Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
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  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention provides methods of treatment and combination therapies using heterobicyclic and related compounds that activate glucocerebrosidase (Gcase), such as in the treatment of endometriosis and Parkinson's disease.
• Gcase glucocerebrosidase
• Parkinson's disease is a degenerative disorder of the central nervous system associated with death of dopamine-containing cells in a region of the midbrain. Parkinson's disease afflicts millions of people, and the incidence of the disease increases with age. Treatment of Parkinson's disease frequently involves use of levodopa and dopamine agonists. However, these drugs can produce significant side effects such as hallucinations, insomnia, nausea, and constipation. Further, patients often develop tolerance to these drugs such that the drugs become ineffective at treating the symptoms of the disease, while sometimes also producing a movement disorder side effect called dyskinesia. Diffuse Lewy Body disease is a dementia that is sometimes confused with Alzheimer's disease.
• Endometriosis is a condition of severe dysmenorrhea, which is often accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity and can lead to infertility.
• the cause of the symptoms of this condition can be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissue may initiate local inflammatory -like responses causing macrophage infiltration and a cascade of events leading to initiation of a painful response.
• the invention provides methods of treatment and combination therapies using heterobicyclic and related compounds that activate glucocerebrosidase (Gcase), such as in the treatment of endometriosis and Parkinson's disease.
• Methods for treating endometriosis comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase.
• the combination therapies for use in treating Parkinson's disease comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase and a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator.
• a heterobicyclic or related compound described herein that activates Gcase and a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator.
• one aspect of the invention provides a method of treating
• the method comprises administering to a patient in need thereof a therapeutically effective amount of a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) treat the endometriosis.
• a Gcase activator compound described herein e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l
• Another aspect of the invention provides a method of treating Parkinson's disease in a patient.
• the method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator, in order treat the Parkinson's disease.
• a Gcase activator compound described herein e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l
• a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator
• Another aspect of the invention provides a method of treating a disorder selected from the group consisting of Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, and open angle glaucoma in a patient.
• the method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) an acid ceramidase inhibitor, in order to treat the disorder.
• a Gcase activator compound described herein e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l
• an acid ceramidase inhibitor e.g., an acid ceramidase inhibitor
• the invention provides methods of treatment and combination therapies using heterobicyclic and related compounds that activate Gcase, such as in the treatment of endometriosis and Parkinson's disease.
• Methods for treating endometriosis comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase.
• the combination therapies for use in treating Parkinson's disease comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase and a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator.
• alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-Ci 2 alkyl, Ci-Cioalkyl, and Ci-Cealkyl, respectively.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methy 1-1 -propyl, 2-methyl-2- propyl, 2-methy 1-1 -butyl, 3 -methyl- 1 -butyl, 2-methy 1-3 -butyl, 2,2-dimethy 1-1 -propyl, 2- methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethy 1-1 -butyl, 3,3-dimethyl-l-butyl, 2-ethy 1-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,
• alkylene refers to a diradical of an alkyl group.
• An exemplary alkylene group is -CH2CH2-.
• haloalkyl refers to an alkyl group that is substituted with at least one halogen.
• halogen for example, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
• heteroalkyl refers to an "alkyl” group in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom).
• the heteroalkyl may be, for example, an -O-Ci-Cioalkyl group, an -Ci-Cealkylene-O-Ci-Cealkyl group, or a C1-C6 alkylene-OH group.
• the "heteroalkyl” may be 2-8 membered heteroalkyl, indicating that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
• the heteroalkyl may be a 2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which may contain for example 1 or 2 heteroatoms selected from the group oxygen and nitrogen).
• One type of heteroalkyl group is an "alkoxyl" group.
• alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2- Ci 2 alkenyl, C 2- Cioalkenyl, and C 2- C 6 alkenyl, respectively.
• alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butene)-pentenyl, and the like.
• alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2- Ci 2 alkynyl, C 2- Cioalkynyl, and C 2- Cealkynyl, respectively.
• exemplary alkynyl groups include ethynyl, prop-l -yn-l-yl, and but-1 - yn-l-yl.
• cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4- 8 cycloalkyl,” derived from a cycloalkane.
• exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.
• cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is not substituted, i.
• cycloalkyle refers to a diradical of an cycloalkyl group.
• An exemplary cycloalkylene group is
• partially unsaturated carbocyclyl refers to a monovalent cyclic hydrocarbon that contains at least one double bond between ring atoms where at least one ring of the carbocyclyl is not aromatic.
• the partially unsaturated carbocyclyl may be characterized according to the number of ring carbon atoms.
• the partially unsaturated carbocyclyl may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, and accordingly be referred to as a 5-14, 5-12, 5-8, or 5-6 membered partially unsaturated carbocyclyl, respectively.
• the partially unsaturated carbocyclyl may be in the form of a monocyclic carbocycle, bicyclic carbocycle, tricyclic carbocycle, bridged carbocycle, spirocyclic carbocycle, or other carbocyclic ring system.
• exemplary partially unsaturated carbocyclyl groups include cycloalkenyl groups and bicyclic carbocyclyl groups that are partially unsaturated.
• partially unsaturated carbocyclyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl.
• the partially unsaturated carbocyclyl is not substituted, i.e., it is unsubstituted.
• cycloalkenyl refers to a monovalent unsaturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons containing one carbon-carbon double bond, referred to herein, e.g., as "C4- gcycloalkenyl,” derived from a cycloalkane.
• exemplary cycloalkenyl groups include, but are not limited to, cyclohexenes, cyclopentenes, and cyclobutenes.
• cycloalkenyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl.
• the cycloalkenyl group is not substituted, i.e., it is unsubstituted.
• aryl is art-recognized and refers to a carbocyclic aromatic group.
• aryl groups include phenyl, naphthyl, anthracenyl, and the like.
• the term "aryl” includes poly cyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls,
• the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, - C(0)alkyl, -C0 2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, -CF 3 , -CN, or the like.
• the aromatic ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, the aromatic ring is not substituted, i.e., it is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure.
• aralkyl refers to an alkyl group substituted with an aryl group.
• bicyclic carbocyclyl that is partially unsaturated refers to a bicyclic carbocyclic group containing at least one double bond between ring atoms and at least one ring in the bicyclic carbocyclic group is not aromatic.
• Representative examples of a bicyclic carbocyclyl that is partially unsaturated include, for example:
• ortho, meta and para are art-recognized and refer to 1 ,2-, 1 ,3- and 1,4- disubstituted benzenes, respectively.
• 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
• heterocyclyl and “heterocyclic group” are art-recognized and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
• the number of ring atoms in the heterocyclyl group can be specified using C x -C x nomenclature where x is an integer specifying the number of ring atoms.
• a C3-Cvheterocyclyl group refers to a saturated or partially unsaturated 3- to 7-membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
• the designation "C3-C7" indicates that the heterocyclic ring contains a total of from 3 to 7 ring atoms, inclusive of any heteroatoms that occupy a ring atom position.
• a C3-C7 indicates that the heterocyclic ring contains a total of
• C 3 heterocyclyl is aziridinyl.
• Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems including a spirocyclic ring system where at least one ring contains a ring heteroatom.
• a heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings.
• Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isooxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl,
• the heterocyclic ring is optionally substituted at one or more positions with substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, oxo, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
• the heterocyclyl group is not substituted, i.e., it is unsubstituted.
• bicyclic heterocyclyl refers to a heterocyclyl group that contains two rings that are fused together.
• Representative examples of a bicyclic heterocyclyl include, for example:
• the bicyclic heterocyclyl is an carbocyclic ring fused to partially unsaturated heterocyclic ring, that together form a bicyclic ring structure having 8-10 ring atoms (e.g., where there are 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur).
• heterocycloalkyl is art-recognized and refers to a saturated heterocyclyl group as defined above.
• the "heterocycloalkyl” is a 3- to 10- membered ring structures, alternatively a 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
• heterocycloalkylene of a heterocycloalkyl group.
• heterocycloalkylene group is heterocycloalkylene may contain, for example, 3-6 ring atom (i.e., a 3-6 membered heterocycloalkylene).
• the heterocycloalkylene is a 3-6 membered heterocycloalkylene containing 1, 2, or 3 three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
• heteroaryl is art-recognized and refers to aromatic groups that include at least one ring heteroatom. In certain instances, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representative examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.
• the heteroaryl ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(0)alkyl, -CC ⁇ alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, -CF 3 , -CN, or the like.
• heteroaryl also includes poly cyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
• the heteroaryl ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl.
• the heteroaryl ring is not substituted, i.e., it is unsubstituted.
• the heteroaryl group is a 5- to 10-membered ring structure, alternatively a 5- to 6-membered ring structure, whose ring structure includes 1, 2, 3, or 4 heteroatoms, such as nitrogen, oxygen, and sulfur.
• heteroarylkyl refers to an alkyl group substituted with a heteroaryl group.
• amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety represented by the general formula -N(R 50 )(R 51 ), wherein R 50 and R 51 each independently represent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, aralkyl, or -(CH 2 ) m -R 61 ; or R 50 and R 51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R 61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a poly cycle; and m is zero or an integer in the range of 1 to 8.
• R 50 and R 51 each independently represent hydrogen, alkyl, alkenyl, or -(CH 2 ) m
• alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
• Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
• An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(CH 2 ) m -R 6 i, where m and R 6 i are described above.
• R g R3 ⁇ 4 and R[ are each independently alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, or sulfonamide.
• Exemplary carbamates include arylcarbamates and heteroaryl carbamates, e.g., wherein at least one of Rg R ⁇ and R[ are independently aryl or heteroaryl, such as phenyl and pyridinyl.
• carbonyl refers to the radical -C(O)-.
• carboxylate refers to the radical -C(0)NRR', where R and R' may be the same or different. R and R' may be independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl.
• carboxy refers to the radical -COOH or its corresponding salts, e.g. -COONa, etc.
• R a, R b and R c are each independently alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro.
• the amide can be attached to another group through the carbon, the nitrogen, R , R c , or R a .
• the amide also may be cyclic, for example R b and R c , R a and R b , or R a and R c may be joined to form a 3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-membered ring.
• alkanoyl refers to a radical -O-CO-alkyl.
• a cyclopentane susbsituted with an oxo group is cyclopentanone.
• sulfonamide or “sulfonamido” as used herein refers to a radical having the structure -N(R r )-S(0)2-R s - or -S(0)2-N(R r )R s , where R r , and R s can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl.
• Exemplary sulfonamides include alkylsulfonamides (e.g., where R s is alkyl), arylsulfonamides (e.g., where R s is aryl), cycloalkyl sulfonamides (e.g., where R s is cycloalkyl), and heterocyclyl sulfonamides (e.g., where R s is heterocyclyl), etc.
• sulfonyl refers to a radical having the structure R U S02-, where R u can be alkyl, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl.
• alkylsulfonyl refers to an alkyl group attached to a sulfonyl group.
• the symbol " - ⁇ > ⁇ " indicates a point of attachment.
• the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
• stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.
• Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or
• diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise.
• Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
• Stereoisomeric mixtures can also be resolved into their component stereoisomers by well- known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Further, enantiomers can be separated using supercritical fluid chromatographic (SFC) techniques described in the literature. Still further, stereoisomers can be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. [0048] Geometric isomers can also exist in the compounds of the present invention. The symbol denotes a bond that may be a single, double or triple bond as described herein.
• the present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
• Substituents around a carbon-carbon double bond are designated as being in the "Z” or configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z” isomers.
• Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
• the arrangement of substituents around a carbocyclic ring are designated as “cis” or “trans.”
• the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
• Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans.”
• the invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, H, 1 C, 14 C, 15 N, 18 0, 17 0, 1 P, 2 P, 5 S, 18 F, and 6 C1, respectively.
• Certain isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
• Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in, e.g., the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• the terms "subject” and "patient” refer to organisms to be treated by the methods of the present invention. Such organisms are preferably mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably humans.
• the term "effective amount” refers to the amount of a compound (e.g. , a compound of the present invention) sufficient to effect beneficial or desired results.
• An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
• the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
• composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
• the term "pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g. , such as an oil/water or water/oil emulsions), and various types of wetting agents.
• the compositions also can include stabilizers and preservatives.
• stabilizers and adjuvants see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
• the term "pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof.
• salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
• acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, gly colic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene- 2-sulfonic, benzenesulfonic acid, and the like.
• Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
• bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g. , magnesium) hydroxides, ammonia, and compounds of formula NW ⁇ 4 + , wherein W is C 1-4 alkyl, and the like.
• alkali metal e.g., sodium
• alkaline earth metal e.g. , magnesium
• W is C 1-4 alkyl
• salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
• salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW ⁇ 4 + (wherein W is a C 1-4 alkyl group), and the like.
• salts of the compounds of the present invention are provided.
• salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
• HATU 0-(7-azabenzotriazol-l-yl)-N,N,N'N'- tetramethyluronium hexafluorophosphate
• DIPEA diisopropylethylamine
• DMF dimethylformamide
• DCM methylene chloride
• Boc tert-butoxycarbonyl
• THF tetrahydrofuran
• THF trifluoroacetic acid
• NMM N-methylmorpholine
• TEA triethylamine
• Boc anhydride ((Boc) 2 0); dimethylsulfoxide (DMSO); diisopropylethylamine (DIEA); N,N-Dimethylpyridin-4-amine (DMAP); flash column chromatography (FCC); and
• compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
• compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
• One aspect of the invention provides a method of treating endometriosis in a patient.
• the method comprises administering to a patient in need thereof a therapeutically effective amount of a Gcase activator compound described herein (e.g., a compound of any one
• Formulae A-1, B-1, B-IIa, B-III, or C-l) treat the endometriosis.
• Another aspect of the invention relates to compounds and compositions described herein for use in treating endometriosis. Another aspect of the invention pertains to use of a compound or composition described herein in the preparation of a medicament for treating endometriosis.
• the invention embraces combination therapy, which includes the administration of a Gcase activator compound described herein (e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l) and a second therapeutic agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
• a Gcase activator compound described herein e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l
• the beneficial effect of the combination may include pharmacokinetic or pharmacodynamic co- action resulting from the combination of therapeutic agents.
• Exemplary second agents for use in treating endometriosis include, for example, progesterone, progestin, a gonadotropin-releasing hormone (GnRH) agonist, and danazol.
• GnRH gonadotropin-releasing hormone
• danazol a gonadotropin-releasing hormone
• One aspect of the invention provides a method of treating Parkinson's disease in a patient.
• the method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator, in order treat the Parkinson's disease.
• a Gcase activator compound described herein e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l
• a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator
• Another aspect of the invention provides a method of treating a disorder selected from the group consisting of Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, and open angle glaucoma in a patient.
• the method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) an acid ceramidase inhibitor, in order to treat the disorder.
• a Gcase activator compound described herein e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l
• an acid ceramidase inhibitor e.g., an acid ceramidase inhibitor
• Each therapeutic agent in a combination therapy of the invention may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order.
• Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (e.g., one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules, e.g., a Gcase activator compound that is administered at least every other day and a second therapeutic agent that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks.
• the Gcase activator compound is administered before administration of the second therapeutic agent, while in other embodiments, the Gcase activator compound is administered after administration of the second therapeutic agent.
• the patient is a human, such as an adult human or pediatric human.
• Another aspect of the invention relates to compounds and compositions described herein for use in treating a disorder described herein. Another aspect of the invention pertains to use of a compound or composition described herein in the preparation of a medicament for treating a disorder described herein. Exemplary Benefits of the Combination Therapy
• the methods and compositions are contemplated to provide various benefits.
• the beneficial effect of the combination may include pharmacokinetic or pharmacodynamic co- action resulting from the combination of therapeutic agents.
• One contemplated benefit is improved efficacy in treating the disorder when a Gcase activator compound is administered with a second therapeutic agent compared to the efficacy observed when the Gcase activator compound is administered alone.
• the improvement may be a 5%, 10%, 20%, 30%, 50%, 75%, 100%, or greater improvement in efficacy in treating the disorder when the Gcase activator compound is administered with a second therapeutic agent compared to the efficacy observed when the Gcase activator compound is administered alone.
• Another contemplated benefit is a reduction in side effects associated with administration of a Gcase activator compound and/or a second therapeutic agent.
• the reduction in side effects may be a 5%, 10%, 20%, 30%, 50%, 75%, 100%, or greater reduction in side effects in a human subject when the Gcase activator compound is administered with the second therapeutic agent compared to the side effects observed when the Gcase activator and/or a second therapeutic agent is administered alone at a dosage necessary to achieve a similar therapeutic effect.
• the administration of a Gcase activator and/or a second therapeutic agent may result in a synergistic effect, e.g., a synergistic improvement in efficacy in treating a disorder described herein.
• the synergistic improvement in efficacy is at least a 5%, 10%, 15%, 20%, 25%, 30%, or greater improvement in efficacy compared to the additive improvement in efficacy associated with administration of the Gcase activator compound and the second therapeutic agent together.
• heterobicyclic compounds for activation of Gcase contemplated for use in the therapeutic methods are provided below.
• the heterobicyclic compound is a substituted pyrrolo[l,2-a]pyrimidine or related organic compound.
• the heterobicyclic compound is a substituted pyrazolo[l,5-a]pyrimidine or related organic compound.
• the heterobicyclic compound is a substituted imidazo[l,5-a]pyrimidine or related organic compound.
• the heterobicyclic compound for activation of Gcase is a substituted pyrrolo[l,2-a]pyrimidine or related organic compound, such as a substituted pyrrolo[l,2-a]pyrimidine or related organic compound embraced by Formula A-I:
• R 1 and R 2 each represent independently for each occurrence hydrogen, deuterium, C alkyl, Ci ⁇ haloalkyl, C1-4 deuteroalkyl, C 1-4 alkoxyl, -(C 1-4 alky lene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, halogen, hydroxyl, or -N(R 4 ) 2 ;
• R 3 represents independently for each occurrence hydrogen, C 1-6 alkyl, or C3-6
• R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, cyclopropyl, or
• R 5 represents independently for each occurrence C 1-4 alkyl or C3-6 cycloalkyl
• X 1 is one of the following:
• a carbonyl-containing linker selected from -C(0)N(H)-v
• an amine-containing linker selected from -(C 1-4 alkylene)-N(H)-v
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• Ci-6 haloalkyl Ci -6 alkyl, halogen, cyano, -C0 2 R 3 , -C(0)R 5 , -S(0) 2 R 5 , -C(0)N(R 5 ) 2 , -C(0)N(R ) 2 , -N(R )C(0)R 5 , or -0-(Ci -8 haloalkyl);
• Y 2 represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0 2 R 3 , or Ci- 6 haloalkyl-substituted C3-6 cycloalkyl;
• n 1 or 2;
• n 1, 2, or 3;
• R 1 or R 2 is other than hydrogen when (i) A 1 is an unsubstituted heterocyclyl, (ii) A 1 is an unsubstituted phenyl or a phenyl substituted only by halogen, or (iii) Y 2 is halogen.
• Definitions of the variables in Formula A-I above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
• R 1 represents independently for each occurrence C 1-4 alkyl, Ci ⁇ haloalkyl, -(C 1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, halogen, or -N(R 4 ) 2 .
• R 1 represents independently for each occurrence Ci-4 alkyl, Ci ⁇ haloalkyl, C 1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
• R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, cyclopropyl, cyano, chloro, or fluoro.
• R 1 is methyl.
• the R 1 groups are located at the 2 and 4 positions of the pyrrolo[l,2- a]pyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• n is 1. In certain other embodiments, m is 2.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
• R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
• X 1 is -0( ⁇ ) ⁇ ( ⁇ )- ⁇ . In certain embodiments, X 1 is
• a 1 is a cyclic group selected from:
• heterocyclyl each of which is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 .
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted once by Y 1 and 0-1 occurrences of Y .
• A is C5-10 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0- 1 occurrences of Y 2 .
• a 1 is a cyclopentyl or cyclohexyl, each of which is substituted once by Y 1 and 0-1 occurrences of Y .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 2 selected from the group consisting of Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, and Ci-6 alkoxyl.
• a 1 is ( Y )m or (Y )m ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence Ci-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxy or cyano. In certain embodiments, A 1
• Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, or C 1-6 alkoxyl.
• any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl. In certain embodiments, Y 2 is cyclopropyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl.
• Y 1 is a 2-8 membered heteroalkyl. [0092] In certain embodiments, Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl).
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 . In certain embodiments, Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• the description above describes multiple embodiments relating to compounds of Formula A-I.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula A-I wherein X 1 is A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula A-I-l :
• R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
• R 3 represents independently for each occurrence hydrogen or C 1-4 alkyl
• R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )2, -(Ci-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl;
• n 1 or 2;
• n 1, 2, or 3;
• R 1 or R 2 is other than hydrogen when (i) A 1 is an unsubstituted heterocyclyl or (ii) Y 2 is halogen.
• Definitions of the variables in Formula A-I-l above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
• R 1 represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 represents independently for each occurrence C1-4 alkyl, C 1-4 haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 is methyl. In certain embodiments, the R 1 groups are located at the 2 and 4 positions of the pyrrolo[l,2- ajpyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• n is 1. In certain other embodiments, m is 2.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
• R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
• X 1 is In certain embodiments, X 1 is
• a 1 is a cyclic group selected from:
• heterocyclyl each of which is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 .
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted once by Y 1 and 0-1 occurrences of Y .
• a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a cyclopentyl or cyclohexyl, each of which is substituted once by Y 1 and 0-1 occurrences of Y .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 2 selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• a 1 is wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano. In certain embodiments, A 1
• Y is ⁇ i ⁇ ( Y )m or ( Y )m ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, or C 1-6 alkoxyl.
• any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently Ci-3 alkyl. In certain embodiments, Y 2 is cyclopropyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
• Y 1 is -0-(C 1-7 alkyl). In certain embodiments, Y 1 is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl).
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2- 6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• the description above describes multiple embodiments relating to compounds of Formula A-I-1.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula A-I wherein X 1 is A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula A-I-la:
• R represents independently for each occurrence C1-4 alkyl
• R 2 and R 3 each represent independently for each occurrence hydrogen or C1-4 alkyl;
• R 4 represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a 1 is a cyclic group selected from:
• phenyl 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y ;
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1 -6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0 2 R 3 , or Ci- 6 haloalkyl-substituted C3-6 cycloalkyl; and
• n 1, 2, or 3.
• Definitions of the variables in Formula A-I-la above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula A-I-A:
• R 1 is independently methyl, isopropyl, cyclopropyl, Ci -2 haloalkyl, -(CH 2 )i -2 -0-(Ci-3 alkyl), chloro, fluoro, or -N(R 4 ) 2 ;
• R 2 is hydrogen; R 3 and R 4 each represent independently for each occurrence hydrogen or C1-4 alkyl; A 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen,
• Ci- 6 haloalkyl C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6
• Definitions of the variables in Formula A-I-A above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 , where Y 1 is a 2-8 membered heteroalkyl.
• a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is phenyl substituted once by Y 1 and 0- 1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or Ci-3 haloalkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is -0-(Ci_ 7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain
• Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2- 6 alkenyl.
• Y 1 is C 2 -6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 . In certain embodiments, Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
• a 1 is an 8-12 membered bicyclic carbocyclyl that is partially unsaturated or an 8-12 membered bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y 2 .
• a 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.
• a 1 is or ( Y )m ; wherein m is 0, 1, or 2;
• Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, or Ci- 6 alkoxyl.
• R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
• R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
• the description above describes multiple embodiments relating to compounds of Formula A-I-A.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula I-A wherein A is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula A-I-Al :
• R 1 is independently methyl, cyclopropyl, or isopropyl
• R 2 is hydrogen
• R 3 and R 4 each represent independently for each occurrence hydrogen or C alkyl;
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C 3 -6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1 -6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.
• Definitions of the variables in Formula A-I-Al above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 , where Y 1 is a 2-8 membered heteroalkyl.
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or Ci- 3 haloalkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is -0-(Ci_ 7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain
• Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1 -6 alkyl, C3-6 cycloalkyl, halogen, C i-6 haloalkyl, C i-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(C i -6 alkylene)-OR 4 , -C ⁇ C-(C i -6 alkylene)-N(R )2, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(C i_6 alkylene)-OR 4 . In certain embodiments, Y 1 is -C ⁇ C-(C i_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y 2 .
• a 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.
• a 1 is or ( Y )m ; wherein m is 0, 1 , or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, or C 1-6
• a 1 is / ( Y )m or ( Y )m ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1 -6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
• R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
• R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
• R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
• the compound is a compound of Formula A-I-B:
• a 1 is a cyclic group selected from phenyl, pyridinyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y :
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl;
• R 4 represents independently for each occurrence hydrogen or C1-4 alkyl.
• Definitions of the variables in Formula A-I-B above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A 1 is phenyl or pyridinyl, each of which is substituted once by Y 1 , where Y 1 is 2-8 membered heteroalkyl.
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or Ci- 3 haloalkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain
• Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is a 3-10 membered heterocyclyl, 6 membered aryl, or -0-(3-6 membered heterocyclyl). In certain embodiments, Y 1 is a 3-10 membered
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• the description above describes multiple embodiments relating to compounds of Formula A-I-B.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula A-I-B wherein A 1 is phenyl or pyridinyl, each of which is substituted once by Y 1 and 0, 1, or I occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula A-I-C:
• a 1 is a bi cyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y :
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl;
• R 4 represents independently for each occurrence hydrogen or C1-4 alkyl.
• Definitions of the variables in Formula A-I-C above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or Ci-3 haloalkyl.
• the compound is one of the compounds listed in Table 1 or 2 below or a pharmaceutically acceptable salt thereof.
• the reaction is performed in a stepwise manner where a bromo or iodo-substituted aromatic or heteraromatic amine is coupled with the Weinreb amide to form the iodo or bromo-substituted amide F.
• the bromo or iodo moiety may be used to couple a variety of functional groups using standard coupling procedures, such as acetylenes using Sonogashira coupling, boronic acids using Suzuki coupling, and amines using Buchwald coupling to produce substituted amide E. SCHEME 2
• a functional group in substituent A 1 and Y 1 can converted to another functional group using standard functional group manipulation procedures known in the art. See, for example, "Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds. , 1991 - 1992).
• the heterobicyclic compound for activation of Gcase is a substituted pyrazolo[l,5-a]pyrimidine or related organic compound, such as a substituted pyrazolo[l,5-a]pyrimidine or related organic compound embraced by Formula B-I:
• R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, Ci- 4 alkoxyl, -(Ci- 4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, or -N(H)(R 3 );
• R 3 represents independently for each occurrence hydrogen or C 1 - 4 alkyl
• R 4 represents independently for each occurrence hydrogen, C 1 - 4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• ⁇ 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, C2-4 alkynyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6
• n 1, 2, or 3.
• Definitions of the variables in Formula B-I above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g. , such as where R is CM alkyl or cyclopropyl, X 1 is -C(0)N(H)- ⁇ , and A 1 is phenyl substituted by 4-8 membered heteroalkyl.
• the compound is a compound of Formula B-I provided that:
• R 1 and R 2 are Ci-4 alkoxyl, -(C1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, or -N(H)(R 3 ); and
• R 1 represents independently for each occurrence C 1-4 alkyl, Ci- 4 haloalkyl, C 1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
• R 1 is methyl.
• the R 1 groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
• R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
• X 1 is
• any occurrence of Y 2 is independently C 1-6 alkyl, C3- 6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl.
• a 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
• a 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 4-8 membered heteroalkyl. In certain embodiments, A 1 is phenyl substituted by -0-(Ci_7 alkyl). In certain embodiments, A 1 is phenyl substituted by -0-(C4_7 alkyl).
• a 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, A 1 is phenyl substituted is -OCH2CH2OCH2CH2.
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl optionally substituted by a 5-10 membered heteroaryl.
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl substituted by a 5-6 membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H).
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-(Ci-6 alkylene)-OR 4 . In certain embodiments, A 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-CH 2 -0-CH 3 . In certain embodiments, A 1 is phenyl substituted by -C ⁇ C-CH 2 -0-CH 3 .
• a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is C5-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1, 2, or 3 occurrences of Y 2 .
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
• Y 1 is 2-8 membered heteroalkyl. In certain embodiments, Y 1 is -0-(Ci-7 alkyl). In certain embodiments, Y 1 is -O-but l, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is -CH 2 - 0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -O-(6-10 membered aryl), or -0-(C2-e alkynyl).
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is 5- membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, C 1-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci-6 alkylene)-OR 4 .
• Y 1 is -C ⁇ C-(Ci-6 alky lene)-0-(C 1-2 alkyl).
• Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• the description above describes multiple embodiments relating to compounds of Formula B-I.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula I wherein X 1 is A 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) 4-8 membered heteroalkyl, and Y 1 is Ci-6 alkyl or halogen.
• the compound is represented by Formula B-I-l :
• R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
• R 3 represents independently for each occurrence hydrogen or C1-4 alkyl
• R 4 represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a 1 is a cyclic group selected from:
• bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences ofY 2 ;
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci- 6 alkyl, C3- 6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 - 6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, C 2 - 4 alkynyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6
• n 1, 2, or 3;
• R 1 or R 2 is other than hydrogen when A 1 is phenyl substituted by heteroalkyl.
• Definitions of the variables in Formula B-I-1 above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g. , such as where R is Ci -4 alkyl or cyclopropyl, X 1 is -C(0)N(H)- ⁇ , and A 1 is phenyl substituted by 4-8 membered heteroalkyl.
• R 1 represents independently for each occurrence C1-4 alkyl, Ci ⁇ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
• R 1 is methyl.
• the R 1 groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
• R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
• X 1 is
• any occurrence of Y 2 is independently Ci- 6 alkyl, C3- 6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C1- 3 alkyl.
• a 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
• a 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 4-8 membered heteroalkyl.
• a 1 is phenyl substituted by -0-(Ci-7 alkyl).
• a 1 is phenyl substituted by -0-(C4_7 alkyl).
• a 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl.
• a 1 is phenyl substituted is -OCH2CH2OCH2CH2.
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl optionally substituted by a 5-10 membered heteroaryl.
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl substituted by a 5-6 membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H).
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-(Ci-6 alkylene)-OR 4 . In certain embodiments, A 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-CH 2 -0-CH 3 . In certain embodiments, A 1 is phenyl substituted by -C ⁇ C-CH 2 -0-CH 3 .
• a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
• Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C ⁇ haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl).
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5- membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO 2 H.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO 2 H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R )2, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
• Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl).
• Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• the description above describes multiple embodiments relating to compounds of Formula B-I-1.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula B-I-1 wherein X 1 is -C(0)N(H)-v
• the compound is a compound of Formula B-I-A:
• R 1 is independently methyl, cyclopropyl, isopropyl, or -(C alkylene)-(2-6 membered heteroalkyl);
• R 2 is hydrogen
• R 3 and R 4 each represent independently for each occurrence hydrogen or C1-4 alkyl;
• a 1 is one of the following: • C3-1 0 cycloalkyl that is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 ; and
• Y 1 represents, independently for each occurrence, a 2-8 membered heteroalkyl
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen,
• Ci- 6 haloalkyl C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.
• Definitions of the variables in Formula B-I-A above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
• any occurrence of Y 2 is independently C1-3 alkyl, halogen, or Ci ⁇ haloalkyl.
• a 1 is C3-1 0 cycloalkyl that is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is 1 ,2,3,4- tetrahydronaphthalenyl substituted by 0, 1 , 2, or 3 occurrences of Y 2 .
• R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
• R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
• the description above describes multiple embodiments relating to compounds of Formula B-I-A.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula B-I-A wherein R 1 is methyl, and A 1 is phenyl substituted by (a) 0, 1 , 2, or 3 occurrences of Y 2 and (b) C4-8 alkoxyl.
• the compound is a compound of Formula B-I-Al :
• R 1 is independently methyl, cyclopropyl, or isopropyl
• R 2 is hydrogen
• R 3 and R 4 each represent independently for each occurrence hydrogen or C alkyl;
• A is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.
• Definitions of the variables in Formula B-I-Al above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where R 1 is methyl, and A 1 is phenyl substituted by C4-8 alkoxyl.
• any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or C 1-3 haloalkyl.
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) C4-8 alkoxyl.
• a 1 is phenyl substituted by -0-(C4_7 alkyl).
• a 1 is phenyl substituted by -0-(C4_7 alkyl) at the para-position of the phenyl group.
• a 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, A 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl at the para-position of the phenyl group. In certain embodiments, A 1 is phenyl substituted is -OCH 2 CH 2 OCH 2 CH 2 .
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-4 membered heteroalkyl substituted by a 5-6 membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , and amide).
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-(Ci-6 alkylene)-OR 4 , where R 4 is Ci-4 alkyl.
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-CH 2 -0-CH 3 .
• a 1 is phenyl substituted by -C ⁇ C-CH 2 -0-CH 3 .
• R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
• R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
• the description above describes multiple embodiments relating to compounds of Formula B-I-Al.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula B-I-Al wherein R 1 is methyl, and A 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) C4-8 alkoxyl.
• the compound is a compound of Formula B-I-B:
• a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) C4-8 alkoxyl or -C ⁇ C- (C1-6 alky lene)-0-(C 1-3 alkyl); and
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, or Ci-6 haloalkyl.
• Definitions of the variables in Formula B-I-B above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
• Another aspect of the invention provides a compound of Formula B-II:
• R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
• R 3 represents independently for each occurrence hydrogen or C1-4 alkyl
• R 4 represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following: (a) a carbonyl-containing linker selected from and -C(0)N(H)(Ci_6 where ⁇ is a bond to A 1 ; or
• A is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
• Y 2 represents, independently for each occurrence, C 1-6 alkyl, C 3 -6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, C 1-6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and
• n 1, 2, or 3.
• Definitions of the variables in Formula B-II above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where R 1 is C M alkyl or cyclopropyl, X 1 is
• a 1 is phenyl substituted by phenyl.
• R 1 represents independently for each occurrence hydrogen, CM alkyl, Ci ⁇ haloalkyl, CM alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
• R 1 is methyl.
• the R 1 groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
• R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
• X 1 is
• any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl.
• Another aspect of the invention provides a compound of Formula B-IIa:
• R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C 1-4 haloalkyl, Ci-4 alkoxyl, -(Ci-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, or fluoro;
• R 3 represents independently for each occurrence hydrogen or C 1-4 alkyl
• R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a 1 is one of the following:
• o a bicyclic carbocyclyl that is partially unsaturated and substituted by (a) a 3-10 membered heterocyclyl, and (b) 0, 1, 2, or 3 occurrences ofY 2 ;
• Y 2 represents, independently for each occurrence, C 1-6 alkyl, C 3 - 6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1- 6 hydroxy alkyl, hydroxyl, C 1-6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1- 6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or C 1-6 haloalkyl-substituted C3-6 cycloalkyl; and
• n 1, 2, or 3;
• X 1 is optionally substituted halophenyl or -phenyl-methoxy, then X 1 is -C(0)N(H)(C 2 -6 branched alkylene)-v
• Definitions of the variables in Formula B-IIa above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where R 1 is CM alkyl or cyclopropyl, X 1 is
• R 1 represents independently for each occurrence C 1-4 alkyl, Ci ⁇ haloalkyl, C 1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 is methyl.
• n is 2.
• R 1 groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.
• X 1 is
• Another aspect of the invention provides a compound of Formula B-III:
• R 1 and R 2 each represent independently for each occurrence hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, -(C 1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, or fluoro;
• R 3 represents independently for each occurrence hydrogen or C 1-4 alkyl
• R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a 1 is a cyclic group selected from:
• o a 5-membered heteroaryl substituted by 0, 1, 2, or 3 occurrences of Y 2 ; o -(Ci -6 alkylene)-C0 2 R 3 ; or
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen,
• Ci- 6 haloalkyl C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and
• n 1, 2, or 3.
• Definitions of the variables in Formula B-III above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g. , such as where R 1 is C1-4 alkyl or cyclopropyl, X 1 is -C(0)N(H)- ⁇ , and A 1 is phenyl substituted by a 5 -membered heteroaryl.
• R 1 represents independently for each occurrence C1-4 alkyl, Ci ⁇ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
• R 1 is methyl.
• the R 1 groups are located at the 5 and 7 positions of the pyrazolo[l ,5-a]pyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl. [00249] In certain embodiments, R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
• X 1 is
• any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl.
• a 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) a 5-membered heteroaryl substituted by 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is phenyl substituted by (a) C 1-6 alkyl or halogen and (b) a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, or oxazolyl.
• a 1 is phenyl substituted by Ci- 6 hydroxyalkyl.
• a 1 is 5-6 membered heteroaryl substituted by 1 or 2 occurrences of Y 1 and a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, or oxazolyl.
• a 1 is pyridinyl substituted by 1 or 2 occurrences of Y 1 and a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, or oxazolyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
• Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, or pyridinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , and amide.
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C 2- 6 alkynyl).
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , and amide.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , and amide.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , and amide.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C 2- 4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-0-(Ci -2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• R 1 is methyl
• X 1 is A 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) a 5-membered heteroaryl.
• the compound is a compound of Formula B-III-A:
• R 1 is independently methyl, cyclopropyl, or isopropyl
• R 2 is hydrogen
• a 1 is phenyl substituted by (a) C 1-6 alkyl or halogen and (b) a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, or oxazolyl C4-8 alkoxyl, each of which is optionally substituted by 1 or substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl.
• Definitions of the variables in Formula B-III-A above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
• the compound is one of the compounds listed in Table 3 or 4 below or a pharmaceutically acceptable salt thereof. TABLE 3.
• ⁇ is a bond to A 1 .
• the reaction is performed in a stepwise manner where a bromo or iodo-substituted aromatic or heteraromatic amine is coupled with the Weinreb amide to form the iodo or bromo-substituted amide E.
• the bromo or iodo moiety may be used to couple a variety of functional groups using standard coupling procedures, such as acetylenes using Sonogashira coupling, boronic acids using Suzuki coupling, and amines using Buchwald coupling to produce substituted amide D.
• a functional group in substituent A 1 and Y 1 can converted to another functional group using standard functional group manipulation procedures known in the art. See, for example, "Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992).
• the heterobicyclic compound for activation of Gcase is a substituted imidazo[l,5-a]pyrimidine or related organic compound, such as a substituted imidazo[l,5-a]pyrimidine or related organic compound embraced by Formula C-I:
• R 1 represents independently for each occurrence hydrogen, Ci- 4 alkyl, Ci ⁇ haloalkyl, Ci.
• R 2 is hydrogen, C 1-4 alkyl, Ci ⁇ haloalkyl, C 1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
• R 3 represents independently for each occurrence hydrogen or C 1-4 alkyl
• R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• an amine-containing linker selected from -(C 1-4 alkylene)-N(H)-v
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0 2 R 3 , or Ci- 6 haloalkyl-substituted C3-6 cycloalkyl; and
• n 1, 2, or 3.
• Definitions of the variables in Formula C-I above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
• R 1 represents independently for each occurrence C1-4 alkyl, Ci ⁇ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 represents independently for each occurrence C1-4 alkyl, Ci ⁇ haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 is methyl. In certain embodiments, the R 1 groups are located at the 2 and 4 positions of the imidazo[l,5- a]pyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• R 1 represents independently for each occurrence hydrogen, Ci-4 alkyl, Ci ⁇ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro; and n is 1.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
• R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen. [00276] In certain embodiments, X 1 is In certain embodiments, X 1 is
• a 1 is a cyclic group selected from:
• phenyl 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 ;
• bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences ofY 2 .
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted once by Y 1 and 0-1 occurrences of Y .
• A is C5-10 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0- 1 occurrences of Y 2 .
• a 1 is a cyclopentyl or cyclohexyl, each of which is substituted once by Y 1 and 0-1 occurrences of Y .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 2 selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• a 1 is or ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
• a 1 is ⁇ ⁇ "" --/ ( Y )m or ( Y )m ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, or C 1-6 alkoxyl.
• any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl. In certain embodiments, R 1 is -OCH2CH2OCH2CH2.
• Y 1 is -0-(C 1-7 alkyl). In certain embodiments, Y 1 is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C ⁇ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 )
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-6 alkynyl).
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2 - 6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 . In certain embodiments, Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• the description above describes multiple embodiments relating to compounds of Formula C-I.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula C-I wherein X 1 is A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula C-I wherein X 1 is A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula
• R 1 represents independently for each occurrence hydrogen, Ci-4 alkyl, Ci ⁇ haloalkyl, Ci_ 4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
• R 2 is hydrogen, C1-4 alkyl, Ci ⁇ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
• R 3 represents independently for each occurrence hydrogen or C1-4 alkyl
• R 4 represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )2, -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and
• n 1, 2, or 3.
• Definitions of the variables in Formula C-I-l above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
• R 1 represents independently for each occurrence C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 represents independently for each occurrence C1-4 alkyl, Ci ⁇ haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 is methyl. In certain embodiments, the R 1 groups are located at the 2 and 4 positions of the imidazo[l,5- a]pyrimidinyl.
• n is 2. In certain other embodiments, n is 1.
• R 1 represents independently for each occurrence hydrogen, Ci-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro; and n is 1.
• R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
• R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen. [00297] In certain embodiments, X 1 is In certain embodiments, X 1 is
• a 1 is a cyclic group selected from:
• phenyl 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 ;
• bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
• a 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 .
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted once by Y 1 and 0-1 occurrences of Y .
• A is C5-10 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0- 1 occurrences of Y 2 .
• a 1 is a cyclopentyl or cyclohexyl, each of which is substituted once by Y 1 and 0-1 occurrences of Y .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 2 selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• a 1 is or ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
• a 1 is ⁇ ⁇ "" --/ ( Y )m or ( Y )m ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, or C 1-6 alkoxyl.
• any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl. In certain embodiments, R 1 is -OCH2CH2OCH2CH2.
• Y 1 is -0-(C 1-7 alkyl). In certain embodiments, Y 1 is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C ⁇ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 )
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-6 alkynyl).
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2 - 6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
• Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl).
• Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• the description above describes multiple embodiments relating to compounds of Formula C-I-l .
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula I wherein X 1 is A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula C-I-la:
• R 1 represents independently for each occurrence C M alkyl
• R 2 and R 3 each represent independently for each occurrence hydrogen or C alkyl;
• R 4 represents independently for each occurrence hydrogen, C alkyl, or -C(0)R 3 ;
• X 1 is one of the following:
• a carbonyl-containing linker selected from -C(0)N(H)(Ci -6 and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- where ⁇ is a bond to A 1 ;
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• heterocyclyl -0(6-10 membered aryl), or -0-(C 2-6 alkynyl); or
• Y 2 represents, independently for each occurrence, C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and
• n 1, 2, or 3.
• Definitions of the variables in Formula C-I- la above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula C-I-A:
• R 1 is independently methyl, cyclopropyl, isopropyl, or -(C alkylene)-(Ci-4 alkoxyl); R 2 is hydrogen;
• R 3 and R 4 each represent independently for each occurrence hydrogen or C1-4 alkyl;
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following: • 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl;
• Y 2 represents, independently for each occurrence, C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or C 1-6
• Definitions of the variables in Formula C-I-A above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 , where Y 1 is a 2-8 membered heteroalkyl.
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or Ci-3 haloalkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is -0-(Ci_ 7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain
• Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-6 alkynyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(C W alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 . In certain embodiments, Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y 2 .
• a 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.
• a 1 is ⁇ ⁇ -- / ( ⁇ )m or ( Y )m ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, or C 1-6
• a 1 is or ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
• the description above describes multiple embodiments relating to compounds of Formula I-A.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula I-A wherein A is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
• R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
• the compound is a compound of Formula C-I-Al :
• R is independently methyl, cyclopropyl, or isopropyl
• R 2 is hydrogen
• R 3 and R 4 each represent independently for each occurrence hydrogen or C1-4 alkyl;
• a 1 is a cyclic group selected from:
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )2, -(Ci-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.
• Definitions of the variables in Formula C-I-Al above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 , where Y 1 is a 2-8 membered heteroalkyl.
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C1-3 alkyl, halogen, or C 1-3 haloalkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.
• Y 1 is -0-(Ci_ 7 alkyl).
• Y 1 is -O-butyl, -O-pentyl, or -O-hexyl.
• Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2- 6 alkenyl.
• Y 1 is C2-6 alkynyl.
• Y 1 is -C ⁇ CH.
• Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 . In certain embodiments, Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 . [00335] In certain embodiments, A 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y 2 .
• a 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.
• a 1 is or ( ⁇ ' )m ⁇ wherein m is 0, 1 , or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, or C 1-6
• a 1 is ⁇ i ⁇ ( Y )m or ( Y )m ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
• R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
• R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
• the compound is a compound of Formula C-I-B:
• a 1 is a cyclic group selected from phenyl, pyridinyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y :
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl;
• R 4 represents independently for each occurrence hydrogen or C1-4 alkyl.
• Definitions of the variables in Formula C-I-B above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A 1 is phenyl or pyridinyl, each of which is substituted once by Y 1 , where Y 1 is 2-8 membered heteroalkyl.
• a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
• a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C1-3 alkyl, halogen, or Ci-3 haloalkyl.
• Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6 membered aryl or a 3-10 membered heterocyclyl.
• Y 1 is -0-(Ci_7 alkyl).
• Y 1 is -O-butyl, -O-pentyl, or -O-hexyl.
• Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
• Y 1 is a 3-10 membered heterocyclyl, 6 membered aryl, or -0-(3-6 membered heterocyclyl). In certain embodiments, Y 1 is a 3-10 membered
• Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
• Y 1 is a 5-membered heteroaryl.
• Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
• Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, and C 1-6 alkoxyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
• Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
• the description above describes multiple embodiments relating to compounds of Formula C-I-B.
• the patent application specifically contemplates all combinations of the embodiments.
• the invention contemplates a compound of Formula I-B wherein A is phenyl or pyridinyl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
• the compound is a compound of Formula C-I-C:
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y :
• Y 1 represents, independently for each occurrence, one of the following:
• Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl;
• R 4 represents independently for each occurrence hydrogen or C 1 -4 alkyl.
• Definitions of the variables in Formula C-I-C above encompass multiple chemical groups.
• the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
• a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrences of Y 2 .
• any occurrence of Y 2 is independently C 1 -3 alkyl, halogen, or Ci- 3 haloalkyl.
• the compound is one of the compounds listed in Table 5 or 6 below or a pharmaceutically acceptable salt thereof.
• the synthetic route illustrated in Scheme 2-B depicts an exemplary procedure for preparing substituted imidazo[l,5-a]pyrimidine compounds.
• coupling of carboxylic acid D with a variety of substituted aromatic or heteraromatic amines may be accomplished using standard peptide coupling procedures, such as HATU and/or HOBT in DMF in the presence of DIPEA.
• carboxylic ester C may be treated with ⁇ 1 ⁇ 3 to afford the intermediate Weinreb amide, which after reaction with an amine provides substituted amide E.
• the reaction is performed in a stepwise manner where a bromo or iodo-substituted aromatic or heteraromatic amine is coupled with the Weinreb amide to form the iodo or bromo-substituted amide F.
• the bromo or iodo moiety may be used to couple a variety of functional groups using standard coupling procedures, such as acetylenes using Sonogashira coupling, boronic acids using Suzuki coupling, and amines using Buchwald coupling to produce substituted amide E.
• a functional group in substituent A 1 and Y 1 can converted to another functional group using standard functional group manipulation procedures known in the art. See, for example, "Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992).
• the invention provides pharmaceutical compositions Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l).
• the pharmaceutical compositions preferably comprise a therapeutically - effective amount of one or more of Gcase activator compounds described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) described above, formulated together with one or more pharmaceutically acceptable carriers.
• compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
• oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions),
• terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
• compositions are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), le
• Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety -nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
• a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
• an aforementioned formulation renders orally bioavailable a compound of the present invention.
• Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
• a compound of the present invention may also be administered as a bolus, electuary or paste.
• the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants,
• pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
• compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, poly oxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydr oxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, poly oxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydr oxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
• Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a
• pharmaceutically-acceptable carrier and with any preservatives, buffers, or propellants which may be required.
• the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
• dosage forms can be made by dissolving or dispersing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
• Ophthalmic formulations are also contemplated as being within the scope of this invention.
• compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
• adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
• a liquid suspension of crystalline or amorphous material having poor water solubility The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
• delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
• the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,
• systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
• These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
• the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
• the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
• the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
• the effective amount may be less than when the agent is used alone.
• the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
• kits for treating a disorder comprises: i) instructions for treating a medical disorder described herein, such as Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy; and ii) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l).
• the kit may comprise one or more unit dosage forms containing an amount of a Gcase activator compound described herein (e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l), that is effective for treating said medical disorder.
• the kit may further comprise a second therapeutic agent described herein.
• Gcase activator compounds e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l
• compositions comprising a Gcase activator compound
• methods of using the Gcase activator compounds and kits.
• the patent application specifically contemplates all combinations and permutations of the aspects and embodiments.
• Exemplary tested compounds are listed in Table 7 and grouped according to their observed Gcase activation value; the GCase activation value is that observed when the test compound was used at a concentration of 1.0 ⁇ .
• Group 1 compounds had a Gcase activation greater value than 60%.
• Group 2 compounds had a Gcase activation value in the range of 30% up to 60%.
• Group 3 compounds had a Gcase activation value less than 30%.

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• 2017
  • 2017-05-04 EP EP17793335.5A patent/EP3452045A1/de not_active Withdrawn
  • 2017-05-04 WO PCT/US2017/031044 patent/WO2017192841A1/en unknown

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