable Membranes, Third ed.", 2001, SINAUER ASSOCIATES, INC.
HUANG, H.L. ET AL.: "Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves", MOL. PAIN, vol. 4, 2008, pages 33, XP021045080, DOI: doi:10.1186/1744-8069-4-33
J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
JOSHI, S.K. ET AL.: "Involvement of the TTX-resistant sodium channel Nav 1. 8 in inflammatory and neuropathic, but not post-operative, pain states", PAIN, vol. 123, no. 1-2, 2006, pages 75 - 82, XP025024615, DOI: doi:10.1016/j.pain.2006.02.011
KRAFTE, D. S.; BANNON, A. W.: "Sodium channels and nociception: recent concepts and therapeutic opportunities", CURR. OPIN. PHARMACOL., vol. 8, no. 1, 2008, pages 50 - 56, XP002540499, DOI: doi:10.1016/j.coph.2007.09.007
LAI, J. ET AL.: "Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na l.8", PAIN, vol. 95, no. 1-2, 2002, pages 143 - 52, XP002374879, DOI: doi:10.1016/S0304-3959(01)00391-8
PROC. NATL. ACAD. SCI. USA, vol. 104, no. 20, 2007, pages 8520 - 5
QIU, F. ET AL.: "Increased expression of tetrodotoxin-resistant sodium channels Na l.8 and Na l.9 within dorsal root ganglia in a rat model of bone cancer pain", NEUROSCI. LETT., vol. 512, no. 2, pages 61 - 6, XP028903612, DOI: doi:10.1016/j.neulet.2012.01.069
RENGANATHAN, M.; T.R. CUMMINS; S.G. WAXMAN: "Contribution of Na( )1.8 sodium channels to action potential electrogenesis in DRG neurons", J. NEUROPHYSIOL., vol. 86, no. 2, 2001, pages 629 - 40
ROBERT S. PORTER AND JUSTIN L. KAPLAN,: "The Merck Manual, Nineteenth Edition,", 2011, MERCK SHARP &DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC.
ROZA, C. ET AL.: "The tetrodotoxin-resistant Na+ channel Na l.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice", J. PHYSIOL., vol. 550, 2003, pages 921 - 6
RUANGSRI, S. ET AL.: "Relationship of axonal voltage-gated sodium channel 1.8 (Na l.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats", J. BIOL. CHEM., vol. 286, no. 46, pages 39836 - 47
RUSH, A.M. ET AL.: "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons", PROC. NATL. ACAD. SCI. USA, vol. 103, no. 21, 2006, pages 8245 - 50
RUSH, A.M.; T.R. CUMMINS: "Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Navl.8 Sodium Channels", MOL. INTERV., vol. 7, no. 4, 2007, pages 192 - 5, XP009165204, DOI: doi:10.1124/mi.7.4.4
S. L. HARBESON; R. D. TUNG: "Deuterium In Drug Discovery and Development", ANN. REP. MED. CHEM., vol. 46, 2011, pages 403 - 417, XP055422117, DOI: doi:10.1016/B978-0-12-386009-5.00003-5
SODERPALM, B.: "Anticonvulsants: aspects of their mechanisms of action", EUR. J. PAIN, 2002, pages 3 - 9, XP003009563, DOI: doi:10.1053/eujp.2001.0315
STRICKLAND, I.T. ET AL.: "Changes in the expression of NaV1.7, Na l.8 and Na l.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain", EUR. J. PAIN, vol. 12, no. 5, 2008, pages 564 - 72, XP022632366, DOI: doi:10.1016/j.ejpain.2007.09.001
SUN, W. ET AL.: "Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats", BRAIN, vol. 135, pages 359 - 75
T.G.M. WUTS ET AL., GREENE'S PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2006
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS
V.S. SHIRLEY; C.M. LEDERER: "Isotopes Project, Nuclear Science Division", January 1980, LAWRENCE BERKELEY LABORATORY
WANG, G. K.; MITCHELL, J.; WANG, S. Y.: "Block of persistent late Na+ currents by antidepressant sertraline and paroxetine", J. MEMBR. BIOL., vol. 222, no. 2, 2008, pages 79 - 90, XP019622596
YIANGOU, Y. ET AL.: "SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves", FEES LETT., vol. 467, no. 2-3, 2000, pages 249 - 52, XP004260962, DOI: doi:10.1016/S0014-5793(00)01166-2

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WO2023211990A1 (en) 2022-04-25 2023-11-02 Siteone Therapeutics, Inc. Bicyclic heterocyclic amide inhibitors of na v1.8 for the treatment of pain
WO2024123815A1 (en) 2022-12-06 2024-06-13 Vertex Pharmaceuticals Incorporated Process for the synthesis of substituted tetrahydrofuran modulators of sodium channels
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EP4660183A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting phenolic compounds, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660181A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting hydrazides, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660182A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting aryl pyridine compounds, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660185A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting amides, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
EP4660184A1 (en) 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting hydroxamates, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
WO2024217344A1 (zh) * 2023-04-19 2024-10-24 中国科学院上海药物研究所 Nav1.8抑制剂及其制备方法和用途
WO2024255834A1 (zh) * 2023-06-14 2024-12-19 上海济煜医药科技有限公司 吡啶氮氧化合物的盐型、共晶及其制备方法和应用
WO2025090465A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2025090480A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2025090516A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Methods of preparing compounds for treating pain and solid forms thereof
WO2025090511A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Methods of preparing modulators of sodium channels and solid forms of the same for treating pain
WO2025122953A1 (en) 2023-12-07 2025-06-12 Vertex Pharmaceuticals Incorporated Dosing regimens and formulations of suzetrigine for use in the treatment of acute and chronic pain
WO2025160286A1 (en) 2024-01-24 2025-07-31 Siteone Therapeutics, Inc. 2-aryl cycloalkyl and heterocycloalkyl inhibitors of nav1.8 for the treatment of pain

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