WO2017210580A1 - Analogues de diamide imidodicarbonimidique - Google Patents

Analogues de diamide imidodicarbonimidique Download PDF

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Publication number
WO2017210580A1
WO2017210580A1 PCT/US2017/035720 US2017035720W WO2017210580A1 WO 2017210580 A1 WO2017210580 A1 WO 2017210580A1 US 2017035720 W US2017035720 W US 2017035720W WO 2017210580 A1 WO2017210580 A1 WO 2017210580A1
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compound
pharmaceutically acceptable
solvate
stereoisomer
acceptable salt
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PCT/US2017/035720
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English (en)
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David Campbell
Michael E. Jung
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Enlibrium, Inc.
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Publication of WO2017210580A1 publication Critical patent/WO2017210580A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

Definitions

  • phenformin is no longer available for the treatment of diabetes in the United States due to its association with an increased risk of lactic acidosis.
  • Metformin another biguanide, has replaced phenformin in the United States for the treatment of diabetes since the incidence of lactic acidosis associated with metformin is significantly less than that observed with phenformin.
  • Metformin has also demonstrated improved survival in several cancers including breast, colon, pancreatic, and prostate.
  • metformin is unlikely to offer true benefit to a wide range of cancer patients due to a lack of potency.
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C h alky! Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently Ci- 6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or Ci- 6 alkyl; or R 5 and R 6 together with the
  • q 0, 1, 2, 3, or 4;
  • Formula (la) is a compound of
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , Ci- 6 alkyl, Ci- 6 haloalkyl, Ci_ ehaloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p is 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , C 1-6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0
  • each R 1 is independently halogen, -CN, -N0 2 , -NR 4 R 4 , C 1-6 alkyl, Ci-6haloalkyl, Ci_
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently C 1-6 alkyl;
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • n 0 or 1 ;
  • p 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -NR 4 R 4 , Q. 6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6
  • each R 1 is independently halogen, - NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R
  • embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci_ 6 haloalkoxy.
  • each R 1 is independently Ci- 6 alkyl.
  • each R 1 is independently -CN, -NR 4 R 4 , Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, - C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , -C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p is 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently -NR 4 R 4 , Ci- 6 haloalkyl,
  • Ci- 6 haloalkoxy optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or -S(0) 2 NR 5 R 6
  • each R 1 is independently -NR 4 R 4 , Ci- 6 haloalkyl, Q. ehaloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • each R 1 is independently Ci- 6 haloalkyl or Ci- 6 haloalkoxy.
  • a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein each R is independently Ci- 6 alkyl or Ci- 6 alkoxy.
  • each q is 2.
  • a pharmaceutical composition comprising a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer is selected from IDH1 mutant cancers and cancers with LKB 1 deficient tumors.
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or
  • stereoisomer thereof in some embodiments is a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or
  • a method of treating polycystic ovarian syndrome in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the methods described herein further comprise the administration of a second therapeutic agent.
  • the second therapeutic agent is a BRAF inhibitor.
  • the second therapeutic agent is a BRAF inhibitor selected from dabrafenib, vemurafenib, encorafenib, TAK-580, LY3009120, BGB-283, HM955573, and PLX8394.
  • the second therapeutic agent is an mTOR inhibitor.
  • the second therapeutic agent is an mTOR inhibitor selected from everolimus, TAK-228, AZD2014, LY3023414, and gedatolisib.
  • a method of increasing the bioavailability of a compound of Formula (I), (la), (II), (III), or (IV) in a subject comprising administering to a subject a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of decreasing the metabolism of a compound of Formula (I), (la), (II), (III), or (IV) in a subject comprising administering to a subject a compound of Formula (I), (la), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • Figure 1 shows tumor volume of a mutant BRAF melanoma (Colo829) through 21 days of treatment with Compound 5, a BRAF inhibitor, or a Compound 5/BRAF inhibitor
  • Figure 2 shows tumor volume of a mutant KRAS, LKB l(-) NSCLC (A549) through 21 days of treatment with Compound 5, an mTOR inhibitor, or a Compound 5/mTOR inhibitor combination.
  • Metformin is an approved type 2 diabetes drug that has demonstrated anti-cancer activity in a number of retrospective analyses. Beginning in 2005, a number of studies have
  • phenformin a member of the biguanide structural class that includes metformin, consistently demonstrates improved potency and activity against a wider set of cancer types than metformin. Phenformin was approved to treat type 2 diabetes in 1959, however the FDA rescinded its approval in the United States in 1978 due to its association with an increased risk of lactic acidosis (0.6 events per 1,000 patient years) compared to metformin (0.1 events per 1,000 patient years). Thus there remains a need to identify compounds that retain phenformin' s superior anticancer and anti-diabetes activity while reducing the risk of lactic acidosis.
  • the high CYP2D6 metabolizers have low levels of phenformin upon dosing, thereby decreasing the desired efficacy.
  • metformin stimulates AMP-activated protein kinase (AMPK) activation.
  • Metformin- induced activation of AMPK inhibits downstream mTORCl which integrates signals from a diverse array of signaling pathways to regulate pancreatic cancer cell survival, growth and metastasis. It is postulated that metformin inhibits pancreatic cancer growth in part via AMPK- mediated inhibition of mTORCl activation.
  • AMPK- mediated inhibition of mTORCl activation independent data show that metformin also disrupts critical cross-talk between insulin/IGF- 1 and GPCR signaling pathways and possibly ERK and Rag GTPase signaling. Further laboratory studies show that metformin markedly inhibits growth of human pancreatic cancer cells xenografted in nude mice.
  • metformin users have a reduced risk of pancreatic cancer; and that metformin use correlates with a survival benefit in patients with diabetes and pancreatic cancer.
  • the median survival is prolonged by four months in cancer patients who are metformin users compared to non-users. It is notable that anticancer effects of metformin increase with increasing doses and/or with IV as compared to oral administration.
  • Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
  • Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • Ci-C x includes Ci-C 2 , C1-C3 . . . Ci-C x .
  • Ci-C x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
  • alkyl group refers to an aliphatic hydrocarbon group.
  • the alkyl group may or may not include units of unsaturation.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon-carbon double bond or a carbon-carbon triple bond).
  • the alkyl group may also be an "unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation.
  • the alkyl moiety, whether saturated or unsaturated may be branched, straight chain, or cyclic.
  • the "alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., "1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group of the compounds described herein may be designated as "Ci-C 6 alkyl" or similar designations.
  • Ci-C 6 alkyl indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.
  • Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
  • alkoxy refers to a "-O-alkyl” group, where alkyl is as defined herein.
  • alkenyl refers to a type of alkyl group which contains at least one double bond that is not part of an aromatic group.
  • the alkenyl moiety may be branched or straight chain.
  • Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).
  • alkynyl refers to a type of alkyl group which contains at least one triple bond.
  • alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 , -C ⁇ CCH 2 CH 3 and - C ⁇ CCH 2 CH 2 CH 3 .
  • Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
  • Amino refers to a -NH 2 group.
  • “Dialkylamino” refers to a -N(alkyl) 2 group, where alkyl is as defined herein.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • Carboxy refers to -C0 2 H.
  • carboxy moieties may be replaced with a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety.
  • a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
  • a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound.
  • a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
  • bioisosteres of a carboxylic acid include, but are not limited to,
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Unless otherwise noted, cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • An N- containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • Polycyclic heteroaryl groups may be fused or non- fused.
  • Illustrative examples of heteroaryl groups include the following moieties:
  • heterocycloalkyl group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur.
  • the radicals may be fused with an aryl or heteroaryl.
  • heterocycloalkyls have from 2 to 10 carbons in the ring.
  • halo or, alternatively, “halogen” means fluoro, chloro, bromo, and iodo.
  • haloalkyl refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH 2 C1, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
  • haloalkoxy refers to an alkoxy group that is substituted with one or more halogens.
  • the halogens may the same or they may be different.
  • fluoroalkyl and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms.
  • fluoroalkyls include -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
  • Non-limiting examples of fluoroalkoxy groups include -OCF 3 , -OCHF 2 , -OCH 2 F, - OCH 2 CF 3 , -OCF 2 CF 3 , -OCF 2 CF 2 CF 3 , -OCF(CH 3 ) 2 , and the like.
  • heteroalkyl refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group.
  • heteroalkyl may have from 1 to 6 carbon atoms.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • moiety refers to a specific segment or functional group of a molecule.
  • Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-C 6 alkylalkyne, halo, acyl, acyloxy, -C0 2 H, -C0 2 -alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di- substituted amino groups (e.g. -NH 2 , -NHR, -N(R) 2 ), and the protected derivatives thereof.
  • an optional substituent may be L S R
  • each R s is independently selected from among H, (Ci-C 6 alkyl), (C 3 - Cscycloalkyl), aryl, heteroaryl, heterocycloalkyl, and Ci-C 6 heteroalkyl.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • treat means to include alleviating or abrogating a disorder, disease, or condition; or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • prevent refers to a method of delaying or precluding the onset of a disorder, disease, or condition; and/or its attendant symptoms, barring a subject from acquiring a disease or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • terapéuticaally effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be
  • pharmaceutically acceptable in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams &
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • substantially pure and substantially homogeneous mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, or biological and pharmacological properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • substantially pure or substantially homogeneous refers to a collection of molecules, wherein at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% of the molecules are a single compound, including a racemic mixture or single stereoisomer thereof, as determined by standard analytical methods.
  • active ingredient and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder or disease.
  • drug refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder or disease.
  • release controlling excipient refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • non-release controlling excipient refers to an excipient whose primary function does not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently Ci- 6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or Ci- 6 alkyl; or R 5 and R 6 together with the
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , C 1-6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R
  • each R 1 is independently -F or -CI.
  • each R 1 is -CF 3 .
  • each R is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R is -CH 3 .
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , -
  • each R is independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently Ci- 6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or Ci- 6 alkyl; or R 5 and R 6 together with the
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6 .
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • each R 1 is independently halogen, -OR 4 , Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 haloalkoxy.
  • each R 1 is independently -CI. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently -OR 4 . In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is
  • R 4 independently -OR 4 and R 4 is C h alky!
  • embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 5. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 4. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 2.
  • Ci- 6 alkyl or Ci- 6 alkoxy is independently Ci- 6 alkyl or Ci- 6 alkoxy.
  • each R is -CH 3 .
  • each R is independently Ci- 6 alkoxy.
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , C 1-6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0
  • each R 1 is independently -F or -CI.
  • each R 1 is independently -OR 4 and R 4 is C h alky!
  • each R 1 is - OCH 3 .
  • each R 1 is -OH.
  • each R 1 is a compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently C h alky!
  • Ci- 6 alkyl or Ci- 6 alkoxy is independently Ci- 6 alkyl or Ci- 6 alkoxy.
  • each R is -CH 3 .
  • each R is independently Ci- 6 alkoxy.
  • each R is -OCH 3 .
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q. 6haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently Ci- 6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or Ci- 6 alkyl; or R 5 and R 6 together with the
  • p is 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6 .
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • each R 1 is independently -OR 4 and R 4 is C h alky!
  • embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 5. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 4. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 2.
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p is 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , C 1-6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0
  • each R 1 is independently -F or -CI.
  • each R 1 is independently -OR 4 and R 4 is C h alky!
  • each R 1 is a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is - OCH 3 .
  • each R 1 is a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is -OH.
  • each R 1 is independently C h alky!
  • embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 5. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 4. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 3. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 2.
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p is 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , C 1-6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6 .
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • each R 1 is independently halogen, -OR 4 , Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 haloalkoxy.
  • each R 1 is independently -OR 4 and R 4 is C h alky!.
  • embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 5.
  • each R 1 is independently halogen, -CN, -N0 2 , -OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Q.
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p is 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -OR 4 , -NR 4 R 4 , C 1-6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6
  • each R 1 is independently halogen, - OR 4 , -NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R
  • each R 1 is independently -F or -CI.
  • each R 1 is independently -OR 4 and R 4 is C h alky!
  • each R 1 is a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is - OCH 3 .
  • each R 1 is -OH.
  • each R 1 is independently C h alky!
  • embodiments is a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 5. In some embodiments is a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 4. In some embodiments is a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 3. In some embodiments is a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 2.
  • each R 1 is independently halogen, -CN, -N0 2 , -NR 4 R 4 , Ci- 6 haloalkyl, Ci_
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently C 1-6 alkyl;
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • n 0 or 1 ;
  • p 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -NR 4 R 4 , Q. 6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6 .
  • each R 1 is independently halogen, - NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • each R 1 is independently halogen, - NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci_ 6 haloalkoxy.
  • each R 1 is independently -F or -CI.
  • each R 1 is -CH 3 .
  • haloalkoxy In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R is -OCF 3 . In some
  • embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 4. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 1.
  • each R is independently Ci- 6 alkyl or Ci- 6 alkoxy.
  • each R is independently Ci- 6 alkoxy.
  • each R 1 is independently halogen, -CN, -N0 2 , -NR 4 R 4 , C 1-6 alkyl, Ci-6haloalkyl, Ci_
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -NR 4 R 4 , Q. 6 alkyl, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or - S(0) 2 NR 5 R 6
  • each R 1 is independently halogen, - NR 4 R 4 , Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 haloalkoxy, -C0 2 R 4 , or
  • embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, C 1-6 alkyl, Ci- 6 haloalkyl, or Q. 6 haloalkoxy.
  • each R 1 is independently -F or -CI.
  • each R 1 is a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is -CH 3 .
  • each R 1 is Q.
  • 6haloalkoxy is a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is -OCF 3 .
  • embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 4. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 3. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 2. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 1.
  • each R 1 is independently halogen, -CN, -N0 2 , -NR 4 R 4 , alkyl, Ci_
  • Ci- 6 heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , - C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 halo alkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently Ci- 6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or Ci- 6 alkyl; or R 5 and R 6 together with the
  • p 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently halogen, -NR 4 R 4 , Q.
  • S(0) 2 NR 5 R 6 is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, -
  • embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, Ci- 6 alkyl, Ci- 6 halo alkyl, or Ci_
  • haloalkoxy in some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen or
  • Ci- 6 alkyl In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently -F or -CI. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently -F. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently -CI.
  • each R 1 is independently C 1-6 alkyl.
  • 6haloalkoxy is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is -OCF 3 .
  • embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 4. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 3. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 2. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each p is 1. In some embodiments is a compound of Formula (Illb), or a
  • each R is independently Ci- 6 alkyl or Ci- 6 alkoxy.
  • each R is independently Ci- 6 alkoxy.
  • each R 1 is independently -CN, -NR 4 R 4 , Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, - C(0)R 3 , -OC(0)R 3 , -C0 2 R 4 , -N(R 4 )C(0)R 3 , -C(0)NR 5 R 6 , -N(R 4 )C(0)NR 5 R 6 , -S(0) 2 R 3 , -N(R 4 )S(0) 2 R 3 , or -S(0) 2 NR 5 R 6 ;
  • each R is independently C 1-6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R is independently C 1-6 alkyl
  • each R 4 is independently H or Ci- 6 alkyl
  • each R 5 and each R 6 are independently H or C 1-6 alkyl; or R 5 and R 6 together with the
  • p is 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • each R 1 is independently -NR 4 R 4 , Ci- 6 haloalkyl, Ci- 6 haloalkoxy, optionally substituted Ci- 6 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(0)R 3 , -C0 2 R 4 , -C(0)NR 5 R 6 , -S(0) 2 R 3 , or -S(0) 2 NR 5 R 6
  • each R 1 is independently -NR 4 R 4 , Ci- 6 haloalkyl, Q.
  • ehaloalkoxy -C0 2 R 4 , or -C(0)NR 5 R 6 .
  • a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein each R 1 is independently Ci- 6 haloalkyl or Ci- 6 haloalkoxy.
  • a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein each p is 3.
  • each R is independently Ci- 6 alkyl or Ci- 6 alkoxy.
  • each R is -OCH 3 .
  • the compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV) described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • Stereoisomers may be performed by chromatography or by the forming diastereomeric and separation by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
  • compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) may exist as tautomers. All tautomers are included within the formulas described herein.
  • the compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) is provided as a pharmaceutically acceptable salt (See, Berge et al., . Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use,” Stah and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,
  • the compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV) is provided as a prodrug, which is a functional derivative of the compound of Formula (I) or Formula (II) and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • the compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) described herein may be labeled isotopically (e.g. with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, photoactivatable or chemiluminescent labels.
  • the compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 C1, respectively.
  • the deuterated compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) also contains less prevalent isotopes for other elements, including, but not limited to, 13 C or 14 C for carbon and 15 N for nitrogen.
  • the deuterated compounds provided herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially decreasing toxicity (reducing the risk of lactic acidosis), increasing the half- life (Ti /2 ), lowering the maximum plasma concentration (C max ) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related toxicity, and/or lowering the probability of drug-drug interactions.
  • the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science
  • a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (lib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition in modified release dosage forms comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more release controlling excipients as described herein.
  • Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof.
  • the pharmaceutical compositions also comprise non-release controlling excipients.
  • a pharmaceutical composition in enteric coated dosage forms comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more release controlling excipients for use in an enteric coated dosage form.
  • the pharmaceutical compositions also comprise non-release controlling excipients.
  • a pharmaceutical composition in effervescent dosage forms comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ma), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more release controlling excipients for use in an enteric coated dosage form.
  • the pharmaceutical compositions also comprise non-release controlling excipients.
  • a pharmaceutical composition in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours.
  • the pharmaceutical compositions comprise a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (He), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more release controlling and non-release controlling excipients, such as those excipients suitable for a disruptable semi-permeable membrane and as swellable substances.
  • a pharmaceutical composition in a dosage form for oral administration to a subject comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.
  • compositions comprising about 0.1 to about 100 mg, about 0.5 to about 50 mg, about 1 to about 20 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg of one or more compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) in the form of tablets for oral administration.
  • the pharmaceutical compositions further comprise hydroxypropyl
  • compositions comprising about 0.1 to about 100 mg, about 0.5 to about 50 mg, about 1 to about 20 mg, about 1 mg, about 2 mg, about 3 mg, about 4mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg of one or more compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) in the form of coated two-layer tablet for oral administration: one layer that releases a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) immediately and another layer that allows a slower release of additional compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV).
  • the pharmaceutical compositions provided herein are provided in unit-dosage forms or multiple-dosage forms.
  • Unit-dosage forms refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampules, syringes, and individually packaged tablets and capsules. Unit-dosage forms may be
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form.
  • Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.
  • the compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV) provided herein is administered alone, or in combination with one or more other compounds provided herein, or one or more other active ingredients.
  • the pharmaceutical compositions that comprise a compound provided herein are formulated in various dosage forms for oral, parenteral, and topical administration.
  • the pharmaceutical compositions are also formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art ⁇ see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).
  • compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the administration of the compounds may be given continuously or temporarily suspended for a certain length of time ⁇ i.e., a "drug holiday").
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long- term basis upon any recurrence of symptoms.
  • the pharmaceutical compositions provided herein are provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye- migration inhibitors, sweetening agents, and flavoring agents.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye- migration inhibitors, sweetening agents, and flavoring agents.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remains intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxye
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof.
  • the binder or filler is present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross- linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre- gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL ® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL ® (Cabot Co. of Boston, MA); and mixtures thereof.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include colloidal silicon dioxide, CAB-O-SIL ® (Cabot Co. of Boston, MA), and asbestos-free talc.
  • Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone.
  • Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • Organic acids include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • the pharmaceutical compositions provided herein are provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric- coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydro xyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms are prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein are provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein are encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • the pharmaceutical compositions provided herein are provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydro alcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol- 350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly-alkylene glycol including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol- 350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates .
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates .
  • the pharmaceutical compositions provided herein are provided as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • compositions provided herein are formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • the pharmaceutical compositions provided herein are co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action, such as other GABA A receptor modulators.
  • the pharmaceutical compositions provided herein are administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial,
  • intramuscular, intrasynovial, and subcutaneous administration are intramuscular, intrasynovial, and subcutaneous administration.
  • the pharmaceutical compositions provided herein are formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science ⁇ see, Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethy lsulfo xide .
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl- and propylparabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium
  • Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including oc- cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- -cyclodextrin, and sulfobutylether 7- -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • cyclodextrins including oc- cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- -cyclodextrin, and sulfobutylether 7- -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • the pharmaceutical compositions provided herein are formulated for single or multiple dosage administration.
  • the single dosage formulations are packaged in an ampule, a vial, or a syringe.
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • compositions provided herein are formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • the pharmaceutical compositions are formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized
  • polyethyleneterephthalate natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include polyethylene, polypropylene,
  • ethylene/propylene copolymers ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated
  • polyethylene polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber
  • epichlorohydrin rubbers ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • the pharmaceutical compositions provided herein are administered topically to the skin, orifices, or mucosa.
  • the topical administration include (intra)dermal, conjuctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, uretheral, respiratory, and rectal administration.
  • the pharmaceutical compositions provided herein are formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal patches.
  • the topical formulation of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
  • Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryopretectants, lyoprotectants, thickening agents, and inert gases.
  • compositions may also be administered topically by
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including such as lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are em
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Cream vehicles may be water- washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers, such as carbomers,
  • carboxypolyalkylenes Carbopol®
  • hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol
  • cellulosic polymers such as hydro xypropyl cellulose, hydro xyethyl cellulose, hydro xypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose
  • gums such as tragacanth and xanthan gum
  • sodium alginate and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • the pharmaceutical compositions provided herein are administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. In some embodiments, combinations of the various vehicles may be used. In some embodiments, rectal and vaginal suppositories are prepared by the compressed method or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • the pharmaceutical compositions provided herein are administered ophthalmic ally in the forms of solutions, suspensions, ointments, emulsions, gel- forming solutions, powders for solutions, gels, ocular inserts, and implants.
  • the pharmaceutical compositions provided herein are administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical compositions are provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using
  • the pharmaceutical compositions are provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.
  • solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer are formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein, a propellant as solvent; and/or an surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the pharmaceutical compositions provided herein are micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • particles of such sizes are prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • capsules, blisters and cartridges for use in an inhaler or insufflator are formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l- leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical compositions provided herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.
  • compositions provided herein for topical administration are formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • the pharmaceutical compositions provided herein are formulated as a modified release dosage form.
  • modified release refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active
  • modified release examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
  • the pharmaceutical compositions provided herein in a modified release dosage form are fabricated using a matrix-controlled release device known to those skilled in the art (see, Takada et al in "Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999).
  • the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water- swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydro xypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB
  • polyvinyl alcohol polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT ® , Rohm America, Inc.,
  • Piscataway, NJ poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3- hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2- dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
  • the pharmaceutical compositions are formulated with a non- erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • Materials suitable for use as a non-erodible matrix device included, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene,
  • ethylene/propylene copolymers ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients in the compositions.
  • compositions provided herein in a modified release dosage form are prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression.
  • the pharmaceutical compositions provided herein in a modified release dosage form are fabricated using an osmotic controlled-release device, including one- chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled-release device including one- chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • such devices have at least two components: (a) the core which contains the active ingredient(s); and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water- swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels,” including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxy ethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
  • polyvinylpyrrolidone PVP
  • crosslinked PVP polyvinyl alcohol
  • PVA polyvinyl alcohol
  • PVA/PVP copolymers PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxy ethyl cellulose (HEC), hydro xypropyl cellulose (HPC), hydro xypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxy ethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
  • HEC hydroxy ethyl cellulose
  • HPC hydro xypropyl cellulose
  • HPMC hydro xypropyl methyl cellulose
  • CMC carboxymethyl cellulose
  • CEC carboxy ethyl, cellulose
  • the other class of osmotic agents are osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic
  • osmotic agents of different dissolution rates are employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core may also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylamino acetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, ⁇ glucan acetate, ⁇ glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxlated ethylene- vinylacetate, EC, PEG, PPG, PEG/PPG
  • copolymers thereof starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • Semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.
  • Such hydrophobic but water- vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane is formed post-coating by mechanical or laser drilling.
  • the delivery port(s) is formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In some embodiments, the delivery port(s) is formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • compositions in an osmotic controlled-release dosage form may further comprise additional conventional excipients as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to
  • the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients. See, U.S. Pat. No. 5,612,059 and WO 2002/17918.
  • the AMT controlled- release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other
  • the pharmaceutical compositions provided herein in a modified release dosage form are fabricated a multiparticulate controlled-release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ to about 3 mm, about 50 ⁇ to about 2.5 mm, or from about 100 ⁇ to about 1 mm in diameter.
  • a multiparticulate controlled-release device which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ to about 3 mm, about 50 ⁇ to about 2.5 mm, or from about 100 ⁇ to about 1 mm in diameter.
  • multiparticulates may be made by the processes know to those skilled in the art, including wet- and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.
  • excipients as described herein are blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates.
  • the resulting particles may themselves constitute the multiparticulate device or may be coated by various film-forming materials, such as enteric polymers, water- swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • the pharmaceutical compositions provided herein are formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems.
  • examples include, but are not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;
  • disclosed herein is a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • disclosed herein is a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of a compound Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • disclosed herein is a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of a compound Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (lib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • disclosed herein is a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of a compound Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • disclosed herein is a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of a compound Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of
  • the disclosed methods are useful in the prevention and treatment of solid tumors, soft tissue tumors, and metastases thereof.
  • solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary.
  • exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.
  • the disclosed methods are useful in the prevention and treatment of LKB 1 deficient tumors.
  • the cancer with LKB 1 deficient tumor is a gastrointestinal cancer.
  • the gastrointestinal cancer is colorectal cancer, small intestinal cancer, gastric cancer, or pancreatic cancer.
  • the cancer with LKB 1 deficient tumor is a gynecological cancer.
  • the gynecological cancer is breast cancer, ovarian cancer, SCTAT, cervical cancer, prostate cancer, or testicular cancer.
  • the cancer with LKB 1 deficient tumor is a lung cancer.
  • the lung cancer is non-small cell lung cancer-adenocarcinoma, non-small cell lung cancer-squamous cell, large cell lung cancer, or non-small cell lung cancer.
  • the cancer with LKB 1 deficient tumor is melanoma.
  • the cancer with LKB 1 deficient tumor is soft tissue cancer.
  • the cancer with LKB 1 deficient tumor is renal cancer.
  • the cancer with LKB 1 deficient tumor is brain cancer.
  • the disclosed methods are also useful in treating non-solid cancers.
  • the disclosed methods are also useful in treating cancers include, but are not limited to: Adrenocortical Carcinoma, AIDS-Related Cancers (Kaposi Sarcoma, AIDS-Related Lymphoma, Primary CNS Lymphoma), Anal Cancer, Appendix Cancer, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor, Central Nervous System, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumor
  • Intraocular Melanoma Retinoblastoma, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Ovarian Cancer, Testicular Cancer, Gestational Trophoblastic Disease, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kidney, Renal Cell, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myelogen
  • Macroglobulinemia Waldenstrom
  • Male Breast Cancer Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye), Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes,
  • Oropharyngeal Cancer Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Epithelial, Germ Cell Tumor, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Osteosarcoma (Bone Cancer),
  • Squamous Cell Carcinoma Squamous Neck Cancer with Occult Primary
  • Stomach (Gastric) Cancer Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Wilms Tumor. Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
  • the cancer is an IDHl mutant cancer.
  • the IDHl mutant cancer is a glioma, for example, a low grade glioma.
  • the IDHl mutant cancer is a sarcoma, for example, chondrosarcoma.
  • the IDHl mutant cancer is a carcinoma, for example, intrahepatic cholangiocarcinoma.
  • the IDHl mutant cancer is a leukemia, for example, Acute Myeloid Leukemia (AML).
  • the IDHl mutant cancer is a neoplasm, for example
  • the IDHl mutant cancer is associated with Maffucci syndrome. In some embodiments, the IDHl mutant cancer is associated with Oilier disease. In some embodiments, the IDHl mutant cancer is colon cancer, melanoma, lung cancer, or prostate cancer.
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered together with an additional cancer treatment.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment.
  • Exemplary cancer treatments include, for example, chemotherapy, targeted therapies such as antibody therapies, immunotherapy, and hormonal therapy. Examples of each of these treatments are provided below.
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered with chemotherapy.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment, wherein the additional cancer treatment is chemotherapy.
  • Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy.
  • Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.
  • chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, toposimerase inhibitors and others).
  • alkylating agents e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, toposimerase inhibitors and others.
  • alkylating agents e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, toposimerase inhibitors and others
  • Lonidamine Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane,
  • Mitomycin Mitoxantrone, Nedap latin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxalip latin, Paclitaxel, Pegaspargase, Pemetrexed, Pento statin, Pirarubicin, Pixantrone,
  • Rubitecan Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur- uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testo lactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin,
  • Triaziquone Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine,
  • Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein because some drugs work better together than alone, two or more drugs are often given at the same time.
  • two or more chemotherapy agents are used as combination chemotherapy.
  • a compound of (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered with a targeted therapy.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment, wherein the additional cancer treatment is a targeted therapy.
  • Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells.
  • Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
  • Prominent examples are the tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and also cyclin- dependent kinase inhibitors such as alvocidib and seliciclib.
  • the targeted therapy is a mutant BRAF inhibitor, such as vemurafenib or dabrafenib.
  • the targeted therapy is a BRAF inhibitor selected from dabrafenib, vemurafenib, encorafenib, TAK-580, LY3009120, BGB-283, HM955573, and PLX8394.
  • the targeted therapy is an mTOR inhibitor.
  • the second therapeutic agent is an mTOR inhibitor selected from everolimus, TAK-228, AZD2014, LY3023414, and gedatolisib.
  • the targeted therapy is a MEK inhibitor, such as tramatinib, cobimetinib, binimetinib, selumetinib.
  • the targeted therapy is a combination of a mutant BRAF inhibitor and a MEK inhibitor, such as a combination of dabrafenib/tramatinib or vemurafenib/cobimetinib.
  • the targeted therapy is a combination of a mutant BRAF inhibitor and a MEK inhibitor, wherein the BRAF inhibitor is selected from dabrafenib, vemurafenib, encorafenib, TAK-580, LY3009120, BGB-283, HM955573, and PLX8394.
  • the targeted therapy is an IDHl inhibitor (for example, AGI-5198, AG- 120 and AG-881), a Non-Small Cell Lung Cancer SOC agents, an androgen receptor antagonist (for example, bicalutamide, flutamide, nitulamide, apalutamide, enzalutamide, abiraterone acetate, ODM-201, or 4-((lR,2R)-2-Hydroxycyclohexyl)- 2(trifluoromethyl)benzonitrile (PF 998425)), or an estrogen receptor antagonist (for example, 7a,17P-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-l,3,5(10)-triene-3,17-diol (ICI 182,780), l,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-
  • Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
  • the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
  • Examples include the anti-HER2/neu antibody trastuzumab typically used in breast cancer, and the anti-CD20 antibody rituximab and tositumomab typically used in a variety of B-cell malignancies.
  • Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab,
  • fusion proteins include aflibercept and denileukin diftitox.
  • Targeted therapy can also involve small peptides as "homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell.
  • RGDs Radionuclides which are attached to these peptides
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered with an immunotherapy.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment, wherein the additional cancer treatment is immunotherapy.
  • a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the additional cancer treatment is immunotherapy.
  • a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered with an immunotherapy wherein the immunotherapy is selected from antibodies against PD1, PD1L, and CTLA4.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie),
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound
  • G-MDSCs granulocytic myeloid-derived suppressor cells
  • a method of modulating granulocytic myeloid-derived suppressor cells (G-MDSCs) in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment, wherein the additional cancer treatment is immunotherapy.
  • a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the additional cancer treatment is immunotherapy.
  • G-MDSCs granulocytic myeloid-derived suppressor cells
  • a method of modulating granulocytic myeloid-derived suppressor cells (G-MDSCs) in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment, wherein the additional cancer treatment is immunotherapy and the immunotherapy is selected from antibodies against PD1, PD1L, and CTLA4.
  • a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the additional cancer treatment is immunotherapy and the immunotherapy is selected from antibodies against PD
  • G-MDSCs granulocytic myeloid-derived suppressor cells
  • a method of modulating granulocytic myeloid-derived suppressor cells (G-MDSCs) in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment, wherein the additional cancer treatment is a PD1 antibody.
  • a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the additional cancer treatment is a PD1 antibody.
  • Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft-versus- tumor effect.
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered with a hormonal therapy.
  • a method of treating cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ma), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional cancer treatment, wherein the additional cancer treatment is hormonal therapy.
  • the cancer growth is inhibited by providing or blocking certain hormones.
  • hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ma), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered with 2-deoxy glucose, monocarboxylate transporters (for example, MCT1 or MCT4), or glucose transporters (for example GLUT4).
  • 2-deoxy glucose for example, MCT1 or MCT4
  • glucose transporters for example GLUT4
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ma), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • disclosed herein is a method of treating diabetes in a subject, comprising administering to a subject a therapeutically effective amount of a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • disclosed herein is a method of treating diabetes in a subject, comprising administering to a subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (Ila), or a
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (lib), or a
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (lie), or a
  • disclosed herein is a method of treating diabetes in a subject, comprising administering to a subject a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • disclosed herein is a method of treating diabetes in a subject, comprising administering to a subject a therapeutically effective amount of a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating diabetes in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • Methods disclose herein are used for the treatment and/or prevention of diabetes, including, for example, type 1 and type 2 diabetes, and related diseases.
  • the methods are used for treating prediabetes, and/or glucose intolerance.
  • the methods help with glycemic control, as monitored by, for example, average glucose and/or glycosylated hemoglobin levels.
  • the patient being treated may suffer from insulin resistance.
  • the present invention provides for treatments and uses in the prevention of diabetes onset in patients afflicted with, for example, insulin resistance, prediabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and acanthosis nigricans.
  • IGF impaired fasting glucose
  • ITT impaired glucose tolerance
  • acanthosis nigricans acanthosis nigricans.
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered together with an additional diabetes treatment.
  • exemplary diabetes treatments include:
  • Insulin and insulin derivatives are selected from insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin degludec, insulin aspart, basal insulin and analogues (e.g. LY2605541, LY2963016, NN1436), PEGylated insulin lispro (e.g. LY-275585), long-acting insulins, intermediate- acting insulins, and fast-acting and short-acting insulins. Also suitable are those insulin derivatives which are bonded to albumin or another protein by a bifunctional linker.
  • GLP-1 GLP-1
  • GLP-1 analogues GLP-1 receptor agonists
  • lixisenatide for example: lixisenatide, exenatide, liraglutide, semaglutide, taspoglutide, albiglutide, dulaglutide, ACP-003, CJC-1 134-PC, GSK-2374697, PB-1023, TTP-054, langlenatide (HM-1 1260C), CM- 3, GLP-1 Eligen, AB-201, ORMD-0901, NN9924, NN9926, NN9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, ZP-3022, CAM- 2036, DA-3091, DA-15864, ARI-2651, ARI- 2255, exenatide-XTEN (VRS-859), exenatide-XTEN + Glucagon- XTEN (VRS-859 + AM
  • Dual GLP-l/GIP agonists e.g. RG-7697 (MAR-701), MAR-709, BHM081, BHM089, BHM098).
  • Dual GLP-l/glucagon receptor agonists e.g. BHM-034, OAP-189 (PF-05212389, TKS- 1225), TT-401/402, ZP2929, LAPS- HMOXM25, MOD-6030).
  • Dual GLP-1 /gastrin agonists e.g. ZP-3022).
  • Glucagon receptor agonists or antagonists glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, ghrelin antagonists or inverse agonists, xenin and analogues thereof, dipeptidyl peptidase-IV (DPP-4) inhibitors, for example: alogliptin, linagliptin, saxagliptin, sitagliptin, anagliptin, teneligliptin, trelagliptin, vildagliptin, gemigliptin, omarigliptin, evogliptin, dutogliptin, DA- 1229, MK-3102, KM-223, KRP-104, PBL-1427, Pinoxacin hydrochloride, and Ari- 2243, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, for example: canagliflozin, dapagliflozin, remogliflo
  • LX-421 1, LIK066) biguanides (e.g. metformin, buformin), thiazolidinediones (e.g. pioglitazone, rosiglitazone), glitazone analogues (e.g. lobeglitazone), peroxisome proliferator-activated receptors (PPAR-)(alpha, gamma or alpha/gamma) agonists or modulators (e.g. saroglitazar), or PPAR gamma partial agonists (e.g. lnt-131).
  • biguanides e.g. metformin, buformin
  • thiazolidinediones e.g. pioglitazone, rosiglitazone
  • glitazone analogues e.g. lobeglitazone
  • PPAR- peroxisome proliferator-activated receptors
  • PPAR- peroxisome proliferator
  • Sulfonylureas e.g. tolbutamide, glibenclamide, glimepiride, glipizide
  • meglitinides e.g. nateglinide, repaglinide, mitiglinide
  • alpha-glucosidase inhibitors e.g.
  • GPR1 19 G-protein coupled receptor 1 19 agonists
  • GSK-1292263 PSN-821, MBX-2982, APD-597, ARRY-981, ZYG-19, DS-8500, HM-47000, YH-Cheml
  • GPR40 agonists e.g.
  • Diabetes immunotherapeutics for example: oral C-C chemokine receptor type 2 (CCR- 2) antagonists (e.g. CCX-140, JNJ-41443532), interleukin 1 beta (IL-1 .beta.) antagonists (e.g. AC-201), or oral monoclonal antibodies (MoA) (e.g. methalozamide, WP808, PAZ-320, P-1736, PF-05175157, PF-04937319).
  • CCR- 2 C-C chemokine receptor type 2
  • IL-1 .beta. interleukin 1 beta
  • MoA oral monoclonal antibodies
  • Ant i- inflammatory agents for the treatment of the metabolic syndrome and diabetes for example: nuclear factor kappa B inhibitors.
  • Adenosine monophosphate-activated protein kinase (AMPK) stimulants for example: Imeglimin (PXL-008), Debio-0930 (MT-63-78), R-l 18.
  • Inhibitors of 1 1 -beta-hydroxysteroid dehydrogenase 1 (11 -beta-HSD-1) e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585).
  • glucokinase e.g. PF-04991532, TTP-399 (GK1 -399), GKM-001 (ADV- 1002401), ARRY-403 (AMG-151), TAK-329, TMG-123, ZYGK1.
  • Inhibitors of diacylglycerol O-acyltransferase (e.g. pradigastat (LCQ-908)), inhibitors of protein tyrosine phosphatase 1 (e.g. trodusquemine), inhibitors of glucose- 6- phosphatase, inhibitors of fructose- 1 ,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrogenase kinase.
  • DGAT diacylglycerol O-acyltransferase
  • LCQ-908 pradigastat
  • protein tyrosine phosphatase 1 e.g. trodusquemine
  • inhibitors of glucose- 6- phosphatase inhibitors of fructose- 1 ,6-bisphosphatase
  • Modulators of glucose transporter-4, somatostatin receptor 3 agonists e.g. MK-4256.
  • One or more lipid lowering agents for example: 3-hydroxy-3-methylglutaryl- coenzym-A-reductase (HMG-CoA-reductase) inhibitors such as simvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, pravastatin, lovastatin, mevastatin, rivastatin, cerivastatin, fibrates such as bezafibrate, ciprofibrate, fenofibrate, gemfibrozil, etofibrate, simfibrate, ronifibrate, clinofibrate, clofibride, nicotinic acid and derivatives thereof (e.g.
  • HMG-CoA-reductase) inhibitors such as simvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, pravastatin, lovastatin, meva
  • niacin including slow release formulations of niacin
  • nicotinic acid receptor 1 agonists e.g. GSK-256073
  • cholesterol absorption inhibitors e.g. ezetimibe, S-556971
  • bile acid-binding substances e.g. cholestyramine, colesevelam
  • IBAT ileal bile acid transport
  • GSK-2330672 ileal bile acid transport
  • MTP microsomal triglyceride transfer protein
  • lomitapide AEGR- 733
  • SLx-4090 granotapide
  • modulators of proprotein convertase subtilisin/kexin type 9 PCSK9
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • alirocumab REGN727/SAR236553
  • AMG-145 LGT-209
  • PF-04950615 MPS K3169 A
  • LY3015014 ALD-306
  • ALN-PCS BMS-962476
  • SPC5001 ISIS-394814
  • 1 B20 LGT-210
  • LDL receptor up- regulators for example liver selective thyroid hormone receptor beta agonists (e.g. eprotirome (KB-21 15), MB0781 1, sobetirome (QRX-431), VIA-3196, ZYT1), HDL-raising compounds such as:
  • CETP cholesteryl ester transfer protein
  • MK0859 cholesteryl ester transfer protein
  • dalcetrapib dalcetrapib
  • evacetrapib JTT-302, DRL- 17822, TA-8995, R- 1658, LY-2484595, DS-1442
  • dual CETP/PCSK9 inhibitors e.g. K-312
  • ATP-binding cassette (ABC1) regulators e.g. BMS-823778, TAP-301, DRL-21994, DRL-21995)
  • PDA2 phospholipase A2
  • darapladib, varespladib, rilapladib), ApoA-1 enhancers e.g. RVX- 208, CER-001, MDCO-216, CSL-1 12
  • cholesterol synthesis inhibitors e.g. ETC- 1002
  • lipid metabolism modulators e.g. BMS-823778, TAP-301, DRL-21994, DRL-21995
  • omega-3 fatty acids and derivatives thereof e.g. icosapent ethyl (AMR101), AKR-063, NKPL-66, PRC- 4016, CAT-2003.
  • Treatment of obesity such as Bromocriptine, phentermine and phentermine formulations or combinations (e.g. Adipex-P, lonamin), benzphetamine, diethylpropion, phendimetrazin, bupropion and combinations, sibutramine, topiramat, zonisamid, tesofensine, opioid antagonists such as naltrexone, cannabinoid receptor 1 (CB 1) antagonists (e.g. TM- 38837), melanin- concentrating hormone (MCH-1) antagonists (e.g. BMS-830216, ALB- 127158(a)), MC4 receptor agonists and partial agonists (e.g.
  • AZD-2820, RM-493 neuropeptide Y5 (NPY5) or NPY2 antagonists (e.g. velneperit, S-234462), NPY4 agonists (e.g. PP-1420), beta-3-adrenergic receptor agonists, leptin or leptin mimetics, agonists of the 5- hydroxytryptamine 2c (5HT2c) receptor (e.g. lorcaserin), pramlintide/metreleptin, lipase inhibitors such as cetilistat, orlistat, angiogenesis inhibitors (e.g. ALS-L1023), betahistidin and histamine H3 antagonists (e.g.
  • HPP-404 AgRP (agouti related protein) inhibitors (e.g. TTP- 435), serotonin re-uptake inhibitors such as fluoxetine, duloxetine, dual or triple monoamine uptake inhibitors (dopamine, norepinephrine and serotonin re-uptake) such as sertraline, tesofensine, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g. beloranib), and antisense oligonucleotides against production of fibroblast growth factor receptor 4 (FGFR4) (e.g. ISIS- FGFR4Rx) or prohibitin targeting peptide- 1.
  • FGFR4 fibroblast growth factor receptor 4
  • Drugs for influencing high blood pressure, chronic heart failure or atherosclerosis for example: nitric oxide donors, ATI antagonists or angiotensin II (AT2) receptor antagonists such as telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan, dual angiotensin receptor blockers (dual ARBs), angiotensin converting enzyme (ACE) inhibitors, ACE-2 activators, renin inhibitors, prorenin inhibitors, endothelin converting enzyme (ECE) inhibitors, endothelin receptor (ET1/ETA) blockers, endothelin antagonists, diuretics, aldosterone antagonists, aldosterone synthase inhibitors, alpha- blockers, antagonists of the alpha-2 adrenergic receptor, beta-blockers, mixed alpha-/beta-block
  • mineralocorticoid/CCBs centrally acting antihypertensives, inhibitors of neutral endopeptidase, aminopeptidase-A inhibitors, vasopeptide inhibitors, dual vasopeptide inhibitors such as neprilysin-ACE inhibitors or neprilysin-ECE inhibitors, dual-acting AT receptor-neprilysin inhibitors, dual ATI/ETA antagonists, advanced glycation end- product (AGE) breakers, recombinant renalase, blood pressure vaccines such as anti- RAAS (renin-angiotensin- aldosteron- system) vaccines, ATI- or AT2-vaccines, drugs based on hypertension
  • RAAS renin-angiotensin- aldosteron- system
  • AT2-vaccines drugs based on hypertension
  • PCOS Polycystic ovarian syndrome
  • PCOS polycystic ovarian syndrome
  • PCOS polycystic ovarian syndrome
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (lib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (Illb), or a
  • PCOS polycystic ovarian syndrome
  • a method of treating polycystic ovarian syndrome (PCOS) in a subject comprising administering to a subject a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered together with an additional polycystic ovarian syndrome (PCOS) treatment.
  • PCOS polycystic ovarian syndrome
  • exemplary treatments include: metformin and oral contraceptive.
  • a method of increasing the bioavailability of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) in a subject comprising administering to a subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (I) in a subject comprising
  • a method of increasing the bioavailability of a compound of Formula (la) in a subject comprising administering to a subject a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (lb) in a subject comprising administering to a subject a compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (II) in a subject comprising administering to a subject a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (Ila) in a subject comprising administering to a subject a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (lib) in a subject comprising administering to a subject a compound of Formula (lib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (lie) in a subject comprising administering to a subject a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (III) in a subject comprising administering to a subject a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (Ilia) in a subject comprising administering to a subject a compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (Illb) in a subject comprising administering to a subject a compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of increasing the bioavailability of a compound of Formula (IV) in a subject comprising administering to a subject a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of decreasing the metabolism of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) in a subject comprising administering to a subject compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Mb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • provided herein is a method of decreasing the metabolism of a compound of Formula (I) in a subject comprising administering to a subject compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of decreasing the metabolism of a compound of Formula (la) in a subject comprising administering to a subject compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • provided herein is a method of decreasing the metabolism of a compound of Formula (lb) in a subject comprising administering to a subject compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of decreasing the metabolism of a compound of Formula (II) in a subject comprising administering to a subject compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • provided herein is a method of decreasing the metabolism of a compound of Formula (Ila) in a subject comprising administering to a subject compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or
  • provided herein is a method of decreasing the metabolism of a compound of Formula (lib) in a subject comprising administering to a subject compound of Formula (lib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of decreasing the metabolism of a compound of Formula (lie) in a subject comprising administering to a subject compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • provided herein is a method of decreasing the metabolism of a compound of Formula (III) in a subject comprising administering to a subject compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of decreasing the metabolism of a compound of Formula (Ilia) in a subject comprising administering to a subject compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • provided herein is a method of decreasing the metabolism of a compound of Formula (Illb) in a subject comprising administering to a subject compound of Formula (Illb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • a method of decreasing the metabolism of a compound of Formula (IV) in a subject comprising administering to a subject compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a cytochrome P450 inhibitor.
  • the cytochrome P450 inhibitor is a cytochrome P450 2D6 inhibitor. In some embodiments, the cytochrome P450 2D6 inhibitor is selected from
  • chlorpromazine cimetidine, cinacalcet, citalopram, clemastine, clomipramine,
  • the cytochrome P450 2D6 inhibitor is quinidine.
  • a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion,
  • subcutaneous injection, or implant inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration, and may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the dose is in the form of one, two, three, four, five, six, or more sub-doses that are administered at appropriate intervals per day.
  • the dose or sub-doses can be administered in the form of dosage units containing from about 0.1 to about 1000 milligram, from about 0.1 to about 500 milligrams, or from 0.5 about to about 100 milligram active ingredient(s) per dosage unit, and if the condition of the patient requires, the dose can, by way of alternative, be administered as a continuous infusion.
  • an appropriate dosage level is about 0.01 to about 100 mg per kg patient body weight per day (mg/kg per day), about 0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, or about 0.05 to about 10 mg/kg per day, which is administered in a single or multiple doses.
  • a suitable dosage level is about 0.01 to about 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about 0.1 to about 10 mg/kg per day.
  • a suitable dosage level within this range is about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per day.
  • kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers can be formed from a variety of materials such as glass or plastic.
  • the container(s) can comprise one or more compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), optionally in a composition or in combination with another agent as disclosed herein.
  • the container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit will typically comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
  • materials such as reagents, optionally in concentrated form, and/or devices
  • Non- limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
  • a set of instructions will also typically be included.
  • a label can be on or associated with the container.
  • a label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label can be used to indicate that the contents are to be used for a specific therapeutic application.
  • the label can also indicate directions for use of the contents, such as in the methods described herein.
  • These other therapeutic agents may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • PDR Physicians' Desk Reference
  • test compounds For test compounds and Cisplatin, prepare lOx serial working solutions with test compound medium.
  • IC50 In order to calculate IC50s, a dose-response curve was fitted using a nonlinear regression model with a sigmoidal dose response. Absolute IC50 were calculated where Y axis set at 50% using XLFit curve fitting software and are shown in Table 1. Table 1 : Tumor Cell Growth Inhibition
  • Working Solution Dilute 50 from intermediate solution (10 mM) with 450 ⁇ 100 nM potassium phosphate buffer (Cone: 10 ⁇ , 4.5% MeOH)
  • Cold CAN including 100 ng/mL tolbutamide and 100 ng/mL labetalol as internal standard.
  • Procedure 1 Add 10 ⁇ -h compound or control working solution/well to all plates (TO, T5, T10, T20,
  • T30, T60, NCF60 except matrix blank.
  • start timer 1 (Time Point: NCF60 - start time 1:00:00 am, end time 12:00:00 am)
  • start timer 2 (Blank - start time 1:00:00 am, end time 12:00:00 am;
  • COL0829 tumor cells were maintained in vitro as a monolayer culture in medium supplemented with 10% fetal bovine serum, at 37°C in an atmosphere of 5% C0 2 in air. The tumor cells were routinely sub-cultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • Animals Balb/C nude, female, 6-8 weeks, weighing approximately 18-22 g. A total of 52 (including 30% extra) animals were needed for the study and were purchased from Shanghai BK Laboratory Animal Co., LTD. or other certified vendors.
  • Tumor Inoculation Animals were inoculated subcutaneously at the right flank with COL0829 tumor cells (5 x 10 6 ) in PBS mixed with Matrigel (50:50) for tumor development.
  • Treatments were started when the average tumor volume reaches average -100 mm (tumor spread: -70-150 mm ). Efficacy Groups and Treatments
  • T-C was calculated with T as the median time (in days) required for the treatment group tumors to reach a predetermined size (e.g., 1000 mm ), and C as the median time (in days) for the control group tumors to reach the same size.
  • the T/C value (in percent) is an indication of antitumor effectiveness
  • T and C are the mean volume of the treated and control groups, respectively, on a given day.
  • A549 tumor cells were maintained in vitro as a monolayer culture in medium supplemented with 10% fetal bovine serum, at 37°C in an atmosphere of 5% C0 2 in air. The tumor cells were routinely sub-cultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • Animals Balb/C nude, female, 6-8 weeks, weighing approximately 18-22 g. A total of 105 (including 30% extra) animals were needed for the study and were purchased from
  • Tumor Inoculation Animals were inoculated subcutaneously at the right flank with A549 tumor cells (5 x 10 6 ) in 100 PBS for tumor development. Treatments were started when the average tumor volume reaches average -100 mm 3 (tumor spread: -70-150 mm 3 ). Efficacy Groups and Treatments
  • T-C was calculated with T as the median time (in days) required for the treatment group tumors to reach a predetermined size (e.g., 1000 mm ), and C as the median time (in days) for the control group tumors to reach the same size.
  • the T/C value (in percent) is an indication of antitumor effectiveness
  • T and C are the mean volume of the treated and control groups, respectively, on a given day.
  • Example 9 Evaluation of Clinical Safety of Combining a Compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) with Anticancer Chemotherapy (Phase 1)
  • the primary endpoint of the study will be to determine whether a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV) can be safely added to a chemotherapy regimen that is previously well tolerated. The rate of dose limiting toxicities will be compared.
  • Secondary endpoints will include assessment of AEs > grade 3 and Serious Adverse Events (SAEs), assessment of safety beyond the first cycle with a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV), and an exploration of compound of Formula (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), or (IV)-chemotherapy drug interactions.
  • SAEs Serious Adverse Events
  • Adequate hepatic parameters including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ⁇ 2.5 x upper limit of normal (ULN), total bilirubin ⁇ 1.5 x ULN, and alkaline phosphatase levels ⁇ 2.5 x ULN;
  • metformin (within 1 week of start of chemotherapy regimen to be assessed);
  • lactic acidosis such as shock or pulmonary insufficiency, alcoholism (acute or chronic), conditions associated with hypoxemia and pancreatitis;

Abstract

La présente invention concerne des composés de diamide imidodicarbonimidique, et leurs sels, solvates ou stéréoisomères pharmaceutiquement acceptables. L'invention concerne également des compositions et l'utilisation de telles compositions dans un procédé de traitement du cancer, du diabète ou du syndrome des ovaires polykystiques.
PCT/US2017/035720 2016-06-03 2017-06-02 Analogues de diamide imidodicarbonimidique WO2017210580A1 (fr)

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WO2023209611A1 (fr) * 2022-04-26 2023-11-02 Beigene Switzerland Gmbh Méthodes de traitement du cancer avec un inhibiteur du b-raf, en particulier le lifirafenib

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WO2023209611A1 (fr) * 2022-04-26 2023-11-02 Beigene Switzerland Gmbh Méthodes de traitement du cancer avec un inhibiteur du b-raf, en particulier le lifirafenib

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