US20140206649A1 - Cannabinoid receptor modulators - Google Patents

Cannabinoid receptor modulators Download PDF

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US20140206649A1
US20140206649A1 US14/001,131 US201214001131A US2014206649A1 US 20140206649 A1 US20140206649 A1 US 20140206649A1 US 201214001131 A US201214001131 A US 201214001131A US 2014206649 A1 US2014206649 A1 US 2014206649A1
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Prior art keywords
pyridin
alkyl
compound
aryl
tetrahydro
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Inventor
Jayant Thatte
Anthony C. Blackburn
Sangdon Han
Robert M. Jones
Jae-Kyu Jung
Anthony Garrido Montalban
Biman B. Pal
Jaimie Karyn Rueter
Sonja Strah-Pleynet
Lars Thoresen
Yifeng Xiong
Dawei Yue
Xiuwen Zhu
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Arena Pharmaceuticals Inc
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Arena Pharmaceuticals Inc
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Priority to US14/001,131 priority Critical patent/US20140206649A1/en
Publication of US20140206649A1 publication Critical patent/US20140206649A1/en
Assigned to ARENA PHARMACEUTICALS, INC. reassignment ARENA PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STRAH-PLEYNET, SONJA, JUNG, JAE-KYU, THORESEN, LARS, MONTALBAN, ANTONIO GARRIDO, HAN, SANGDON, PAL, Biman B., XIONG, YIFENG, YUE, DAWEI, JONES, ROBERT M., BLACKBURN, ANTHONY C., RUETER, JAMIE KARYN, ZHU, XIUWEN, THATTE, JAYANT
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    • 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
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Definitions

  • Cannabinoids are a group of extracellular signaling molecules that are found in both plants and animals. Signals from these molecules are mediated in animals by two G-protein coupled receptors, Cannabinoid Receptor 1 (CB 1 ) and Cannabinoid Receptor 2 (CB 2 ).
  • CB 1 is expressed most abundantly in the neurons of the CNS but is also present at lower concentrations in a variety of peripheral tissues and cells (Matsuda, L. A. et al. (1990) Nature 346:561-564).
  • CB 2 is expressed predominantly, although not exclusively, in non-neural tissues, e.g.
  • CB 1 is believed to be primarily responsible for mediating the psychotropic effects of cannabinoids on the body, whereas CB 2 is believed to be primarily responsible for most of their non-neural effects.
  • composition comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof:
  • R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:
  • composition comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof, one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents, and a pharmaceutically acceptable carrier.
  • Also provided is a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof, and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • Also provided is a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof, one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents, and a pharmaceutically acceptable carrier.
  • composition obtained by any of the methods described herein.
  • a compound of Formula Ia for use in a method for the treatment of pain in an individual in need thereof, comprising administering to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a compound of Formula Ia for use in a method for the treatment of pain in an individual in need thereof, comprising prescribing to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a compound of Formula Ia for use in a method for the management of pain in an individual in need thereof, comprising administering to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a compound of Formula Ia for use in a method for the management of pain in an individual in need thereof, comprising prescribing to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof, and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents; for treating pain in an individual.
  • a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof, and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents; for managing pain in an individual.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof, and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents in the manufacture of a medicament for treating pain in an individual.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof, and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents in the manufacture of a medicament for managing pain in an individual.
  • FIG. 1 shows the effect of Compound 493 in the FCA-induced hyperalgesia model of inflammatory pain in rats at 1 h post dosing. See Example 7.
  • FIG. 2 shows the effect of Compound 493 in the monosodium iodoacetate (MIA) model of osteoarthritis in rats at 1 h post dosing. See Example 5.
  • FIG. 3 shows the effect of 10 mg/kg of Compound 493 on paclitaxel-induced allodynia in rats. See Example 8.
  • FIG. 4 shows the effect of Compound 493 on the skin incision model of postoperative pain in rats. See Example 6.
  • FIG. 5 shows a general synthesis of compounds described herein wherein X is CC(O)N(R 8 )R 9 and Y is NR 7 .
  • a 2-(but-3-enyl)oxirane derivative is cyclized by treatment with a base.
  • the resulting bicyclic alcohol is oxidized to the ketone and reacted with a dialkyl oxalate derivative in the presence of a base.
  • the pyrazole ring is then formed by reaction with a substituted hydrazine and the resulting ester is hydrolyzed and coupled with an amine to form compounds described herein.
  • FIG. 6 shows a general synthesis of compounds described herein in which R 7 is a 4-oxy-pyrazin-2-yl group.
  • FIG. 7 shows a general synthesis of compounds described herein similar to the one shown in FIG. 5 except the group R 7 is introduced subsequent to the formation of a tri-substituted pyrazole.
  • FIG. 8 shows a general synthesis of compounds described herein in which R 7 is either a 5-substituted-pyridin-2-yl group or a 5-substituted-pyrazin-2-yl group.
  • FIG. 9 shows a general synthesis of compounds described herein in which R 7 is a 4-substituted-pyridin-2-yl group.
  • FIG. 10 shows a general synthesis of compounds described herein wherein X is NR 7 and Y is CC(O)N(R 8 )R 9 .
  • a bicyclo[3.1.0]hexan-3-ol derivative is oxidized and the resulting ketone is reacted with a dialkyl oxalate derivative in the presence of a base.
  • the pyrazole ring is then formed by reaction with a substituted hydrazine and the resulting ester is hydrolyzed and coupled with an amine to form compounds described herein.
  • FIG. 11 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 699 CH 2 Cl 2 solvate and a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 699 CH 2 Cl 2 solvate.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 12 shows an overlay of a powder X-ray diffraction pattern (PXRD) for a sample containing a crystalline form of Compound 699 CH 2 Cl 2 solvate obtained from recrystallization using CH 2 Cl 2 /hexane (Top Trace) and a powder X-ray diffraction pattern (PXRD) for a sample containing a crystalline form of Compound 699 CH 2 Cl 2 solvate obtained by slurrying non-solvated Compound 699 in CH 2 Cl 2 (Bottom Trace).
  • the PXRD showed the crystalline solvate obtained from the CH 2 Cl 2 slurry is substantially indistinguishable from the crystalline solvate resulting from recrystallized from CH 2 Cl 2 /hexane.
  • FIG. 13 shows the effect of Compound 699 (10 mpk) compared to vehicle (methyl cellulose) in the STZ-induced PDPN Model. See Example 12.
  • FIG. 14 shows the effect of Compound 919 (10 mpk) compared to vehicle (methyl cellulose) in the STZ-induced PDPN Model. See Example 12.
  • FIG. 15 shows the effect of Compound 699 (1 mpk) and morphine (1 mpk) in relieving osteoarthritis pain. See Example 13.
  • FIG. 16 shows a powder X-ray diffraction pattern (PXRD) for a sample containing an anhydrous crystalline form of Compound 699.
  • FIG. 17 shows a differential scanning calorimetry (DSC) thermogram for a sample containing an anhydrous crystalline form of Compound 699 and a thermogravimetric analysis (TGA) thermogram of a sample containing an anhydrous crystalline form of Compound 699.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 18 shows an adsorption and desorption isotherm, Dyanmic Moisture Sorption (DMS), for a sample containing anhydrous crystalline form of Compound 699.
  • DMS Dyanmic Moisture Sorption
  • acute pain is intended to mean pain from a specific cause (such as injury, infection, inflammation, etc.) that has lasted for a limited period of time (as opposed to chronic pain).
  • chronic pain is intended to mean pain that persists or recurs for greater than about 3 months and/or persists for greater than 1 month after resolution of an acute tissue injury, or accompanies a nonhealing lesion.
  • causes include chronic disorders (eg, cancer, arthritis, diabetes) and injuries (eg, herniated disk, torn ligament), and many primary pain disorders (eg, neuropathic pain, fibromyalgia, chronic headache).
  • inflammatory pain is intended to describe the subset of acute and chronic pain that results from inflammatory processes, such as may arise in the case of infections, arthritis and neoplasia or tumor related hypertrophy. Tumor or cancer associated pain is, therefore, considered to fall within the category of inflammatory pain.
  • conditions associated with inflammatory pain include rheumatoid arthritis, osteo-arthritis, psoriatic arthropathy, arthritis associated with other inflammatory and autoimmune conditions, degenerative conditions such as back strain and mechanical back pain or disc disease, post operative pain, pain from an injury such as a soft tissue bruise or strained ligament or broken bone, abscess or cellulitis, fibrositis or myositis.
  • analgesic agent is intended to mean any biomolecule, drug or active agent that alleviates or prevents pain.
  • co-analgesic agent is intended to mean a drug that typically addresses indications other than pain relief, but possesses analgesic action for certain painful conditions.
  • agonist is intended to mean a moiety that interacts with and activates a G-protein-coupled receptor, for instance a cannabinoid receptor, and can thereby initiate a physiological or pharmacological response characteristic of that receptor.
  • a G-protein-coupled receptor for instance a cannabinoid receptor
  • an agonist may activate an intracellular response upon binding to a receptor, or enhance GTP binding to a membrane.
  • antagonist is intended to mean a moiety that competitively binds to the receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist.
  • An antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • hydrate as used herein means a compound described herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvate means a compound described herein or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • the solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • in need of treatment and the term “in need thereof” when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds described herein. Accordingly, the compounds described herein can be used in a protective or preventive manner; or compounds described herein can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • a caregiver e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals
  • mice are intended to mean any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and in some embodiments, humans.
  • inverse agonist is intended to mean a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist, or decreases GTP binding to a membrane.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, such as by at least 50% and for example, by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
  • modulate or modulating is intended to mean an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
  • composition is intended to mean a composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds described herein, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
  • terapéuticaally effective amount is intended to mean the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver or by an individual, which includes one or more of the following:
  • Preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomotology of the disease;
  • Inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomotology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomotology); and
  • Ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomotology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomotology).
  • C 1 -C 4 acyl is intended to mean a radical comprising a C 1 -C 4 alkyl group attached to the carbon of a carbonyl group, wherein C 1 -C 4 alkyl has the same definition as found herein. Examples include, but are not limited to acetyl, propionyl, butyryl, isobutyryl, pivaloyl, and the like.
  • amino is intended to mean the group —NH 2 .
  • aryl is intended to mean a ring system containing 6 to 10 carbon atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic. Examples include phenyl, indanyl, and naphthyl.
  • arylamino is intended to mean a radical comprising an aryl group, attached to a nitrogen, wherein aryl has the same definition as found herein. Examples include, but are not limited to, phenylamino and naphthylamino.
  • arylcarbonyl is intended to mean a radical comprising an aryl group, attached to the carbon atom of a carbonyl group, wherein aryl has the same definition as found herein. Examples include, but are not limited to, benzoyl and naphthylcarbonyl.
  • aryloxy is intended to mean a radical comprising an aryl group, attached to an oxygen, wherein aryl has the same definition as found herein. Examples include, but are not limited to, phenoxy and naphthyloxy.
  • C 1 -C 6 alkoxy is intended to mean a radical comprising a C 1 -C 6 alkyl group attached directly to an oxygen atom, wherein C 1 -C 6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons. Examples include, but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, s-butoxy, and the like.
  • C 1 -C 6 alkoxycarbonyl is intended to mean a radical comprising a single C 1 -C 6 alkoxy group attached to the carbon of a carbonyl group, wherein C 1 -C 6 alkoxy has the same definition as found herein.
  • the alkoxycarbonyl group may be represented by the following:
  • C 1 -C 6 alkyl is intended to mean a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons.
  • alkyl group examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, neopentyl, 1-methylbutyl [i.e., —CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutyl [i.e., —CH 2 CH(CH 3 )CH 2 CH 3 ], n-hexyl, and the like.
  • C 1 -C 4 alkyl is intended to mean a straight or branched carbon radical containing 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons. Examples of an alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, and the like.
  • C 1 -C 6 alkylamino is intended to mean a radical comprising one C 1 -C 6 alkyl group attached to an NH group, wherein C 1 -C 6 alkyl has the same meaning as described herein. Some examples include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, s-butylamino, isobutylamino, t-butylamino, and the like. Some embodiments are “C 1 -C 2 alkylamino.”
  • C 1 -C 6 alkylcarboxamide is intended to mean a single C 1 -C 6 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein C 1 -C 6 alkyl has the same definition as found herein.
  • the C 1 -C 6 alkylcarboxamido group may be represented by the following:
  • Examples include, but are not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n-propylcarboxamide, N-isopropylcarboxamide, N-n-butylcarboxamide, N-s-butylcarboxamide, N-isobutylcarboxamide, N-t-butylcarboxamide, and the like.
  • C 1 -C 6 alkylene is intended to mean a straight or branched, saturated aliphatic, divalent radical having 1 to 6 carbon atoms. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons.
  • Examples include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, s-butylene, isobutylene, t-butylene, pentylene, isopentylene, t-pentylene, neopentylene, 1-methylbutylene [i.e., —CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutylene [i.e., —CH 2 CH(CH 3 )CH 2 CH 3 ], n-hexylene, and the like.
  • C 1 -C 6 alkylsulfonyl is intended to mean a radical comprising a C 1 -C 6 alkyl group attached to the sulfur of a sulfonyl group, wherein the C 1 -C 6 alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, s-butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl, and the like.
  • C 5 -C 11 bicycloalkyl is intended to mean a radical comprising two fused or bridged, saturated rings containing 5 to 11 ring carbon atoms.
  • Examples of a bicycloalkyl group include, but are not limited to, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, and the like.
  • C 3 -C 7 cycloalkenylene is intended to mean is intended to mean a mono unsaturated ring di-radical containing 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropenediyl, cyclobutenediyl, cyclopentenediyl, cyclohexenediyl, cycloheptenediyl, and the like.
  • C 3 -C 7 cycloalkyl is intended to mean a saturated ring radical containing 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • C 3 -C 7 cycloalkylamino is intended to mean a radical comprising a C 3 -C 7 cycloalkyl attached the nitrogen of an amino group, wherein C 3 -C 7 cycloalkyl has the same definition as found herein. Examples include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like.
  • C 3 -C 7 cycloalkylene is intended to mean a saturated ring di-radical containing 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, and the like.
  • C 3 -C 7 cycloalkylene is selected from: 1,1-cyclopropanediyl, 1,1-cyclobutanediyl, 1,1-cyclopentanediyl, 1,1-cyclohexanediyl, 1,1-cycloheptanediyl, and the like.
  • C 3 -C 7 cycloalkylene is selected from: 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, 1,2-cyclopentanediyl, 1,2-cyclohexanediyl, 1,2-cycloheptanediyl, and the like.
  • carbo-C 1 -C 6 -alkoxy is intended to mean a C 1 -C 6 alkyl ester of a carboxylic acid, wherein C 1 -C 6 alkyl has the same definition as found herein. Examples include, but are not limited to, carbomethoxy [—C(O)OCH 3 ], carboethoxy, carbo-n-propoxy, carboisopropoxy, carbo-n-butoxy, carbo-s-butoxy, carbo-isobutoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-isopentoxy, carbo-t-pentoxy, carbo-neopentoxy, carbo-n-hexyloxy, and the like.
  • carboxylic acid group is intended to mean the group —CONH 2 .
  • carboxy is intended to mean the group —CO 2 H; also referred to as a carboxylic acid group.
  • cyano is intended to mean the group —CN.
  • C 2 -C 8 dialkylamino is intended to mean a radical comprising an amino group substituted with two of the same or different C 1 -C 4 alkyl groups, wherein C 1 -C 4 alkyl has the same definition as found herein.
  • Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino, and the like.
  • Some embodiments are C 2 -C 4 dialkylamino.
  • C 2 -C 8 dialkylsulfonamide is intended to mean is intended to mean one of the following groups shown below:
  • C 1 -C 4 alkyl has the same definition as found herein.
  • C 1 -C 6 haloalkoxy is intended to mean a radical comprising a C 1 -C 6 haloalkyl group directly attached to an oxygen atom, wherein C 1 -C 6 haloalkyl has the same definition as found herein. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.
  • C 1 -C 6 haloalkyl is intended to mean a radical comprising a C 1 -C 6 alkyl group substituted with one or more halogens, wherein C 1 -C 6 alkyl has the same definition as found herein.
  • the C 1 -C 6 haloalkyl may be fully substituted in which case it can be represented by the formula C n L 2n+1 , wherein L is a halogen and “n” is 1, 2, 3, 4, 5 or 6. When more than one halogen is present then they may be the same or different and selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons.
  • haloalkyl contains 1 to 4 carbons. In some embodiments, haloalkyl contains 1 to 3 carbons. In some embodiments, haloalkyl contains 1 or 2 carbons. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
  • halogen is intended to mean to a fluoro, chloro, bromo or iodo group.
  • heteroaryl is intended to mean a ring system containing 5 to 14 ring atoms, that may contain a single ring, two fused rings or three fused rings, and wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from, for example: O, S and N, wherein N is optionally substituted with H, C 1 -C 4 acyl, C 1 -C 4 alkyl, or oxide (i.e., together with an aromatic ring nitrogen form an N-oxide).
  • Some embodiments contain 5 to 6 ring atoms for example furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
  • Some embodiments contain 8 to 14 ring atoms for example quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl.
  • heteroarylene is intended to mean is intended to mean an aromatic ring di-radical containing 5 to 14 ring atoms that may be a single ring, two fused rings or three fused rings, wherein at least one aromatic ring atom is a heteroatom selected from, for example: O, S, and N, wherein N is optionally substituted with H, C 1 -C 4 acyl, C 1 -C 4 alkyl, or oxide (i.e., together with an aromatic ring nitrogen form an N-oxide).
  • Some embodiments contain 5 to 6 ring atoms for example furandiyl, thiophenediyl, pyrrolediyl, imidazolediyl, oxazolediyl, thiazolediyl, isoxazolediyl, pyrazolediyl, isothiazolediyl, oxadiazolediyl, triazolediyl, thiadiazolediyl, pyridinediyl, pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, and the like.
  • Some embodiments contain 8 to 14 ring atoms for example quinolizinediyl, quinolinediyl, isoquinolinediyl, cinnolinediyl, phthalazinediyl, quinazolinediyl, quinoxalinediyl, triazinediyl, indolediyl, isoindolediyl, indazolediyl, indolizinediyl, purinediyl, naphthyridinediyl, pteridinediyl, carbazolediyl, acridinediyl.
  • quinolizinediyl for example quinolizinediyl, quinolinediyl, isoquinolinediyl, cinnolinediyl, phthalazinediyl, quinazolinediyl, quinoxalinediyl, triazinediyl,
  • phenazinediyl phenothiazinediyl, phenoxazinediyl, benzoxazolediyl, benzothiazolediyl, 1H-benzimidazolediyl, imidazopyridinediyl, benzothienediyl, benzofurandiyl, isobenzofurandiyl, and the like.
  • heteroaryloxy is intended to mean a radical comprising a heteroaryl group, attached to an oxygen, wherein heteroaryl has the same definition as found herein.
  • heterocyclyl is intended to mean a radical comprising two fused or bridged, non-aromatic rings containing 5 to 11 ring atoms wherein one, two, three or four ring atoms are heteroatoms selected from, for example: O, S, and N, wherein N is substituted with H, C 1 -C 4 acyl or C 1 -C 4 alkyl, and S is optionally substituted with one or two oxygens.
  • heterobicyclyl group examples include, but are not limited to, octahydropyrrolo[1,2-a]pyrazinyl, 1-aza-bicyclo[2.2.2]octyl, 9-aza-bicyclo[3.3.1]nonyl, and the like.
  • heterocyclyl is intended to mean a non-aromatic ring radical containing 3 to 8 ring atoms, wherein one, two or three ring atoms are heteroatoms selected from, for example: O, S, and N, wherein N is substituted with H, C 1 -C 4 acyl or C 1 -C 4 alkyl, and S is optionally substituted with one or two oxygens.
  • heterocyclyl group examples include, but are not limited to, aziridinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, [1,3]-dioxolanyl, thiomorpholinyl, [1,4]oxazepanyl, 1,1-dioxothiomorpholinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo-hexahydro-1 ⁇ -thiopyranyl, 1,1-dioxo-hexahydro-1 ⁇ -thiopyranyl, and the like.
  • heterocyclylene is intended to mean a non-aromatic ring di-radical containing 3 to 8 ring atoms, wherein one, two or three ring atoms are heteroatoms selected from, for example: O, S, and N, wherein N is substituted with H, C 1 -C 4 acyl or C 1 -C 4 alkyl, and S is optionally substituted with one or two oxygens.
  • heterocyclylene group examples include, but are not limited to, aziridinediyl, azetidinediyl, piperidinediyl, morpholinediyl, piperazinediyl, pyrrolidinediyl, [1,3]-dioxolanediyl, thiomorpholinediyl, [1,4]oxazepanediyl, 1,1-dioxothiomorpholinediyl, azepanediyl, tetrahydrofurandiyl, and the like.
  • hydroxyl is intended to mean the group —OH.
  • phosphonooxy is intended to mean the group —OP(O)(OH) 2 .
  • ureyl is intended to mean the group —NH 2 C(O)NH 2 .
  • compositions comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents. Also provided is a composition comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • compositions comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents, and a pharmaceutically acceptable carrier.
  • a composition comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents, and a pharmaceutically acceptable carrier.
  • a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a composition obtained by a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • compositions comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents. Also provided is a composition obtained by a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents, and a pharmaceutically acceptable carrier.
  • compositions obtained by a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents, and a pharmaceutically acceptable carrier.
  • compositions comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents. Also provided is a composition obtained by a method for preparing a composition comprising the step of admixing a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • the compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and the one or more known pharmaceutical agents are admixed with a pharmaceutically acceptable carrier.
  • the compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof and the one or more known pharmaceutical agents are each admixed with a different pharmaceutically acceptable carrier.
  • the pharmaceutical carrier generally is compatible with the other ingredients in the composition and should be tolerated by the individual recipient.
  • Other physiologically active ingredients can be incorporated into the pharmaceutical composition if desired, and if such ingredients are compatible with the other ingredients in the composition.
  • Conventional excipients such as binding agents, fillers, acceptable wetting agents, tabletting lubricants, and disintegrants can be used in tablets and capsules for oral administration.
  • compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
  • the compositions for oral administration can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants can be added.
  • Compositions for parenteral administration can be prepared by dissolving the compounds in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples of the many appropriate methods well known in the art for preparing compositions for oral or parenteral administration.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the treatment of pain in an individual in need thereof, comprising administering to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the treatment of pain in an individual in need thereof, comprising administering to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the treatment of pain in an individual in need thereof, comprising prescribing to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the treatment of pain in an individual in need thereof, comprising prescribing to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the management of pain in an individual in need thereof, comprising administering to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the management of pain in an individual in need thereof, comprising administering to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the management of pain in an individual in need thereof, comprising prescribing to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein for use in a method for the management of pain in an individual in need thereof, comprising prescribing to said individual said compound and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents for use in combination with a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein. Also provided is one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents, for use in combination with a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein.
  • one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents for use in a method for the treatment of pain in an individual in need thereof, said method comprises administering to said individual one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents and a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein.
  • one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents for use in a method for the treatment of pain in an individual in need thereof, said method comprises prescribing to said individual one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents and a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein.
  • one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents for use in a method for the management of pain in an individual in need thereof, said method comprises administering to said individual one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents and a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein.
  • one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents for use in a method for the management of pain in an individual in need thereof, said method comprises administering to said individual one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents and a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein.
  • a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents; for treating pain in an individual.
  • a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents; for treating pain in an individual.
  • a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents; for managing pain in an individual.
  • a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • the pharmaceutical product comprises a pharmaceutical composition.
  • the pharmaceutical product comprises a formulation.
  • the pharmaceutical product comprises a dosage form.
  • the pharmaceutical product comprises a combined preparation.
  • the pharmaceutical product comprises a twin pack.
  • the pharmaceutical product comprises a kit.
  • the kit comprises a first package comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein or a pharmaceutical composition thereof, and a second package comprising one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents or a pharmaceutical composition thereof.
  • the kit comprises a first package comprising a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein or a pharmaceutical composition thereof, and a second package comprising one or more known pharmaceutical agents selected from analgesic agents and antidiabetic agents.
  • a method for the treatment of pain in an individual in need thereof comprising administering to said individual, a therapeutically effective amount of a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a method for the treatment of pain in an individual in need thereof comprising prescribing to said individual, a therapeutically effective amount of a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a method for the management of pain in an individual in need thereof comprising administering to said individual, a therapeutically effective amount of a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • a method for the management of pain in an individual in need thereof comprising prescribing to said individual, a therapeutically effective amount of a compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and one or more known pharmaceutical agents selected from analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • the individual is a human.
  • the one or more known pharmaceutical agents are administered to the individual simultaneously, separately, or sequentially.
  • the compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and the one or more known pharmaceutical agents are administered simultaneously.
  • the compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and the one or more known pharmaceutical agents are administered separately.
  • the compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and the one or more known pharmaceutical agents are administered sequentially.
  • the amount of the compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein alone and the amount of the one or more known pharmaceutical agents alone are therapeutically ineffective.
  • the combination of a compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof described herein and the one or more known pharmaceutical agents results in a supra additive or synergistic effect on relief of pain (see, e.g., FIG. 15 ).
  • a synergistic effect means that the effect on pain, as demonstrated, e.g., by an increase in PWT or another measure of pain intensity or severity as described herein, observed with the combination therapy is greater than that seen by adding the effect on pain of each compound together.
  • One advantage of using a synergistic combination therapy is that less of each compound is required to achieve a significant effect on pain and so fewer side effects can result from treatment.
  • the side effect profile of one drug can mitigate or average out the side effect profile of the other drug.
  • one of the drugs may result in increased blood pressure and the other drug results in lowered blood pressure so that the combination therapy does not effect blood pressure.
  • Another potential advantage of combination therapy is that, since less compound is required, the cost of therapy can be reduced.
  • the pain is chosen from bone and joint pain, pain associated with osteoarthritis, hyperalgesia, allodynia, inflammatory pain, inflammatory hyperalgesia, neuropathic pain, neuropathic hyperalgesia, acute nociception, muscle pain, dental pain, migraine and other headache pain, pain that occurs as an adverse effect of therapeutics in an individual, and pain associated with a disorder selected from: cancer, multiple sclerosis, allergic reactions, nephritic syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, HIV related-neuropathy, sciatica, and autoimmune conditions.
  • the pain is chosen from bone and joint pain, pain associated with osteoarthritis, muscle pain, dental pain, migraine and other headache pain, inflammatory pain, neuropathic pain, pain that occurs as an adverse effect of therapeutics, pain associated with osteoarthritis; pain associated cancer, hyperalgesia; allodynia; inflammatory hyperalgesia; neuropathic hyperalgesia; and acute nociception.
  • the pain is mild to moderate pain.
  • pain is moderate to moderately severe pain.
  • the individual has a visual analogue scale pain score of ⁇ 40 mm.
  • the individual has a Likert numerical rating scale pain score of ⁇ 4.
  • the pain is moderate to severe pain requiring continuous, around-the-clock opioid therapy an extended period of time.
  • the pain is acute pain.
  • the method is for short-term use (five days or less).
  • the pain is chronic pain.
  • Suitable pharmaceutical agents that can be used in combination with the compounds described herein include analgesic agents, antidiabetic agents, osteoarthritis agents, and anticancer agents.
  • the analgesic agent is chosen from non-opioid drugs, opioid drugs, and co-analgesic medications.
  • the non opioid drug is chosen from non steroidal anti-inflammatory agents, choline magnesium trisalicylate, sulfasalazine, olsalazin, phenacetin, tenoxicam, phenylbutazone, oxyphenthartazone, tapentadol, celecoxib, etoricoxib, lumiracoxib, rofecoxib, parecoxib, and ziconotide.
  • the non steroidal anti-inflammatory agent is chosen from acemetacin, acetaminophen, aminoprofen, aspirin, benoxaprofen, bucloxic acid, carprofen, choline magnesium salicylate, choline salicylate, clidanac, diclofenac, diflunisal, diflurisal, etodolac, fenoprofen, fenoprofen calcium, fentiazac, flosulide, flubufen, flufenamic acid, flufenisal, flurbiprofen, fluprofen, ibuprofen, indoprofen, indomethacin, isoxicam, ketoprofen, ketorolac tromethamine, lornoxicam, magnesium salicylate, meclofenamic acid, meclofenamate sodium, mefenamic acid, meloxicam, muroprofen, nabumet
  • the opioid drug is chosen from alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dilaudid, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodeine, hydrocodone, hydromorphone, hydroxypethidine
  • the at least one analgesic agent comprises an NSAID and an opiod drug.
  • the at least one analgesic agent is chosen from vicodin (acetaminophen and hydrocodone), percocet (oxycodone and acetaminophen), norco (hydrocodone bitartrate and acetaminophen), lorcet (acetaminophen and hydrocodone), darvocet (acetaminophen and propoxyphene), and percodan (aspirin and oxycodone).
  • the at least one analgesic agent is at least one co-analgesic medication chosen from antidepressants, anti-anxiety medications, migraine medications, and gabapentin.
  • the migraine medication is chosen from alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine, methysergide oxetorone, and pizotyline.
  • the antidepressant is chosen from escitalopram, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexi
  • the anti-anxiety medication is chosen from alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam, buspirone; and barbituates.
  • the pain is neuropathic pain associated with diabetic peripheral neuropathy.
  • the one or more known pharmaceutical agents is chosen from antidiabetic agents.
  • the antidiabetic agent is chosen from sulfonylurea, meglitinide, biguanide, alpha-glucosidase inhibitor, thiazolidinedione, insulin analog, and chromium picolinate/biotin.
  • the antidiabetic agent is a sulfonylurea chosen from glibenclamide, glipizide, gliclazide, and glimepiride.
  • the antidiabetic agent is a meglitinide chosen from repaglinide and nateglinide.
  • the antidiabetic agent is a biguanide chosen from metformin.
  • the antidiabetic agent is an alpha-glucosidase inhibitor chosen from acarbose, epalrestat, miglitol, and voglibose.
  • the antidiabetic agent is a thiazolidinedione chosen from rosiglitazone and pioglitazone.
  • the antidiabetic agent is insulin or an analog thereof chosen from insulin lispro, insulin aspart, and insulin glargine.
  • the pain is pain associated with osteoarthritis.
  • the one or more known pharmaceutical agents is chosen from osteoarthritis agents.
  • the osteoarthritis agent is chosen from localized injections, topical patches, creams and gels, glucosamine, chondroitin sulfate, and vitamins.
  • the localized injection is chosen from a corticosteroid injection and an injection of hyaluronan.
  • the topical patches, creams and gels are chosen from civamide patch, diclofenac patch, topical strontium chloride hexahydrate, diclofenac sodium topical solution, capsaicin cream and methylsalicylate cream.
  • the osteoarthritis agent is chosen from valdecoxib, meloxicam, etodolac, naproxen sodium, diacerhein, tetracycline, antimalarial therapies, Gen-S, JNJ-39439335, JNJ-42160443 (a monoclonal antibody against nerve growth factor (NGF)), JNS013 (combination of tramadol and acetaminophen), ABT-102 (N-[5-tert-butyl-2,3-dihydro-1H-inden-1(R)-yl]-N′-(1H-indazol-4-yl)urea), SAR114137, MEDI-578, LY545694 (iGluR5 antagonist), BEMA buprenorphine (CA Index Name: 6,14-ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- ⁇ -(1,1-dimethylethyl)-4,5-epoxy
  • the osteoarthritis agent ABT-102 is N-[5-tert-butyl-2,3-dihydro-1H-inden-1(R)-yl]-N′-(1H-indazol-4-yl)urea, and the chemical structure is:
  • the osteoarthritis agent BEMA buprenorphine has the CA Index Name: 6,14-ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- ⁇ -(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy- ⁇ -methyl-, ( ⁇ S,5 ⁇ ,7 ⁇ )-hydrochloride, and the chemical structure is:
  • the osteoarthritis agent PH-797804 has the CA Index Name: benzamide, 3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxo-1(2H)-pyridinyl]-N,4-dimethyl-), and the chemical structure is:
  • the osteoarthritis agent NT-11624 has the CA Index Name: 1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione, dihydro-), and the chemical structure is:
  • pain is pain associated with cancer.
  • the pain is breakthrough pain in cancer patient.
  • the individual is already receiving and is tolerant to opioid therapy for the cancer pain.
  • the one or more known pharmaceutical agents is chosen from anticancer agents.
  • the pain is pain that occurs as an adverse effect of the anticancer agent.
  • the anticancer agent is paclitaxel.
  • the cancer is chosen from prostrate cancer, pancreatic cancer, lung cancer, and breast cancer.
  • the cancer is chosen from pancreatic cancer, lung cancer, and breast cancer.
  • the anticancer agent is chosen from acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cir
  • the anticancer agent is chosen from 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arg
  • the anticancer agent is chosen from eribulin mesylate, cabazitaxel, sipuleucel-T, degarelix, raloxifene, topotecan hydrochloride, ixabepilone, lapatinib, erlotinib, gefitinib, abarelix, leuprolide acetate, fulvestrant, letrozole, triptorelin pamoate, herceptin, nolvadex, photofrin, xeloda, letrozole, anastrozole, flutamide, gemcitabine HCl, docetaxel, goserelin acetate, bevacizumab, celecoxib, cetuximab, denosumab, ibandronic acid, thyrotropin alfa, trabectedin, and Pemetrexed.
  • combination-therapy of the compound of Formula Ia or a pharmaceutically acceptable salt, solvate, and hydrate thereof described herein with other pharmaceutical agents is not limited to those listed herein but includes in principle any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of diseases, conditions or disorders that are linked to pain.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;
  • X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or
  • X is CC(O)N(R 8 )R 9 and Y is NR 7 ;
  • R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:
  • R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;
  • R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R H is absent;
  • R 12 is C 1 -C 6 alkylene; or R 12 is absent;
  • R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl;
  • R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:
  • R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R 14 is absent;
  • R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent;
  • R 16 is C 1 -C 6 alkylene; or R 16 is absent;
  • R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino, aryl,
  • R 9 is selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: Carbo-C 1 -C 6 -alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl.
  • some embodiments of the present invention include every combination of one or more embodiments pertaining to the chemical groups represented by the variables and generic chemical formulae as described herein or every combination of one or more compounds of Formula (Ia) together/in combination with every combination of the one or more known pharmaceutical agents either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited.
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when “substituted” it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds described herein.
  • the present disclosure includes all isotopes of atoms occurring in the present compounds, salts and crystalline forms thereof.
  • Compounds described herein can also include all isotopes of atoms occurring in the intermediates and/or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include 2 H (deuterium) and 3 H (tritium).
  • Isotopes of carbon include 13 C and 14 C.
  • R 1 is selected from: H and C 1 -C 6 alkyl.
  • R 1 is H.
  • R 1 is C 1 -C 6 alkyl.
  • R 1 is methyl
  • R 1 is isopropyl
  • R 2 is selected from: H and C 1 -C 6 alkyl.
  • R 2 is H.
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is methyl
  • R 2 is isopropyl
  • R 3 is selected from: H and C 1 -C 6 alkyl.
  • R 3 is H.
  • R 3 is C 1 -C 6 alkyl.
  • R 3 is methyl
  • R 3 is isopropyl.
  • R 4 is selected from: H and C 1 -C 6 alkyl.
  • R 4 is H.
  • R 4 is C 1 -C 6 alkyl.
  • R 4 is methyl
  • R 4 is isopropyl.
  • R 5 is selected from: H and C 1 -C 6 alkyl.
  • R 5 is H.
  • R 5 is C 1 -C 6 alkyl.
  • R 5 is methyl
  • R 5 is isopropyl
  • R 6 is selected from: H and C 1 -C 6 alkyl.
  • R 6 is H.
  • R 6 is C 1 -C 6 alkyl.
  • R 6 is methyl
  • R 6 is isopropyl.
  • X is NR 7 ; wherein R 7 is —R 10 —R 11 —R 12 —R 13
  • X is CCONR 8 R 9 .
  • X is CC(O)NHR 8 .
  • Y is NR 7 ; wherein R 7 is —R 10 —R 11 —R 12 —R 13
  • Y is CCONR 8 R 9 .
  • Y is CC(O)NHR 8 .
  • R 7 is —R 10 —R 11 —R 12 —R 13 , or an N-oxide thereof.
  • R 7 is —R 10 —R 11 —R 12 —R 13 .
  • R 7 is selected from: aryl and heteroaryl; wherein said aryl and heteroaryl are each optionally substituted with one or two substituents selected from: cyano and halogen.
  • R 7 is selected from: aryl and heteroaryl; wherein said aryl and heteroaryl are each optionally substituted with one or two substituents selected from: fluoro, chloro, and cyano.
  • R 7 is selected from: 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 5-chloro-pyridin-2-yl, 5-cyano-pyrazin-2-yl, pyrazin-2-yl, 5-fluoro-pyridin-2-yl, 4-chloro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 4-cyano-pyridin-2-yl, and 4-oxy-pyrazin-2-yl.
  • R 7 is selected from: 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 5-chloro-pyridin-2-yl, 5-cyano-pyrazin-2-yl, pyrazin-2-yl, 5-fluoro-pyridin-2-yl, 4-chloro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 4-cyano-pyridin-2-yl, and 4-oxy-pyrazin-2-yl.
  • R 7 is selected from: 2,4-difluoro-phenyl, 5-bromo-pyridin-2-yl, 4-cyano-phenyl, pyridin-3-yl, pyridin-2-yl, 5-thiazol-2-yl-pyridin-2-yl, 5-trifluoromethyl-pyridin-2-yl, 5-o-tolyl-pyridin-2-yl, 5-dimethylamino-pyrazin-2-yl, 2,4-dichloro-phenyl, 5-isopropyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 5-(4-methoxy-phenyl)-pyridin-2-yl, 2-fluoro-4-methanesulfonyl-phenyl, 2-fluoro-phenyl, 5-chloro-pyridin-2-yl, 5-bromo-pyridin-3-yl, tert-butyl, 2-methoxy-pyri
  • R 7 is selected from: 2,4-difluoro-phenyl, 5-bromo-pyridin-2-yl, 4-cyano-phenyl, pyridin-3-yl, pyridin-2-yl, 5-thiazol-2-yl-pyridin-2-yl, 5-trifluoromethyl-pyridin-2-yl, 5-o-tolyl-pyridin-2-yl, 5-dimethylamino-pyrazin-2-yl, 2,4-dichloro-phenyl, 5-isopropyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 5-(4-methoxy-phenyl)-pyridin-2-yl, 2-fluoro-4-methanesulfonyl-phenyl, 2-fluoro-phenyl, 5-chloro-pyridin-2-yl, 5-bromo-pyridin-3-yl, tert-butyl, 2-methoxy-pyri
  • R 7 is 2,4-difluoro-phenyl. In some embodiments, R 7 is 5-bromo-pyridin-2-yl. In some embodiments, R 7 is 4-cyano-phenyl. In some embodiments, R 7 is pyridin-3-yl. In some embodiments, R 7 is pyridin-2-yl. In some embodiments, R 7 is 5-thiazol-2-yl-pyridin-2-yl. In some embodiments, R 7 is 5-trifluoromethyl-pyridin-2-yl. In some embodiments, R 7 is 5-o-tolyl-pyridin-2-yl. In some embodiments, R 7 is 5-dimethylamino-pyrazin-2-yl.
  • R 7 is 2,4-dichloro-phenyl. In some embodiments, R 7 is 5-isopropyl-pyridin-2-yl. In some embodiments, R 7 is 5-methyl-pyridin-2-yl. In some embodiments, R 7 is 5-(4-methoxy-phenyl)-pyridin-2-yl. In some embodiments, R 7 is 2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R 7 is 2-fluoro-phenyl. In some embodiments, R 7 is 5-chloro-pyridin-2-yl. In some embodiments, R 7 is 5-bromo-pyridin-3-yl.
  • R 7 is tert-butyl. In some embodiments, R 7 is 2-methoxy-pyridin-4-yl. In some embodiments, R 7 is 2,2-dimethyl-propyl. In some embodiments, R 7 is tetrahydro-pyran-4-ylmethyl. In some embodiments, R 7 is phenyl. In some embodiments, R 7 is 4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 7 is 6-chloro-pyrazin-2-yl. In some embodiments, R 7 is 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl. In some embodiments, R 7 is 5-morpholin-4-yl-pyridin-2-yl.
  • R 7 is 6-bromo-pyridin-3-yl. In some embodiments, R 7 is 5-methoxy-pyridin-2-yl. In some embodiments, R 7 is 5,6-difluoro-pyridin-3-yl. In some embodiments, R 7 is 6-methoxy-pyridazin-3-yl. In some embodiments, R 7 is 2-chloro-pyridin-4-yl. In some embodiments, R 7 is 5-cyclopropyl-pyrazin-2-yl. In some embodiments, R 7 is 1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 7 is 1-benzyl-piperidin-4-yl.
  • R 7 is 6-cyano-pyrazin-2-yl. In some embodiments, R 7 is 2-hydroxy-2-methyl-propyl. In some embodiments, R 7 is 4-fluoro-phenyl. In some embodiments, R 7 is 5-ethyl-pyridin-2-yl. In some embodiments, R 7 is isopropyl. In some embodiments, R 7 is 5-phenyl-pyridin-2-yl. In some embodiments, R 7 is pyridin-4-yl. In some embodiments, R 7 is 2,5-difluoro-phenyl. In some embodiments, R 7 is 3-fluoro-phenyl. In some embodiments, R 7 is pyrimidin-4-yl.
  • R 7 is 2-(tetrahydro-pyran-4-yl)-ethyl. In some embodiments, R 7 is 3,5-difluoro-pyridin-2-yl. In some embodiments, R 7 is pyrazin-2-yl. In some embodiments, R 7 is tetrahydro-thiopyran-4-yl. In some embodiments, R 7 is 5-p-tolyl-pyridin-2-yl. In some embodiments, R 7 is 4-methoxy-phenyl. In some embodiments, R 7 is 2-morpholin-4-yl-ethyl. In some embodiments, R 7 is 5-cyano-pyridin-2-yl.
  • R 7 is 5-cyano-pyrazin-2-yl. In some embodiments, R 7 is 6′-methyl-[3,3′]bipyridinyl-6-yl. In some embodiments, R 7 is 6-chloro-pyridazin-3-yl. In some embodiments, R 7 is 5-fluoro-pyridin-2-yl. In some embodiments, R 7 is 5-ethyl-pyrazin-2-yl. In some embodiments, R 7 is 6-methoxy-pyrazin-2-yl. In some embodiments, R 7 is 5-dimethylamino-pyridin-2-yl. In some embodiments, R 7 is 1-(4-fluoro-phenyl)-1-methyl-ethyl.
  • R 7 is 5-pyrimidin-5-yl-pyridin-2-yl. In some embodiments, R 7 is 4-methyl-pyridin-2-yl. In some embodiments, R 7 is 5-methoxy-pyrazin-2-yl. In some embodiments, R 7 is 5-propyl-pyridin-2-yl. In some embodiments, R 7 is 5-m-tolyl-pyridin-2-yl. In some embodiments, R 7 is 5-hydroxy-pyrazin-2-yl. In some embodiments, R 7 is cyclopropyl-pyridin-2-yl. In some embodiments, R 7 is 2,6-difluoro-phenyl.
  • R 7 is 3-fluoro-pyridin-4-yl. In some embodiments, R 7 is 5-isopropyl-pyrazin-2-yl. In some embodiments, R 7 is 5-bromo-pyrazin-2-yl. In some embodiments, R 7 is 5-cyclopentyl-pyridin-2-yl. In some embodiments, R 7 is o-tolyl. In some embodiments, R 7 is 4-fluoro-benzyl. In some embodiments, R 7 is 3-methyl-pyridin-2-yl. In some embodiments, R 7 is 6-methyl-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 7 is 6-dimethylamino-pyrazin-2-yl.
  • R 7 is 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl. In some embodiments, R 7 is 5-(4-fluoro-phenyl)-pyridin-2-yl. In some embodiments, R 7 is 5-cyclopropyl-pyridin-2-yl. In some embodiments, R 7 is 6-ethyl-pyrazin-2-yl. In some embodiments, R 7 is 5-methylamino-pyrazin-2-yl. In some embodiments, R 7 is dichloro-phenyl. In some embodiments, R 7 is 5-methyl-pyrazin-2-yl. In some embodiments, R 7 is 3-fluoro-pyridin-2-yl.
  • R 7 is 5-cyclobutyl-pyrazin-2-yl. In some embodiments, R 7 is 5-ethoxy-pyrazin-2-yl. In some embodiments, R 7 is 5-trifluoromethyl-pyrazin-2-yl. In some embodiments, R 7 is 5-cyano-pyridin-3-yl. In some embodiments, R 7 is 5-cyclopropylmethyl-pyrazin-2-yl. In some embodiments, R 7 is 5-pentafluoroethyl-pyrazin-2-yl. In some embodiments, R 7 is 5-heptafluoropropyl-pyrazin-2-yl. In some embodiments, R 7 is 5-chloro-4-methyl-pyridin-2-yl.
  • R 7 is 5-chloro-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 7 is 4-bromo-pyridin-2-yl. In some embodiments, R 7 is 4-chloro-pyridin-2-yl. In some embodiments, R 7 is 4-fluoro-pyridin-2-yl. In some embodiments, R 7 is 4-oxy-pyrazin-2-yl. In some embodiments, R 7 is 4-cyclopropyl-pyridin-2-yl. In some embodiments, R 7 is 4-cyano-pyridin-2-yl. In some embodiments, R 7 is 4-methanesulfonyl-pyridin-2-yl.
  • R 7 is 4-methoxy-pyridin-2-yl. In some embodiments, R 7 is piperidin-4-yl. In some embodiments, R 7 is tetrahydro-pyran-4-yl. In some embodiments, R 7 is 3-methyl-1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 7 is 5-chloro-3-fluoro-pyridin-2-yl. In some embodiments, R 7 is 3-fluoro-5-methoxy-pyridin-2-yl. In some embodiments, R 7 is 2-chloro-4-fluoro-phenyl. In some embodiments, R 7 is 6-fluoro-pyridin-3-yl.
  • R 7 is 6-cyano-pyridin-3-yl. In some embodiments, R 7 is 3-hydroxy-3-methyl-butyl. In some embodiments, R 7 is 4-iodo-pyridin-2-yl. In some embodiments, R 7 is 1-oxy-pyridin-3-yl. In some embodiments, R 7 is 4-tert-butylcarbamoyl-pyridin-2-yl. In some embodiments, R 7 is 4-hydroxy-pyridin-2-yl.
  • R 8 is —R 14 —R 15 —R 16 —R 17 .
  • R 8 is selected from: 1-hydroxymethyl-2,2-dimethyl-propyl, 2-hydroxy-1,1-dimethyl-ethyl, 1-hydroxymethyl-cyclopropyl, 2-hydroxy-indan-1-yl, 1-hydroxymethyl-cyclobutyl, tert-butyl, 2-hydroxy-1-phenyl-ethyl, 2-hydroxy-1-hydroxymethyl-1-methyl-ethyl, tert-butylamino, 2,2,2-trifluoro-1,1-dimethyl-ethyl, 2-methyl-1-(phosphonooxy)propan-2-yl, 1-methyl-cyclobutyl, 1-hydroxymethyl-2-methyl-propyl, cyano-dimethyl-methyl, 2,2-dimethyl-1-(methylcarbamoyl)-propyl, 3,3-dimethyl-1-(phosphonooxy)butan-2-yl, 2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl, 1,2-dimethyl-propy
  • R 8 is selected from: H, 2-methyl-2-morpholin-4-yl-propyl, 1-hydroxymethyl-2,2-dimethyl-propyl, 2-(tert-butoxycarbonylamino)cyclohexyl, 1-phenyl-cyclopropyl, 5-trifluoromethyl-pyridin-2-yl, 1-methyl-1-phenyl-ethyl, 1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl, 1-(methoxycarbonyl)cyclopropyl, tetrahydro-pyran-4-ylmethyl, 1-(tert-butoxycarbonyl)piperidin-4-yl, 1-(4-fluoro-phenyl)-cyclopropyl, 6-methyl-pyridin-3-ylmethyl, 2-hydroxy-1-phenyl-ethyl, 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl, 2-hydroxy-1,1-dimethyl-ethyl, 2-(tert-but
  • R 8 is selected from: H, 2-methyl-2-morpholin-4-yl-propyl, 1-hydroxymethyl-2,2-dimethyl-propyl, 2-(tert-butoxycarbonylamino)cyclohexyl, 1-phenyl-cyclopropyl, 5-trifluoromethyl-pyridin-2-yl, 1-methyl-1-phenyl-ethyl, 1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl, 1-(methoxycarbonyl)cyclopropyl, tetrahydro-pyran-4-ylmethyl, 1-(tert-butoxycarbonyl)piperidin-4-yl, 1-(4-fluoro-phenyl)-cyclopropyl, 6-methyl-pyridin-3-ylmethyl, 2-hydroxy-1-phenyl-ethyl, 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl, 2-hydroxy-1,1-dimethyl-ethyl, 2-(tert-but
  • R 8 is H. In some embodiments, R 8 is 2-methyl-2-morpholin-4-yl-propyl. In some embodiments, R 8 is 1-hydroxymethyl-2,2-dimethyl-propyl. In some embodiments, R 8 is 2-(tert-butoxycarbonylamino)cyclohexyl. In some embodiments, R 8 is 1-phenyl-cyclopropyl. In some embodiments, R 8 is 5-trifluoromethyl-pyridin-2-yl. In some embodiments, R 8 is 1-methyl-1-phenyl-ethyl. In some embodiments, R 8 is 1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl.
  • R 8 is 1-(methoxycarbonyl)cyclopropyl. In some embodiments, R 8 is tetrahydro-pyran-4-ylmethyl. In some embodiments, R 8 is 1-(tert-butoxycarbonyl)piperidin-4-yl. In some embodiments, R 8 is 1-(4-fluoro-phenyl)-cyclopropyl. In some embodiments, R 8 is 6-methyl-pyridin-3-ylmethyl. In some embodiments, R 8 is 2-hydroxy-1-phenyl-ethyl. In some embodiments, R 8 is 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl.
  • R 8 is 2-hydroxy-1,1-dimethyl-ethyl. In some embodiments, R 8 is 2-(5-hydroxy-1H-indol-3-yl)-ethyl. In some embodiments, R 8 is 1-hydroxymethyl-cyclopropyl. In some embodiments, R 8 is 3-chloro-5-methyl-pyridin-2-yl. In some embodiments, R 8 is 6-fluoro-pyridin-3-yl. In some embodiments, R 8 is 1-(3-fluoro-phenyl)-cyclobutyl. In some embodiments, R 8 is 2-methyl-pyridin-3-yl.
  • R 8 is 2-hydroxy-1-(tetrahydro-furan-3-yl)-ethyl. In some embodiments, R 8 is 2-(pyridin-3-yloxy)-propyl. In some embodiments, R 8 is carbamoyl-phenyl-methyl. In some embodiments, R 8 is 5-fluoro-2-methoxy-phenyl. In some embodiments, R 8 is 2-methoxy-ethyl. In some embodiments, R 8 is 2,3-dihydroxy-propyl. In some embodiments, R 8 is 1-(tert-butoxycarbonyl)pyrrolidin-3-yl. In some embodiments, R 8 is 2-oxo-2-phenyl-ethyl.
  • R 8 is 1-(3,3,3-trifluoro-propyl)-azetidin-3-yl. In some embodiments, R 8 is 2-hydroxy-1-pyridin-2-yl-ethyl. In some embodiments, R 8 is 3-hydroxy-pyridin-4-yl. In some embodiments, R 8 is 1-methyl-1-pyridin-4-yl-ethyl. In some embodiments, R 8 is 1-hydroxymethyl-2-3H-imidazol-4-yl-ethyl. In some embodiments, R 8 is 4-hydroxy-3-methoxy-benzyl. In some embodiments, R 8 is 5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl.
  • R 8 is 1-(4-fluoro-phenyl)-3-hydroxy-propyl. In some embodiments, R 8 is 1-pyridin-4-yl-cyclopropyl. In some embodiments, R 8 is 2-hydroxy-1-pyridin-3-yl-ethyl. In some embodiments, R 8 is 1,1-dimethyl-2-(4-methyl-piperidin-1-yl)-ethyl. In some embodiments, R 8 is 6-cyano-pyridin-3-yl. In some embodiments, R 8 is 5-fluoro-pyridin-2-yl. In some embodiments, R 8 is 2,5-dimethyl-benzyl.
  • R 8 is 1-isopropyl-piperidin-4-yl. In some embodiments, R 8 is 2-methoxy-1-methoxymethyl-ethyl. In some embodiments, R 8 is 2,3-dimethyl-benzyl. In some embodiments, R 8 is 1-pyridin-2-yl-ethyl. In some embodiments, R 8 is 6-chloro-pyridin-3-ylmethyl. In some embodiments, R 8 is 3-methyl-pyridin-2-yl. In some embodiments, R 8 is 2-hydroxy-indan-1-yl. In some embodiments, R 8 is (1S,2S)-2-hydroxy-indan-1-yl.
  • R 8 is (1S,2R)-2-hydroxy-indan-1-yl. In some embodiments, R 8 is (1R,2R)-2-hydroxy-indan-1-yl. In some embodiments, R 8 is (1R,2S)-2-hydroxy-indan-1-yl. In some embodiments, R 8 is 1-hydroxymethyl-cyclobutyl. In some embodiments, R 8 is 2-(4-chloro-phenyl)-1,1-dimethyl-ethyl. In some embodiments, R 8 is 3-hydroxy-pyridin-2-ylmethyl. In some embodiments, R 8 is 3-methyl-pyridin-4-yl. In some embodiments, R 8 is 5-tert-butyl-isoxazol-3-yl.
  • R 8 is 1-(6-methoxy-pyridin-3-yl)-1-methyl-ethyl. In some embodiments, R 8 is 1H-benzoimidazol-2-yl. In some embodiments, R 8 is tert-butyl. In some embodiments, R 8 is 4-phenyl-thiazol-2-yl. In some embodiments, R 8 is 1-(2-fluoro-phenyl)-cyclobutyl. In some embodiments, R 8 is 2,4-dimethoxy-benzyl. In some embodiments, R 8 is 5-bromo-3-methyl-pyridin-2-yl. In some embodiments, R 8 is 4-benzyl-morpholin-2-ylmethyl.
  • R 8 is 6-trifluoromethyl-pyridin-3-ylmethyl. In some embodiments, R 8 is tetrahydro-furan-3-yl. In some embodiments, R 8 is pyridin-3-ylmethyl. In some embodiments, R 8 is pyrazin-2-yl. In some embodiments, R 8 is piperidin-4-yl. In some embodiments, R 8 is 1-(6-hydroxy-pyridin-3-yl)-1-methyl-ethyl. In some embodiments, R 8 is 1-methyl-1-pyridin-2-yl-ethyl. In some embodiments, R 8 is 1-hydroxymethyl-cyclopentyl.
  • R 8 is 1-aza-bicyclo[2.2.2]oct-3-yl. In some embodiments, R 8 is 2-hydroxy-cyclopentyl. In some embodiments, R 8 is 2-hydroxy-1-(hydroxymethyl)-propyl. In some embodiments, R 8 is 1-(tert-butoxycarbonyl)piperidin-4-yl)methyl. In some embodiments, R 8 is 3,5-dimethoxy-phenyl. In some embodiments, R 8 is 6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl. In some embodiments, R 8 is 4,6-dimethyl-pyridin-2-yl.
  • R 8 is 1,1-dimethyl-2-morpholin-4-yl-ethyl. In some embodiments, R 8 is 2-hydroxy-cyclohexylmethyl. In some embodiments, R 8 is 1-(4-methoxy-phenyl)-cyclopropyl. In some embodiments, R 8 is 1-ethyl-pyrrolidin-2-ylmethyl. In some embodiments, R 8 is indan-1-yl. In some embodiments, R 8 is pyrimidin-4-yl. In some embodiments, R 8 is 2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R 8 is 6-hydroxy-pyridin-2-yl. In some embodiments, R 8 is cyclobutyl.
  • R 8 is 1-(3-methoxy-phenyl)-cyclopropyl. In some embodiments, R 8 is 1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-yl. In some embodiments, R 8 is 2-hydroxy-pyridin-3-yl. In some embodiments, R 8 is 4-difluoromethoxy-benzyl. In some embodiments, R 8 is 1-piperidin-1-yl-cyclopentylmethyl. In some embodiments, R 8 is 3-hydroxy-3-methyl-butyl. In some embodiments, R 8 is 1-(4-fluoro-phenyl)-cyclobutyl. In some embodiments, R 8 is 4-methoxy-benzyl.
  • R 8 is pyridin-2-yl. In some embodiments, R 8 is 2-hydroxy-2-phenyl-ethyl. In some embodiments, R 8 is 2-hydroxymethyl-2,3-dihydro-indol-1-yl. In some embodiments, R 8 is 3-hydroxy-pyridin-2-yl. In some embodiments, R 8 is 4-dimethylamino-tetrahydro-pyran-4-ylmethyl. In some embodiments, R 8 is 2-(4-fluoro-phenyl)-ethyl. In some embodiments, R 8 is 1-(2-methoxy-ethyl)-piperidin-4-ylmethyl.
  • R 8 is 2-morpholin-4-yl-ethyl. In some embodiments, R 8 is 1-(tert-butoxycarbonyl)-4-carboxypiperidin-4-yl. In some embodiments, R 8 is quinolin-3-yl. In some embodiments, R 8 is 1-morpholin-4-ylmethyl-cyclopentyl. In some embodiments, R 8 is 1,4-dimethyl-1H-pyrrol-2-ylmethyl. In some embodiments, R 8 is 2-hydroxy-2-pyridin-2-yl-ethyl. In some embodiments, R 8 is pyridin-3-yl. In some embodiments, R 8 is 2-dimethylamino-benzyl.
  • R 8 is tetrahydro-thiopyran-4-yl. In some embodiments, R 8 is 1-m-tolyl-cyclopropyl. In some embodiments, R 8 is 1-(2-methoxy-ethyl)-piperidin-3-yl. In some embodiments, R 8 is 5-methoxy-pyridin-2-ylmethyl. In some embodiments, R 8 is 2-hydroxy-1-pyridin-4-yl-ethyl. In some embodiments, R 8 is 4-methyl-pyridin-2-yl. In some embodiments, R 8 is 4-carboxy-2-fluorophenyl. In some embodiments, R 8 is 6-methanesulfonyl-pyridin-3-yl.
  • R 8 is 1-o-tolyl-cyclobutyl. In some embodiments, R 8 is 1,1-dimethyl-2-pyrrolidin-1-yl-ethyl. In some embodiments, R 8 is 2,6-dimethoxy-pyridin-3-yl. In some embodiments, R 8 is pyridin-2-yl. In some embodiments, R 8 is 4-hydroxymethyl-tetrahydro-pyran-4-yl. In some embodiments, R 8 is 2-(1H-imidazol-4-yl)-ethyl. In some embodiments, R 8 is 3-fluoro-pyridin-4-yl. In some embodiments, R 8 is 1-carbamoyl-2-phenyl-ethyl.
  • R 8 is oxazol-4-ylmethyl. In some embodiments, R 8 is 6-methoxy-pyrimidin-4-yl. In some embodiments, R 8 is 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl. In some embodiments, R 8 is 1-methoxy-1-oxo-3-phenylpropan-2-yl. In some embodiments, R 8 is 1-(2-methoxy-ethyl)-pyrrolidin-3-yl. In some embodiments, R 8 is 1-(6-methyl-pyridin-2-yl)-ethyl. In some embodiments, R 8 is 2-hydroxy-1-(4-hydroxy-phenyl)-ethyl.
  • R 8 is 2-methoxy-pyridin-4-yl. In some embodiments, R 8 is 1-pyridin-2-yl-cyclopropyl. In some embodiments, R 8 is 1-(tert-butoxycarbonyl)piperidin-3-yl. In some embodiments, R 8 is 3-methyl-pyridin-2-ylmethyl. In some embodiments, R 8 is 3-fluoro-pyridin-2-yl. In some embodiments, R 8 is 1-pyridin-4-yl-cyclobutyl. In some embodiments, R 8 is 2-carboxy-1-(pyridin-3-yl)ethyl. In some embodiments, R 8 is 2-hydroxy-1-methyl-ethyl.
  • R 8 is 1-(methoxycarbonyl)cyclohexyl. In some embodiments, R 8 is 3-hydroxymethyl-pyridin-4-yl. In some embodiments, R 8 is 2-hydroxy-1-phenyl-ethyl. In some embodiments, R 8 is 3-dimethylamino-tetrahydro-thiophen-3-ylmethyl. In some embodiments, R 8 is tetrahydro-pyran-4-yl. In some embodiments, R 8 is 5-chloro-pyridin-2-yl. In some embodiments, R 8 is 1-carbamoyl-cyclobutyl. In some embodiments, R 8 is 5-fluoro-2-methyl-benzyl.
  • R 8 is 2-morpholin-4-yl-2-pyridin-3-yl-ethyl. In some embodiments, R 8 is 1-(3-methoxy-phenyl)-cyclobutyl. In some embodiments, R 8 is 5-methyl-pyridin-2-yl. In some embodiments, R 8 is 1-(tetrahydro-furan-2-yl)methyl. In some embodiments, R 8 is 1-dimethylaminomethyl-cyclopentyl. In some embodiments, R 8 is 2-(4-fluoro-phenyl)-1-methyl-ethyl. In some embodiments, R 8 is benzothiazol-2-yl.
  • R 8 is 1-(2-fluoro-phenyl)-cyclopropyl. In some embodiments, R 8 is 1-(2-methoxy-ethyl)-piperidin-4-yl. In some embodiments, R 8 is 2-hydroxy-1-pyridin-4-yl-ethyl. In some embodiments, R 8 is 1-(3,3,3-trifluoro-propyl)-azetidin-3-ylmethyl. In some embodiments, R 8 is 6-pyrrolidin-1-yl-pyridin-2-ylmethyl. In some embodiments, R 8 is 1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl.
  • R 8 is 2,3-dimethoxy-benzyl. In some embodiments, R 8 is 3-cyano-5-methyl-pyridin-2-yl. In some embodiments, R 8 is 2,3-dihydro-benzofuran-3-yl. In some embodiments, R 8 is 1-hydroxymethyl-cyclohexyl. In some embodiments, R 8 is 2,5-difluoro-benzyl. In some embodiments, R 8 is 4-dimethylamino-benzyl. In some embodiments, R 8 is 4-hydroxy-1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 8 is 4-trifluoromethyl-pyridin-2-yl.
  • R 8 is 5-methyl-thiazol-2-yl. In some embodiments, R 8 is 6-trifluoromethyl-pyridin-3-yl. In some embodiments, R 8 is 5-hydroxy-1H-pyrazol-3-yl. In some embodiments, R 8 is 2-thiomorpholin-4-yl-ethyl. In some embodiments, R 8 is benzo[1,3]dioxol-5-ylmethyl. In some embodiments, R 8 is 2-amino-cyclohexyl. In some embodiments, R 8 is 3-dimethylamino-1-oxo-tetrahydro-1 ⁇ 4 -thiophen-3-ylmethyl. In some embodiments, R 8 is 4-methyl-morpholin-2-ylmethyl.
  • R 8 is 1-(2-methoxy-phenyl)-cyclopropyl. In some embodiments, R 8 is 2-carboxy-1-(4-fluorophenyl)propan-2-yl. In some embodiments, R 8 is pyridin-2-ylmethyl. In some embodiments, R 8 is pyridazin-3-yl. In some embodiments, R 8 is 4-pyridin-2-yl-thiazol-2-yl. In some embodiments, R 8 is 1-(3,3,3-trifluoro-propyl)-piperidin-4-ylmethyl. In some embodiments, R 8 is 6-chloro-2-methyl-pyridin-3-yl.
  • R 8 is 6-hydroxy-pyridin-3-yl. In some embodiments, R 8 is 3-trifluoromethoxy-benzyl. In some embodiments, R 8 is 1-morpholin-4-yl-cyclopentylmethyl. In some embodiments, R 8 is 1-pyridin-2-yl-cyclobutylmethyl. In some embodiments, R 8 is 2-hydroxy-1-hydroxymethyl-1-methyl-ethyl. In some embodiments, R 8 is 5-hydroxymethyl-pyridin-2-yl. In some embodiments, R 8 is 5-fluoro-1-oxy-pyridin-2-yl. In some embodiments, R 8 is 6-methoxy-pyridin-2-yl.
  • R 8 is 1-methyl-1-pyridin-3-yl-ethyl. In some embodiments, R 8 is 6-methyl-pyridin-3-yl. In some embodiments, R 8 is 2-hydroxy-1-hydroxymethyl-propyl. In some embodiments, R 8 is 2-chloro-pyridin-3-yl. In some embodiments, R 8 is 3-methyl-3H-imidazol-4-ylmethyl. In some embodiments, R 8 is 6-fluoro-pyridin-2-yl. In some embodiments, R 8 is 3-dimethylamino-benzyl. In some embodiments, R 8 is 6-morpholin-4-yl-pyridin-3-yl.
  • R 8 is 1-o-tolyl-cyclopropyl. In some embodiments, R 8 is 1-(3,3,3-trifluoro-propyl)-piperidin-3-yl. In some embodiments, R 8 is 6-methanesulfonyl-4-methyl-pyridin-3-yl. In some embodiments, R 8 is 2-methyl-quinolin-4-yl. In some embodiments, R 8 is 1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-ylmethyl. In some embodiments, R 8 is benzooxazol-2-yl. In some embodiments, R 8 is 1-methyl-piperidin-4-ylmethyl.
  • R 8 is 2-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl. In some embodiments, R 8 is 1-methyl-piperidin-2-ylmethyl. In some embodiments, R 8 is pyridin-4-ylmethyl. In some embodiments, R 8 is 4-hydroxymethyl-pyridin-2-yl. In some embodiments, R 8 is 5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl. In some embodiments, R 8 is 6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl. In some embodiments, R 8 is 1-(5-methyl-pyridin-2-yl)-ethyl.
  • R 8 is 2-fluoro-pyridin-3-yl. In some embodiments, R 8 is morpholin-4-yl. In some embodiments, R 8 is 2-hydroxy-2-pyridin-4-yl-ethyl. In some embodiments, R 8 is pyridin-4-yl. In some embodiments, R 8 is 4-hydroxy-pyridin-2-yl. In some embodiments, R 8 is 3-methoxy-benzyl. In some embodiments, R 8 is 1-oxy-pyridin-2-yl. In some embodiments, R 8 is 1-ethyl-propyl. In some embodiments, R 8 is 6-carboxypyridin-2-yl.
  • R 8 is 1,2,2,6,6-pentamethyl-piperidin-4-yl. In some embodiments, R 8 is 6-methoxy-pyridin-3-yl. In some embodiments, R 8 is cyclopentyl. In some embodiments, R 8 is morpholin-2-ylmethyl. In some embodiments, R 8 is 1-(tert-butoxycarbonyl)azetidin-3-yl)methyl. In some embodiments, R 8 is 2-dimethylamino-2-pyridin-3-yl-ethyl. In some embodiments, R 8 is 1-(4-methoxy-phenyl)-cyclobutyl. In some embodiments, R 8 is 3-hydroxy-benzyl.
  • R 8 is tetrahydro-furan-2-ylmethyl. In some embodiments, R 8 is 4-(tert-butoxycarbonyl)morpholin-2-ylmethyl. In some embodiments, R 8 is 1-(3-fluoro-phenyl)-cyclopropyl. In some embodiments, R 8 is 2-o-tolyl-ethyl. In some embodiments, R 8 is 3-hydroxymethyl-1-isobutyl-pyrrolidin-3-yl. In some embodiments, R 8 is 1-(2-methoxy-ethyl)-azetidin-3-yl. In some embodiments, R 8 is 6-morpholin-4-yl-pyridin-2-ylmethyl.
  • R 8 is 1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-ylmethyl. In some embodiments, R 8 is 2-(4-fluoro-phenoxy)-ethyl. In some embodiments, R 8 is 2,6-dimethyl-pyrimidin-4-yl. In some embodiments, R 8 is 1-hydroxymethyl-2-(3H-imidazol-4-yl)-ethyl. In some embodiments, R 8 is 4-methanesulfonyl-benzyl. In some embodiments, R 8 is 1-pyridin-3-yl-cyclopropyl. In some embodiments, R 8 is 9-methyl-9-aza-bicyclo[3.3.1]non-1-yl.
  • R 8 is 2,6-dimethyl-pyridin-3-yl. In some embodiments, R 8 is 4-hydroxy-benzyl. In some embodiments, R 8 is 2-oxo-2-phenyl-ethyl). In some embodiments, R 8 is 1-methyl-1H-pyrazol-3-ylmethyl. In some embodiments, R 8 is pyrimidin-2-yl. In some embodiments, R 8 is 5-methyl-pyrazin-2-yl. In some embodiments, R 8 is 1-(2-methoxy-pyridin-3-yl)-1-methyl-ethyl. In some embodiments, R 8 is 6-methanesulfonyl-2-methyl-pyridin-3-yl.
  • R 8 is 2-hydroxy-benzyl. In some embodiments, R 8 is 6-bromo-2-methyl-pyridin-3-yl. In some embodiments, R 8 is 2-methoxy-pyridin-3-yl. In some embodiments, R 8 is 1-(4-chloro-phenyl)-cyclobutyl. In some embodiments, R 8 is 2-(pyridine-2-sulfonyl)-ethyl. In some embodiments, R 8 is 1-pyridin-2-yl-cyclopropylmethyl. In some embodiments, R 8 is 1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl. In some embodiments, R 8 is benzyl.
  • R 8 is 6-methyl-pyridin-2-yl. In some embodiments, R 8 is 3-difluoromethoxy-benzyl. In some embodiments, R 8 is 4-hydroxy-1-methyl-piperidin-4-ylmethyl. In some embodiments, R 8 is 1-(2,5-dimethylpyrrolidine-1-carbonyl)cyclopentyl. In some embodiments, R 8 is 2-methoxy-benzyl. In some embodiments, R 8 is 6-methyl-pyridin-2-ylmethyl. In some embodiments, R 8 is 3-chloro-pyridin-4-yl. In some embodiments, R 8 is 2-carboxypropan-2-yl. In some embodiments, R 8 is 6-chloro-pyridin-3-yl.
  • R 8 is 2-hydroxy-2-pyridin-3-yl-ethyl. In some embodiments, R 8 is 1-p-tolyl-cyclopropyl. In some embodiments, R 8 is 1-(3,3,3-trifluoro-propyl)-piperidin-4-yl. In some embodiments, R 8 is 4-methoxy-pyridin-2-yl. In some embodiments, R 8 is 3-azepan-1-yl-2,2-dimethyl-propyl. In some embodiments, R 8 is 1-(tert-butoxycarbonyl)azetidin-3-yl. In some embodiments, R 8 is 5-methyl-pyrazin-2-ylmethyl.
  • R 8 is 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl. In some embodiments, R 8 is 2-(2-chloro-phenyl)-ethyl. In some embodiments, R 8 is 3-chloro-5-trifluoromethyl-pyridin-2-ylmethyl. In some embodiments, R 8 is 2-hydroxy-1-hydroxymethyl-ethyl. In some embodiments, R 8 is (1-methyl-pyrrolidin-2-yl)-pyridin-2-yl. In some embodiments, R 8 is 5-fluoro-2-hydroxy-phenyl. In some embodiments, R 8 is methyl.
  • R 8 is 4-(methoxycarbonyl)-1-methylpiperidin-4-yl. In some embodiments, R 8 is 4-hydroxymethyl-1-methyl-piperidin-4-yl. In some embodiments, R 8 is 2-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl. In some embodiments, R 8 is 1-phenyl-cyclohexyl. In some embodiments, R 8 is 3-methyl-1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 8 is 1-cyano-cyclohexyl.
  • R 8 is 1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl. In some embodiments, R 8 is 2-cyanopropan-2-yl. In some embodiments, R 8 is 3-methyl-1-phenylureido. In some embodiments, R 8 is 1-carbamoyl-2,2-dimethyl-propyl. In some embodiments, R 8 is tert-butylamino. In some embodiments, R 8 is 2,2,2-trifluoro-1,1-dimethyl-ethyl. In some embodiments, R 8 is 2,2-dimethyl-1-methylcarbamoyl-propyl.
  • R 8 is 1-cyclopropyl-ethyl. In some embodiments, R 8 is amino. In some embodiments, R 8 is N-tert-butylmethylsulfonamido. In some embodiments, R 8 is 1,1-dimethyl-prop-2-ynyl. In some embodiments, R 8 is 2-methyl-1-(phosphonooxy)propan-2-yl. In some embodiments, R 8 is 1-tert-butyl-3-methylureido. In some embodiments, R 8 is 4-cyano-tetrahydro-pyran-4-yl. In some embodiments, R 8 is 1-methyl-cyclobutyl. In some embodiments, R 8 is 1-hydroxymethyl-2-methyl-propyl.
  • R 8 is cyclobutylamino. In some embodiments, R 8 is 1-cyano-cyclopentyl. In some embodiments, R 8 is cyano-dimethyl-methyl. In some embodiments, R 8 is 2,2-dimethyl-1-(methylcarbamoyl)-propyl. In some embodiments, R 8 is phenylamino. In some embodiments, R 8 is 1-hydroxymethyl-propyl. In some embodiments, R 8 is 1-methyl-1-(1H-tetrazol-5-yl)-ethyl. In some embodiments, R 8 is 3,3-dimethyl-1-(phosphonooxy)butan-2-yl).
  • R 8 is 2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl. In some embodiments, R 8 is 1,2-dimethyl-propyl. In some embodiments, R 8 is 1-pyridin-2-yl-cyclobutyl. In some embodiments, R 8 is 1-hydroxymethyl-2-phenyl-ethyl. In some embodiments, R 8 is 4-methylcarbamoyl-tetrahydro-pyran-4-yl. In some embodiments, R 8 is 1-methyl-1-methylcarbamoyl-ethyl. In some embodiments, R 8 is 2,2-dimethyl-1-morpholin-4-ylmethyl-propyl.
  • R 8 is 1-methylcarbamoyl-cyclopent-3-enyl. In some embodiments, R 8 is 2-methoxy-2-oxo-1-(pyridin-2-yl)ethyl. In some embodiments, R 8 is methylcarbamoyl-pyridin-2-yl-methyl. In some embodiments, R 8 is 1-methylcarbamoyl-cyclopentyl. In some embodiments, R 8 is 1-(tert-butylcarbamoyl)-2,2-dimethyl-propyl. In some embodiments, R 8 is 2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl.
  • R 8 is 1-(pyridin-2-ylcarbamoyl)-cyclobutyl. In some embodiments, R 8 is 1-methylcarbamoyl-cyclobutyl. In some embodiments, R 8 is 2-(methylamino)-2-oxo-1-phenylethyl. In some embodiments, R 8 is pyrrolidin-1-yl. In some embodiments, R 8 is piperidin-1-yl. In some embodiments, R 8 is 2,6-dimethyl-piperidin-1-yl. In some embodiments, R 8 is 1-cyclopropylcarbamoyl-2,2-dimethyl-propyl.
  • R 8 is 2,2-dimethyl-1-(2,2,2-trifluoro-ethylcarbamoyl)-propyl. In some embodiments, R 8 is 1-ethylcarbamoyl-2,2-dimethyl-propyl. In some embodiments, R 8 is 2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl. In some embodiments, R 8 is N-cyclobutylmethylsulfonamido. In some embodiments, R 8 is N-phenylmethylsulfonamido. In some embodiments, R 8 is 1-cyclopropyl-2-hydroxy-ethyl. In some embodiments, R 8 is 1,2,2-trimethyl-propyl.
  • R 8 is 2-oxo-1-(pyridin-2-yl)-2-(2,2,2-trifluoroethylamino)ethyl. In some embodiments, R 8 is 2,2-dimethyl-1-pyridin-2-yl-propyl. In some embodiments, R 8 is 1-methoxy-3,3-dimethyl-1-oxobutan-2-yl. In some embodiments, R 8 is 1-carboxy-2,2-dimethylpropyl. In some embodiments, R 8 is 1-(hydroxy-methyl-carbamoyl)-2,2-dimethyl-propyl. In some embodiments, R 8 is 1-dimethylcarbamoyl-2,2-dimethyl-propyl.
  • R 8 is 1-(azetidine-1-carbonyl)-2,2-dimethyl-propyl. In some embodiments, R 8 is 1-methoxycarbamoyl-2,2-dimethyl-propyl. In some embodiments, R 8 is 1-(methoxy-methyl-carbamoyl)-2,2-dimethyl-propyl. In some embodiments, R 8 is 1-tert-butoxycarbamoyl-2,2-dimethyl-propyl. In some embodiments, R 8 is 2,2-dimethyl-1-pyridin-2-yl-propyl. In some embodiments, R 8 is fluoromethyl. In some embodiments, R 8 is 2,2,2-trifluoroethylamino.
  • R 8 is (1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl)amino. In some embodiments, R 8 is 1-hydroxycarbamoyl-2,2-dimethyl-propyl. In some embodiments, R 8 is 1-hydroxymethyl-2-methyl-butyl. In some embodiments, R 8 is 1-(2-hydroxy-ethylcarbamoyl)-2,2-dimethyl-propyl. In some embodiments, R 8 is 1,1-bis-hydroxymethyl-propyl. In some embodiments, R 8 is 1-(5-fluoro-pyridin-2-yl)-2,2-dimethyl-propyl.
  • R 8 is 4-hydroxymethyl-tetrahydro-2H-pyran-4-yl. In some embodiments, R 8 is 1-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-2-methylpropan-2-yl. In some embodiments, R 8 is 1-(2-amino-3-methylbutanoyloxy)-3-methylbutan-2-yl. In some embodiments, R 8 is 1-(2-amino-3-methylbutanoyloxy)-2-methylpropan-2-yl. In some embodiments, R 8 is 2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-ethyl.
  • R 8 is 1-(4-carboxybutanoyloxy)-2-methylpropan-2-yl. In some embodiments, R 8 is 1-(4-carboxybutanoyloxy)-3-methylbutan-2-yl. In some embodiments, R 8 is 1-(4-carboxybutanoyloxy)-3,3-dimethylbutan-2-yl. In some embodiments, R 8 is 1-(2-amino-3-methylbutanoyloxy)-3,3-dimethylbutan-2-yl. In some embodiments, R 8 is 2-(2-amino-3-methylbutanoyloxy)-1-(tetrahydro-2H-pyran-4-yl)ethyl.
  • R 8 is 3,3,3-trifluoro-1-hydroxymethyl-propyl. In some embodiments, R 8 is 3-fluoro-1-methoxy-3-methyl-1-oxobutan-2-yl. In some embodiments, R 8 is 1-ethoxy-4,4,4-trifluoro-1-oxo-3-(trifluoromethyl)butan-2-yl. In some embodiments, R 8 is 2-fluoro-1-hydroxymethyl-2-methyl-propyl. In some embodiments, R 8 is 1-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-3,3-dimethylbutan-2-yl.
  • R 8 is 4,4,4-trifluoro-1-methoxy-1-oxobutan-2-yl. In some embodiments, R 8 is 2-fluoro-1,1-dimethyl-ethyl. In some embodiments, R 8 is 3-fluoro-2-(fluoromethyl)-1-methoxy-1-oxopropan-2-yl. In some embodiments, R 8 is 2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl. In some embodiments, R 8 is 3-hydroxy-1-methoxy-2-methyl-1-oxopropan-2-yl. In some embodiments, R 8 is 2-carboxy-1-hydroxypropan-2-yl.
  • R 8 is 2,2,2-trifluoroethylamino. In some embodiments, R 8 is 1-fluoromethyl-2-methyl-propyl. In some embodiments, R 8 is 1-fluoromethyl-2,2-dimethyl-propyl. In some embodiments, R 8 is 3-methyl-oxetan-3-yl. In some embodiments, R 8 is 1-fluoromethyl-cyclobutyl. In some embodiments, R 8 is 1,1-bis-hydroxymethyl-2-methyl-propyl.
  • R 8 is 1-trifluoromethyl-cyclopropyl. In some embodiments, R 8 is 1-methyl-cyclopropyl. In some embodiments, R 8 is 1-trifluoromethyl-cyclobutyl.
  • R 9 is selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl.
  • R 9 is C 1 -C 6 alkyl.
  • R 9 is C 3 -C 7 cycloalkyl.
  • R 9 is selected from H, methyl, tert-butyl, and cyclobutyl.
  • R 9 is H.
  • R 9 is methyl
  • R 9 is tert-butyl
  • R 9 is cyclobutyl
  • R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene.
  • R 10 is selected from: 1,1-dimethylethylene, 1,1-dimethylmethylene, ethylene, methylene, 1,4-piperidinylene, 2,5-pyrazinylene, and 2,4-pyridinylene.
  • R 10 is C 1 -C 6 alkylene.
  • R 10 is selected from: 1,1-dimethylethylene, 1,1-dimethylmethylene, ethylene, and methylene.
  • R 10 is 1,1-dimethylethylene
  • R 10 is 1,1-dimethylmethylene.
  • R 10 is ethylene
  • R 10 is methylene
  • R 10 is heteroarylene
  • R 10 is selected from: 2,5-pyrazinylene, and 2,4-pyridinylene.
  • R 10 is heterocyclylene.
  • R 10 is 1,4-piperidinylene.
  • R 10 is absent.
  • R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene.
  • R 11 is selected from: —C(O)NH— and methylene.
  • R 11 is —C(O)NH—.
  • R 11 is C 1 -C 6 alkylene.
  • R 11 is methylene
  • R 11 is absent.
  • R 12 is C 1 -C 6 alkylene.
  • R 12 is methylene
  • R 12 is 1,1-dimethyl-methylene.
  • R 12 is absent.
  • R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl.
  • R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: fluoro, bromo, chloro, iodo, methoxy, cyano, methyl, tert-butyl, isopropyl, hydroxyl, ethyl, heptafluoropropyl, cyclobutyl, trifluoromethyl, cyclopropyl, dimethylamino, methoxy, ethoxy, methylamino, propyl, amino, and methanesulfonyl.
  • R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: fluoro, bromo, chloro, methoxy, cyano, methyl, tert-butyl, isopropyl, hydroxyl, ethyl, heptafluoropropyl, cyclobutyl, trifluoromethyl, cyclopropyl, dimethylamino, methoxy, ethoxy, methylamino, propyl, amino, and methanesulfonyl.
  • R 13 is selected from: 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2-fluoro-4-methanesulfonyl-phenyl, 2,6-difluoro-phenyl, 2,5-difluoro-phenyl, 4-methoxy-phenyl, 4-cyano-phenyl, 4-fluoro-phenyl, phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, o-tolyl, tert-butyl, isopropyl, 2,2-dimethylpropyl, hydroxyl, 2-hydroxy-2-methylpropyl, 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl, 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl, tetrahydrothiopyran-4-yl, morpholin-4-yl, tetrahydro
  • R 13 is selected from: 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2-fluoro-4-methanesulfonyl-phenyl, 2,6-difluoro-phenyl, 2,5-difluoro-phenyl, 4-methoxy-phenyl, 4-cyano-phenyl, 4-fluoro-phenyl, phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, o-tolyl, tert-butyl, isopropyl, 2,2-dimethylpropyl, hydroxyl, 2-hydroxy-2-methylpropyl, 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl, 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl, tetrahydrothiopyran-4-yl, morpholin-4-yl, tetrahydro
  • R 13 is 2,4-difluoro-phenyl. In some embodiments, R 13 is 2,4-dichloro-phenyl. In some embodiments, R 13 is 2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R 13 is 2,6-difluoro-phenyl. In some embodiments, R 13 is 2,5-difluoro-phenyl. In some embodiments, R 13 is 4-methoxy-phenyl. In some embodiments, R 13 is 4-cyano-phenyl. In some embodiments, R 13 is 4-fluoro-phenyl. In some embodiments, R 13 is phenyl. In some embodiments, R 13 is 2-fluoro-phenyl.
  • R 13 is 3-fluoro-phenyl. In some embodiments, R 13 is o-tolyl. In some embodiments, R 13 is tert-butyl. In some embodiments, R 13 is isopropyl. In some embodiments, R 13 is 2,2-dimethylpropyl. In some embodiments, R 13 is hydroxyl. In some embodiments, R 13 is 2-hydroxy-2-methylpropyl. In some embodiments, R 13 is 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl. In some embodiments, R 13 is 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl.
  • R 13 is tetrahydrothiopyran-4-yl. In some embodiments, R 13 is morpholin-4-yl. In some embodiments, R 13 is tetrahydro-pyran-4-yl. In some embodiments, R 13 is 1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 13 is pyrazin-2-yl. In some embodiments, R 13 is 5-ethyl-pyrazin-2-yl. In some embodiments, R 13 is 5-hydroxy-pyrazin-2-yl. In some embodiments, R 13 is 5-isopropyl-pyrazin-2-yl.
  • R 13 is 5-heptafluoropropyl-pyrazin-2-yl. In some embodiments, R 13 is 5-cyclobutyl-pyrazin-2-yl. In some embodiments, R 13 is 5-methyl-pyrazin-2-yl. In some embodiments, R 13 is 6-ethyl-pyrazin-2-yl. In some embodiments, R 13 is 5-trifluoromethyl-pyrazin-2-yl. In some embodiments, R 13 is cyclopropyl. In some embodiments, R 13 is 5-cyclopropyl-pyrazin-2-yl. In some embodiments, R 13 is 6-chloro-pyrazin-2-yl.
  • R 13 is 5-dimethylamino-pyrazin-2-yl. In some embodiments, R 13 is 4-cyano-phenyl. In some embodiments, R 13 is 6-methoxy-pyridazin-3-yl. In some embodiments, R 13 is 6-chloro-pyridazin-3-yl. In some embodiments, R 13 is pyrimidin-5-yl. In some embodiments, R 13 is 6-dimethylamino-pyrazin-2-yl. In some embodiments, R 13 is 6-methoxy-pyrazin-2-yl. In some embodiments, R 13 is 2-pyrimidin-4-yl. In some embodiments, R 13 is 5-bromo-pyrazin-2-yl.
  • R 13 is 5-hydroxy-pyrazin-2-yl. In some embodiments, R 13 is 5-methoxy-pyrazin-2-yl. In some embodiments, R 13 is 5-ethoxypyrazin-2-yl. In some embodiments, R 13 is 5-methylamino-pyrazin-2-yl. In some embodiments, R 13 is 5-bromo-pyridin-2-yl. In some embodiments, R 13 is pyridin-3-yl. In some embodiments, R 13 is 5-trifluoromethyl-pyridin-2-yl. In some embodiments, R 13 is 5-isopropyl-pyridin-2-yl. In some embodiments, R 13 is 5-isopropyl-pyridin-2-yl. In some embodiments, R 13 is 5-isopropyl-pyridin-2-yl.
  • R 13 is 5-methyl-pyridin-2-yl. In some embodiments, R 13 is 5-ethyl-pyridin-2-yl. In some embodiments, R 13 is 5-methoxy-pyridin-2-yl. In some embodiments, R 13 is 4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 13 is 5-cyano-pyridin-2-yl. In some embodiments, R 13 is 5-dimethylamino-pyridin-2-yl. In some embodiments, R 13 is 4-methyl-pyridin-2-yl. In some embodiments, R 13 is 5-chloro-4-methyl-pyridin-2-yl.
  • R 13 is 5-chloro-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 13 is 4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 13 is 3-fluoro-pyridin-2-yl. In some embodiments, R 13 is 6-methyl-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 13 is 3-methyl-pyridin-2-yl. In some embodiments, R 13 is 5-propyl-pyridin-2-yl. In some embodiments, R 13 is 5-cyclopropyl-pyridin-2-yl. In some embodiments, R 13 is 5-fluoro-pyridin-2-yl.
  • R 13 is 3,5-difluoro-pyridin-2-yl. In some embodiments, R 13 is 6-bromo-pyridin-3-yl. In some embodiments, R 13 is 5-bromo-pyridin-3-yl. In some embodiments, R 13 is 5,6-difluoro-pyridin-3-yl. In some embodiments, R 13 is 6-chloro-pyridin-3-yl. In some embodiments, R 13 is 3-fluoro-pyridin-4-yl. In some embodiments, R 13 is 5-cyano-pyridin-3-yl. In some embodiments, R 13 is pyridin-4-yl. In some embodiments, R 13 is 2-chloro-pyridin-4-yl.
  • R 13 is 2-methoxy-pyridin-4-yl. In some embodiments, R 13 is 6-methyl-pyridin-3-yl. In some embodiments, R 13 is m-tolyl. In some embodiments, R 13 is thiazol-2-yl. In some embodiments, R 13 is cyclopentyl. In some embodiments, R 13 is 4-amino-pyridin-2-yl. In some embodiments, R 13 is 4-methoxy-pyridin-2-yl. In some embodiments, R 13 is 4-choro-pyridin-2-yl. In some embodiments, R 13 is 4-fluoro-pyridin-2-yl.
  • R 13 is 4-cyclopropyl-pyridin-2-yl. In some embodiments, R 13 is 4-bromo-pyridin-2-yl. In some embodiments, R 13 is 4-methanesulfonyl-pyridin-2-yl. In some embodiments, R 13 is 4-cyano-pyridin-2-yl. In some embodiments, R 13 is hydroxymethyl. In some embodiments, R 13 is 4-oxy-pyrazin-2-yl. In some embodiments, R 13 is 3-methyl-1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 13 is 5-chloro-3-fluoro-pyridin-2-yl.
  • R 13 is 3-fluoro-5-methoxy-pyridin-2-yl. In some embodiments, R 13 is 2-chloro-4-fluoro-phenyl. In some embodiments, R 13 is 6-fluoro-pyridin-3-yl. In some embodiments, R 13 is 6-cyano-pyridin-3-yl. In some embodiments, R 13 is 4-iodo-pyridin-2-yl. In some embodiments, R 13 is 1-oxy-pyridin-3-yl. In some embodiments, R 13 is 4-hydroxy-pyridin-2-yl.
  • R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl.
  • R 14 is selected from: C 1 -C 6 alkylene and C 3 -C 7 cycloalkylene; wherein said C 1 -C 6 alkylene is optionally substituted with one or more substituents selected from: C 1 -C 6 alkyl, aryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl is optionally substituted with one substituent selected from: halogen, and hydroxyl.
  • R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl, pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl, carboxy, methoxymethyl, hydroxyethyl, tetrahydro-furanyl, 3H-imidazolylmethyl, hydroxyl, pyrrolidinyl, cyclopropyl, sec-butyl, 2,2,2-trifluoroethyl, 2-fluoropropan-2-yl, 1,1,1,3,3,3-hex
  • R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl, pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl, carboxy, methoxymethyl, hydroxyethyl, tetrahydro-furanyl, 3H-imidazolylmethyl, hydroxyl, pyrrolidinyl, and cyclopropyl.
  • R 14 is selected from: C 1 -C 6 alkylene and C 3 -C 7 cycloalkylene; wherein said C 1 -C 6 alkylene is optionally substituted with one or more substituents selected from: tetrahydro-2H-pyranyl, hydroxyl, 2,2,2-trifluoroethyl, and fluoromethyl.
  • R 14 is selected from: methylene, ethylene, cyclopropylene, cyclobutylene, piperidinylene, pyridinylene, tetrahydropyranylene, thiazolylene, cyclohexylene, cyclopentylene, cyclopentenylene, dioxohexahydrothiopyranylene, pyrrolidinylene, tetrahydrothiophenylene, propylene, 3,3-oxetanylene, and —SO 2 —; wherein said ethylene, methylene, piperidinylene, propylene, and pyrrolidinylene are each optionally substituted with one or more substituents selected from: methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl, pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl,
  • R 14 is selected from: methylene, ethylene, cyclopropylene, cyclobutylene, piperidinylene, pyridinylene, tetrahydropyranylene, thiazolylene, cyclohexylene, cyclopentylene, cyclopentenylene, dioxohexahydrothiopyranylene, pyrrolidinylene, tetrahydrothiophenylene, propylene, and —SO 2 —; wherein said ethylene, methylene, piperidinylene, propylene, and pyrrolidinylene are each optionally substituted with one or more substituents selected from: methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl, pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl, carboxy, methoxymethyl, hydroxy
  • R 14 is selected from: methylene, ethylene, 1,1-cyclopropylene, 1,1-dimethyl-methylene, 1,1-cyclobutylene, tert-butyl-methylene, 1-methyl-4,4-piperidinylene, 4,4-tetrahydro-2H-pyranylene, methyl-methylene, 1,1-cyclohexylene, 1,2-cyclohexylene, 1,1-dimethyl-ethylene, 1-tert-butyl-ethylene, 1-ethyl-ethylene, 1-methyl-ethylene, 1-(tetrahydro-2H-pyran-4-yl)-ethylene, isopropyl-methylene, 1,1-cyclopentylene, benzyl-methylene, 4,4-cyclopent-1-enylene, 1,1-dioxo-hexahydro-1 ⁇ 6 -4,4-thiopyranylene, 1-tert-butoxycarbonyl-4,4-piperidinylene, 1-(pyridin-4-yl
  • R 14 is selected from: methylene, ethylene, 1,1-cyclopropylene, 1,1-dimethyl-methylene, 1,1-cyclobutylene, tert-butyl-methylene, 1-methyl-4,4-piperidinylene, 4,4-tetrahydro-2H-pyranylene, methyl-methylene, 1,1-cyclohexylene, 1,2-cyclohexylene, 1,1-dimethyl-ethylene, 1-tert-butyl-ethylene, 1-ethyl-ethylene, 1-methyl-ethylene, 1-(tetrahydro-2H-pyran-4-yl)-ethylene, isopropyl-methylene, 1,1-cyclopentylene, benzyl-methylene, 4,4-cyclopent-1-enylene, 1,1-dioxo-hexahydro-1 ⁇ 6 -4,4-thiopyranylene, 1-tert-butoxycarbonyl-4,4-piperidinylene, 1-(pyridin-4-yl
  • R 14 is selected from: 1,1-cyclopropylene, 1,1-dimethyl-methylene, 1,1-cyclobutylene, tert-butyl-methylene, 1,1-dimethyl-ethylene, 1-tert-butyl-ethylene, 1-(tetrahydro-2H-pyran-4-yl)-ethylene, isopropyl-methylene, 1-hydroxymethyl-1-methyl-ethylene, phenyl-methylene, 1-isopropyl-ethylene, 1-(2,2,2-trifluoroethyl)-ethylene, and 1,1-di(fluoromethyl)-ethylene.
  • R 14 is methylene. In some embodiments, R 14 is ethylene. In some embodiments, R 14 is 1,1-cyclopropylene. In some embodiments, R 4 is 1,1-dimethyl-methylene. In some embodiments, R 14 is 1,1-cyclobutylene. In some embodiments, R 14 is tert-butyl-methylene. In some embodiments, R 4 is 1-methyl-4,4-piperidinylene. In some embodiments, R 14 is 4,4-tetrahydro-2H-pyranylene. In some embodiments, R 14 is methyl-methylene. In some embodiments, R 14 is 1,1-cyclohexylene. In some embodiments, R 14 is 1,2-cyclohexylene.
  • R 14 is 1,1-dimethyl-ethylene. In some embodiments, R 14 is 1-tert-butyl-ethylene. In some embodiments, R 14 is 1-ethyl-ethylene. In some embodiments, R 14 is 1-methyl-ethylene. In some embodiments, R 14 is 1-(tetrahydro-2H-pyran-4-yl)-ethylene. In some embodiments, R 14 is isopropyl-methylene. In some embodiments, R 14 is 1,1-cyclopentylene. In some embodiments, R 14 is benzyl-methylene. In some embodiments, R 14 is 4,4-cyclopent-1-enylene.
  • R 14 is 1,1-dioxo-hexahydro-1 ⁇ 6 -4,4-thiopyranylene. In some embodiments, R 14 is 1-tert-butoxycarbonyl-4,4-piperidinylene. In some embodiments, R 14 is 1-(pyridin-4-yl)-ethylene. In some embodiments, R 14 is 1-(pyridin-3-yl)-ethylene. In some embodiments, R 14 is 1-(pyridin-2-yl)-ethylene. In some embodiments, R 14 is 1-(4-fluoro-phenyl)-ethylene. In some embodiments, R 14 is 1-hydroxymethyl-1-methyl-ethylene. In some embodiments, R 14 is 1-carboxy-1-methyl-ethylene.
  • R 14 is 1-methoxymethyl-ethylene. In some embodiments, R 14 is 1-hydroxymethyl-ethylene. In some embodiments, R 14 is 1-(1-hydroxyethyl)-ethylene. In some embodiments, R 14 is 1,1-dimethyl-ethylene. In some embodiments, R 14 is 1-(tetrahydro-furan-3-yl)-ethylene. In some embodiments, R 14 is phenyl-methylene. In some embodiments, R 14 is 1-(3H-imidazol-4-ylmethyl)-ethylene. In some embodiments, R 14 is 1-(4-hydroxy-phenyl)-ethylene. In some embodiments, R 14 is benzyl-ethylene. In some embodiments, R 14 is (1-hydroxymethyl-2-methyl)-ethylene.
  • R 14 is 1-isopropyl-ethylene. In some embodiments, R 14 is pyridin-2-yl-methylene. In some embodiments, R 14 is 1,1-dimethyl-propylene. In some embodiments, R 14 is 2-hydroxy-propylene. In some embodiments, R 14 is (1-isobutyl-pyrrolidin-3-yl)-methylene. In some embodiments, R 14 is 1,3-azetidinylene. In some embodiments, R 14 is 1,3-pyrrolidinylene. In some embodiments, R 14 is 1,3-piperidinylene. In some embodiments, R 14 is 1,4-piperidinylene. In some embodiments, R 14 is 2,4-thiazolylene.
  • R 14 is 3,4-pyridinylene. In some embodiments, R 14 is 2,4-pyridinylene. In some embodiments, R 14 is 2,5-pyridinylene. In some embodiments, R 14 is —SO 2 —. In some embodiments, R 14 is 2,5-pyridinylene. In some embodiments, R 14 is 1-cyclopropyl-ethylene. In some embodiments, R 14 is 1-(sec-butyl)-ethylene. In some embodiments, R 14 is 1-hydroxymethyl-1-ethyl-ethylene. In some embodiments, R 14 is 1-isopropyl-ethylene. In some embodiments, R 14 is 1-(2,2,2-trifluoroethyl)-ethylene.
  • R 14 is (2-fluoropropan-2-yl)-methylene. In some embodiments, R 14 is (1,1,1,3,3,3-hexafluoropropan-2-yl)-methylene. In some embodiments, R 14 is 1-(2-fluoropropan-2-yl)-ethylene. In some embodiments, R 14 is (2,2,2-trifluoroethyl)-methylene. In some embodiments, R 14 is 1,1-di(fluoromethyl)-ethylene. In some embodiments, R 14 is (hydroxymethyl)(methyl)methylene. In some embodiments, R 14 is (hydroxymethyl)(methyl)methylene. In some embodiments, R 14 is 3,3-oxetanylene. In some embodiments, R 14 is 1-hydroxymethyl-1-isopropyl-ethylene.
  • R 14 is absent.
  • R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl.
  • R 15 is selected from: —C(O)NH—, —C(O)—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl.
  • R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with methyl.
  • R 15 is selected from: —C(O)NH—, —C(O)—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with methyl.
  • R 15 is selected from: pyrrolidinylene, piperidinylene, pyridinylene, azetidinylene, —C(O)NH—, —C(O)—, —C(O)O—, morpholinylene, methylene, ethylene, cyclopropylene, tetrahydropyranylene, cyclopentylene, tetrahydrothiophenylene, oxotetrahydrothiophenylene; wherein said piperidinylene is optionally substituted with methyl.
  • R 15 is selected from: pyrrolidinylene, piperidinylene, pyridinylene, azetidinylene, —C(O)NH—, —C(O)—, morpholinylene, methylene, ethylene, cyclopropylene, tetrahydropyranylene, cyclopentylene, tetrahydrothiophenylene, oxotetrahydrothiophenylene; wherein said piperidinylene is optionally substituted with methyl.
  • R 15 is selected from: 1,3-pyrrolidinylene, 1,4-piperidinylene, 2,6-pyridinylene, 1,3-azetidinylene, —C(O)NH—, —C(O)—, —C(O)O—, 1,2-pyrrolidinylene, 2,4-morpholinylene, ethylene, methylene, 1,1-cyclopentylene, 4,4-tetrahydro-2H-pyranylene, 3,3-tetrahydro-thiophenylene, 1,1-cyclopropylene, 1-methyl-4,4-piperidinylene, and 1-oxo-tetrahydro-1 ⁇ 4 -3,3-thiophenylene.
  • R 15 is selected from: 1,3-pyrrolidinylene, 1,4-piperidinylene, 2,6-pyridinylene, 1,3-azetidinylene, —C(O)NH—, —C(O)—, 1,2-pyrrolidinylene, 2,4-morpholinylene, ethylene, methylene, 1,1-cyclopentylene, 4,4-tetrahydro-2H-pyranylene, 3,3-tetrahydro-thiophenylene, 1,1-cyclopropylene, 1-methyl-4,4-piperidinylene, and 1-oxo-tetrahydro-1 ⁇ 4 -3,3-thiophenylene.
  • R 15 is selected from: —C(O)NH— and —C(O)O—.
  • R 15 is 1,3-pyrrolidinylene. In some embodiments, R 15 is 1,4-piperidinylene. In some embodiments, R 15 is 2,6-pyridinylene. In some embodiments, R 15 is 1,3-azetidinylene. In some embodiments, R 15 is —C(O)NH—. In some embodiments, R 15 is —C(O)—. In some embodiments, R 15 is 1,2-pyrrolidinylene. In some embodiments, R 15 is 2,4-morpholinylene. In some embodiments, R 15 is ethylene. In some embodiments, R 15 is methylene. In some embodiments, R 15 is 1,1-cyclopentylene.
  • R 15 is 4,4-tetrahydro-2H-pyranylene. In some embodiments, R 15 is 3,3-tetrahydro-thiophenylene. In some embodiments, R 15 is 1,1-cyclopropylene. In some embodiments, R 15 is 1-methyl-4,4-piperidinylene. In some embodiments, R 15 is 1-oxo-tetrahydro-1 ⁇ 4 -3,3-thiophenylene.
  • R 15 is absent.
  • R 16 is C 1 -C 6 alkylene.
  • R 16 is selected from: ethylene, methylene, isopropyl-methylene, and propylene.
  • R 16 is selected from: methylene, isopropyl-methylene, and propylene.
  • R 16 is selected from: ethylene, and methylene.
  • R 16 is ethylene
  • R 16 is methylene
  • R 16 is absent.
  • R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, ary
  • R 17 is selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, amino, aryl, carboxy, cyano, C 1 -C 6 haloalkyl, heteroaryl, hydroxyl, and phosphonooxy; wherein said aryl is optionally substituted with one hydroxyl group.
  • R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino,
  • R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, ary
  • R 17 is selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heteroaryl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said aryl and C 3 -C 7 cycloalkyl are each optionally substituted with one or more substituents selected from: hydroxyl and trifluoromethyl.
  • R 17 is selected from: H, amino, 1-tert-butoxycarbonylamino, morpholin-4-yl, 4-methyl-piperidin-1-yl, piperidin-4-yl, 1-tert-butoxycarbonyl-piperidin-3-yl, tetrahydro-thiopyran-4-yl, 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl, tetrahydro-pyran-4-yl, pyrrolidin-1-yl, 1-tert-butoxycarbonyl-azetidin-3-yl, 2,6-dimethyl-morpholin-4-yl, piperidin-1-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl, tetrahydro-furan-2-yl, 1-ethyl-pyrrolidin-2-yl, 1-methyl
  • R 17 is selected from: H, amino, 1-tert-butoxycarbonylamino, morpholin-4-yl, 4-methyl-piperidin-1-yl, piperidin-4-yl, 1-tert-butoxycarbonyl-piperidin-3-yl, tetrahydro-thiopyran-4-yl, 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl, tetrahydro-pyran-4-yl, pyrrolidin-1-yl, 1-tert-butoxycarbonyl-azetidin-3-yl, 2,6-dimethyl-morpholin-4-yl, piperidin-1-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl, tetrahydro-furan-2-yl, 1-ethyl-pyrrolidin-2-yl, 1-methyl
  • R 17 is selected from: is selected from: amino, 2-hydroxy-indan-1-yl, hydroxyl, carboxy, trifluoromethyl, methyl, tert-butyl, cyano, tert-butylamino, phosphonooxy, pyridin-2-yl, and fluoromethyl.
  • R 17 is H. In some embodiments, R 17 is amino. In some embodiments, R 17 is 1-tert-butoxycarbonylamino. In some embodiments, R 17 is morpholin-4-yl. In some embodiments, R 17 is 4-methyl-piperidin-1-yl. In some embodiments, R 17 is piperidin-4-yl. In some embodiments, R 17 is 1-tert-butoxycarbonyl-piperidin-3-yl. In some embodiments, R 17 is tetrahydro-thiopyran-4-yl. In some embodiments, R 17 is 1-oxo-hexahydro-1 ⁇ 4 -thiopyran-4-yl.
  • R 17 is tetrahydro-pyran-4-yl. In some embodiments, R 17 is pyrrolidin-1-yl. In some embodiments, R 17 is 1-tert-butoxycarbonyl-azetidin-3-yl. In some embodiments, R 17 is 2,6-dimethyl-morpholin-4-yl. In some embodiments, R 17 is piperidin-1-yl.
  • R 17 is 1-tert-butoxycarbonyl-piperidin-4-yl. In some embodiments, R 17 is 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl. In some embodiments, R 17 is tetrahydro-furan-2-yl. In some embodiments, R 17 is 1-ethyl-pyrrolidin-2-yl. In some embodiments, R 17 is 1-methyl-pyrrolidin-2-yl. In some embodiments, R 17 is morpholin-2-yl. In some embodiments, R 17 is 1-methyl-piperidin-2-yl. In some embodiments, R 17 is 1-methyl-piperidin-4-yl.
  • R 17 is 4-hydroxy-1-methyl-piperidin-4-yl. In some embodiments, R 17 is thiomorpholin-4-yl. In some embodiments, R 17 is tetrahydro-furan-3-yl. In some embodiments, R 17 is 1-tert-butoxycarbonyl-pyrrolidin-4-yl. In some embodiments, R 17 is 1,2,2,6,6-pentamethyl-piperidin-4-yl. In some embodiments, R 17 is 1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 17 is 4-methyl-morpholin-2-yl.
  • R 17 is 4-tert-butoxycarbonyl-morpholin-2-yl. In some embodiments, R 17 is 1-isopropyl-piperidin-4-yl. In some embodiments, R 17 is 4-hydroxy-1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 17 is 3-methyl-1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl. In some embodiments, R 17 is phenyl. In some embodiments, R 17 is 2-hydroxy-indan-1-yl. In some embodiments, R 17 is indan-1-yl. In some embodiments, R 17 is cyclopentyl.
  • R 17 is 2-hydroxy-cyclopentyl. In some embodiments, R 17 is cyclobutyl. In some embodiments, R 17 is 2-hydroxy-cyclohexyl. In some embodiments, R 17 is 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl. In some embodiments, R 17 is 6,6-dimethyl-bicyclo[3.1.1]hept-2-yl. In some embodiments, R 17 is 1-aza-bicyclo[2.2.2]oct-3-yl. In some embodiments, R 17 is 9-methyl-9-aza-bicyclo[3.3.1]non-1-yl. In some embodiments, R 17 is 3-azepan-1-yl.
  • R 17 is 2-fluoro-phenyl. In some embodiments, R 17 is 2-chloro-phenyl. In some embodiments, R 17 is 4-fluoro-phenyl. In some embodiments, R 17 is 4-chloro-phenyl. In some embodiments, R 17 is 3-fluoro-phenyl. In some embodiments, R 17 is 5-fluoro-2-methoxy-phenyl. In some embodiments, R 17 is 2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R 17 is 4-carboxy-2-fluoro-phenyl. In some embodiments, R 17 is 2,5-difluoro-phenyl.
  • R 17 is m-tolyl. In some embodiments, R 17 is o-tolyl. In some embodiments, R 17 is 2,5-dimethyl-phenyl. In some embodiments, R 17 is 2,3-dimethyl-phenyl. In some embodiments, R 17 is 4-hydroxy-3-methoxy-phenyl. In some embodiments, R 17 is 2,4-dimethoxy-phenyl. In some embodiments, R 17 is 2,3-dimethoxy-phenyl. In some embodiments, R 17 is 3,5-dimethoxy-phenyl. In some embodiments, R 17 is 4-methoxy-phenyl. In some embodiments, R 17 is 3-methoxy-phenyl. In some embodiments, R 17 is 2-methoxy-phenyl. In some embodiments, R 17 is 3-hydroxy-phenyl. In some embodiments, R 17 is 4-hydroxy-phenyl. In some embodiments, R 17 is 2-hydroxy-phenyl.
  • R 17 is 5-fluoro-2-hydroxy-phenyl. In some embodiments, R 17 is 3-trifluoromethoxy-phenyl. In some embodiments, R 17 is 4-difluoromethoxy-phenyl. In some embodiments, R 17 is 3-difluoromethoxy-phenyl. In some embodiments, R 17 is 4-fluoro-phenoxy. In some embodiments, R 17 is 2-dimethylamino-phenyl. In some embodiments, R 17 is 4-dimethylamino-phenyl. In some embodiments, R 17 is 6-fluoro-4H-benzo[1,3]dioxin-8-yl.
  • R 17 is benzo[1,3]dioxol-5-yl. In some embodiments, R 17 is pyrimidin-2-yl. In some embodiments, R 17 is pyrimidin-4-yl. In some embodiments, R 17 is 2,6-dimethyl-pyrimidin-4-yl. In some embodiments, R 17 is pyridazin-3-yl. In some embodiments, R 17 is 5-methyl-pyrazin-2-yl. In some embodiments, R 17 is 6-methoxy-pyrimidin-4-yl. In some embodiments, R 17 is pyrazin-2-yl. In some embodiments, R 17 is 3,5-dimethyl-pyrazin-2-yl.
  • R 17 is 5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl. In some embodiments, R 17 is hydroxyl. In some embodiments, R 17 is methoxycarbonyl. In some embodiments, R 17 is ethoxycarbonyl. In some embodiments, R 17 is carboxy. In some embodiments, R 17 is 1-piperidin-1-yl. In some embodiments, R 17 is carboxamide. In some embodiments, R 17 is methoxy. In some embodiments, R 17 is trifluoromethyl. In some embodiments, R 17 is methyl. In some embodiments, R 17 is tert-butyl. In some embodiments, R 17 is diethylamino.
  • R 17 is dimethylamino. In some embodiments, R 17 is cyano. In some embodiments, R 17 is tert-butylamino. In some embodiments, R 17 is cyclopropyl. In some embodiments, R 17 is pyridin-3-yloxy. In some embodiments, R 17 is 1H-tetrazol-5-yl. In some embodiments, R 17 is 5-methyl-[1,2,4]oxadiazol-3-yl. In some embodiments, R 17 is phosphonooxy. In some embodiments, R 17 is cyclobutylamino. In some embodiments, R 17 is phenylamino. In some embodiments, R 17 is 1-tert-butyl-3-methylureido.
  • R 17 is 3-methyl-1-phenylureido. In some embodiments, R 17 is N-tert-butylmethylsulfonamido. In some embodiments, R 17 is 1-cyclobutyl-3-methylureido. In some embodiments, R 17 is methylcarbamoyl. In some embodiments, R 17 is 5-hydroxy-1H-indol-3-yl. In some embodiments, R 17 is 1H-benzoimidazol-2-yl. In some embodiments, R 17 is 5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl. In some embodiments, R 17 is 1H-benzoimidazol-2-yl.
  • R 17 is 2-(tert-butoxycarbonyl)-3,4-dihydro-1H-isoquinoline-2-yl. In some embodiments, R 17 is quinolin-3-yl. In some embodiments, R 17 is quinolin-4-yl. In some embodiments, R 17 is 2-methyl-quinolin-4-yl. In some embodiments, R 17 is benzooxazol-2-yl. In some embodiments, R 17 is 1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl. In some embodiments, R 17 is 2,3-dihydro-benzofuran-3-yl. In some embodiments, R 17 is benzothiazol-2-yl.
  • R 17 is 1,4-dimethyl-1H-pyrrol-2-yl. In some embodiments, R 17 is 3-methyl-3H-imidazol-4-yl. In some embodiments, R 17 is 1H-imidazol-4-yl. In some embodiments, R 17 is 5-hydroxy-1H-pyrazol-3-yl. In some embodiments, R 17 is 1-methyl-1H-pyrazol-3-yl. In some embodiments, R 17 is 4-pyridin-2-yl-thiazol-2-yl. In some embodiments, R 17 is 5-methyl-thiazol-2-yl. In some embodiments, R 17 is oxazol-4-yl. In some embodiments, R 17 is 4-phenyl-thiazol-2-yl.
  • R 17 is 5-tert-butyl-isoxazol-3-yl. In some embodiments, R 17 is pyridin-2-yl. In some embodiments, R 17 is pyridin-3-yl. In some embodiments, R 17 is pyridin-4-yl. In some embodiments, R 17 is 3-hydroxy-pyridin-2-yl. In some embodiments, R 17 is 6-hydroxy-pyridin-3-yl. In some embodiments, R 17 is 3-hydroxy-pyridin-4-yl. In some embodiments, R 17 is 4-hydroxy-pyridin-2-yl. In some embodiments, R 17 is 6-hydroxy-pyridin-2-yl. In some embodiments, R 17 is 2-hydroxy-pyridin-3-yl.
  • R 17 is 2-methoxy-pyridin-3-yl. In some embodiments, R 17 is 5-methoxy-pyridin-2-yl. In some embodiments, R 17 is 4-methoxy-pyridin-2-yl. In some embodiments, R 17 is 2-methoxy-pyridin-4-yl. In some embodiments, R 17 is 6-methoxy-pyridin-2-yl. In some embodiments, R 17 is 6-methoxy-pyridin-3-yl. In some embodiments, R 17 is 3-fluoro-pyridin-2-yl. In some embodiments, R 17 is 2-fluoro-pyridin-3-yl. In some embodiments, R 17 is 6-fluoro-pyridin-2-yl.
  • R 17 is 5-fluoro-pyridin-2-yl. In some embodiments, R 17 is 6-fluoro-pyridin-3-yl. In some embodiments, R 17 is 3-fluoro-pyridin-4-yl. In some embodiments, R 17 is 3-methyl-pyridin-2-yl. In some embodiments, R 17 is 3-methyl-pyridin-4-yl. In some embodiments, R 17 is 6-methyl-pyridin-2-yl. In some embodiments, R 17 is 4-methyl-pyridin-2-yl. In some embodiments, R 17 is 6-methyl-pyridin-3-yl. In some embodiments, R 17 is 2-methyl-pyridin-3-yl.
  • R 17 is 5-trifluoromethyl-pyridin-2-yl. In some embodiments, R 17 is 6-trifluoromethyl-pyridin-3-yl. In some embodiments, R 17 is 4-trifluoromethyl-pyridin-2-yl. In some embodiments, R 17 is 3-chloro-5-trifluoromethyl-pyridin-2-yl. In some embodiments, R 17 is 4,6-dimethyl-pyridin-2-yl. In some embodiments, R 17 is 4,6-dimethyl-pyridin-2-yl. In some embodiments, R 17 is 3-chloro-5-methyl-pyridin-2-yl. In some embodiments, R 17 is 6-cyano-pyridin-3-yl.
  • R 17 is 3-cyano-5-methyl-pyridin-2-yl. In some embodiments, R 17 is 3-cyano-5-methyl-pyridin-2-yl. In some embodiments, R 17 is 3-chloro-5-methyl-pyridin-2-yl. In some embodiments, R 17 is 2-chloro-pyridin-3-yl. In some embodiments, R 17 is 5-chloro-pyridin-2-yl. In some embodiments, R 17 is 6-chloro-2-methyl-pyridin-3-yl. In some embodiments, R 17 is 6-chloro-pyridin-3-yl. In some embodiments, R 17 is 3-chloro-pyridin-4-yl.
  • R 17 is 6-bromo-2-methyl-pyridin-3-yl. In some embodiments, R 17 is 5-bromo-3-methyl-pyridin-2-yl. In some embodiments, R 17 is 6-carboxypyridin-2-yl. In some embodiments, R 17 is 6-methanesulfonyl-4-methyl-pyridin-3-yl. In some embodiments, R 17 is 6-methanesulfonyl-4-methyl-pyridin-3-yl. In some embodiments, R 17 is 6-methanesulfonyl-2-methyl-pyridin-3-yl. In some embodiments, R 17 is 6-methanesulfonyl-pyridin-3-yl.
  • R 17 is 2,6-dimethoxy-pyridin-3-yl. In some embodiments, R 17 is 5-fluoro-1-oxy-pyridin-2-yl. In some embodiments, R 17 is 1-oxy-pyridin-2-yl. In some embodiments, R 17 is 6-pyrrolidin-1-yl-pyridin-2-ylmethyl. In some embodiments, R 17 is 5-(1-methyl-pyrrolidin-2-yl)-pyridin-2-yl. In some embodiments, R 17 is 6-morpholin-4-yl-pyridin-2-yl. In some embodiments, R 17 is 6-morpholin-4-yl-pyridin-3-yl. In some embodiments, R 17 is ethynyl.
  • R 17 is tert-butyl(methyl)amino. In some embodiments, R 17 is 2,2,2-trifluoroethyl. In some embodiments, R 17 is N-cyclobutylmethylsulfonamido. In some embodiments, R 17 is N-phenylmethylsulfonamido. In some embodiments, R 17 is hydroxy(methyl)amino. In some embodiments, R 17 is methoxy(methyl)amino. In some embodiments, R 17 is azetidin-1-yl. In some embodiments, R 17 is tert-butoxy. In some embodiments, R 17 is fluoromethyl. In some embodiments, R 17 is 2,2,2-trifluoroethylamino. In some embodiments, R 17 is (1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophen-3-yl)amino.
  • R 15 is selected from: —C(O)NH—, —C(O)—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent; and
  • R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, aryl, ary
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl.
  • R 1 and R 6 are each independently selected from: H, and C 1 -C 6 alkyl; and R 2 , R 3 , R 4 , and R 5 are each H.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H, methyl, and isopropyl.
  • R 1 is selected from: H and methyl; R 2 , R 3 , R 4 , and R 5 are each H; and R 6 is selected from: H and is isopropyl.
  • R 1 is methyl
  • R 2 , R 3 , R 4 , and R 5 are each H
  • R 6 is isopropyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each H.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: carbo-C 1 -C 6 -alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-cyclohexylmethyl-piperazin-1-yl, hexahydro-pyrrolo[1,2-a]pyrazin-2-yl, 5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl, 4-methoxy-2,3-dihydro-indol-1-yl, 2-phenyl-pyrrolidin-1-yl, 2-pyridin-2-yl-thiomorpholin-4-yl, 2-hydroxymethyl-2,3-dihydro-indol-1-yl, 4-hydroxy-piperidin-1-yl, hexahydro-pyrrolo[1,2-a]pyrazin-2-yl, 7-(methoxycarbonyl)-3,4-dihydro-1H-isoquinolin-2-yl, 7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl,
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-cyclohexylmethyl-piperazin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form hexahydro-pyrrolo[1,2-a]pyrazin-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-methoxy-2,3-dihydro-indol-1-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-phenyl-pyrrolidin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-pyridin-2-yl-thiomorpholin-4-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-hydroxymethyl-2,3-dihydro-indol-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-hydroxy-piperidin-1-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form hexahydro-pyrrolo[1,2-a]pyrazin-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 7-(methoxycarbonyl)-3,4-dihydro-1H-isoquinolin-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 5-fluoro-1,3-dihydro-isoindol-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3-hydroxy-7,8-dihydro-5H-[1,6]naphthyridin-6-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 1,3-dihydro-isoindol-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-morpholin-4-yl-piperidin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3,4-dihydro-1H-isoquinolin-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3-hydroxy-piperidin-1-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-(3-chloro-phenyl)-piperazin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form morpholin-4-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-hydroxymethyl-pyrrolidin-1-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3-pyridin-4-yl-pyrrolidin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-(pyridin-2-yloxy)-piperidin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3-pyridin-2-yl-pyrrolidin-1-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 7-methyl-3,4-dihydro-2H-[1,8]naphthyridin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3-pyridin-3-yl-pyrrolidin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 3-hydroxy-pyrrolidin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 4-(4,6-dimethyl-pyrimidin-2-yl)-piperazin-1-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-methyl-3,4-dihydro-2H-quinolin-1-yl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-phenyl-morpholin-4-yl or pyrazin-2-yl.
  • the compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof is selected from compounds of Formula Ie and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:
  • R 9 is selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: carbo-C 1 -C 6 -alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl.
  • the compound of Formula Ia is selected from the following compounds and pharmaceutically acceptable salts, solvates, hydrates and/or N-oxides thereof:
  • the compound of Formula Ia is selected from the following compounds and pharmaceutically acceptable salts, solvates, hydrates and/or N-oxides thereof:
  • the compound of Formula Ia is (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide or a pharmaceutically acceptable salt, solvate, and/or hydrate, thereof.
  • FIG. 16 Peaks of about ⁇ 8.7% relative intensity at 8.5, 9.8, 10.7, 11.1, 11.8, 14.5, 16.5, 16.9, 17.4, 18.9, 22.1, and 25.4 °2 ⁇ TGA
  • FIG. 17 Decrease in weight of about 0.24% out to about 150° C.
  • DSC FIG. 17: Endotherm extrapolated onset temperature: about 162° C.
  • DMS FIG. 18: The adsorption/desorption isotherm shows about 1.0% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.1% or less weight change after a 10% RH to 90% RH back to 10% RH cycle, See Example 17.
  • RH relative humidity
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.5° ⁇ 0.2°, and 10.7° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, and 16.9° ⁇ 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 25.4° ⁇ 0.2°, and 11.1° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 25.4° ⁇ 0.2°, 11.1° ⁇ 0.2°, 9.8° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 25.4° ⁇ 0.2°, 11.1° ⁇ 0.2°, 9.8° ⁇ 0.2°, 17.4° ⁇ 0.2°, 22.1° ⁇ 0.2°, and 16.5° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 25.4° ⁇ 0.2°, 11.1° ⁇ 0.2°, 9.8° ⁇ 0.2°, 17.4° ⁇ 0.2°, 22.1° ⁇ 0.2°, 16.5° ⁇ 0.2°, 14.5° ⁇ 0.2°, 11.8° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 16 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ .
  • the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 159.6° C. and about 169.6° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 160.6° C. and about 168.6° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 162.6° C. and about 166.6° C.
  • the anhydrous crystalline form has having a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 163.6° C. and about 165.6° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 164.6° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in FIG. 17 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4° C. and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.5% weight loss below about 135° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.25% weight loss below about 135° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05% weight loss below about 135° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 17 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C., and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • anhydrous crystalline form having:
  • thermogravimetric analysis profile showing about 0.5% weight loss below about 135° C.
  • anhydrous crystalline form having:
  • thermogravimetric analysis profile showing about 0.25% weight loss below about 135° C.
  • anhydrous crystalline form having:
  • thermogravimetric analysis profile showing about 0.05% weight loss below about 135° C.
  • anhydrous crystalline form having:
  • thermogravimetric analysis profile showing about 0.05% weight loss below about 135° C.
  • anhydrous crystalline form having:
  • thermogravimetric analysis profile showing about 0.05% weight loss below about 135° C.
  • anhydrous crystalline form having:
  • thermogravimetric analysis profile showing about 0.05% weight loss below about 135° C.
  • anhydrous crystalline form having:
  • thermogravimetric analysis profile substantially as shown in FIG. 17 .
  • the compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof is (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide or a pharmaceutically acceptable salt, solvate, and/or hydrate thereof and the one or more known pharmaceutical agent is morphine.
  • chemical genera and individual compounds encompass all pharmaceutically acceptable salts, solvates, and particularly hydrates, and N-oxides thereof:
  • the compounds of the Formula Ia may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples. Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]).
  • the present invention embraces each diastereoisomer, each enantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers (such as, by chiral HPLC, recrystallization of diastereoisomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
  • the combinations disclosed herein are useful in the treatment of pain, and in the amelioration of symptoms thereof.
  • the analgesic properties of cannabinoids have been recognized for many years.
  • animal studies have demonstrated that the CB 1 /CB 2 agonists anandamide, THC, CP55,940 and WIN 55212-2 are effective against acute and chronic pain from chemical, mechanical, and thermal pain stimuli (reviewed in Walker and Huang (2002) Pharmacol. Ther. 95:127-135; reviewed in Pacher, P et al. (2006) Pharmacol. Rev. 58(3): 389-462).
  • topical administration of the CB 1 /CB 2 agonist HU-210 attenuates capsaicin-induced hyperalgesia and allodynia (Rukwied, R. et al. (2003) Pain 102:283-288), and co-administration of the CB 1 /CB 2 agonist THC and cannabidiol (nabiximols, trademark Sativex®) provides relief from cancer-associated pain (GW Pharmaceuticals press release Jan. 19, 2005, Jun. 19, 2007) and multiple-sclerosis-associated pain and spasticity (GW Pharmaceuticals press release Sep. 27, 2005, Mar. 11, 2009).
  • CB 1 The role of CB 1 in mediating these analgesic effects is well-documented (reviewed in Manzanares, J. et al. (2006) Current Neuropharmacology 4:239-57; reviewed in Pacher, P. et al. (2006) Pharmacol. Rev. 58(3): 389-462).
  • blockade of peripheral or central CB 1 leads to hyperalgesia (Richardson, J. D. et al. (1997) Eur. J. Pharmacol. 345:145-153; Calignano, A. et al.
  • CB 2 also plays a role in mediating analgesic effects of cannabinoids (reviewed in Guindon and Hohmann (2008) Br. J. Pharmacol. 153:319-334).
  • systemic delivery of the CB 2 -selective agonist AM1241 suppresses hyperalgesia induced in the carrageenan, capsaicin, and formalin models of inflammatory pain in rodents (reviewed in Guindon and Hohmann (2008) Br. J. Pharmacol. 153:319-334).
  • Local (subcutaneous) or systemic administration of AM1241 also reverses tactile and thermal hypersensitivity in rats following ligation of spinal nerves in the chronic constriction injury model of neuropathic pain (Malan, T.
  • CB 2 -specific agonists and/or CB 1 /CB 2 agonists find use in the treatment and/or prophylaxis of acute nociception and inflammatory hyperalgesia, as well as the allodynia and hyperalgesia produced by neuropathic pain.
  • these agonists are useful as an analgesic to treat pain arising from autoimmune conditions; allergic reactions; bone and joint pain; muscle pain; dental pain; nephritic syndrome; scleroderma; thyroiditis; migraine and other headache pain; pain associated with diabetic neuropathy; fibromyalgia, HIV-related neuropathy, sciatica, and neuralgias; pain arising from cancer; and pain that occurs as an adverse affect of therapeutics for the treatment of disease.
  • the severity of the pain can be assessed with self-reported measures as is known in the art. Generally, pain is assessed at rest, with appropriate activity (e.g., ambulation, cough), at baseline (prior to administration of the compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof and at regular intervals thereafter.
  • Some of the most commonly used pain assessment instruments include the visual analog scale (VAS), numeric rating scale (NRS), and categorical Likert scale.
  • VAS is a written assessment that typically utilizes a unmarked 100-mm line with the left end marked as “no pain” and the right end marked as “worst pain imaginable.” Subjects put a mark on the line corresponding to their level of pain.
  • the NRS can be applied in either written or verbal form and typically utilizes a rating from 0 (corresponding to “no pain”) to 10 (corresponding to “worst pain imageinable”).
  • Likert scales are typically four- or five-item instruments (e.g., ratings of “none”, “mild”, “moderate”, “severe”) that attempt to quantify pain.
  • the compounds described herein can be administrated in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a solvate or hydrate thereof. Moreover, various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K. J.
  • Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphs show the same properties in the liquid or gaseous state but they behave differently in the solid state.
  • drugs can also exist as salts and other multicomponent crystalline phases.
  • solvates and hydrates may contain an API host and either solvent or water molecules, respectively, as guests.
  • the guest compound is a solid at room temperature, the resulting form is often called a cocrystal.
  • Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as pseudopolymorphs of one another.
  • Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.
  • FIGS. 5 through 10 Illustrated syntheses for compounds described herein are shown in FIGS. 5 through 10 where the symbols have the same definitions as used throughout this disclosure.
  • TLC Thin-layer chromatography
  • LCMS spec HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC system controller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.
  • Step A Preparation of (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid Ethyl Ester.
  • Step B Preparation of (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid.
  • the remaining aqueous solution was diluted to 150 mL with water and then acidified to pH 2 by addition of 6 M HCl while stirring vigorously. The precipitate was collected by filtration, rinsed with water, and then dried under reduced pressure to give the title compound as a tan solid (15.62 g).
  • Step A Preparation of Potassium 2-Ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate
  • Step B Preparation of (1aR,5aR)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid Ethyl Ester.
  • Step C Preparation of (1aR,5aR)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid.
  • Step A Preparation of (1aR,5aR)-2-(5-Fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid Ethyl Ester
  • Step B Preparation of (1aR,5aR)-2-(5-Fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step C Preparation of (1aR,5aR)-2-(5-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (2-Hydroxy-1,1-dimethyl-ethyl)-amide
  • Step A Preparation of (1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step B Preparation of (1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide
  • thermogravimetric analysis (TGA) thermogram for this solvate showed a loss of ⁇ 5% weight occurring with a melting endotherm at 164° C.
  • aqueous sodium hypochlorite (1.54 M, 1059 mL, 1630 mmol) was added dropwise over 70 min while maintaining the internal temperature between ⁇ 10 and 0° C. Stirring was continued at 0° C. for another hour.
  • Sodium sulfite 50 g was added to quench excess sodium hypochlorite (temperature rose to 12° C.).
  • the layers were separated and the aqueous layer was extracted twice more with MTBE (500 mL then 250 mL).
  • the combined organic layers (total volume ca. 1600 mL) were dried (MgSO 4 ) then filtered.
  • the solution was concentrated (ca. 300 mL).
  • Step C Preparation of (1aS,5aS)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid Ethyl Ester.
  • Step D Preparation of (1aS,5aS)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (Intermediate 4).
  • Method LLL Preparation of (1aS,5aS)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (Intermediate 4).
  • Step A Preparation of (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid Ethyl Ester
  • Step B Preparation of (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step C Preparation of (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (2-Fluoro-1,1-dimethyl-ethyl)-amide (Compound 897)
  • Step B Preparation of (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (1-Trifluoromethyl-cyclobutyl)-amide (Compound 765)
  • Step B Preparation of (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (1-Trifluoromethyl-cyclopropyl)-amide (Compound 764)
  • Step B Preparation of (1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid Ethyl Ester
  • Step C Preparation of (1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step D Preparation of (1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step E Preparation of (1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (Compound 820)
  • Step A Preparation of (R)—N—((S)-2,2-Dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide and (R)—N—((R)-2,2-Dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide
  • Step B Preparation of (S)-2,2-Dimethyl-1-(pyridin-2-yl)propan-1-amine and (R)-2,2-Dimethyl-1-(pyridin-2-yl)propan-1-amine
  • the mixtures were diluted with water (25 mL), extracted with dichloromethane (3 ⁇ 25 mL), and the dichloromethane extracts discarded.
  • the aqueous solutions were basified with 2 M aqueous NaOH (25 mL) then extracted with dichloromethane (3 ⁇ 25 mL).
  • Step C Preparation of (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-2,2-Dimethyl-1-pyridin-2-yl-propyl)-amide
  • Step A Preparation of (1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide
  • Step B Preparation of (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide
  • Step C Preparation of (S)-2-tert-Butoxycarbonylamino-3-methyl-butyric Acid (S)-3,3-Dimethyl-2- ⁇ [(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino ⁇ -butyl Ester
  • Step D Preparation of (1aS,5aS)—(S)-2-Amino-3-methyl-butyric Acid (S)-3,3-Dimethyl-2- ⁇ [2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino ⁇ -butyl Ester
  • Step B Preparation of (1aR,5aR)-2-(4-Iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid Ethyl Ester
  • Step C Preparation of (1aR,5aR)-2-(4-Iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step D Preparation of (1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step E Preparation of (1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (2-Hydroxy-1,1-dimethyl-ethyl)-amide
  • the title compound was prepared in a manner similar to that described in Method G using 2-amino-2-methylpropane-1,3-diol and (1aR,5aR)-2-(5-Chloropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid.
  • the aforementioned acid was prepared in a similar method as described in Method A and B using (1R,5S)-bicyclo[3,1,0]hexan-2-one and 5-chloro-2-hydrazinylpyridine.
  • (S)-2-Amino-N-methyl-2-phenylacetamide was prepared in a manner similar to that described in Method HHH and III using (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid and methylamine.
  • the title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (S)-2-amino-N-methyl-2-phenylacetamide.
  • Step B Preparation of 2- ⁇ [(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino ⁇ -3-fluoro-2-fluoromethyl-propionic Acid Methyl Ester
  • Step C Preparation of (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (2-Fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl)-amide
  • Step A Preparation of (1aS,5aS)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step B Preparation of (1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid
  • Step D Preparation of (1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-3,3,3-Trifluoro-1-hydroxymethyl-propyl)-amide
  • Step F Preparation of (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-1-Fluoromethyl-2,2-dimethyl-propyl)-amide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017180528A1 (en) * 2016-04-10 2017-10-19 Arena Pharmaceuticals, Inc. Methods of treatment with selective cb2 receptor agonists
US11771695B2 (en) 2011-02-25 2023-10-03 Arena Pharmaceuticals, Inc. Cannabinoid receptor modulators
US12201633B2 (en) 2022-06-21 2025-01-21 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of visceral pain

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103539785B (zh) 2009-08-28 2015-09-23 艾尼纳制药公司 大麻素受体调节剂
KR102036932B1 (ko) 2011-02-25 2019-10-25 아레나 파마슈티칼스, 인크. 축합 아자사이클 (칸나비노이드 수용체 조절제)의 결정질 형태 및 제조 방법
US9597340B2 (en) 2011-02-25 2017-03-21 Arena Pharmaceuticals, Inc. Cannabinoid receptor modulators
CA3042642A1 (en) 2013-08-12 2015-02-19 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
EP2845625A1 (en) * 2013-09-04 2015-03-11 Grünenthal GmbH Tapentadol for use in the treatment of fibromyalgia and chronic fatigue syndrome
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
WO2016010771A1 (en) 2014-07-17 2016-01-21 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
WO2016064873A1 (en) 2014-10-20 2016-04-28 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
WO2021047581A1 (zh) * 2019-09-12 2021-03-18 四川海思科制药有限公司 一种六氢化苯并吡唑衍生物及其制备
WO2021047583A1 (zh) * 2019-09-12 2021-03-18 四川海思科制药有限公司 一种三环吡唑衍生物及其制备
EP4426703A1 (en) 2021-11-04 2024-09-11 Skyhawk Therapeutics, Inc. Triazine amino derivatives for treating sca3
WO2023212237A1 (en) 2022-04-27 2023-11-02 Skyhawk Therapeutics, Inc. Compositions useful for modulating splicing
WO2023220439A1 (en) 2022-05-12 2023-11-16 Skyhawk Therapeutics, Inc. Compositions useful for modulating splicing

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130165412A1 (en) * 2009-08-28 2013-06-27 Robert M. Jones Cannabinoid receptor modulators

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US236010A (en) 1880-12-28 Wilhelm effer
US5605906A (en) 1995-03-24 1997-02-25 Merck Frosst Canada, Inc. Cannabinoid receptor agonists
JP3964478B2 (ja) 1995-06-30 2007-08-22 エーザイ・アール・アンド・ディー・マネジメント株式会社 ヘテロ環含有カルボン酸誘導体及びそれを含有する医薬
US7308894B2 (en) 1998-06-03 2007-12-18 Scott Laboratories, Inc. Apparatuses and methods for providing a conscious patient relief from pain and anxiety associated with medical or surgical procedures according to appropriate clinical heuristics
PL196957B1 (pl) 1999-04-28 2008-02-29 Sanofi Aventis Deutschland Pochodne kwasu diarylowego, kompozycja farmaceutyczna zawierająca te pochodne, zastosowanie pochodnych kwasu diarylowego
CA2468794A1 (en) 2001-12-07 2003-06-19 Virginia Commonwealth University Treatment of neoplasia
IL150302A (en) 2002-01-31 2008-07-08 Naim Menashe Bicyclic cb2 cannabinoid receptor ligands
SE0300010D0 (sv) 2003-01-07 2003-01-07 Astrazeneca Ab Novel Compounds
WO2005123677A1 (en) 2004-06-16 2005-12-29 Actelion Pharmaceuticals Ltd 4-carbonyl substituted 1,1,2-trimethyl-1a,4,5,5a-tetrahydro-1h-4-aza-cyclopropa'a!pentalene derivatives as agonists for the g-protein-coupled receptor s1p1/edg1 and immunosuppressive agents
CN101014605A (zh) 2004-07-12 2007-08-08 卡地拉健康护理有限公司 用作大麻素受体调节物的三环吡唑衍生物
FR2875230A1 (fr) 2004-09-13 2006-03-17 Sanofi Aventis Sa Derives de pyrazole condense, leur preparation et leur application en therapeutique
DE102004054666A1 (de) 2004-11-12 2006-05-18 Bayer Cropscience Gmbh Substituierte Pyrazol-3-carboxamide, Verfahren zur Herstellung und Verwendung als Herbizide und Pflanzenwachstumsregulatoren
PE20060949A1 (es) * 2004-12-23 2006-10-11 Arena Pharm Inc Derivados fusionados de pirazol como agonistas del receptor de niacina
EP1902034B1 (en) * 2005-06-02 2011-03-30 Glenmark Pharmaceuticals S.A. Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
US7597910B2 (en) 2005-08-20 2009-10-06 Slgm Medical Research Institute Compositions and methods for treating prostate disorders
AU2006292051B2 (en) * 2005-09-23 2012-11-15 Janssen Pharmaceutica, N.V. Tetrahydro-cyclopentyl pyrazole cannabinoid modulators
SI2081572T1 (sl) 2006-07-04 2010-06-30 Janssen Pharmaceutica Nv Benzimidazolni kanabinoidni agonisti ki nosijo substituirano heterociklično skupino
EA200900403A1 (ru) 2006-09-25 2009-10-30 Бёрингер Ингельхайм Интернациональ Гмбх Соединения, которые модулируют рецептор св2
US8481574B2 (en) 2006-10-12 2013-07-09 Abbott Laboratories Compounds as cannabinoid receptor ligands
US7928103B2 (en) 2006-10-17 2011-04-19 Boehringer Ingelheim International Gmbh Compounds which modulate the CB2 receptor
US20080200501A1 (en) 2006-11-03 2008-08-21 Glenmark Pharmaceuticals S.A. Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and processes for their preparation
WO2008064054A2 (en) 2006-11-21 2008-05-29 Boehringer Ingelheim International Gmbh Compounds which modulate the cb2 receptor
US9763894B2 (en) 2006-12-05 2017-09-19 Virginia Commonwealth University Inflammation therapy
EP2120938A4 (en) 2006-12-20 2010-12-08 Merck Sharp & Dohme IMIDAZOPYRIDINE ANALOGUE AS CB2 RECEPTOR MODULATORS FOR THE TREATMENT OF PAIN, RESPIRATORY AND NON-RESPIRATORY DISEASES
WO2008079316A1 (en) 2006-12-20 2008-07-03 Cara Therapeutics, Inc. Tetrahydroquinolinones, tetrahydronaphthyridones and derivatives thereof
US20080214537A1 (en) 2007-03-02 2008-09-04 Cara Therapeutics, Inc. Bridged phenanthridines
US8193369B2 (en) 2007-03-30 2012-06-05 Janssen Pharmaceutica Nv Benzimidazole cannabinoid agonists
US20090209536A1 (en) 2007-06-17 2009-08-20 Kalypsys, Inc. Aminoquinazoline cannabinoid receptor modulators for treatment of disease
CA2691776C (en) 2007-06-21 2016-05-10 R. Paul Beckett Substituted imidazoheterocycles
US8338623B2 (en) 2007-07-09 2012-12-25 Abbvie Inc. Compounds as cannabinoid receptor ligands
US7943658B2 (en) 2007-07-23 2011-05-17 Bristol-Myers Squibb Company Indole indane amide compounds useful as CB2 agonists and method
WO2009025785A2 (en) 2007-08-21 2009-02-26 Merck & Co., Inc. Cb2 receptor ligands for the treatment of pain
UA104010C2 (en) 2008-12-18 2013-12-25 Эли Лилли Энд Компани Purine compounds
US7741350B1 (en) 2009-01-28 2010-06-22 Cara Therapeutics, Inc. Bicyclic pyrazolo-heterocycles
WO2010088050A2 (en) * 2009-01-28 2010-08-05 Cara Therapeutics, Inc. Bicyclic pyrazolo-heterocycles
US9597340B2 (en) 2011-02-25 2017-03-21 Arena Pharmaceuticals, Inc. Cannabinoid receptor modulators
KR102036932B1 (ko) 2011-02-25 2019-10-25 아레나 파마슈티칼스, 인크. 축합 아자사이클 (칸나비노이드 수용체 조절제)의 결정질 형태 및 제조 방법
WO2012116278A1 (en) 2011-02-25 2012-08-30 Arena Pharmaceuticals, Inc. Cannabinoid receptor modulators
AU2012222149B2 (en) 2011-02-25 2017-06-29 Arena Pharmaceuticals, Inc. Cannabinoid receptor modulators

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130165412A1 (en) * 2009-08-28 2013-06-27 Robert M. Jones Cannabinoid receptor modulators
US8778950B2 (en) * 2009-08-28 2014-07-15 Arena Pharmaceuticals, Inc. Cannabinoid receptor modulators

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11771695B2 (en) 2011-02-25 2023-10-03 Arena Pharmaceuticals, Inc. Cannabinoid receptor modulators
WO2017180528A1 (en) * 2016-04-10 2017-10-19 Arena Pharmaceuticals, Inc. Methods of treatment with selective cb2 receptor agonists
US12201633B2 (en) 2022-06-21 2025-01-21 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of visceral pain

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