Fused bicyclic SGC stimulators

Abstract

Stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations containing same, and their uses, alone or in combination with one or more additional agents, for treating various diseases are provided. The stimulator of soluble guanylate cyclase is a compound of formula (I). TIFF2022084863000137.tif5769

Description

[Technical Field]

[0001] Related Applications

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of the filing dates of U.S. Provisional Patent Application No. 62 / 382,942, filed September 2, 2016; U.S. Provisional Patent Application No. 62 / 423,445, filed November 17, 2016; U.S. Provisional Patent Application No. 62 / 468,598, filed March 8, 2017; and U.S. Provisional Patent Application No. 62 / 482,486, filed April 6, 2017. The entire contents of each of the above applications are incorporated herein by reference.

[0002] This disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations containing same, and their use, alone or in combination with one or more additional agents, to treat various diseases in which elevated levels of nitric oxide (NO) or cyclic guanosine 3',5'-monophosphate (cGMP), or both, or upregulation of the NO pathway, are desirable. [Background technology]

[0003] Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in vivo. sGC can be activated through both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine 5'-triphosphate (GTP) to the second messenger cyclic GMP (cGMP). Elevated levels of cGMP regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels.

[0004]

[0004] In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by the sequential reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II), found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long-term potentiation; and constitutive endothelial NOS (eNOS or NOS III), which regulates smooth muscle relaxation and blood pressure. Experimental and clinical evidence indicates that reduced concentrations, bioavailability, and / or reduced responsiveness to endogenously produced NO contribute to pathogenesis.

[0005]

[0005] NO-independent, heme-dependent sGC stimulators have several important distinguishing properties compared with other types of sGC modulators, including a critical dependence of their activity on the presence of the reduced prosthetic heme moiety, strong synergistic enzyme activation when combined with NO, and stimulation of cGMP synthesis through direct stimulation of sGC independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Since then, additional sGC stimulators with improved potency and specificity for sGC have been developed.

[0006]

[0006] Compounds that stimulate sGC independently of NO offer significant advantages over other current alternative therapies that target aberrant NO pathways or diseases in which upregulation of the NO pathway is beneficial. There is a need for the development of novel sGC stimulators. These compounds are useful in treating a variety of diseases or disorders that would benefit from stimulation of sGC or increased concentrations of nitric oxide (NO) or cyclic guanosine 3',5'-monophosphate (cGMP), or both, or in which upregulation of the NO pathway is desirable. Summary of the Invention

[0007] The present invention is directed to compounds of formula I or pharmaceutically acceptable salts thereof:

[0008] [ka]

[0009] [In formula: Rings E and A form the core of the molecule and are aromatic; each instance of X and Y is independently selected from N or C; in this regard, up to four instances of X and Y are simultaneously N; W is i) does not exist, J B is directly attached to a carbon atom bearing two J groups, each J being independently selected from hydrogen or methyl, n is 1, and J B C may be substituted by up to 9 fluorines 1-7 Is an alkyl chain; or ii) Ring B, wherein Ring B is phenyl, C 3-7 a cycloalkyl ring or a 5- or 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; In this regard, when ring B is a phenyl or 5- or 6-membered heteroaryl ring; each J is independently selected from hydrogen or methyl; n is an integer selected from 0 to 3; and each J B are independently halogen, -CN, C 1-6 Aliphatic group, -OR B , or C 3-8 alicyclic rings; Ring B is C 3-7 When the ring is a cycloalkyl ring, each J is hydrogen; n is an integer selected from 0 to 3, and each J B are independently halogen, -CN, C 1-6 Aliphatic group or -OR B1 Selected from; C 1-6 Each J is an aliphatic group B , and C 3-8 Each J is an alicyclic ring B R for up to three cases independently 3 may be substituted with; Each R B independently, C 1-6 Aliphatic group or C 3-8 alicyclic rings; B R for up to three cases independently 3a may be substituted with; Each R B1 are independently hydrogen, C 1-6 Aliphatic group or C 3-8 alicyclic rings; 1-6 Each of the aliphatic groups, and the C 3-8 Each of the alicyclic rings may independently have up to three instances of R 3b may be substituted with; Each R 3 , R 3a and R 3b is, in each instance, independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -O(C 1-4 alkyl) or -O(C 1-4 haloalkyl); p is an integer selected from 1, 2, or 3; each J C are independently hydrogen, halogen, C 1-4 aliphatic group, C 1-4 alkoxy or —CN; 1-4 Aliphatic groups and C 1-4 Alkoxy may independently be up to three instances of C 1-4 Alkoxy, C 1-4 haloalkoxy, optionally substituted by -OH or halogen; Q, G, and Z are each independently N, S, or O, whereby at least two of Q, G, and Z are N; q is 0, 1 or 2; R 10 is independently 0 to 3 occurrences of R 15 C optionally substituted with 1-6 alkyl, independently 0 to 3 occurrences of R 15phenyl, optionally substituted with 0 to 3 independently occurring R 15 5- or 6-membered heteroaryl optionally substituted with, independently, 0 to 3 occurrences of R 15 C optionally substituted with 3-8 cycloalkyl, or independently 0 to 3 occurrences of R 15 wherein each of said 5- to 6-membered heteroaryl rings and each of said 3- to 8-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; R 11 -H, -NR a2 R b2 , -C(O)NR a2 R b2 , -C(O)R 15a , -SO2R b2 , -SR b2 , halo, -OCF3, -CN, hydroxyl, independently 0 to 2 occurrences of R b2 C optionally substituted with 2-6 alkenyl, independently 0 to 2 occurrences of R b2 C optionally substituted with 2-6 Alkynyl; independently 0 to 3 occurrences of R 15 C optionally substituted with 1-6 alkyl, independently 0 to 5 occurrences of R 15 C optionally substituted with 1-6 Alkoxy, independently 0 to 3 occurrences of R 15 phenyl, optionally substituted with 0 to 3 independently occurring R 15 5-6 membered heteroaryl optionally substituted with, independently, 0-3 occurrences of R 15 C optionally substituted with 3-8 cycloalkyl, or independently 0 to 3 occurrences of R 15 wherein each of said 5- to 6-membered heteroaryls and each of said 3- to 8-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; or R 10 is a substituent of Z, R10 and R 11 Z, and R 11 Together with the carbon to which it is attached, there are 0 to 3 independently present R 15 wherein each of said 3- to 10-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; R 15 , halo, -OR b2 , -SR b2 , -NR a2 R b2 , -C(O)R b2 , -C(O)NR a2 R b2 , -NR b2 C(O)OR b2 , -OC(O)NR a2 R b2 , C 2-4 Alkenoxy, independently 0 to 3 occurrences of R 18 C optionally substituted with 3-8 Cycloalkyl, independently 0 to 3 occurrences of R 18 phenyl, optionally substituted with 0 to 3 independently occurring R 18 or 0 to 3 occurrences of R 18 wherein each of said 5- or 6-membered heteroaryl rings and each of said 3- to 10-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; R 15a is independently 0 to 3 R 18 C optionally substituted with 3-8 Cycloalkyl, independently 0 to 3 occurrences of R 18 phenyl, optionally substituted with 0 to 3 independently occurring R 18 or 0 to 3 occurrences of R 18wherein each of said 5- or 6-membered heteroaryl rings and each of said 3- to 10-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; Each R 18 are independently halo, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 selected from haloalkyl or phenyl; R a2 is hydrogen, -C(O)R b2 , C 1-6 Alkyl or C 1-6 is haloalkyl; and R b2 is hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl].

[0010] The present invention is also directed to a pharmaceutical composition comprising a compound according to Formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient or carrier. The present invention is also directed to a pharmaceutical formulation or dosage form comprising the pharmaceutical composition.

[0011]

[0009] The present invention also provides a method for treating or preventing a disease, condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination therapy; in this regard, the disease would benefit from stimulation of sGC or increased concentrations of NO or cGMP or both, or upregulation of the NO pathway. [Brief explanation of the drawings]

[0012] [Figure 1]

[0010] Figure 1 is a plot of long-term potentiation in wild-type (WT) mouse hippocampal slices (top curve), R6 / 2 mouse hippocampal slices (bottom curve), and R6 / 2 mouse hippocampal slices treated with 7 nM compound I-1 (middle curve). [Figure 2]

[0011] Figure 2 is a plot of long-term potentiation in wild-type (WT) mouse hippocampal slices (top curve, overlapping with the middle curve), R6 / 2 mouse hippocampal slices (bottom curve), and R6 / 2 mouse hippocampal slices treated with 46 nM compound I-1 (middle curve, overlapping with the top curve). [Figure 3]

[0012] Figure 3 is a plot of long-term potentiation in wild-type (WT) mouse hippocampal slices (top curve, overlapping with the middle curve), R6 / 2 mouse hippocampal slices (bottom curve), and R6 / 2 mouse hippocampal slices treated with 308 nM compound I-1 (middle curve, overlapping with the top curve). [Figure 4]

[0013] FIG. 4 shows photographs of the brain of a rat treated with a peripherally restricted sGC stimulator (left) and a compound of the present invention (right). DETAILED DESCRIPTION OF THE INVENTION

[0013]

[0014] Specific embodiments of the present invention will now be described in detail, examples of which are illustrated in the accompanying structures and chemical formulas. While the present invention will be described in conjunction with the enumerated embodiments, it will be understood that this is not intended to limit the invention to those embodiments. Rather, the present invention is intended to cover all alternatives, modifications, and equivalents that may be encompassed within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein, but encompasses all methods and materials similar or equivalent to those described herein that can be used in practicing the present invention. In the event that one or more of the incorporated references, patents, or similar materials differs from or conflicts with this application, including, but not limited to, defined terms, term usage, described techniques, etc., this application controls. Definitions and General Terminology

[0015] For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry are covered in "Organic Chemistry" "Advanced Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th ed., Smith, M.B. and March, J., eds., John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entireties.

[0014]

[0016] As described herein, compounds of Formula I may be optionally substituted with one or more substituents, such as those exemplified generally below or by specific classes, subclasses, and species of the present invention. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position, unless otherwise specified. The term "optionally and independently" may be used to describe this condition. As an example, one of the substituents disclosed herein is R 10 , which, among other options, independently represents 0 to 3 possible R 15 C optionally substituted with 1-6 In this case, C 1-6 An alkyl can be "optionally substituted": it is unsubstituted (i.e., 0 occurrences of R15 ) or substituted (i.e., 1, 2, or 3 occurrences of R 15 ) can be. 15 (for example, two), each R 15 can be the same substituent (e.g., two fluoro atoms) or can be different (e.g., —OH and chloro). As would be apparent to one skilled in the art, groups such as —H, halogen, —NO, —CN, —OH, —NH, or —OCF would not be substitutable groups.

[0015]

[0017] As used herein, the phrase "up to" refers to zero or any integer that is less than or equal to the number following the phrase. For example, "up to 3" means any one of 0, 1, 2, or 3. As used herein, a specified number range of atoms includes any integer within that range. For example, a group having 1 to 4 atoms can have 1, 2, 3, or 4 atoms. A group having 0 to 3 atoms can have 0, 1, 2, or 3 atoms. When any variable occurs more than one time at any position, the definition for each occurrence is independent of all other occurrences.

[0016]

[0018] The selection of substituents and combinations envisioned by the present disclosure are only those that result in the formation of stable or chemically feasible compounds. Such choices and combinations will be apparent to those of ordinary skill in the art and can be determined without undue experimentation. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that allow for its production, detection, and, in some embodiments, recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound is one that remains substantially unchanged when maintained at a temperature of 25°C or less in the absence of moisture or other chemically reactive conditions for at least one week. Chemically feasible compounds are compounds that can be prepared by one of ordinary skill in the art based on the disclosures herein, supplemented, if necessary, by relevant knowledge in the art.

[0017]

[0019] Compounds such as those of Formula I or Table I or other compounds disclosed herein can exist in a free form (e.g., an amorphous form, or a crystalline form, or a polymorph). Under certain conditions, the compounds may also form co-forms. As used herein, co-form is synonymous with the term multi-component crystalline form. Salt formation is determined by the magnitude of the pKa difference between the mixture-forming partners. For purposes of this disclosure, compounds encompass pharmaceutically acceptable salts, even if the term "pharmaceutically acceptable salt" is not explicitly mentioned.

[0018]

[0020] Unless only one of the isomers is specifically depicted or named, structures depicted herein are also intended to encompass all stereoisomeric (e.g., enantiomers, diastereomers, atropisomers, and cis-trans isomeric) forms of the structure; for example, R and S configurations about each asymmetric center, Ra and Sa configurations about each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Thus, single stereochemical isomers of the present compounds as well as racemates and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational isomers) are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are intended to encompass all tautomeric forms of the compounds of the disclosure. Any such embodiment is within the scope of the present invention.

[0019]

[0021] The present disclosure also encompasses isotopically labeled compounds that are identical to the compounds listed herein, but in fact one or more atoms are replaced by atoms with atomic masses or mass numbers different from those usually found in nature.All isotopes of any particular atom or element specified are intended to be within the scope of the compounds of the present invention and their use.Representative isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, for example, 2 H, 3 H,11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C isotopes are useful because they are easy to prepare and highly detectable. 2 Substitution with heavier isotopes, such as H), may offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferable in some circumstances. 15 O. 13 N, 11 C and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following schemes and / or examples herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0020]

[0022] As used herein, the terms "aliphatic" or "aliphatic group" or "aliphatic chain" mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation. Unless otherwise specified, an aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-3 or 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Illustrative examples of aliphatic groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propargyl, acetylene, and the like. x-y In this regard, x and y are the minimum and maximum number of carbon atoms forming the aliphatic chain.

[0021]

[0023] As used herein, the term "alkyl" (as in "alkyl chain" or "alkyl group") refers to a saturated, linear or branched chain monovalent hydrocarbon group. Unless otherwise specified, an alkyl group contains 1 to 20 carbon atoms (e.g., 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and the like. An alkyl group is defined as "C x-y In this regard, x and y are the minimum and maximum number of carbon atoms forming the alkyl chain.

[0022]

[0024] The term "alkenyl" (as in "alkenyl chain" or "alkenyl group") refers to an alkyl group that is linear or branched and has at least one site of unsaturation, i.e., carbon-carbon. elementary, sp 2 Alkenyl refers to a monovalent hydrocarbon group having a double bond, and includes groups having "cis" and "trans" orientations, or "E" and "Z" orientations. Unless otherwise specified, alkenyl groups contain 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms, or 2-3 carbon atoms). Examples include, but are not limited to, vinyl, allyl, and the like. An alkenyl group is a "C x-y In this regard, x and y are the minimum and maximum number of carbon atoms forming the alkenyl chain.

[0023]

[0025] The term "alkynyl" (as in "alkynyl chain" or "alkynyl group") refers to a monovalent hydrocarbon radical, linear or branched, having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2 to 20 carbon atoms (e.g., 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms). Examples include, but are not limited to, ethynyl, propynyl, and the like. An alkynyl group is defined as "C x-y In this regard, x and y are the minimum and maximum number of carbon atoms forming the alkynyl chain.

[0024]

[0026] The term "carbocyclic" refers to a ring system formed solely by carbon and hydrogen atoms. Unless otherwise specified, throughout this disclosure, carbocyclic is used synonymously with "non-aromatic carbocyclic" or "alicyclic." In some cases, the term can be used in the phrase "aromatic carbocyclic," which in turn refers to an "aryl group," as defined below.

[0025]

[0027] The term "alicyclic" (or "non-aromatic carbocycle", "non-aromatic carbocyclyl", "non-aromatic carbocyclic" or "alicyclic ring") refers to a cyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation but is not aromatic and has one point of attachment to the rest of the molecule. In one embodiment, the term "alicyclic" refers to a monocyclic C 3-12 It refers to hydrocarbons. Alicyclic rings are "C x-y wherein x and y are the minimum and maximum number of carbon atoms forming the alicyclic ring. Suitable alicyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of alicyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0026]

[0028] As used herein, "cycloalkyl" or "cycloalkyl ring" refers to a ring system that is fully saturated and has one point of attachment to the rest of the molecule. In one embodiment, the term "cycloalkyl" refers to a monocyclic C 3-12 It refers to a saturated hydrocarbon. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. A cycloalkyl ring is defined as "C x-y In this regard, x and y are the minimum and maximum number of carbon atoms forming the cycloalkyl ring.

[0027]

[0029] As used herein, "heterocycle" (or "heterocyclyl" or "heterocyclic" or "heterocyclic ring") refers to a ring system in which one or more ring members are independently selected heteroatoms, which is fully saturated or contains one or more units of unsaturation but is not aromatic, and which has one point of attachment to the rest of the molecule. Unless otherwise specified, the terms "heterocycle" and "heterocyclyl" are used in the context of this disclosure. Throughout, heterocycle is used synonymously with "non-aromatic heterocycle." In some instances, the term may be used in the phrase "aromatic heterocycle," which refers to a "heteroaryl group," as defined below. In some embodiments, the heterocycle has 3 to 10 ring members, with one or more ring members being a heteroatom independently selected from oxygen or nitrogen. In other embodiments, the heterocycle can be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms).

[0028]

[0030] Examples of heterocyclic rings include, but are not limited to, the following monocyclic rings: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydro Iromylopiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl.

[0029]

[0031] The term "heteroaryl" (or "heteroaromatic" or "heteroaryl group" or "heteroaromatic ring" or "heteroaryl ring"), used alone or as part of a larger moiety, as in "heteroarylalkyl" or "heteroarylalkoxy," refers to a ring system that is aromatic, contains one or more heteroatoms, has 5 to 6 ring members, and has one point of attachment to the rest of the molecule. Heteroaryl rings include, but are not limited to, the following monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl). , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl.

[0030]

[0032] The term "ring atom" refers to an atom such as C, N, O, or S that is part of an aromatic, alicyclic, heterocyclic, or heteroaryl ring. A "substitutable ring atom" is a ring carbon or nitrogen atom that is bonded to at least one hydrogen atom. The hydrogen can be replaced with a suitable substituent, if desired. Thus, the term "substitutable ring atom" does not include a ring nitrogen or carbon atom that is shared when two rings are fused. In addition, "substitutable ring atom" does not include a ring carbon or nitrogen atom if the structure depicts that the ring carbon or nitrogen atom is already attached to one or more moieties other than hydrogen, and no hydrogen is available for substitution.

[0031]

[0033] A "heteroatom" is any oxidized form of nitrogen, sulfur, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, e.g., N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or NR + It refers to one or more of oxygen, sulfur, and nitrogen, including those in N-substituted pyrrolidinyl.

[0032]

[0034] In some embodiments, two independently occurring variables, together with the atom(s) to which each variable is attached, can form a 5- to 8-membered aryl or heteroaryl ring, or a 3- to 8-membered alicyclic ring or heterocyclyl. Representative rings formed when two independently occurring substituents, together with the atom(s) to which each variable is attached, include, but are not limited to, a) two independently occurring substituents attached to the same atom that together form a ring, where both occurrences of the substituents, together with the atoms to which they are attached, form a heterocyclyl, heteroaryl, alicyclic, or aryl ring, which is attached to the rest of the molecule by a single point of attachment; and b) two independently occurring substituents attached to different atoms that, together with both atoms, form a heterocyclyl, heteroaryl, alicyclic, or aryl ring, where the resulting ring has two points of attachment to the rest of the molecule.

[0033]

[0035] It will be apparent that a variety of other rings may be formed when two independently occurring substituents are taken together with the atom(s) to which each substituent is attached, and the examples detailed above are not intended to be limiting.

[0034]

[0036] As described herein, a bond drawn from a substituent to the center of one of the rings in a polycyclic ring system (shown below) represents substitution of the substituent at any substitutable position on any of the rings in the polycyclic ring system. For example, Formula D3 represents possible substitution at any position shown in Formula D4:

[0035] [ka]

[0036]

[0037] This also applies to polycyclic ring systems (represented by dotted lines) that are fused to optional ring systems. For example, in formula D5, X is an optional substituent on both ring A and ring B.

[0037] [ka]

[0038] However, when each of the two rings in a polycyclic ring system has different substituents derived from the center of each ring, unless otherwise specified, each substituent represents only the substituent on the ring to which it is attached. For example, in formula D6, Y is an optional substituent on ring A only, and X is an optional substituent on ring B only.

[0039] [ka]

[0040] As used herein, the term "alkoxy," as defined above, refers to an alkyl group attached to a molecule or other chain or ring through an oxygen ("alkoxy," i.e., --O-alkyl) atom.

[0041] As used herein, "halogen" or "halo" means F, Cl, Br, or I. The terms "haloalkyl," "haloalkenyl," "haloaliphatic," and "haloalkoxy" refer to alkyl, alkenyl, aliphatic, or alkoxy, optionally substituted with one or more halogen atoms. For example, C 1-3 Haloalkyl can be -CFHCHCHF, C 1-2 Haloalkoxy can be -OC(Br)HCHF2. This term encompasses perfluorinated alkyl groups such as -CF3 and -CF2CF3.

[0042] As used herein, the term "cyano" refers to --CN or --C.ident.N.

[0043] The terms "cyanoalkyl," "cyanoalkenyl," "cyanoaliphatic," and "cyanoalkoxy" refer to alkyl, alkenyl, aliphatic, or alkoxy, optionally substituted with one or more cyano groups. For example, C 1-3 Cyanoalkyl can be -C(CN)CHCH, where C 1-2 The cyanoalkenyl can be =CHC(CN)H2.

[0043]

[0044] As used herein, an "amino" group refers to -NH2.

[0045] The terms "aminoalkyl," "aminoalkenyl," "aminoaliphatic," and "aminoalkoxy" refer to alkyl, alkenyl, aliphatic, or alkoxy, optionally substituted with one or more amino groups. For example, C 1-3 The aminoalkyl can be —CH(NH)CHCHNH, where C 1-2 The aminoalkoxy can be —OCH 2 CH 2 NH 2 .

[0044]

[0046] The terms "hydroxyl" or "hydroxy" refer to --OH.

[0047] "Hydroxyalkyl", "hydroxyalkenyl", "hydroxyaliphatic" And the term "hydroxyalkoxy" refers to alkyl, alkenyl, aliphatic or alkoxy optionally substituted with one or more -OH groups. For example, C 1-3 The hydroxyalkyl can be -CH2(CH2OH)CH3, and the C4 hydroxyalkoxy can be -OCH2C(CH3)(OH)CH3.

[0045]

[0048] As used herein, "carbonyl," used alone or in connection with other groups, refers to -C(O)- or -C(O)H. For example, as used herein, "alkoxycarbonyl" refers to groups such as -C(O)O(alkyl).

[0046]

[0049] As used herein, "oxo" refers to =O. In this regard, the oxo is usually, but not necessarily, attached to a carbon atom (e.g., it can be attached to a sulfur atom). The aliphatic chain can optionally be interrupted by a carbonyl group or optionally substituted by an oxo group, and both terms refer to the same thing: e.g., -CH2-C(O)-CH3. When an "oxo" group is listed as a possible substituent on a ring or other moiety or group (e.g., an alkyl chain), it will be understood that the bond between the oxygen in said oxo group and the ring or moiety to which it is attached is a double bond, even though in some cases it is drawn as a single line inclusively. For example, in the example depicted below, the J attached to the ring D J can be selected from several different substituents. D If is oxo, J D It will be understood that the bond between J and the ring is a double bond. D If is a halogen, J DIt will be understood that the bond between the oxo group and the ring is a single bond. In some cases, for example, when the ring contains unsaturation or has aromatic character, the compound can exist in two or more possible tautomeric forms. In one of these, the bond between the oxo group and the ring will be a double bond. In the other, a hydrogen bond is exchanged between an atom and a substituent in the ring, thereby converting the oxo to a hydroxy and forming an additional double bond in the ring. Whether a compound is represented as D7 or D8, both are considered to represent a family of all tautomers of a particular compound.

[0047] [ka]

[0048]

[0050] In all other contexts, as used herein, "linker" refers to a divalent group in which the two free valences can be on different atoms (e.g., carbon or heteroatom) or on the same atom but substituted by two different substituents. For example, a methylene group can be substituted by two different groups, one for each free valence (e.g., as in Ph-CH-Ph, where the methylene serves as a linker between two phenyl rings). Ethylene can be a C alkyl linker (-CHCH-) in which the two free valences are on different atoms. For example, an amide group can serve as a linker when placed in an internal position in the chain (e.g., -CONH-). The compounds of the present invention are defined herein by their chemical structure and / or chemical name. If a compound is described by both chemical structure and chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0049] Compound Aspects

[0051] The present invention is directed to compounds of formula I, or pharmaceutically acceptable salts thereof:

[0050] [ka]

[0051] [In formula: Rings E and A form the core of the molecule and are aromatic; each instance of X and Y is independently selected from N or C; in this regard, up to four instances of X and Y are simultaneously N; W is i) does not exist, J B is directly attached to a carbon atom bearing two J groups, each J being independently selected from hydrogen or methyl, n is 1, and J B C may be substituted by up to 9 fluorines 1-7 Is an alkyl chain; or ii) Ring B, wherein Ring B is phenyl, C 3-7 a cycloalkyl ring or a 5- or 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; In this regard, when ring B is a phenyl or 5- or 6-membered heteroaryl ring; each J is independently selected from hydrogen or methyl; n is an integer selected from 0 to 3; and each J B are independently halogen, -CN, C 1-6 Aliphatic group, -OR B , or C 3-8 alicyclic rings; Ring B is C 3-7 When the ring is a cycloalkyl ring, each J is hydrogen; n is an integer selected from 0 to 3, and each J B are independently halogen, -CN, C 1-6 Aliphatic group or -OR B1 Selected from; C 1-6 Each J is an aliphatic group B , and C 3-8 Each J is an alicyclic ring B R for up to three cases independently 3 may be substituted with; Each R B independently, C 1-6 Aliphatic group or C 3-8 alicyclic rings; B R for up to three cases independently3a may be substituted with; Each R B1 are independently hydrogen, C 1-6 Aliphatic group or C 3-8 alicyclic rings; 1-6 Each of the aliphatic groups, and the C 3-8 Each of the alicyclic rings may independently have up to three instances of R 3b may be substituted with; Each R 3 , R 3a and R 3b is, in each instance, independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -O(C 1-4 alkyl) or -O(C 1-4 haloalkyl); p is an integer selected from 1, 2, or 3; each J C are independently hydrogen, halogen, C 1-4 aliphatic group, C 1-4 alkoxy or —CN; 1-4 aliphatic groups and each of the C 1-4 Alkoxy may independently be up to three instances of C 1-4 Alkoxy, C 1-4 haloalkoxy, optionally substituted by -OH or halogen; Q, G and Z are each independently N, S or O, and in this regard, Q, G and Z are each independently N, S or O. and at least two of Z are N; q is 0, 1 or 2; R 10 is independently 0 to 3 R 15 C optionally substituted with 1-6 alkyl, independently 0 to 3 occurrences of R 15 phenyl, optionally substituted with 0 to 3 independently occurring R 15 5- or 6-membered heteroaryl optionally substituted with, independently, 0 to 3 occurrences of R 15 C optionally substituted with 3-8cycloalkyl, or independently 0 to 3 occurrences of R 15 wherein each of said 5- to 6-membered heteroaryl rings and each of said 3- to 8-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; R 11 -H, -NR a2 R b2 , -C(O)NR a2 R b2 , -C(O)R 15a , -SO2R b2 , -SR b2 , halo, -OCF3, -CN, hydroxyl, independently 0 to 2 occurrences of R b2 C optionally substituted with 2-6 alkenyl, independently 0 to 2 occurrences of R b2 C optionally substituted with 2-6 Alkynyl; 0 to 5 independently occurring R 15 C optionally substituted with 1-6 alkyl, independently 0 to 3 occurrences of R 15 C optionally substituted with 1-6 Alkoxy, independently 0 to 3 occurrences of R 15 phenyl, optionally substituted with 0 to 3 independently occurring R 15 5-6 membered heteroaryl optionally substituted with, independently, 0-3 occurrences of R 15 C optionally substituted with 3-8 cycloalkyl, or independently 0 to 3 occurrences of R 15 wherein each of said 5- to 6-membered heteroaryls and each of said 3- to 8-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; or R 10 is a substituent of Z, R 10 and R 11 Z, and R 11 Together with the carbon to which it is attached, there are 0 to 3 independently present R 15wherein each of said 3- to 10-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; R 15 , halo, -OR b2 , -SR b2 , -NR a2 R b2 , -C(O)R b2 , -C(O)NR a2 R b2 , -NR b2 C(O)OR b2 , -OC(O)NR a2 R b2 , C 2-4 Alkenoxy, independently 0 to 3 occurrences of R 18 C optionally substituted with 3-8 Cycloalkyl, independently 0 to 3 occurrences of R 18 phenyl, optionally substituted with 0 to 3 independently occurring R 18 or 0 to 3 occurrences of R 18 wherein each of said 3- to 10-membered heterocyclyls contains up to 3 ring heteroatoms independently selected from N, O, or S; R 15a is independently 0 to 3 R 18 C optionally substituted with 3-8 Cycloalkyl, independently 0 to 3 occurrences of R 18 phenyl, optionally substituted with 0 to 3 independently occurring R 18 or 0 to 3 occurrences of R 18 wherein each of said 5- or 6-membered heteroaryl rings and each of said 3- to 10-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O, or S; Each R 18 are independently halo, hydroxyl, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 selected from haloalkyl or phenyl; R a2 is hydrogen, -C(O)R b2 , C 1-6 Alkyl or C 1-6 is haloalkyl; and R b2 is hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl].

[0052] In some embodiments of Formula I, W is absent and the compound is one of Formula IIA:

[0053] [ka]

[0054] [In the formula, J B C may be substituted by up to 9 fluorines 1-7 In some embodiments of Formula IIA, J B may be substituted by fluorine in up to five cases 1-4 In another embodiment, J B may be substituted by fluorine in up to five cases 1-2 In yet another embodiment, J is an alkyl chain. B is an ethyl chain optionally substituted by 3 or 5 instances of fluorine.

[0055] In some embodiments of Formula I, W is ring B and the compound is one of Formula IIB, or a pharmaceutically acceptable salt thereof:

[0056] [ka]

[0057] In some embodiments of Formula IIB, n is an integer selected from 1 or 2, and each J B are independently halogen, C 1-4 Alkyl, -OR B -OR B1 In other embodiments, each J B is independently selected from halogen atoms. B is independently selected from fluoro or chloro. B is fluoro.

[0058] In some embodiments of Formula IIB, each J B is C 1-4 In some of these embodiments, J is alkyl. B is ethyl or methyl. In some embodiments, J B is methyl.

[0059] In some embodiments of Formula IIB, n is 0. In some embodiments of Formula IIB, n is 1. In some embodiments of Formula IIB, n is 1 and J B are independently halogen, C 1-4 Alkyl, -OR B -OR B1 In some embodiments, J B is a halogen. In some embodiments, J B is chloro or fluoro. B is fluoro. B is C 1-4 In yet another embodiment, J is alkyl. B is methyl or ethyl.

[0060] In some embodiments of Formula IIB, n is 2 and each J B is a halogen atom In some of these embodiments, each J B is independently selected from chloro or fluoro. B is fluoro and the other J B is chloro. In still other embodiments, each J B is fluoro.

[0061] In some embodiments of Formula IIB, ring B is phenyl. In some of these embodiments, n is 1 or 2. In some of these embodiments, J B is ortho to the attachment of the methylene linker between ring B and the core of the molecule, and J B is halogen. In some of these embodiments, J B is chloro. In other embodiments, J B is fluoro.

[0062]

[0061] In some embodiments of Formula IIB, Ring B is a 6-membered heteroaryl ring. In other embodiments, Ring B is a pyridyl ring. In still other embodiments, Ring B is a pyrimidinyl ring.

[0063] In some embodiments of formula IIB, ring B is C 3-7 It is a cycloalkyl ring. In some embodiments of Formula I, Formula IIA, or Formula IIB, G, Z, and Q are each N.

[0064] In some embodiments of Formula I or Formula IIB, the compound is one of Formula III, or a pharmaceutically acceptable salt thereof, or any tautomer thereof:

[0065] [ka]

[0066] In some embodiments of Formula I, Formula IIA, Formula IIB, and Formula III, R 11 H, NRa2 R b2 , -C(O)NR a2 R b2 , -C(O)R 15a , -SO2R b2 , -SR b2 , halo, -OCF3, -CN, hydroxyl, independently 0 to 2 occurrences of R b2 C optionally substituted with 2-6 alkenyl, independently 0 to 2 occurrences of R b2 C optionally substituted with 2-6 Alkynyl; 0 to 5 independently occurring R 15 C optionally substituted with 1-6 alkyl, independently 0 to 3 occurrences of R 15 C optionally substituted with 1-6 Alkoxy, independently 0 to 3 occurrences of R 15 phenyl, optionally substituted with 0 to 3 independently occurring R 15 5- or 6-membered heteroaryl optionally substituted with, independently, 0 to 3 occurrences of R 15 C optionally substituted with 3-8 cycloalkyl, or independently 0 to 3 occurrences of R 15 In some other embodiments, R 11 is H or independently 0 to 5 occurrences of R 15 C optionally substituted with 1-6 In some other embodiments, R 11 is 0 to 5 R 15 C optionally substituted with 1-6 In some other embodiments, R 11 is 0 to 3 R 15 In some other embodiments, R 11 is 0 to 3 R 15 methyl optionally substituted with R 15 is halo (e.g., fluoro). In some other embodiments, R 11 is 0 to 3 R 15 methyl optionally substituted with R15 In some other embodiments, R 11 is unsubstituted methyl In some other embodiments, R 11 is the existence of two R 15 In some other embodiments, R 11 is the existence of two R 15 is methyl substituted with R 15 In some other embodiments, R 11 In some embodiments, R 11 is the existence of three R 15 In some embodiments, R 11 is the existence of three R 15 is methyl substituted with R 15 is halo. In some embodiments, R 11 is -CF3.

[0067] In some embodiments of Formula I, Formula IIA, Formula IIB, and Formula III, R 11 is 0 to 5 R 15 In some other embodiments, R 11 is the R of 5 existences 15 is ethyl substituted with R 15 In some other embodiments, R 11 is the R of 5 existences 15 is ethyl substituted with R 15 is fluoro.

[0068] In some embodiments of Formula III, n is an integer selected from 1 or 2, and each J B are independently halogen, C 1-4 Alkyl, -OR B -OR B1 In other embodiments, each J B is independently selected from halogen atoms. Bis independently selected from fluoro or chloro. B is fluoro.

[0069] In some embodiments of Formula III, each J B is C 1-4 In some of these embodiments, J is alkyl. B is ethyl or methyl. In some embodiments, J B is methyl.

[0070] In some embodiments of Formula III, n is 0. In some embodiments of Formula III, n is 1.

[0071] In some embodiments of Formula III, n is 1 and each J B are independently halogen, C 1-4 Alkyl, -OR B -OR B1 In some embodiments, J B is a halogen. In some embodiments, J B is chloro or fluoro. B is fluoro. B is C 1-4 In yet another embodiment, J is alkyl. B is methyl or ethyl.

[0071]

[0072] In some embodiments of Formula III, n is 2 and each J B is a halogen atom. In some of these embodiments, each J B is independently selected from chloro or fluoro. B is fluoro and the other J B is chloro. In still other embodiments, each J B is fluoro.

[0072]

[0073] In some embodiments of Formula III, ring B is phenyl. In some of these embodiments, n is 1 or 2. In some of these embodiments, J B is ortho to the attachment of the methylene linker between ring B and the core of the molecule, and J B is halogen. In some of these embodiments, J B is chloro. In other embodiments, J B is fluoro.

[0073]

[0074] In some embodiments of Formula III, Ring B is a 6-membered heteroaryl ring. In other embodiments, Ring B is a pyridyl ring. In yet other embodiments, Ring B is a pyrimidinyl ring.

[0074]

[0075] In some embodiments of Formula III, ring B is C 3-7 It is a cycloalkyl ring.

[0076] In some embodiments of Formula I, Formula IIA, Formula IIB, and Formula III, q is 0. In some of these embodiments, R 11 is independently 0 to 3 R 15 in Optionally substituted C 1-6 In some other embodiments, R 11 is independently 0 to 3 R 15 methyl optionally substituted with R 15 is halo (e.g., fluoro). In some other embodiments, R 11 There are two independent R 15 is methyl substituted with R 15 is halo (e.g., fluoro). In some embodiments, R 11 There are three independent R 15 is methyl substituted with R 15 is halo (e.g., fluoro).

[0075]

[0077] In some embodiments of Formula I, Formula IIA, Formula IIB, and Formula III, the core formed by rings E and A is selected from the following:

[0076] [ka]

[0077] [wherein the symbol * The C atom marked with represents the point of attachment to the ring containing G, Z, and Q, and is marked with the symbol ** represent the attachment points of the two instances of J. In some of these embodiments, C is hydrogen.

[0078] In some embodiments of Formula I, Formula IIA, Formula IIB, and Formula III, the core formed by rings E and A is selected from the following:

[0079] [ka]

[0080] In some of these embodiments, J in each case C is hydrogen. In some embodiments of Formula I, Formula IIA, Formula IIB, and Formula III, Q, G, and Z are each independently N, NH, S, or O, and wherein at least two of Q, G, and Z are N or NH.

[0081] In some embodiments of Formula I, the compound is one of Formula IV, or a pharmaceutically acceptable salt thereof:

[0082] [ka]

[0083] [In formula: Each Y is independently N, NJ c , CH or CJ cSelected from; Each X is N, NJ c , CH or CJ c Either; In this regard, up to three instances of X and Y can be simultaneously N or NJ c and; J c is halo or CN, or C optionally substituted with 1 to 3 halo 1-3 is alkyl; each J B are independently halo or C 1-4 alkyl; n is 0, 1, 2 or 3; R 10 are independently halo, -C(O)R b2 C optionally substituted with 1, 2 or 3 groups selected from phenyl and 5- or 6-membered heteroaryl 1-4 alkyl, in which case phenyl and 5- or 6-membered heteroaryl may be selected from the group consisting of 1, 2, or 3 halo or C 1-4 optionally substituted with alkyl, heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; q is 0 or 1; R 11 H, halo, -NR a2 R b2 , C 1-4 Alkyl, 5-6 membered heteroaryl , or C 3-6 cycloalkyl, and in this regard, C 1-4 Alkyl, 5-6 membered heteroaryl and C 3-6 Each cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo, and heteroaryl contains 1, 2, or 3 heteroatoms independently selected from N, O, and S; R a2 is hydrogen or C 1-4 is alkyl; and R b2 is hydrogen or C 1-4 alkyl].

[0084] In some embodiments of Formula I, the compound is one of Formula V, or a pharmaceutically acceptable salt thereof:

[0085] [ka]

[0086] [In formula: Y is N or CH; each J B are independently halo or C 1-4 alkyl; n is 0, 1, 2 or 3; R 11 H, halo, -NR a2 R b2 , C 1-4 Alkyl, 5-6 membered heteroaryl, or C 3-6 cycloalkyl, and in this regard, C 1-4 Alkyl, 5-6 membered heteroaryl and C 3-6 Each cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo; R a2 is hydrogen or C 1-4 is alkyl; and R b2 is hydrogen or C 1-4 alkyl].

[0087] In some embodiments of Formula I, the compound is one of Formula VI, or a pharmaceutically acceptable salt thereof:

[0088] [ka]

[0089] [In formula: Y is N or CH; each J B are independently halo or C 1-4 alkyl; n is 0, 1, 2 or 3; R 11 H, halo, -NR a2 R b2 , C 1-4 Alkyl, 5-6 membered heteroaryl, or C 3-6 cycloalkyl, and in this regard, C 1-4 Alkyl, 5-6 membered heteroaryl and C 3-6 Each cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo; R a2 is hydrogen or C 1-4 is alkyl; and R b2 is hydrogen or C 1-4 alkyl].

[0090] In some embodiments of Formulas IV, V, and VI, R 11 C optionally substituted with 1, 2 or 3 halo 1-4 It is alkyl. In some embodiments, the compound of Formula I is selected from those listed in Table I.

[0091] [Table 1]

[0092] [Table 2]

[0093] [Table 3]

[0094] [Table 4]

[0095] [Table 5]

[0096] [Table 6]

[0097] [Table 7]

[0098] In some embodiments, the compound of formula I is in its neutral form or as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the present invention As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of Formula I. Pharmaceutically acceptable salts of compounds of Formula I are used in medicines. However, non-pharmaceutically acceptable salts may be useful in the preparation of compounds of Formula I or their pharmaceutically acceptable salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples in which multiple charged atoms are part of the pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have more than one charged atom and / or more than one counterion.

[0099] Pharmaceutically acceptable salts of the compounds described herein include those derived from compounds containing inorganic acids, organic acids, or bases. In some embodiments, the salts are In other embodiments, the salts can be prepared from the free form of the compound in a separate synthetic step.

[0100]

[0087] If the compound of formula I is acidic or contains a sufficiently acidic bioisostere, Where appropriate, "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0101]

[0088] When the compound of Formula I is basic or contains a sufficiently basic bioisostere, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. Other representative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0102] The preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is fully described in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, the entire contents of which are incorporated herein by reference. and is incorporated herein by reference.

[0103]

[0090] The compounds described herein, as well as their pharmaceutically acceptable salts, can be employed in compositions for treating or preventing the diseases identified herein. Pharmaceutical compositions and methods of administration.

[0104] The compounds disclosed herein, and their pharmaceutically acceptable salts, can be formulated as pharmaceutical compositions or "formulations." A typical formulation is prepared by mixing a compound of Formula I or a pharmaceutically acceptable salt thereof with a carrier, diluent, or excipient. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent, or excipient used will depend on the means and purpose for which the compound of Formula I is being formulated. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for mammalian administration (GRAS—Generally Regarded as Safe). Generally, safe solvents are non-toxic aqueous solvents, such as water, and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. The formulation can also include other types of excipients, such as one or more buffering agents, stabilizers, anti-adherents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or sustained release), preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, and other known additives to provide a pleasing appearance to the drug product (i.e., a compound of Formula I or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a drug product).

[0105]

[0093] Formulations can be prepared using conventional dissolution and mixing procedures. For example, bulk drug substance (i.e., a compound of Formula I, a pharmaceutically acceptable salt thereof, or a stabilized form of the compound, e.g., a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the above-described excipients. The compound having the desired purity may be mixed with a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer in the form of a lyophilized formulation, a milled powder, or an aqueous solution. Formulation can be carried out by mixing with a physiologically acceptable carrier at ambient temperature, a suitable pH, and the desired purity. The pH of the formulation depends primarily on the specific application and concentration of the compound, but can range from about 3 to about 8. When the agents described herein are solid amorphous dispersions formed by a solvent process, additives may be added directly to the spray-drying solution as the mixture is formed, so that the additives are dissolved or suspended in the solution as a slurry that can then be spray-dried. Alternatively, additives may be added after the spray drying process to aid in the formation of the final compounded product.

[0106]

[0094] The compound of Formula I or a pharmaceutically acceptable salt thereof is typically formulated into a pharmaceutical dosage form that provides an easily controllable drug dosage and enables patient compliance with the prescribed regimen. Pharmaceutical formulations of the compound of Formula I or a pharmaceutically acceptable salt thereof can be prepared for various routes and types of administration. Different medical conditions will naturally require different routes of administration, so various dosage forms can exist for the same compound.

[0107] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans can contain about 1 to 1,000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which can be about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosage amounts. For example, an aqueous solution intended for intravenous infusion can contain about 3 to 500 μg of active ingredient per milliliter of solution to provide a suitable infusion volume at a rate of about 30 mL / hour. As a general guideline, the initial pharmaceutically effective amount of inhibitor administered will range from about 0.01 to 100 mg / kg per dose, i.e., about 0.1 to 20 mg / kg per kg of patient body weight per day, with a typical initial range of 0.3 to 15 mg / kg / day for the compound used.

[0108] As used herein, the term "therapeutically effective amount" refers to the biological or physiological effect in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician. It refers to the amount of an active compound or pharmaceutical agent that produces a pharmaceutical response. A therapeutically or pharmaceutically effective amount of a compound administered is subject to such considerations and is the minimum amount necessary to ameliorate, cure or treat a disease or disorder or one or more symptoms thereof.

[0109] Pharmaceutical compositions of Formula I may be prepared by the methods consistent with good medical practice. That is, formulated, dosed, and administered in an amount, concentration, schedule, course, vehicle, and route of administration. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.

[0110] The term "prophylactically effective amount" refers to an amount effective to prevent a disease or disorder or substantially reduce the likelihood of acquiring a disease or disorder, reduce the severity of the disease or disorder before it is acquired, or reduce the severity of one or more symptoms before the symptoms appear. Broadly, prophylactic strategies are divided into primary prevention (preventing the onset of the disease) and secondary prevention (protecting the patient from worsening the course of the disease once it has already appeared).

[0111] Acceptable diluents, carriers, excipients, and stabilizers are those that are non-toxic to recipients at the dosages and concentrations employed and include buffers, e.g., phosphate, citrate, and other organic acids; antioxidants, e.g., ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); proteins, e.g., serum albumin; Examples of suitable active pharmaceutical ingredients include albumin, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates such as glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, for example, hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively. Such techniques are disclosed in Remington's: The Science and Practice of Pharmacy, 21st ed., edited by University of the Sciences in Philadelphia, 2005 (hereinafter "Remington's").

[0112]

[0100] In a "controlled drug delivery system," the drug is delivered to the patient in a controlled manner, in a manner that is intimately linked to the drug and the condition being treated. The primary objective is to achieve therapeutic drug concentrations at the site of action over a desired sustained period. The term "controlled release" is often used to refer to various methods of modifying the release of a drug from a dosage form. This term encompasses preparations known as "sustained release," "delayed release," "modified release," or "extended release." In general, controlled release of the drugs described herein can be provided by the use of a wide variety of polymeric carriers and controlled release systems, including erodible and nonerodible matrices, osmotic controlled devices, various reservoir devices, enteric coatings, and multiparticulate controlled devices.

[0113] "Sustained release preparations" are the most common application of controlled release. Suitable examples of the preparation include semipermeable matrices of solid hydrophobic polymers containing the compound, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.

[0114] "Immediate release preparations" can also be prepared. The purpose of these formulations is to The goal is to get the drug into the bloodstream and reach the site of action as quickly as possible. For example, to achieve rapid dissolution, most tablets are designed to undergo rapid disintegration into granules followed by deaggregation into fine particles. This exposes a larger surface area to the dissolution medium. This results in a faster dissolution rate.

[0115] The agents described herein may be administered in an erodible or non-erodible polymer matrix system. The erodible matrix can be incorporated into a controlled release device. An erodible matrix means that it is erodible, swellable, or soluble in pure water, or that it is aqueous-erodible, water-swellable, or water-soluble, in the sense that the presence of an acid or base is required to sufficiently ionize the polymer matrix so that erosion or dissolution occurs. Upon contact with an aqueous use environment, the erodible polymer matrix absorbs water to form an aqueous-swollen gel or matrix, which incorporates the drug described herein. The aqueous-swollen matrix gradually erodes, swells, disintegrates, or dissolves in the use environment, thereby controlling the release of the compound described herein into the use environment. One component of this water-swollen matrix is ​​a water-swellable, erodible, or soluble polymer, which may generally be described as an osmopolymer, hydrogel, or water-swellable polymer. Such polymers can be linear, branched, or crosslinked. The polymer can be a homopolymer or a copolymer. In certain embodiments, these can be synthetic polymers derived from vinyl, acrylate, methacrylate, urethane, ester, and oxide monomers. In other embodiments, they can be derivatives of naturally occurring polymers, such as polysaccharides (e.g., chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan), starches (e.g., dextrin and maltodextrin), hydrophilic colloids (e.g., pectin), phospholipids (e.g., lecithin), alginates (e.g., ammonium alginate, sodium, potassium, or calcium alginate, propylene glycol alginate), gelatin, collagen, and cellulosic materials. Cellulosic materials are cellulose polymers in which at least a portion of the hydroxyl groups on the sugar repeating units have been modified by reacting with a compound to form ester- or ether-linked substituents.For example, cellulose-based ethyl cellulose has ether-linked ethyl substituents attached to the sugar repeating units, and cellulose-based cellulose acetate has ester-linked acetate substituents. In certain embodiments, the cellulosic material for the erodible matrix comprises a water-soluble material, and aqueous-erodible cellulosic materials can include, for example, ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC). In certain embodiments, the cellulosic material is available in various grades of low viscosity (molecular weights of 50,000 Daltons or less, e.g., Dow Methocel. TM series E5, E15LV, E50LV and K100LY) and high viscosity (molecular weight above 50,000 Daltons, e.g., E4MCR, E10MCR, K4M, K15M and K100M, and Methocel TM Other commercially available types of HPMC include Shin Etsu Metolose 90SH series.

[0116] Other materials useful as erodible matrix materials include, but are not limited to: However, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America , Inc., Piscataway, New Jersey), as well as other acrylic acids Derivatives include, for example, homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0117] Alternatively, the agents of the present invention are administered via a non-erodible matrix device. The drug may be dispersed in or incorporated into an inert matrix. In such devices, the drug described herein is dispersed in an inert matrix. The drug is released by diffusion through the inert matrix. Examples of materials suitable for the inert matrix include insoluble plastics (e.g., methyl acrylate-methyl methacrylate copolymer, polyvinyl chloride, polyethylene), hydrophilic polymers (e.g., ethyl cellulose, cellulose acetate, cross-linked polyvinylpyrrolidone (also known as crospovidone)), and fatty compounds (e.g., carnauba wax, microcrystalline wax, and triglycerides). Such devices are described in Remington: The Science and Further described in Practice of Pharmacy, 20th Edition (2000).

[0118] As noted above, the agents described herein may be incorporated into an osmotic control device. Such devices generally comprise a core containing one or more drugs as described herein and a water-permeable, non-dissolving, non-erodible coating surrounding the core, which controls the influx of water from the aqueous use environment into the core, such that extrusion of part or all of the core into the use environment results in drug release. In certain embodiments, the coating is polymeric, water-permeable, and has at least one delivery port. The core of an osmotic device may contain an osmotic agent that acts to absorb water from the surrounding environment through such a semipermeable membrane. The osmotic agent contained in the core of the device can be a water-swellable hydrophilic polymer or an osmogen, also known as an osmagent. Pressure is generated within the device, which forces the drug(s) out of the device through an orifice (sized to minimize solute diffusion while preventing a buildup of hydrostatic head). Non-limiting examples of osmotic control devices are disclosed in U.S. Patent Application Publication No. 09 / 495,061.

[0119] The amount of water-swellable hydrophilic polymer present in the core can range from about 5 to about 80% by weight (e.g., 10 to 50% by weight). Non-limiting examples of core materials include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly Examples of suitable materials include (methacrylic) acid, polyvinylpyrrolidone (PVP) and crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers and PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate, vinyl acetate, etc., hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), carboxymethyl cellulose (CMC), and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate. Other materials include hydrogels comprising interpenetrating networks of polymers that can be formed by addition or condensation polymerization, and their components can include hydrophilic and hydrophobic monomers such as those just mentioned. Water-swellable hydrophilic polymers include, but are not limited to, PEO, PEG, PVP, croscarmellose sodium, HPMC, sodium starch glycolate, polyacrylic acid, and crosslinked versions or mixtures thereof.

[0120]

[0108] The core may also contain an osmogen (or osmagent). The amount of osmogen present can range from about 2 to about 70% by weight (e.g., 10 to 50% by weight, etc.). Typical classes of suitable osmogens are water-soluble organic acids, salts, and sugars that can absorb water, thereby creating an osmotic pressure gradient across the surrounding coating barrier. Exemplary useful osmogens include, but are not limited to, magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, fructose, lactose, citric acid, succinic acid, tartaric acid, and mixtures thereof. In certain embodiments, the osmogen is glucose, lactose, sucrose, mannitol, xylitol, sodium chloride, including combinations thereof.

[0121] The rate of drug delivery depends on the permeability and thickness of the coating, the osmotic pressure of the drug-containing layer, It is controlled by factors such as the degree of hydrophilicity of the hydrogel layer and the surface area of ​​the device. One skilled in the art will understand that the release rate decreases as the coating thickness increases, but any of the following will increase the release rate: increasing the permeability of the coating; increasing the hydrophilicity of the hydrogel layer; increasing the osmotic pressure of the drug-containing layer; or increasing the surface area of ​​the device.

[0122] In certain embodiments, the particles of the agents described herein have such permeability It is desirable for the particles to be entrained in the fluid that is extruded during operation of the device. To ensure sufficient particle entrainment, the pharmaceutical drug form is dispersed in the fluid before the particles are allowed to settle into the tablet core. One means of achieving this is by adding a disintegrant, which serves to break down the compressed core into its particulate components. Non-limiting examples of standard disintegrants include sodium starch glycolate (e.g., Explotab TM CLV), microcrystalline cellulose (e.g., Avicel TM), microcrystalline silicified cellulose (e.g., ProSolv TM ) and croscarmellose sodium (e.g., Ac-Di-Sol TM ), as well as other disintegrants known to those skilled in the art. Depending on the particular formulation, some disintegrants work better than others. Some disintegrants form gels when swelled with water, which tend to interfere with drug delivery from the device. Non-gelling, non-swelling disintegrants result in more rapid dispersion of drug particles within the core once water enters the core. In certain embodiments, the non-gelling, non-swelling disintegrant is a resin, e.g., an ion exchange resin. In one embodiment, the resin is Amberlite TM IRP88 (available from Rohm and Haas, Philadelphia, PA). The disintegrant is present in an amount ranging from about 1 to 25% of the core drug.

[0123]

[0111] Another example of an osmotic device is an osmotic capsule. A portion of the capsule shell can be semipermeable. The capsule can be filled with either a powder or liquid consisting of the drug described herein, an excipient that absorbs water to provide permeability, and / or a water-swellable polymer, or optionally a solubilizing excipient. The capsule core can also be made to have two or multiple layers similar to the bilayer, trilayer, or concentric configurations described above.

[0124] Another class of osmotic devices useful in the present invention is described in European Patent No. EP 378404. Coated swellable tablets include coated swellable tablets, such as those described in 2002. Coated swellable tablets include a tablet core containing a drug and a swellable material, preferably a hydrophilic polymer, as described herein, coated with a membrane containing holes or pores through which the hydrophilic polymer can extrude and release the drug in an aqueous use environment. Alternatively, the membrane can contain a polymer or a low molecular weight water-soluble porosigen. The porosigen dissolves in an aqueous use environment, creating pores through which the hydrophilic polymer and drug can be extruded. Examples of porosigen include water-soluble polymers such as HPMC and PEG, and low-molecular-weight compounds such as glycerol, sucrose, glucose, and sodium chloride. Additionally, pores can be formed in the coating by drilling holes in the coating using a laser or other mechanical means. In this class of osmotic devices, the membrane material can comprise any film-forming polymer, e.g., a water-permeable or impermeable polymer, provided that the membrane deposited on the tablet core is porous, contains a water-soluble porosigen, or has macroscopic holes for water ingress and drug release. Embodiments of this class of sustained-release devices can also be multilayered, as described, for example, in European Patent EP 378404.

[0125]

[0113] When the drug described herein is a liquid or oil, such as a lipid vehicle formulation as described in International Publication WO05 / 011634, the osmotic controlled-release device can include a softgel or gelatin capsule formed with a composite wall and containing the liquid formulation, wherein the wall includes a barrier layer formed on the outer surface of the capsule, an effervescent layer formed on the barrier layer, and a semipermeable layer formed on the effervescent layer. A delivery port connects the liquid formulation to an aqueous use environment. Such devices are described, for example, in U.S. Patent Publications Nos. 6,419,952, 6,342,249, 5,324,280, 4,672,850, 4,627,850, 4,203,440, and 3,995,631.

[0126]

[0114] As further noted above, the agents described herein generally have a particle size of about 10 μm to about The multiparticulates may be provided in the form of microparticles ranging in size from about 100 μm to 1 mm in diameter. Such multiparticulates may be packaged in capsules, such as gelatin capsules or capsules formed from water-soluble polymers such as HPMCAS, HPMC, or starch; administered as a suspension or slurry in a liquid; or formed into tablets, caplets, or pills by compression or other processes known in the art. Such multiparticulates may be made by any known process, such as wet and dry granulation processes, extrusion / spheronization, roller compaction, melt congealing, or by spray coating seed cores. For example, in wet and dry granulation processes, the agents described herein and optional excipients may be granulated to form multiparticulates of the desired size.

[0127]

[0115] Drugs are stabilized by an interfacial film of surfactant molecules, such as oil and water. It is a generally thermodynamically stable and isotropically clear dispersion of two immiscible liquids. It can be incorporated into microemulsions (Encyclopedia of Pharmaceutical Technology, New York: Marcel Dekker, 1992, Vol. 9). To prepare a microemulsion, a surfactant (emulsifier), a cosurfactant (co-emulsifier), an oil phase, and an aqueous phase are required. Suitable surfactants include any surfactant useful in preparing emulsions, such as emulsifiers typically used in preparing creams. The co-surfactant (or "co-emulsifier") is generally selected from the group consisting of polyglycerol derivatives, glycerol derivatives, and fatty alcohols. Preferred emulsifier / co-emulsifier combinations are generally, but not necessarily, selected from the group consisting of glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and caprylic and capric triglycerides and oleoyl macrogolglycerides. The aqueous phase typically includes not only water but also a buffer, glucose, propylene glycol, polyethylene glycol, preferably low molecular weight polyethylene glycol (e.g., PEG300 and PEG400), and / or glycerol, while the oil phase generally includes, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono-, di-, and triglycerides, mono- and di-esters of PEG (e.g., oleoyl macrogolglyceride), and the like.

[0128] The compounds described herein may be formulated into pharmaceutically acceptable nanoparticles, nanospheres, and Nanocapsules can be incorporated into formulations (Delie and Blanco-Prieto, 2005, Molecule 10:65-80). Nanocapsules are generally stable. To avoid side effects due to intracellular polymer overload, polymers that can be degraded in vivo (e.g., biodegradable polymers) can be used. Using alkyl-cyanoacrylate nanoparticles, ultrafine particles (sizes of about 0.1 μm) can be engineered. Such particles have been described in the prior art.

[0129]

[0117] An implantable device coated with the compound of the present invention may be used in combination with another In one embodiment, the compound can be coated onto an implantable medical device, such as a bead, or formulated with a polymer or other molecule to provide a "drug depot," allowing for drug release over a longer period than would be achieved by administration of an aqueous solution of the drug. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Publications Nos. 6,099,562; 5,886,026; and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart controlled-release properties to the composition.

[0130]

[0118] Formulations include those suitable for the administration routes detailed herein. The formulations can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's. Such methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0131] "Administer" and "Administering" with Reference to Compounds, Compositions, or Formulations of the Invention Alternatively, the term "administering" refers to introducing the compound into the organ system of an animal in need of treatment. When the compounds of the invention are provided in combination with one or more other active agents, "Administering" and variations thereof are understood to encompass simultaneous and / or sequential introduction of the compound and other active agent, respectively.

[0132] The compositions described herein may be administered in a variety of dosage forms depending on the severity and type of disease being treated. and can be administered systemically or locally, for example, orally (e.g., with capsules, powders, solutions, suspensions, tablets, sublingual tablets, etc.), by inhalation (e.g., with aerosols, gases, inhalers, nebulizers, etc.), auricularly (e.g., with ear drops), topically (e.g., with creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), ophthalmically (e.g., with eye drops, ophthalmic gels, ointments), rectally (e.g., with enemas or suppositories), nasally, bucally, vaginally (e.g., with irrigation solutions, intrauterine devices, vaginal suppositories, vaginal rings, or vaginal tablets, etc.), via an implanted reservoir, or parenterally. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0133] The pharmaceutical compositions described herein can be administered in any orally acceptable dosage form, e.g. The active ingredient can be orally administered in the form of, but not limited to, capsules, tablets, aqueous suspensions, or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents.

[0134]

[0122] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is incorporated into at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, or the like. The tablet is mixed with a tablet-forming agent such as corn starch, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution inhibitors such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. The tablet may be uncoated or may be coated by known techniques, such as microencapsulation, to mask unpleasant taste or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time. For example, a time-delaying material such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax, may be used. Water-soluble taste-masking agents such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may also be used.

[0135] Formulations of compounds of formula I suitable for oral administration may be in the form of tablets, pills, troches, lozenges, They may be prepared as discrete units such as aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups, or elixirs. Formulations of compounds intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0136] Compressed tablets are tablets that contain the active ingredient in a free-flowing form, such as a powder or granules, in a desired amount. They can be prepared by mixing with a binder, lubricant, inert diluent, preservative, surface active agent or dispersing agent and compressing in a suitable machine. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

[0137] Formulations for oral use may be prepared in which the active ingredient is dissolved in an inert solid diluent, such as calcium carbonate. The active ingredient may also be provided as a hard gelatin capsule in which the active ingredient is mixed with an aqueous carrier, such as polyethylene glycol, or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0138] The active compounds can also be in microencapsulated form with one or more excipients as noted above. There can be something too. When aqueous suspensions are desired for oral use, the active ingredient may be added to emulsifying and suspending agents. The syrup and elixir may be combined with a sweetener, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such preparations may also contain a demulcent, a preservative, a flavoring and coloring agent, and an antioxidant.

[0139] Sterile injectable forms (e.g., for parenteral administration) of the compositions described herein may be prepared in the following form: It can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution, and physiological saline. In addition, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any sterile, fixed oil can be employed, for example, synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, for example, olive oil or castor oil, especially polyoxyethylated versions. These oily solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, such as emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for injectable formulation purposes.

[0140] Oily suspensions may be prepared by dissolving a compound of Formula I in a vegetable oil, for example, peanut oil, olive oil, or gum agar. The compositions can be formulated by suspending them in a mineral oil such as mayonnaise or coconut oil or liquid paraffin. Oily suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. To provide a palatable oral preparation, sweeteners and flavoring agents such as those mentioned above can be added. These compositions can be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

[0141] Aqueous suspensions of compounds of Formula I contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, and dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0142] Injectable formulations may be prepared, for example, by filtration through a bacteria-retaining filter or Alternatively, sterilization can be achieved by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0143] To prolong the effect of the compounds described herein, the compounds may be administered by subcutaneous or intramuscular injection. Slow absorption of a compound from injection is often desirable. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. Thus, the rate of absorption of a compound depends on its rate of dissolution, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0144] The injectable solution or microemulsion is administered to the patient by local bolus injection. The compound can be introduced into the bloodstream. Alternatively, it may be advantageous to administer a solution or microemulsion so that a constant blood concentration of the compound is maintained. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS TM It is a model 5400 intravenous pump.

[0145] Compositions for rectal or vaginal administration may comprise a compound described herein, as appropriate. Suppositories are preferred, which can be prepared by mixing the active ingredient with a non-irritating excipient or carrier, such as cocoa butter, beeswax, polyethylene glycol, or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound. Other formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays.

[0146] The pharmaceutical compositions described herein are particularly useful when the target of treatment is the eye, ear, skin or It involves areas or organs that are easily reached by topical application, such as diseases of the lower intestinal tract. If present, they may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs.

[0147] Dosage forms for topical or transdermal administration of the compounds described herein include soft These formulations include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as desired. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable vehicle. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel. Topical application for the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or a suitable enema formulation. Topical transdermal patches can also be used.

[0148] For topical application, the pharmaceutical compositions may be suspended or dissolved in one or more carriers. It can be formulated into a suitable ointment containing active ingredients.The carrier for topical application of the compound of the present invention includes but is not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, pharmaceutical compositions can be formulated into a suitable lotion or cream containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

[0149] For ophthalmic use, the pharmaceutical composition may be prepared in the presence of a preservative such as benzylalkonium chloride. The active ingredient(s) may be formulated as a micronized suspension in, with or without, pH-adjusted isotonic sterile saline, or preferably as a solution in pH-adjusted isotonic sterile saline. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum. For treatment of the eye or other external tissues, such as the mouth and skin, the formulation may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w / w. When formulated in an ointment, the active ingredient(s) may be used with either an oily, paraffinic, or water-miscible ointment base.

[0150] Alternatively, the active ingredients may be formulated into a cream using an oil-in-water cream base. If desired, the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations can desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0151] The oily phase of the emulsions prepared using the compounds of formula I can be prepared by known methods and in known manners. The phase may be composed of ingredients. The phase may contain only an emulsifier (otherwise known as an emulgent), but preferably contains a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. A hydrophilic emulsifier may also be included together with a lipophilic emulsifier, which acts as a stabilizer. In some embodiments, the emulsifier , oils and fats. Taken together, the emulsifier(s) with or without the stabilizer(s) provide a so-called emulsifying wax, which, together with the oils and fats, forms the oily dispersed phase of a cream formulation, a so-called emulsifying ointment base. Suitable emulgents and emulsion stabilizers for use in formulating compounds of Formula I include Tween TM -60, Span TM -80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0152] The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Formulations suitable for pulmonary or nasal administration can have, for example, particle sizes in the range of 0.1 to 500 microns (including particles in the range of 0.1 to 500 microns in micron increments, e.g., 0.5, 1, 30, 35 microns), and can be administered by rapid inhalation through the nasal passages to reach the alveolar sacs or by inhalation through the mouth.

[0153] The pharmaceutical composition (or formulation) for use will depend on the method used to administer the drug. The packaging can be done in a variety of ways depending on the product. Generally, the product will include a container containing the pharmaceutical formulation in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-evident assemblage to prevent indiscreet access to the contents of the package. In addition, a label describing the contents of the container is attached to the top of the container. The label may also include appropriate warnings.

[0154] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and and vials and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile injectable liquid carrier, e.g., water, immediately prior to use. Extemporaneous injection solutions or suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0155] In another aspect, the compounds of Formula I or pharmaceutically acceptable salts thereof are used in veterinary medicine. The active ingredient can be formulated into a veterinary composition containing a suitable carrier. The veterinary carrier is a material useful for the purpose of administering the composition and can be a normally inert solid, liquid, or gaseous material that is compatible with the active ingredient in the veterinary field. These veterinary compositions can be administered parenterally, orally, or by any other desired route. treatment method In a third aspect, the present invention provides sGC stimulators, either alone or in combination, or The present invention relates to the treatment of certain disorders in patients in need thereof by using the compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

[0156] The present disclosure provides a method for treating conditions in which increased NO levels or increased cGMP levels may be desirable. This invention relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations thereof, and their use, alone or in combination with one or more additional agents, for treating and / or preventing various diseases, including, but not limited to, pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, renal fibrosis and failure, cirrhosis of the liver, erectile dysfunction, female sexual dysfunction, diabetes-related diseases, eye diseases, and other related cardiovascular diseases.

[0157]

[0147] Increased cGMP concentration has the effects of vasodilation, inhibition of platelet aggregation and adhesion, and hypotension. sGC stimulators have anti-inflammatory, anti-remodeling, anti-apoptotic, anti-inflammatory, and neuronal signaling effects. Therefore, sGC stimulators can be used to treat a variety of diseases and disorders, including, but not limited to, peripheral, pulmonary, hepatic, liver, cardiac, or cerebrovascular / endothelial diseases or conditions, genitourinary-gynecological, or sexual disorders or conditions, thromboembolic diseases, ischemic diseases, fibrotic diseases, topical or dermatological diseases, pulmonary or respiratory diseases, renal or hepatic diseases, metabolic disorders, atherosclerosis, or lipid-related diseases.

[0158] In other embodiments, the compounds disclosed herein have the ability to inhibit the undesirable action of NO. In one embodiment, the sGC stimulators may be useful in the prevention and / or treatment of diseases and disorders characterized by reduced bioavailability and / or sensitivity, such as diseases and disorders associated with conditions of oxidative or nitrosative stress.

[0159] In other embodiments, the compounds disclosed herein may be used to treat neuroinflammatory diseases by increasing neuroinflammation. These are sGC stimulators that may be useful in the prevention and / or treatment of the diseases and disorders characterized. One aspect of the invention is a method of reducing neuroinflammation in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17 through I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 through I-60, I-62 through I-68, I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof. In particular, the diseases and disorders are central nervous system diseases or disorders described in items (9) to (16) below.

[0160] In other embodiments, the compounds disclosed herein may be used to treat rheumatoid arthritis by increasing neurotoxicity. These are sGC stimulators that may be useful in the prevention and / or treatment of the diseases and disorders characterized. One aspect of the present invention is a method of reducing neurotoxicity in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17 through I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 through I-60, I-62 through I-68, I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof. In particular, the diseases and disorders are central nervous system diseases or disorders described in items (9) to (16) below.

[0161] In other embodiments, the compounds disclosed herein are useful in treating neurodegenerative disorders caused by impaired neuronal regeneration. These are sGC stimulators that may be useful in the prevention and / or treatment of the diseases and disorders characterized. One aspect of the present invention is a method of restoring nerve regeneration in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I I-16, I-17 to I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 to I-60, I-62 to I-68, I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof. In particular, the diseases and disorders are central nervous system diseases or disorders described in items (9) to (16) below.

[0162] In other embodiments, the compounds disclosed herein are useful for treating neurodegenerative disorders caused by impaired synaptic function. These are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by: One aspect of the present invention is a method of restoring synaptic function in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, I-17 to I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 to I-60, I-62 to I-68, I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof. In particular, the diseases and disorders are central nervous system diseases or disorders described in items (9) to (16) below.

[0163] In other embodiments, the compounds disclosed herein are useful for downregulating neurotransmitters. and the like. These are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders characterized by sGC regulation. One aspect of the present invention is a method of normalizing neurotransmitters in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, I-17 through I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 through I-60, I-62 through I-68, I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof. In particular, the diseases and disorders are central nervous system diseases or disorders described in the following items (9) to (16). Specifically, the disease is Alzheimer's disease. Specifically, the disease is mixed dementia.

[0164] In other embodiments, the compounds disclosed herein are useful in treating conditions characterized by impaired cerebral blood flow. These are sGC stimulators that may be useful in the prevention and / or treatment of diseases and disorders associated with the disease. One aspect of the present invention is a method of restoring cerebral blood flow in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, I-17 to I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 to I-60, I-62 to I-68, I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof. In particular, the diseases and disorders are central nervous system diseases or disorders described in the following items (9) to (16). Specifically, the disease is vascular dementia or Alzheimer's disease. Specifically, the disease is mixed dementia. In other embodiments, the central nervous system disorder is selected from traumatic (closed or open penetrating head injury), traumatic brain injury (TBI), or non-traumatic (stroke, aneurysm, hypoxia) injury to the brain, or cognitive dysfunction or dysfunction resulting from brain injury or neurodegenerative disease.

[0165] In other embodiments, the compounds disclosed herein are useful for treating neurodegeneration by increasing neuronal degeneration. One aspect of the present invention is a method for reducing neurodegeneration in a subject in need thereof, comprising administering to the subject a compound of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, I-17 to I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 to I-60, I-62 to I-68, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-96, I-97, I-98, I-99, I-10, I-11, I-10 The method comprises administering any one of the compounds I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof, to the patient. In particular, the disease or disorder is a central nervous system disease or disorder described in items (9) to (16) below.

[0166] In other embodiments, the compounds disclosed herein are neuroprotective sGC The compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, I-17 to I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 to I-60, I-62 to I-68, I-70, I-7, and I-72, or pharmaceutically acceptable salts thereof, can be useful for neuroprotection in subjects in need of neuroprotection. In particular, the diseases and disorders are central nervous system diseases or disorders described in sections (9) to (16) below.

[0167] In other embodiments, the compounds disclosed herein are useful for preventing and / or treating orphan pain indications. One aspect of the present invention is a method of treating an uncommon pain indication in a subject in need thereof by administering to the subject any one of the compounds of Formula I, IIA, IIB, II, III, IV, V, VI, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, I-17 to I-39, I-41, I-42, I-47, I-48, I-50, I-51, I-53, I-54, I-56 to I-60, I-62 to I-68, I-70, I-7, and I-72, or a pharmaceutically acceptable salt thereof. Among others, orphan pain indications include acetazolamide-responsive myotonia, autologous red blood cell sensitization syndrome, autosomal dominant Charcot-Marie-Tooth disease type 2V, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2, congenital insensitivity to pain associated with channelopathy, chronic pain requiring intrathecal analgesia, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, congenital insensitivity to pain with hyperhidrosis, congenital insensitivity to pain with severe intellectual disability, congenital insensitivity to pain-hypohidosia syndrome, diffuse palmoplantar keratoderma with painful cracks, familial incident pain syndrome, familial incident pain syndrome predominantly involving the lower extremities, familial incident pain syndrome predominantly involving the upper body, hereditary painful calluses, hereditary sensory and autonomic neuropathy. Type 4, hereditary sensory and autonomic neuropathy; Type 5, hereditary sensory and autonomic neuropathy; Type 7, selected from interstitial cystitis, painful orbital and generalized neurofibromas-marfanoid habitus syndrome, paroxysmal severe pain disorder, persistent idiopathic facial pain, qualitative or quantitative calpain deficiency, and Tolosa-Hunt syndrome.

[0168] Throughout this disclosure, the terms "hypertension," "arterial hypertension," or "high blood pressure (HBs)" are used. The term "hypertension" (BP) is used interchangeably to refer to an extremely common, highly preventable, chronic condition in which arterial blood pressure (BP) is higher than normal. If not properly controlled, it represents a significant risk factor for several serious cardiovascular and renal conditions. Hypertension can be a primary disease, termed "essential hypertension" or "idiopathic hypertension," or it can result from other diseases, in which case it is classified as "secondary hypertension." Essential hypertension accounts for 90-95% of all cases.

[0169] As used herein, the term "resistant hypertension" refers to hypertension caused by the administration of different antihypertensive agents. This refers to hypertension in which blood pressure remains above target (usually <140 / 90 mmHg, although a lower target of <130 / 80 mmHg is recommended for patients with diabetes or renal disease with complications) despite the concurrent use of three antihypertensive drugs in the same class. Individuals who require four or more medications to control their blood pressure are also considered to have resistant hypertension. Hypertension is a very common comorbid condition in diabetes, affecting approximately 20% to 60% of diabetic patients, depending on obesity, ethnicity, and age. This type of hypertension is referred to herein as "diabetic hypertension." In type 2 diabetes, hypertension often manifests as part of the metabolic syndrome of insulin resistance, which also includes central obesity and dyslipidemia. In type 1 diabetes, hypertension may reflect the development of diabetic nephropathy.

[0170] As used herein, "pulmonary hypertension (PH)" refers to blood vessels in the pulmonary vasculature (pulmonary arteries, pulmonary veins, etc.). PH is a disease characterized by persistently elevated blood pressure in the right heart (the pulmonary artery and pulmonary capillaries), leading to right-sided hypertrophy and ultimately right-sided heart failure and death. Common symptoms of PH include shortness of breath, dizziness, and syncope, all of which worsen with strenuous exercise. Without treatment, the average life expectancy after diagnosis is 2.8 years. PH exists in a variety of forms and is classified according to etiology. Categories include pulmonary arterial hypertension (PAH), PH associated with left heart disease, PH associated with pulmonary disease and / or hypoxemia, PH due to chronic thrombotic and / or embolic disease, and mixed PH. PAH is rare in the general population, but its prevalence increases in association with certain common conditions, such as HIV infection, scleroderma, and sickle cell disease. Other forms of PH are generally more common than PAH; for example, the association of PH with chronic obstructive pulmonary disease (COPD) is of particular concern. Current treatment of pulmonary hypertension depends on the stage and mechanism of the disease.

[0171] As used herein, "heart failure" refers to the progression of left ventricular (LV) myocardial remodeling. Heart failure is a progressive disorder that ultimately results in a complex clinical syndrome characterized by cardiac dysfunction and circulatory congestion, resulting in inadequate delivery of blood and nutrients to body tissues. The condition occurs when the heart is damaged or overworked and unable to pump all of the blood returning from the systemic circulation. Because less blood is being pumped, blood returning to the heart backfires, causing fluid to accumulate in other parts of the body. Heart failure also impairs the kidneys' ability to remove sodium and water, further exacerbating fluid retention. Heart failure is characterized by autonomic dysfunction, neurohormonal activation, and cytokine overproduction, which contribute to progressive circulatory problems. Symptoms of heart failure include: dyspnea (shortness of breath) during exercise or rest and sudden awakenings at night due to breathlessness, both of which suggest pulmonary edema; generalized fatigue or weakness; edema of the feet, ankles, and legs; sudden weight gain; and chronic coughs, including those that produce mucus or blood. Depending on the clinical presentation, heart failure is classified as de novo, transient, or chronic. The rapid or gradual onset of symptoms can occur de novo or as a result of chronic heart failure that has become decompensated. Diabetes is a common comorbidity in patients with heart failure and is associated with poor outcomes and may compromise the efficacy of treatment. Other important comorbidities include systemic hypertension, chronic airflow obstruction, sleep apnea, cognitive impairment, anemia, chronic kidney disease, and arthritis. Chronic left heart failure is often associated with the development of pulmonary hypertension. The frequency of specific comorbidities varies by gender: hypertension and thyroid disease are more common in women, while men more commonly suffer from chronic obstructive pulmonary disease (COPD), peripheral vascular disease, coronary artery disease, and renal failure. Depression is a frequent comorbidity in heart failure, and the two conditions can and often do exacerbate each other. Cachexia has long been recognized as a serious and frequent complication of heart failure, affecting up to 15% of all heart failure patients and associated with a poor prognosis. Cardiac cachexia is defined as a non-edematous, involuntary loss of at least 6% of body weight over a 6-month period.

[0172]

[0162] The term "sleep apnea" refers to the most common type of sleep-disordered breathing. It is a condition characterized by intermittent, periodic reductions or complete cessation of airflow, which may or may not involve upper airway obstruction. There are three types of sleep apnea: obstructive sleep apnea, the most common form; central sleep apnea; and mixed sleep apnea. Sleep apnea.

[0173]

[0163] “Central sleep apnea (CSA)” is a condition that occurs not due to a physical blockage of the airway, but rather due to a blockage of the brain. It is caused by a malfunction of the normal respiratory signal of the respiratory system. The lack of respiratory effort leads to an increase in blood carbon dioxide, which can wake the patient. CSA is rare in the general population but occurs relatively commonly in patients with systolic heart failure.

[0174] As used herein, "metabolic syndrome," "insulin resistance," The term "metabolic syndrome" or "syndrome X" refers to a group or cluster of metabolic conditions (abdominal obesity, elevated fasting glucose, "dyslipidemia" (i.e., elevated lipid levels), and elevated blood pressure (HBP)) that occur together more often than by chance alone and together promote the development of type 2 diabetes and cardiovascular disease. Metabolic syndrome is characterized by a specific lipid profile of elevated triglycerides, low high-density lipoprotein cholesterol (HDL-cholesterol), and sometimes modestly elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, as well as: It is characterized by the accelerated progression of "atherosclerotic disease" due to the pressure of structural risk factors. There are several types of lipid abnormalities: "hypercholesterolemia" refers to elevated levels of cholesterol. Familial hypercholesterolemia is a specific form of hypercholesterolemia caused by a deletion on chromosome 19 (19p13.1-13.3). "Hyperglyceridemia" refers to elevated levels of glycerides (e.g., "hypertriglyceridemia" includes elevated levels of triglycerides). "Hyperlipoproteinemia" refers to elevated levels of lipoproteins (usually LDL unless otherwise specified).

[0175] As used herein, the term "peripheral vascular disease (PVD)" generally refers to Also called "peripheral arterial disease (PAD)" or "peripheral arterial occlusive disease (PAOD)," PVD refers to blockages of large arteries that are not within the coronary arteries, the aortic arch vasculature, or the brain. PVD can result from atherosclerosis, an inflammatory process leading to stenosis, embolism, or thrombus formation. It can cause either acute or chronic "ischemia (insufficient blood supply)." PVD is a term often used to refer to atherosclerotic blockages found in the lower extremities. PVD also encompasses a subset of diseases classified as microvascular diseases resulting from occasional arterial narrowing (e.g., "Raynaud's phenomenon") or dilation (erythromelalgia), i.e., vasospasm.

[0176] The term "thrombosis" refers to a blood clot ("thrombus") inside a blood vessel that blocks blood flow through the circulatory system. " refers to the formation of a blood clot. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Alternatively, blood clots can form in the body if the right conditions exist, even when the blood vessel is not injured. If clotting is severe enough to cause the clot to break free, the traveling clot is known herein as an "embolus." The term "thromboembolism" refers to the combination of thrombosis and its major complication, "embolism." When a blood clot occupies more than 75% of the surface area of ​​the arterial lumen, the blood flow supplied to tissues is reduced sufficiently to cause symptoms due to decreased oxygen (hypoxia) and the accumulation of metabolic products such as lactic acid ("gout"). Blockages of greater than 90% can result in anoxia, a complete lack of oxygen, and "infarction," a mode of cell death.

[0177]

[0167] "Embolism" (plural embolisms) is the process by which an embolus (a blood clot) penetrates an arterial capillary vessel at a site distant from the source. This is an event in which a detached intravascular mass (a detached intravascular mass capable of blocking the bed) becomes lodged within the small capillaries of an arterial bed and causes blockage (vaso-occlusion) in a distant part of the body. This should not be confused with a thrombus, which blocks at the site of origin.

[0178] A "stroke" or cerebrovascular accident (CVA) results from an interruption in the blood supply to the brain. This is the sudden loss of one or more brain functions due to blockage (thrombosis, arterial embolism) or This can be due to "ischemia" (lack of blood flow) caused by hemorrhagic stroke (blood leakage). As a result, the affected area of ​​the brain cannot function, and patients may be unable to move one or more limbs on one side of the body, be unable to understand or organize speech, or be unable to see on one side of the field of vision. Risk factors for stroke include older age, high blood pressure, a history of stroke or transient ischemic attack (TIA), diabetes, high cholesterol, smoking, and atrial fibrillation. High blood pressure is the most important modifiable risk factor for stroke. "Ischemic stroke" is sometimes treated in the hospital with thrombolysis (also known as "clot buster"), and some hemorrhagic strokes benefit from neurosurgery. Prevention of recurrence can include the administration of antiplatelet drugs such as aspirin and dipyridamole, control and reduction of high blood pressure, and the use of statins. In selected patients, carotid endarterectomy and the use of anticoagulants may be effective.

[0179] "Ischemia" is a restriction in blood supply to a tissue (which maintains tissue viability). Ischemia is a condition that causes a lack of oxygen and glucose, which are necessary for cellular metabolism (for blood flow). Ischemia is generally caused by problems related to blood vessels, resulting in tissue damage or dysfunction. It also refers to local anemia in a given area of ​​the body, which can result from blood congestion (such as vasoconstriction, thrombosis, or embolism).

[0180]

[0170] American Psychiatric Association's According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the term "sexual dysfunction" encompasses a range of conditions "characterized by disturbances in the psychophysiological changes associated with sexual desire and the sexual response cycle; whereas, problems of this type are common, sexual dysfunction is considered to exist only when the patient experiences the problem as distressing. Sexual dysfunction can be either physical or psychological in origin. It can exist as a primary condition, generally hormonal in nature, but is most often secondary to other medical conditions or medications for said conditions. All types of sexual dysfunction can be further classified as lifelong, acquired, situational, or generalized (or a combination thereof).

[0181]

[0171] DSM-IV-TR Clarifies Five Major Categories of “Female Sexual Dysfunction” Presents: Sexual desire / interest disorder; "sexual arousal disorder (including genital, subjective, and combined)"; orgasmic disorder; dyspareunia and vaginal pain; and persistent sexual arousal disorder.

[0182] "Female Sexual Arousal Disorder (FSAD)" is defined as the inability to achieve or maintain a satisfactory level of sexual arousal. FSAD is defined as a persistent or recurring inability to maintain sexual arousal, resulting in personal distress. FSAD encompasses both a lack of subjective sensations of arousal (i.e., subjective sexual arousal disorder) and a lack of physical responses such as lubrication and swelling (i.e., genital / physical sexual arousal disorder). While FSAD can be strictly psychological in origin, it is commonly caused or exacerbated by medical or physiological factors. Hypoestrogenism is the most common physiological condition associated with FSAD, resulting in urogenital atrophy and decreased vaginal lubrication.

[0183] As used herein, "erectile dysfunction (ED)" refers to the inability to achieve erection of the penis during sexual activity. Penile erection is a male sexual dysfunction characterized by the inability to develop or maintain erectile dysfunction. Penile erection is the hydraulic action of blood entering the penis and being held in the corpora cavernosa. This process often begins when signals are transmitted from the brain to the nerves of the penis as a result of sexual arousal. Erectile dysfunction is indicated when erection is difficult to achieve. The most important organic causes are cardiovascular disease and diabetes, neurological problems (e.g., trauma from prostatectomy), hormone deficiency (hypogonadism), and drug side effects.

[0184] As used herein, the term "bronchoconstriction" refers to a decrease in the tension of the surrounding smooth muscles. It is used to define the constriction of the lung airways due to pulmonary obstruction, resulting in coughing, wheezing, and shortness of breath. The condition has several causes, the most common being asthma. Exercise and allergies can cause symptoms in normally asymptomatic individuals. Other conditions, such as chronic obstructive pulmonary disease (COPD), can also present with bronchoconstriction.

[0185] Treating and / or preventing by administering the sGC stimulators of the present invention Specific diseases or disorders that may be affected include, but are not limited to, hypertension (e.g., diabetic hypertension, arterial hypertension, pulmonary hypertension, resistant hypertension, peripheral arterial disease, etc.), heart failure (e.g., left ventricular diastolic dysfunction (LVDD) and left ventricular systolic dysfunction (LVSD), sleep apnea associated with heart failure), arteriosclerotic diseases (e.g., atherosclerosis), thromboembolic disorders (e.g., chronic thromboembolic pulmonary hypertension, thrombosis, stroke (especially ischemic stroke), embolism, pulmonary embolism), Alzheimer's disease, kidney diseases (e.g., renal fibrosis, ischemic kidney disease, renal failure, renal insufficiency, chronic kidney disease), liver diseases (e.g., liver cirrhosis, liver cirrhosis, liver ulcers ... , liver fibrosis or cirrhosis), respiratory diseases (e.g., pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, interstitial lung disease), sexual disorders (e.g., erectile dysfunction, male and female sexual dysfunction, vaginal atrophy), sickle cell anemia, neuroinflammatory diseases or disorders, and metabolic disorders (e.g., lipid-related diseases).

[0186] Treating and / or preventing by administering the sGC stimulators of the present invention Other specific diseases or disorders that may be affected include, but are not limited to, age-associated memory impairment, mixed dementia, sleep-wake disorders, and Sneddon syndrome.

[0187] Treating and / or preventing by administering an sGC stimulator of the present invention Other specific diseases or disorders that may be treated include, but are not limited to, acute pain, central pain syndromes, chemotherapy-induced neuropathy and neuropathic pain, diabetic neuropathy, fibromyalgia, inflammatory pain, neuropathic pain, neuropathic pain associated with central nervous system disease, painful diabetic peripheral neuropathy, post-operative pain, persistent pain, and visceral pain.

[0188] Treating and / or preventing by administering an sGC stimulator of the present invention Other specific diseases or disorders that may be affected include, but are not limited to, high altitude (mountain) sickness, cerebral small vessel disease, cerebral vasculitis, cerebral vasospasm, diabetic heart failure (diabetic HF), diabetic angiopathy, diabetic macular edema, diabetic microangiopathy, heart failure with preserved ejection fraction (HFpEF), hepatic encephalopathy, moyamoya disease, non-diabetic nephropathy, and dysphagia in Parkinson's disease.

[0189] Treating and / or preventing by administering the sGC stimulators of the present invention Other specific diseases or disorders that may be affected include, but are not limited to, angina pectoris, ataxia telangliectasia, autism spectrum disorder, chronic fatigue, chronic traumatic encephalopathy (CTE), cognitive impairment associated with diabetes, cognitive impairment associated with multiple sclerosis, cognitive impairment associated with obstructive sleep apnea, cognitive impairment associated with schizophrenia (CIAS), sickle cell associated cognitive impairment, concussion, dysphagia, ocular fibrosis, Fabry disease, Gaucher disease, glioblastoma, inflammation due to cerebral malaria (SoC), inflammation due to infectious diseases, intellectual disability, microvascular angina, myopic choroidal neovascularization, optic nerve Myelitis, neuropathic pain associated with multiple sclerosis, neuropathic pain associated with shingles (herpes zoster), neuropathic pain associated with spinal surgery, dementia in Parkinson's disease, peripheral and autonomic neuropathies, peripheral retinal degeneration, post-traumatic stress syndrome, post-herpetic neuralgia, post-operative dementia, proliferative vitroretinopathy, radiation-induced fibrosis, radiculopathy, refractory epilepsy, retinal vein occlusion, Sjogren's syndrome, spinal cord injury, spinal muscular atrophy, vertebral subluxation, tauopathy, ulcers, and wet age-related macular degeneration.

[0190] The compounds of Formula I and pharmaceutically acceptable salts thereof, as sGC stimulators, are It is useful for the prevention and / or treatment of the following types of diseases, conditions and disorders in which upregulation of the C-stimulation or NO pathway may be beneficial: (1) Peripheral, pulmonary, hepatic, renal, cardiac, or cerebral vascular / endothelial disorders / conditions or other circulation-related diseases: Disorders associated with hypertension and reduced coronary blood flow, such as acute and chronic elevated coronary artery blood pressure, arterial hypertension, and vascular disorders resulting from cardiac and renal complications (e.g., heart disease, stroke, cerebral ischemia, renal failure); resistant hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; cardiac arrhythmias; reduced ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or damage; Thromboembolic disorders and ischemia, e.g., myocardial infarction, stroke (especially ischemic stroke), transient ischemic attack (TIA); thromboangiitis obliterans; stable or unstable angina; coronary artery spasm, variant angina, Prinzmetal angina; prevention of restenosis after thrombolytic therapy; thrombosis disorders; Peripheral arterial disease, peripheral occlusive arterial disease; peripheral vascular disease; hypertonia; Raynaud's syndrome or phenomenon, critical limb ischemia, vasculitis; peripheral embolism; intermittent claudication; vaso-occlusive crisis; Duchenne and Becker muscular dystrophy; microcirculatory abnormalities; vascular leakage or permeability control; Shock; sepsis; cardiogenic shock; control of leukocyte activation; inhibition or regulation of platelet aggregation; Pulmonary / respiratory conditions, e.g., pulmonary hypertension, pulmonary arterial hypertension, and associated pulmonary vascular remodeling (e.g., focal thrombosis and right ventricular hypertrophy); pulmonary muscle hypertonia; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, multifactorial pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis, lung transplant; Pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, WHO group I, II, III, IV, and V hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous return, pulmonary veno-occlusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar hypoventilation, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, pulmonary embolism (due to tumor, parasite, or foreign body), connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, lymphangiomatosis, and compressed pulmonary vessels (e.g., due to adenosis, tumor, or fibrosing mediastinitis); Arteriosclerotic diseases or conditions, such as atherosclerosis (e.g., associated with endothelial injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation and migration); restenosis (e.g., occurring after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) and bypass surgery); inflammation; Cardiovascular diseases associated with metabolic syndrome (e.g., obesity, dyslipidemia, diabetes, hypertension); lipid-related diseases, e.g., dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; preeclampsia; polycystic kidney disease progression; subcutaneous fat; obesity; Chronic liver disease, liver fibrosis, hepatic stellate cell activation, hepatic fibrocollagen and total collagen accumulation-related liver cirrhosis; necrotic, inflammatory and / or immune-derived liver diseases; and genitourinary system diseases, e.g., renal fibrosis and renal failure due to chronic kidney disease or renal insufficiency (e.g., due to accumulation / deposition and tissue damage, progressive sclerosis, glomerulonephritis); prostatic hyperplasia, systemic sclerosis; cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; nonalcoholic steatohepatitis or NASH; (2) Ischemia and reperfusion injury; ischemia / reperfusion associated with organ transplantation, lung transplantation, and heart transplantation; blood substitute maintenance in trauma patients; (3) Sexual, gynecological, and urological disorders, including the following conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction (e.g., female sexual arousal dysfunction, hyposexual arousal disorder), vaginal atrophy, dyspareunia, atrophic vaginitis; benign prostatic hyperplasia (BPH) or hypertrophy or enlargement, bladder outlet obstruction; bladder pain syndrome (BPS), interstitial cystitis (IC), overactive bladder, neurogenic bladder and incontinence; diabetic nephropathy; (4) eye diseases or disorders: glaucoma, retinopathy, diabetic retinopathy (including proliferative and nonproliferative), blepharitis, dry eye syndrome, Sjögren's syndrome; (5) Hearing diseases or disorders: hearing loss, partial or total hearing loss; partial or total hearing loss; tinnitus; noise-induced hearing loss; (6) local or cutaneous diseases or conditions: dermal fibrosis, scleroderma, dermal fibrosis; (7) Wound healing: e.g., in diabetic patients; improving microvascular perfusion (e.g., after injury, to counteract the inflammatory response in perioperative care), anal fissures, diabetic ulcers; (8) Other diseases or conditions: cancer metastasis, osteoporosis, gastroparesis; functional dyspepsia; diabetic complications, diseases related to endothelial dysfunction, and neurological disorders related to decreased nitric oxide production; achalasia or esophageal achalasia. (9) A central nervous system disease, condition, or disorder selected from the following: Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Down syndrome, dementia, vascular dementia, vascular cognitive impairment, mixed dementia, Binswanger dementia (subcortical arteriosclerotic encephalopathy), autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CADASIL syndrome), frontotemporal lobar degeneration or dementia, HIV-associated dementia (e.g., asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia (HAD) (e.g., AIDS dementia complex [ADC] or HIV encephalopathy). dementia with Lewy bodies, presenile dementia (mild cognitive impairment, MCI), glaucoma, Huntington's disease (or chorea, HD), or cognitive deficits associated with HD; multiple sclerosis (MS) (including clinically isolated syndrome (CIS), relapsing-remitting MS (PPMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS)); multiple system atrophy (MSA), Parkinson's disease, parkinsonism-plus, spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD); (10) a central nervous system disorder or condition selected from Alzheimer's disease or pre-Alzheimer's disease, mild-to-moderate Alzheimer's disease, or moderate-to-severe Alzheimer's disease; (11) The central nervous system disorder is selected from traumatic (closed or open, penetrating head injury), traumatic brain injury (including TBI, e.g., concussion and chronic traumatic encephalopathy (CTE)), or non-traumatic (stroke (including ischemic stroke), aneurysm, hypoxia) injury to the brain, or cognitive dysfunction or dysfunction resulting from brain injury or neurodegenerative disease; (12) The central nervous system disease or condition is selected from dystonia, such as generalized, focal, segmental, sexual, intermediate, acute dystonia response, and hereditary / primary dystonia; and movement disorders, such as acute, chronic / late-onset, and non-motor and levodopa-induced movement disorders (LID); (13) The central nervous system disease or condition is selected from disorders characterized by a relative decrease in synaptic plasticity and synaptic processes, such as fragile X, Rhett's disorder, Williams syndrome, Renpenning's syndrome, autism spectrum disorders, such as autism, Asperger's syndrome, pervasive developmental disorder, and childhood disintegrative disorder; (14) Central nervous system disorders are neuropathic pain; (15) The central nervous system disorder is a psychiatric, mental, mood, or affective disorder selected from bipolar disorder, schizophrenia, general psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depressive disorder, anxiety disorder, panic disorder, and post-traumatic stress disorder (PTSD); or (16) The central nervous system disorder is selected from chemobrain, levodopa-induced addictive behavior, alcoholism, drug addiction (e.g., but not limited to, amphetamine, opiates, or other substances), and substance abuse.

[0191] In another embodiment, the compounds of formula I and pharmaceutically acceptable salts thereof are sGC It is useful in the prevention and / or treatment of the following types of diseases, conditions and disorders in which stimulation or upregulation of the NO pathway may be beneficial: Hypertension, resistant hypertension, diabetic hypertension, pulmonary hypertension (PH), pulmonary arterial hypertension, PH associated with COPD, chronic airflow obstruction, asthma or pulmonary fibrosis, thrombosis, embolism, thromboembolic disorders, Alzheimer's disease, atherosclerosis, right heart hypertrophy, heart failure, diastolic dysfunction, systolic dysfunction, sleep apnea associated with heart failure, cirrhosis, renal fibrosis, renal failure due to chronic kidney disease or renal insufficiency, metabolic disorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis, erectile dysfunction, female sexual dysfunction, female sexual arousal dysfunction and vaginal atrophy.

[0192] In some embodiments, the present invention provides a method for detecting a disease, condition, or The present invention relates to a method for treating a disorder, comprising administering a therapeutically effective amount of a compound of any of the above formulas or a pharmaceutically acceptable salt thereof to a subject in need of treatment, wherein the disease, condition or disorder is selected from one of the diseases listed above.

[0193] In other embodiments, the disease, condition, or disorder is selected from the following: vascular / endothelial disorders or conditions of the lungs, liver, kidneys, heart or brain, or other diseases related to the circulation: vascular disorders due to acute and chronic elevated coronary artery blood pressure, arterial hypertension, and cardiac and renal complications, heart disease, stroke (especially ischemic stroke), cerebral ischemia, renal failure; resistant hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; reduced ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or damage; myocardial infarction; stroke or transient ischemic attack (TIA); thromboangiitis obliterans; stable or unstable angina; coronary artery spasm, variant angina, Prinzmetal angina; restenosis and thrombosis disorders due to thrombolytic therapy.

[0194] In yet another embodiment, the disease, condition, or disorder is selected from the following: , peripheral vascular / endothelial disorders or conditions, or other circulation-related diseases selected from: peripheral arterial disease, peripheral occlusive arterial disease; peripheral vascular disease; hypertonia; Raynaud's syndrome or phenomenon or disease; critical limb ischemia; vasculitis; peripheral embolism; intermittent claudication; vaso-occlusive crisis; Duchenne and Becker muscular dystrophy; microcirculatory abnormalities; and vascular leakage or permeability problems.

[0195] In yet another embodiment, the disease, condition, or disorder is selected from the following: , a pulmonary disorder or condition, or other circulation-related disease: pulmonary hypertension; pulmonary arterial hypertension and associated pulmonary vascular remodeling; focal thrombosis; right ventricular hypertrophy; pulmonary muscle hypertonia; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, multifactorial pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis and lung transplantation. In some of these embodiments, the pulmonary hypertension is pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, WHO Group I, II, III, IV, and V hypertension, mitral valve disease, constrictive pericarditis, aortic valve stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous return, pulmonary veno-occlusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar hypoventilation, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, coagulation disorders, chronic thromboembolism; pulmonary embolism due to tumors, parasites, or foreign bodies; connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X; lymphangiomatosis, and compressed pulmonary vessels due to adenosis, tumors, or fibrosing mediastinitis.

[0196] In yet another embodiment, the condition or disorder is selected from the following: vascular or endothelial disorders or conditions, or other circulation-related diseases: arteriosclerotic diseases; atherosclerosis, atherosclerosis associated with endothelial injury, atherosclerosis associated with platelet and monocyte adhesion and aggregation, atherosclerosis associated with smooth muscle proliferation and migration; restenosis, restenosis occurring after thrombolytic therapy; restenosis occurring after percutaneous transluminal angioplasty; restenosis occurring after percutaneous transluminal coronary angioplasty and bypass surgery; inflammation; cardiovascular disease associated with metabolic syndrome, obesity, dyslipidemia, diabetes, or hypertension; lipid-related diseases, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; preeclampsia; polycystic kidney disease progression; and subcutaneous fat.

[0197] In yet another embodiment, the disease, condition, or disorder is cirrhosis of the liver, chronic liver disease , cirrhosis associated with hepatic fibrosis, hepatic stellate cell activation, hepatic fibrocollagen and total collagen accumulation; and necrotic inflammatory or immune-derived liver diseases.

[0198] In yet other embodiments, the disease, condition, or disorder is renal fibrosis; chronic kidney disease; renal failure due to kidney disease or renal insufficiency; renal failure due to accumulation or deposits and tissue damage, progressive sclerosis or glomerulonephritis; and prostatic hyperplasia.

[0199] In yet another embodiment, the disease, condition, or disorder is systemic sclerosis . In yet another embodiment, the disease, condition, or disorder is cardiac interstitial fibrosis; The cardiac disease is selected from: cardiac remodeling and fibrosis and cardiac hypertrophy.

[0200] In some embodiments, the disease is a central nervous system disease selected from the following: Condition or disorder: Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Down syndrome, dementia, vascular dementia, mixed dementia, vascular cognitive impairment, Binswanger dementia (subcortical arteriosclerotic encephalopathy), autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CADASIL syndrome), frontotemporal lobar degeneration or dementia, HIV-associated dementia (e.g., asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia) (HAD) (also known as AIDS Dementia Complex [ADC] or HIV encephalopathy), dementia with Lewy bodies, presenile dementia (mild cognitive impairment, MCI), glaucoma, Huntington's disease (or chorea, HD), or cognitive deficits associated with HD; multiple sclerosis (MS), multiple system atrophy (MSA), Parkinson's disease, parkinsonism-plus, spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD).

[0201] In some embodiments, the disease, condition, or disorder is Alzheimer's disease or The central nervous system disorder or condition is selected from pre-Alzheimer's disease, mild to moderate Alzheimer's disease, or moderate to severe Alzheimer's disease.

[0202] In another embodiment, the central nervous system injury is a traumatic injury (closed or open) to the brain. encephalopathy due to traumatic brain injury (TBI), or non-traumatic (stroke (especially ischemic stroke), aneurysm, hypoxia) injury, or cognitive impairment resulting from brain injury or neurodegenerative disease Selected from cognitive impairment or dysfunction.

[0203] In other embodiments, the central nervous system disease or condition is dystonosis, e.g., generalized and movement disorders such as acute, chronic / late-onset, and non-motor and levodopa-induced movement disorders (LID).

[0204] In another aspect, the central nervous system disease or condition is a disorder characterized by a loss of synaptic plasticity and synaptic function. The disorder is selected from disorders characterized by a relative decline in neural processes, such as fragile X, Rett syndrome, Williams syndrome, Rempenning syndrome, autism spectrum disorders, such as autism, Asperger's syndrome, pervasive developmental disorder, and childhood disintegrative disorder.

[0205] In another embodiment, the central nervous system disorder is neuropathic pain. In other embodiments, the central nervous system disorder is bipolar disorder, schizophrenia, general psychosis, or the like. The disorder is a psychiatric, mental, mood or affective disorder selected from the group consisting of: psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depressive disorder, anxiety disorder, panic disorder, and post-traumatic stress disorder (PTSD).

[0206] In another embodiment, the central nervous system disorder is chemobrain, levodopa-induced addiction The disorder is selected from sexual behavior, alcoholism, drug addiction (for example, but not limited to, amphetamine, opiates or other substances) and substance abuse.

[0207] In some embodiments, the disease or disorder is achalasia or esophageal achalasia. A. In other embodiments, the disease or disorder is nonalcoholic steatohepatitis or NAS. It's H.

[0208] In other embodiments, the disease, condition, or disorder is ischemia, reperfusion injury; organ transplantation transplantation, lung transplantation, ischemia / reperfusion associated with lung or heart transplantation; blood substitute maintenance in trauma patients.

[0209] In other embodiments, the disease, condition, or disorder is selected from the following: Gynecological and urological disorders or conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal dysfunction; hyposexual arousal disorder; vaginal atrophy, dyspareunia, atrophic vaginitis; benign prostatic hyperplasia (BPH) or hypertrophy or enlargement; bladder outlet obstruction; painful bladder syndrome (BPS); interstitial cystitis (IC); overactive bladder, neurogenic bladder and incontinence; diabetic nephropathy.

[0210] In other embodiments, the disease, condition, or disorder is vaginal atrophy, dyspareunia, and atrophy. and selected from: contractile vaginitis. In other embodiments, the disease, condition, or disorder is benign prostatic hyperplasia (BPH). ) or hypertrophy or enlargement; bladder outlet obstruction; bladder pain syndrome (BPS); interstitial cystitis (IC); overactive bladder, neurogenic bladder and incontinence.

[0211] In other embodiments, the disease, condition, or disorder is erectile dysfunction; impotence; The sexual condition is selected from premature ejaculation; female sexual dysfunction; female sexual arousal dysfunction and hypoactive sexual arousal disorder.

[0212] In another embodiment, the disease or disorder is diabetic nephropathy. In other embodiments, the disease, condition, or disorder is Duchenne and Becca syndrome. He has type 2 muscular dystrophy.

[0213] In other embodiments, the disease is glaucoma, retinopathy, diabetic retinopathy (proliferative and The ocular disease or disorder is selected from the group consisting of glaucoma, glaucoma, glaucoma, glaucoma-associated ...

[0214] In other embodiments, the condition is hearing loss, partial or total hearing loss; partial or total hearing loss is a hearing disease or disorder selected from total hearing loss; tinnitus; and noise-induced hearing loss.

[0215] In other embodiments, the disease is selected from dermal fibrosis, scleroderma, and dermal fibrosis. It is a topical or skin disease or condition that is caused by In other embodiments, the treatment is wound healing; wound healing in diabetic patients; microvascular These include improving vascular perfusion; correcting microvascular perfusion problems after injury; treating anal fissures; and treating diabetic ulcers.

[0216] In other embodiments, the disease or disorder is cancer metastasis; osteoporosis; gastroparesis; diabetic complications; diseases associated with endothelial dysfunction, and neuropathy associated with decreased nitric oxide production.

[0217] In other embodiments, the disease or disorder is age-associated memory impairment, mixed dementia, sleep-wake disorder, and Sneddon's syndrome. In other embodiments, the disease or disorder is acute pain, central pain syndrome, chemotherapy The pain is selected from surgery-induced neuropathy and neuropathic pain, diabetic neuropathy, fibromyalgia, inflammatory pain, neuropathic pain, neuropathic pain associated with central nervous system disease, painful diabetic peripheral neuropathy, post-operative pain, persistent pain, and visceral pain.

[0218] In another embodiment, the disease or disorder is high altitude (mountain) sickness, cerebral small vessel disease, cerebral hemorrhage, Selected from vasculitis, cerebral vasospasm, diabetic heart failure (diabetic HF), diabetic angiopathy, diabetic macular edema, diabetic microangiopathy, heart failure with preserved ejection fraction (HFpEF), hepatic encephalopathy, moyamoya disease, non-diabetic nephropathy, and Parkinson's disease dysphagia.

[0219] In other embodiments, the disease or disorder is angina pectoris, ataxia telangiectasia, autistic syndrome, or the like. Spectrum disorders, chronic fatigue, chronic traumatic encephalopathy (CTE), cognitive impairment associated with diabetes, cognitive impairment associated with multiple sclerosis, cognitive impairment associated with obstructive sleep apnea, cognitive impairment associated with schizophrenia (CIAS), cognitive impairment associated with sickle cell disease, concussion, dysphagia, ocular fibrosis, Fabry disease, Gaucher disease, glioblastoma, inflammation due to cerebral malaria (SoC), inflammation due to infectious diseases, intellectual disability, microvascular angina, myopic choroidal neovascularization, neuromyelitis optica, multiple The pain is selected from neuropathic pain associated with rheumatoid sclerosis, neuropathic pain associated with shingles (herpes zoster), neuropathic pain associated with spinal surgery, dementia in Parkinson's disease, peripheral and autonomic neuropathies, peripheral retinal degeneration, post-traumatic stress syndrome, post-herpetic neuralgia, post-operative dementia, proliferative vitreoretinopathy, radiation-induced fibrosis, radiculopathy, refractory epilepsy, retinal vein occlusion, Sjogren's syndrome, spinal cord injury, spinal muscular atrophy, vertebral subluxation, tauopathy, ulcer, and wet age-related macular degeneration.

[0220] In other embodiments, the disease or disorder is selected from orphan pain indications. Among other orphan pain indications are acetazolamide-responsive myotonia, autologous red blood cell sensitization syndrome, autosomal dominant Charcot-Marie-Tooth disease type 2V, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2, congenital insensitivity to pain associated with channelopathy, and chronic pain requiring intrathecal analgesia. Selected from pain, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, congenital insensitivity to pain with hyperhidrosis, congenital insensitivity to pain with severe intellectual disability, congenital insensitivity to pain-hypohidosia syndrome, diffuse palmoplantar keratoderma with painful cracks, familial incident pain syndrome, familial incident pain syndrome primarily involving the lower extremities, familial incident pain syndrome primarily involving the upper body, hereditary painful calluses, hereditary sensory and autonomic neuropathy type 4, hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 7, interstitial cystitis, painful orbital and generalized neurofibromas-Marfanoid habitus syndrome, paroxysmal severe pain disorder, persistent idiopathic facial pain, qualitative or quantitative calpain deficiency, and Tolosa-Hunt syndrome.

[0221] In another embodiment, the compounds of the present invention are used in implantable devices such as stents. Stents can be delivered in the form of a mesh "tube" that is inserted into natural passageways / conduits of the body to prevent or prevent disease-induced localized flow obstruction. The term can also refer to tubes used to temporarily hold open such natural conduits to allow access for surgical procedures.

[0222]

[0219] Drug-eluting stents (DES) are used to treat narrowed or diseased peripheral or coronary arteries. A peripheral or coronary stent (scaffold) is placed in the stent to slowly release a drug to block cell growth, usually smooth muscle cell growth. This prevents fibrosis, which could otherwise form into a blood clot (thrombus) and block the stented artery, a process called restenosis. Stents are typically placed in peripheral or coronary arteries by an interventional cardiologist or interventional radiologist during an angioplasty procedure. Drugs commonly used in DES to block cell growth include paclitaxel or rapamycin analogs.

[0223] In some embodiments of the present invention, the sGC stimulator of the present invention is The sGC stimulating agent can be delivered by a drug-eluting stent coated with the agent. The drug-eluting stent coated with the sGC stimulating agent of the present invention can be useful for preventing stent restenosis and thrombosis during percutaneous coronary intervention. The drug-eluting stent coated with the sGC stimulating agent of the present invention can prevent smooth muscle cell proliferation and also assist in the revascularization and regeneration of the endothelial tissue of the artery into which the stent is inserted.

[0224]

[0221] Percutaneous coronary intervention for treating refractory angina due to coronary artery obstructive disease An alternative to venous bypass is a procedure called coronary artery bypass grafting (CABG). CABG is the only mitigation of an ongoing process that is further exacerbated by the rapid development of graft atherosclerosis. Saphenous vein grafts are the most commonly used conduits in CABG surgery. The long-term clinical success of venous CABG is hampered by three main reasons: accelerated graft atherosclerosis, incomplete endothelialization, and thrombus formation.

[0225] In some embodiments, the sGC stimulator of the present invention is administered to the saphenous graft during CABG. The compounds of the present invention can be used to prevent thrombus formation by supporting the endothelialization process. In this application, the sGC stimulator is delivered locally in the form of a gel.

[0226] As used herein, the terms "disease," "disorder," and "condition" refer to the They can be used interchangeably to refer to medical or pathological conditions mediated by MPs and / or NO.

[0227] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quail, or turkeys, or mammals), specifically "mammals," including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), more specifically humans. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In some embodiments, the subject is a human.

[0228] The present invention also provides a method for treating one of the above diseases, conditions, and disorders in a subject. The present invention provides a method for treating one of these diseases, conditions, and disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Alternatively, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in a subject in need thereof in the treatment of one of these diseases, conditions, and disorders. The present invention further provides a method for making or manufacturing a medicament useful in treating one of these diseases, conditions, and disorders, comprising using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0229] As used herein, the term "biological sample" refers to an in vitro or refers to an ex vivo sample, including, without limitation, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous fluid, cerebrospinal fluid (CSF), or other bodily fluid, or extract thereof.

[0230] "Treat," "treating," or "treatment," with respect to a disorder or disease, includes: "Treat," "treatment," and "treating" refer to reducing or preventing the cause and / or effects of a disorder or disease. As used herein, the terms "treat," "treatment," and "treating" refer to a reduction or amelioration of the progression, severity, and / or duration of an sGC-, cGMP-, and / or NO-mediated condition, or an improvement in one or more symptoms (preferably one or more discernible symptoms) of the condition (i.e., "control" without "curing" the condition) resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the present invention). In specific embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one measurable physical parameter of an sGC-, cGMP-, and / or NO-mediated condition. In other embodiments, the terms "treat," "treatment," and "treating" refer to inhibiting the progression of an sGC-, cGMP-, and / or NO-mediated condition physically, e.g., by stabilization of a discernible symptom, or physiologically, e.g., by stabilization of a physical parameter, or both.

[0231] As used herein, the term "preventing" refers to preventing one or more of a disease or disorder. "Prevent" refers to administering a medication in advance to avoid or forestall the onset of the above symptoms. Those skilled in the medical field will recognize that the term "prevent" is not an absolute term. In the medical field, it is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or the symptoms of that condition, and this is the meaning intended in this disclosure. The Physician's Desk Reference, a standard text in the field, uses the term "prevent" hundreds of times. As used in this text, the terms "prevent," "preventing," and "prevention" in reference to a disorder or disease refer to avoiding the cause, effects, symptoms, or progression of a disease or disorder before the disease or disorder fully manifests.

[0232] In one embodiment, the methods of the present invention involve the use of sGC, cGMP, and / or NO. The therapeutic agent is a preventative or "preemptive" measure for patients, particularly humans, who are predisposed (eg, genetically predisposed) to developing the associated disease, disorder, or condition.

[0233] In another embodiment, the methods of the present invention involve the use of sGC, cGMP, or NO-associated A preventative or "preemptive" measure for a patient, particularly a human, suffering from a disease, disorder or condition that places them at risk of developing the disease, disorder or condition.

[0234] The compounds and pharmaceutical compositions described herein inhibit sGC, cGMP and / or or can be used alone or in combination therapy to treat or prevent diseases or disorders mediated, modulated, or affected by NO.

[0235] The compounds and compositions disclosed herein are useful for companion animals, exotic animals, The compounds are also useful for veterinary treatment of animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs, and cows.

[0236] In another aspect, the present invention provides a method for stimulating sGC activity in a biological sample. The present invention also provides a method for the treatment of sGC stimulating agents, which comprises contacting the biological sample with the compound or composition of the present invention.The use of sGC stimulating agents in biological samples is useful for various purposes known to those skilled in the art.Examples of such purposes include, but are not limited to, biological assays and biological sample storage.

[0237] Combination therapy The compounds and pharmaceutical compositions described herein may be administered in combination with one or more additional therapeutic agents. It can be used in combination therapy.When combined treatment with more than one active agent in which the active agent is in a separate dosage form, the active agent can be administered separately or together.In addition, the administration of one element can be before, simultaneously with, or after the administration of other agents.

[0238] When co-administered with other drugs, e.g., other pain medications, The "effective amount" of a drug described herein depends on the type of drug used. Suitable dosages are known for approved drugs and can be adjusted by one of ordinary skill in the art according to the condition of the subject, the type of condition(s) being treated, and the amount of the compound described herein used. When an amount is not specified, an effective amount should be inferred. For example, the compounds described herein can be administered to a subject in the following dosage ranges: about 0.01 to about 10,000 mg / kg body weight / day, about 0.01 to about 5,000 mg / kg body weight / day, about 0.01 to about 3,000 mg / kg body weight / day, about 0.01 to about 1,000 mg / kg body weight / day, about 0.01 to about 500 mg / kg body weight / day, about 0.01 to about 300 mg / kg body weight / day, and about 0.01 to about 100 mg / kg body weight / day.

[0239] When "combination therapy" is employed, an effective amount is a first amount of a compound of Formula I or a pharmaceutical agent. This can be achieved using a physiologically acceptable salt thereof and a second amount of an additional suitable therapeutic agent.

[0240] In one aspect of the invention, a compound of formula I or a pharmaceutically acceptable salt thereof, and and the additional therapeutic agent are each administered in an effective amount (i.e., an amount that would each be therapeutically effective if administered alone). In other embodiments, the compound of Formula I and the additional therapeutic agent are each administered in an amount that does not provide a therapeutic effect alone (a subtherapeutic dose). In yet other embodiments, the compound of Formula I can be administered in an effective amount, but the additional therapeutic agent is administered in a subtherapeutic dose. In still other embodiments, the compound of Formula I can be administered in a subtherapeutic dose, but the additional therapeutic agent, e.g., a suitable cancer therapeutic, is administered in an effective amount.

[0241] As used herein, the terms "in combination with" or "co-administration" The terms "prophylactic" and "therapeutic" can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject.

[0242] Co-administration can involve administering a first and second amount of the compound, e.g., a fixed ratio of first and second amounts. The simultaneous administration of the compounds includes administering the first and second amounts of the compound of Formula I and the second therapeutic agent substantially simultaneously, either in a single pharmaceutical composition, such as a capsule or tablet containing the first and second amounts, or in multiple separate capsules or tablets. In addition, such simultaneous administration also encompasses sequential use of each compound in any order. When simultaneous administration involves separately administering a first amount of the compound of Formula I and a second amount of the additional therapeutic agent, the compounds are administered close enough in time to have the desired therapeutic effect. For example, the time between administrations that can produce the desired therapeutic effect can range from minutes to hours and can be determined by taking into account the characteristics of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. For example, the compound of Formula I and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other.

[0243] More particularly, the first treatment (e.g., a prophylactic treatment such as a compound described herein) The prophylactic or therapeutic agent) can be administered to the subject prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second treatment (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent).

[0244]

[0241] Compounds of Formula I or pharmaceutically acceptable salts thereof, administered separately or in the same pharmaceutical composition, Examples of other therapeutic agents that can be combined with acceptable salts thereof include, but are not limited to, the following: (1) Endothelium-derived releasing factor (EDRF) or NO gas.

[0245] (2) NO donors, such as nitrosothiols, nitrites, sydnonimines, NONOates, N-nitrosamines, N-hydroxylnitrosamines, nitrosimines, nitrotyrosines, diazetine dioxide, oxatriazole 5-imines, oximes, hydroxylamines, N-hydroxyguanidines, hydroxyureas, or furoxans. Some examples of these types of compounds include: glyceryl trinitrate (GTN, also known as nitroglycerin, nitroglycerine, and trinitroglycerin), the nitrate ester of glycerol; sodium nitroprusside (SNP), in which a nitric oxide molecule is coordinated to metallic iron to form a square bipyramidal complex; 3-morpholinosydnonimine (SIN-1), a zwitterionic compound formed by the combination of morpholine and sydnonimine; S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acid derivative with a nitrosothiol functionality; diethylenetriamine / NO (DETA / NO), a nitric oxide compound covalently bound to diethylenetriamine; and m-nitroxymethylphenyl ester of acetylsalicylic acid.Some more specific examples of these classes of NO donors include: standard nitrovasodilators, such as organic nitrates and nitrites, e.g., nitroglycerin, amyl nitrite, isosorbide dinitrate, 5-isosorbide mononitrate, and nicorandil; isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Isordil®, Titradose®, Monoket®), 3-morpholinosydnonimine; linsidomine chlorohydrate (“SIN-1”); S-nitroso-N-acetylpenicillamine (“SNAP”); S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione Monoethyl ester (GSNO-ester), 6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexanamine or diethylamine NONOate.

[0246] (3) Other substances that increase cGMP concentrations, such as protoporphyrin IX, arachidonic acid, and phenylhydrazine derivatives. (4) Nitric oxide synthase substrates: for example, N-hydroxyguanidine-based analogs, such as N[G]-hydroxy-L-arginine (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine, and PR5 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine); L-arginine derivatives (e.g., homo-Arg, homo-NOHA, N-tert-butyloxy- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilon guanidine-caproic acid (carbohydrate); acid), agmatine, hydroxyl-agmatine, and L-tyrosyl-L-arginine; N-alkyl-N'-hydroxyguanidines (such as N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hydroxyguanidine), N-aryl-N'-hydroxyguanidines (such as N-phenyl-N'-hydroxyguanidine and its para-substituted derivatives with -F, -Cl, -methyl, and -OH substituents, respectively); guanidine derivatives such as 3-(trifluoromethyl)propylguanidine.

[0247] (5) Compounds that enhance eNOS transcription. (6) NO-independent heme-independent sGC activators, for example, but not limited to, BAY58-2667 (described in Patent Publication DE19943635)

[0248] [ka]

[0249] HMR-1766 (ataciguat sodium, described in Patent Publication WO2000002851)

[0250] [ka]

[0251] S3448 (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (Patent Publication (described in DE19830430 and WO2000002851)

[0252] [ka]

[0253] and HMR-1069 (Sanofi-Aventis). (7) Heme-dependent NO-independent sGC stimulators, including but not limited to: YC-1 (see patent publications EP667345 and DE19744026)

[0254] [ka]

[0255] Riociguat (BAY63-2521, Adempas®, described in DE 19834044)

[0256] [ka]

[0257] Nericiguat (BAY60-4552, described in WO2003095451)

[0258] [ka]

[0259] Vericiguat (BAY1021189)

[0260] [ka]

[0261] BAY41-2272 (described in DE No. 19834047 and DE No. 19942809)

[0262] [ka]

[0263] BAY41-8543 (described in DE No. 19834044)

[0264] [ka]

[0265] Etriciguat (described in WO2003086407)

[0266] [ka]

[0267] CFM-1571 (described in Patent Publication WO2000027394)

[0268] [ka]

[0269] A-344905, its acrylamide analog A-350619 and aminopyrimidine analog A-778935

[0270] [ka]

[0271] and publications: U.S. Patent Application Publication No. 20090209556, U.S. Patent Application Publication No. 8455638, U.S. Patent Application Publication No. 20110118282 (WO2009032249), U.S. Patent Application Publication No. 20100292192, U.S. Patent Application Publication No. 20110201621, U.S. Patent Application Publication No. 7947664, U.S. Patent Application Publication No. 8053455 (WO2009094242), U.S. Patent Application Publication No. 20100216764, U.S. Patent Application Publication No. 8 507512, (WO2010099054), US Patent Application Publication No. 20110218202 (WO2010065275), US Patent Application Publication No. 20130012511 (WO2011119518), US Patent Application Publication No. 20130072492 (WO2011149921), US Patent Application Publication No. 20130210798 (WO2012058132), and other compounds described in Tetrahedron Letters (2003), 44 (48): 8661-8663.

[0272] (8) Compounds that inhibit the degradation of cGMP, such as: PDE5 inhibitors, such as sildenafil (Viagra®), and related agents, such as avanafil, lodenafil, mirodenafil, sildenafil citrate (Revatio®), tadalafil (Cialis® or Adcirca®), vardenafil (Levitra®), and udenafil; alprostadil; dipyridamole and PF-00489791; and PDE9 inhibitors, such as PF-04447943; and PDE10 inhibitors, such as PF-02545920 (PF-10).

[0273] (9) Calcium channel blockers of the following types: Dihydropyridine calcium channel blockers, such as amlodipine (Norvasc®), aranidipine (Sapresta®), azelnidipine (Calblock®), barnidipine (HypoCa®), benidipine (Coniel®), cilnidipine (Atelec®, Cinalong®, Siscard®), clevidipine (Cleviprex®), diltiazem, efonidipine (Landel®), felodipine (Plendil®), lacidipine (Motens®, Lacipil®), lercanidipine (Zanidip®), manidipine, thiazolidine (Calslot®, Madipine®), nicardipine (Cardene®, Carden SR®), nifedipine (Procardia®, Adalat®), nilvadipine (Nivadil®), nimodipine (Nimotop®), nisoldipine (Baymycard®, Sular®, Syscor®), nitrendipine (Cardif®, Nitrepin®, Baylotensin®), pranidipine (Acalas®), isradipine (Lomir®); Phenylalkylamine calcium channel blockers, e.g., verapamil (Calan®, Isoptin®)

[0274] [ka]

[0275] and gallopamil (Procorum®, D600); Benzothiazepines, such as diltiazem (Cardizem®);

[0276] [ka]

[0277] and Non-selective calcium channel blockers, such as mibefradil, bepridil, fluspirilene, and fendiline.

[0278] (10) Endothelin receptor antagonists (ERAs), such as dual (ET A and E.T. B ) the endothelin receptor antagonists bosentan (Tracleer®), sitaxsentan (Thelin®), or ambrisentan (Letairis®).

[0279] (11) Prostacyclin derivatives or analogs, such as prostacyclin (prostaglandin I2), epoprostenol (synthetic prostacyclin), Flolan ( treprostinil (Remodulin®), iloprost (I lomedin®), iloprost (Ventavis®); oral and inhaled forms of Remodulin® are under development.

[0280] (12) Antihyperlipidemic drugs, such as the following types: Bile acid sequestrants, such as cholestyramine, colestipol, colestilan, colesevelam, or sevelamer; Statins, such as atorvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin and pravastatin; Cholesterol absorption inhibitors, such as ezetimibe; Other lipid-lowering drugs, such as icosapent ethyl ester, omega-3-acid ethyl ester, Reducol; Fibric acid derivatives, such as clofibrate, bezafibrate, clinofibrate, gemfibrozil, lonifibrate, binifibrate, fenofibrate, ciprofibrate, cholinefenofibrate; Nicotinic acid derivatives, such as acipimox and niacin; Combinations of statins, niacin and intestinal cholesterol absorption inhibitor supplements (such as ezetimibe) and fibrates; and 10. Antiplatelet therapy, e.g., clopidogrel bisulfate.

[0281] (13) Anticoagulants, such as the following types: Coumarins (vitamin K antagonists), such as warfarin (Coumadin®), cenocoumarol, phenprocoumon, and phenindione; Heparin and derivatives, such as low molecular weight heparin, fondaparinux and idraparinux; Direct thrombin inhibitors, such as argatroban, lepirudin, bivalirudin, dabigatran, and ximelagatran (Exanta®); and Tissue plasminogen activators, such as alteplase, used to dissolve blood clots and unblock arteries.

[0282] (14) Antiplatelet drugs: for example, tropidogrel, ticlopyridine, dipyridamole, and aspirin. (15) ACE inhibitors, such as the following types: Sulfhydryl-containing drugs, such as captopril (Capoten®) and zofenopril; Dicarboxylate-containing drugs, such as enalapril (Vasotec / Renitec®), ramipril (Altace® / Tritace® / Ramace® / Ramiwin®), quinapril (Accupril®), perindopril (Coversyl® / Aceon®), lisinopril (Lisodur® / Lopril® / Novatec® / Prinivil® / Zestril®) and benazepril (Lotensin®); phosphonate-containing drugs, such as fosinopril; Naturally occurring ACE inhibitors, such as casekinins and lactokines, which are breakdown products of casein and whey that occur naturally after the consumption of dairy products, especially fermented milk; The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro, produced by the probiotic Lactobacillus helveticus or derived from casein, also have ACE inhibitory and antihypertensive properties; Other ACE inhibitors, such as alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril, and pilapril.

[0283] (16) Supplemental oxygen therapy. (17) Beta-blockers, such as the following types: Nonselective drugs, such as alprenolol, bucidolol, carteolol, and carvedilol ol, labetalol, nadolol, penbutolol, pindolol, oxprenonol, acebutolol, sotalol, mepindolol, celiprolol, adolol Rotinolol, tertatolol, amosulalol, nipradilol, propranolol and timolol; β1 selective drugs, such as cebutolol, atenolol, betaxolol , bisoprolol, celiprolol, dobutamine hydrochloride, irsogladine maleate, carvedilol, talinolol, esmolol, metroprolol and nebivolol; and β2 selective agents, such as butaxamine.

[0284] (18) Antiarrhythmic drugs, such as the following types: Type I (sodium channel blockers), e.g., quinidine, lidocaine, phenytoin, propafenone; Type III (potassium channel blockers), such as amiodarone, dofetilide, and sotalol; and Type V, e.g., adenosine and digoxin.

[0285] (19) Diuretics, such as thiazide diuretics, for example, chlorothiazide, chlorthalidone and hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, polythiazide, quinethazone, xipamide, metolazone, indapamide, cicletanine; loop diuretics, for example, furosemide and toresamide; potassium-sparing diuretics, for example, amiloride, spironolactone, potassium canrenoate, eplerenone and triamterene; combinations of these drugs; other diuretics, for example, acetazolamide and carperitide.

[0286] (20) Direct acting vasodilators, such as hydralazine hydrochloride, diazoxide, sodium nitroprusside, cadralazine; other vasodilators, such as isosorbide dinitrate and 5-isosorbide mononitrate.

[0287] (21) Exogenous vasodilators, such as Adenocard® and alpha-blockers. (22) Alpha-1-adrenergic receptor antagonists, such as prazosin, indoramin, urapidil, bunazosin, terazosin, and doxazosin; atrial natriuretic peptide (ANP), ethanol, histamine inducers, tetrahydrocannabinol (THC), and papaverine.

[0288] (23) Bronchodilators of the following types: Short-acting beta-2 agonists, such as albutamol or albuterol (Ventolin®) and terbutaline; Long-acting beta-2 agonists (LABAs), such as salmeterol and formoterol; Anticholinergics, such as pratropium and tiotropium; and Theophylline, a bronchodilator and phosphodiesterase inhibitor.

[0289] (24) Corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide, hydrocortisone, and corticosteroid analogs, such as budesonide.

[0290] (25) Dietary supplements, such as omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo biloba, pine bark, Tribulus terrestris, arginine, Avena sativa, horny goat weed, maca root, and muirapu. Flax, saw palmetto, and Swedish flower pollen; Vitamin C, Vitamin E, Vitamin K2; testosterone supplements, testosterone transdermal patches; Zoraxel, naltrexone, bremelanotide, and melanotan II.

[0291] (26) PGD2 receptor antagonist. (27) Immunosuppressants, such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (Sirolimus®, Rapamune®) and other FK-506 type immunosuppressants, mycophenolates, such as mycophenolate mofetil (CellCept®).

[0292] (28) Non-steroidal antiasthmatic drugs, such as β2-agonists, for example, terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, salmeterol, bitolterol and pirbuterol; β2-agonist-corticosteroid combinations, for example, salmeterol-fluticasone (Advair®), formoterol-budesonide (Symbicort®), theophylline, cromolyn, cromolyn sodium, nedocromil, atropine, ipratropium, ipratropium bromide, leukotriene biosynthesis inhibitors (zileuton, BAY1005).

[0293] (29) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives, such as alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen; acetic acid derivatives, such as indomethacin, acemetacin, alclofenac, clida diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxipinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac; fenamic acid derivatives such as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid; biphenylcarboxylic acid derivatives such as diflunisal and flufenisal; oxicams such as isoxicam, piroxicam, sudoxicam and tenoxicam; salicylic acid ates, such as acetylsalicylic acid and sulfasalazine; and pyrazolones, such as apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, and phenylbutazone.

[0294] (30) Cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib, and lumiracoxib; opioid analgesics, such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine.

[0295] (31) Antidiabetic drugs, such as insulin and insulin mimetics; sulfonylureas, such as glyburide, glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, amides and olazamide; biguanides, such as metformin (Gluco phage®); α-glucosidase inhibitors such as acarbose, epalrestat, voglibose, miglitol; thiazolidinone compounds such as rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and englitazone; insulin sensitizers such as pioglitazone and rosiglitazone; insulin secretagogues such as repaglinide, nateglinide and mitiglinide; incretin mimetics such as exanatide and liraglutide; amylin analogues such as pram glucose-lowering drugs, such as chromium picolinate, which may be combined with biotin; dipeptidyl peptidase IV inhibitors, such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin.

[0296] (32) HDL cholesterol-raising agents, such as anacetrapib and dalcetrapib. (33) Antiobesity drugs, such as methamphetamine hydrochloride, amfepramone hydrochloride (Tenuate®), phentermine (Ionamin®), benzphetamine hydrochloride (Didrex®), phendimetrazine tartrate (Bontril®, Prelu-2®, Plegine®), mazindol (Sanorex®), orlistat (Xenical®), sibutramine hydrochloride monohydrate (Meridia®, Reductil®), rimonabant (Acomplia®), amfepramone, chromium picolinate; Combinations such as phentermine / topiramate, bupropion / naltrexone, sibutramine / metformin, bupropion SR / zonisamide SR, salmeterol, xinafoate / fluticasone propionate; lorcaserin hydrochloride, phentermine / topiramate, cetilistat, exenatide, liraglutide, metformin hydrochloride, sibutramine / metformin, bupropion SR / zonisamide SR, CORT-108297, canagliflozin, chromium picolinate, GSK-1521498, LY-377604, metreleptin, obinepitide, P-57AS3, PSN-821, xinafoate Salmeterol fonate / fluticasone propionate, sodium tungstate, somatropin (recombinant), tesamorelin, tesofensine, velneperit, zonisamide, beloranib hemioxalate, insulinotropin, resveratrol , sobetirom, tetrahydrocannabivarin, and beta-lapachone.

[0297] (34) Angiotensin receptor blockers, such as losartan, valsartan, candesartan, cilexetil, eprosartan, irbesartan, and telmisartan Olmesartan, Olmesartran, Medoxomil, Azilsartan and Medoxomil .

[0298] (35) Renin inhibitors, such as aliskiren hemifumirate. (36) Centrally acting alpha-2-adrenergic receptor agonists, such as methyldopa, clonidine, and guanfacine.

[0299] (37) Adrenergic neuron blocking agents, such as guanethidine and guanadrel. (38) Imidazoline I-1 receptor agonists, such as rimenidine dihydrogen phosphate and moxonidine hydrochloride hydrate.

[0300] (39) Aldosterone antagonists, such as spironolactone and eplerenone. (40) Potassium channel activators, such as pinacidil.

[0301] (41) Dopamine D1 agonists, such as fenoldopam mesylate; other dopamine agonists, such as ibopamine, dopexamine, and docarpamine. (42) 5-HT2 antagonists, such as ketanserin.

[0302] (43) Vasopressin antagonists, such as tolvaptan. (44) Calcium channel sensitizers, e.g., levosimendan, or activators such as nicorandil.

[0303] (45) PDE-3 inhibitors, such as amrinone, milrinone, enoximone, vesnarinone, pimobendan, and olprinone. (46) Adenylate cyclase activators, such as colforsin dapropate hydrochloride.

[0304] (47) Positive inotropic agents, such as digoxin and methyldigoxin; metabolic inotropes, such as ubidecarenone; brain natriuretic peptides, such as nesiritide. (48) Drugs used to treat erectile dysfunction, such as alprostadil, aviptadil, and phentolamine mesylate.

[0305] (49) Drugs used in the treatment of obesity, including but not limited to: Methamphetamine hydrochloride (Desoxyn®), amfepramone hydrochloride (Tenuate®), phentermine (Ionamin®), benzphetamine hydrochloride (Didrex®), phendimetrazine hydrochloride (Bontril®, Prelu-2®, Plegine®), mazindol (Sanorex®), and orlistat (Xenical®).

[0306] (50) Drugs used to treat Alzheimer's disease and dementia, such as the following types: Acetylcholinesterase inhibitors, such as galantamine (Razadyne®), rivastigmine (Exelon®), donepezil (Aricept®), and tacrine (Cognex®); NMDA receptor antagonists, such as memantine (Namenda®); and 107. Oxidoreductase inhibitors such as idebenone.

[0307] (51) Psychiatric medications such as the following types: Ziprasidone (Geodon TM ), risperidone (Risperdal TM ), O Lanzapine (Zyprexa TM ), valproate; Dopamine D4 receptor antagonists, such as clozapine; Dopamine D2 receptor antagonists, such as nemonapride; mixed dopamine D1 / D2 receptor antagonists, such as zuclopenthixol; GABA A receptor modulators, such as carbamazepine; sodium channel blockers, e.g., lamotrigine; Monoamine oxidase inhibitors, such as moclobemide and indeloxazine; primavanserin, perospirone; and 10. PDE4 inhibitors, such as rolumilast.

[0308] (52) Drugs used to treat movement disorders, such as the following types: Catechol-O-methyltransferase inhibitors, such as entacapone; Monoamine oxidase B inhibitors, such as selegiline; dopamine receptor modulators, such as levodopa; Dopamine D3 receptor agonists, such as pramipexole; decarboxylase inhibitors, such as carbidopa; Other dopamine receptor agonists, such as pergolide, ropinirole, cabergoline; ritigonide, istradefylline, talipexole, zonisamide, and safinamide; and 10. Synaptic vesicle amine transporter inhibitors, such as tetrabenazine.

[0309] (53) Medications used to treat mood or affective disorders or OCD, such as the following types: Tricyclic antidepressants, such as amitriptyline (Elavil®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine (Asendin®), nortriptyline and clomipramine; Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®), and citralopram (Celexa®); doxepin (Sinequan®), trazodone (Desyrel®) and agomelatine; Selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, reboxetine, and atomoxetine; dopaminergic antidepressants, such as bupropion and amineptine.

[0310] (54) Drugs for enhancing synaptic plasticity, such as the following types: Nicotinic receptor antagonists, such as mecamylamine; and 10. Mixed 5-HT, dopamine and norepinephrine receptor agonists, such as lurasidone.

[0311] (55) Drugs used in the treatment of ADHD, such as amphetamines; 5-HT receptor modulators, such as vortioxetine, and alpha-2-adrenergic receptor agonists, such as clonidine.

[0312] (56) Neutral endopeptidase (NEP) inhibitors, such as sacubitril and omapatrilat; and (57) Methylene blue (MB). kit The compounds and pharmaceutical formulations described herein can be contained in kits. The kit can include single or multiple doses of two or more agents, each individually packaged or combined, or single or multiple doses of two or more agents packaged or combined in combination. Thus, one or more agents can be present in a first container, and the kit can optionally include one or more agents in a second container. The container or containers are placed within a package, which can optionally include instructions for administration or dosage. The kit can include additional components, such as a syringe or other means for administering the agents and diluent, or other combination means. Thus, the kit can include: a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle, or diluent; and b) a container or package. The kit can optionally include instructions for use of the pharmaceutical composition in one or more methods described herein (e.g., prevention or treatment of one or more of the diseases and disorders described herein). The kit can optionally include a combination of agents for simultaneous therapy. A second pharmaceutical composition containing one or more additional agents described herein for use, optionally including a pharmaceutically acceptable carrier, vehicle, or diluent, may be included. The pharmaceutical composition containing the compounds described herein and the second pharmaceutical composition contained in the kit may be combined into the same pharmaceutical composition, if desired.

[0313] The kit includes a container or package for containing the pharmaceutical composition, and a divided bottle. Or it can include divided containers such as divided foil packets. The container can be, for example, a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (e.g., for holding "refills" of tablets to be placed in another container), or a blister pack with individual doses to be pushed out of the pack according to a treatment schedule. It is feasible for more than one container to be used together in a single package to market a single dosage form. For example, tablets can be placed in a bottle, which is placed in a box.

[0314]

[0244] An example of a kit is a so-called blister pack. Blister packs are used in the packaging industry. Blister packs are well known in the pharmaceutical industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses may be the size and shape of individual tablets or capsules to be packed, or may be the size and shape to accommodate multiple tablets and / or capsules to be packed. The tablets or capsules are then placed in the recesses as appropriate, and the sheet of relatively stiff material is sealed to the plastic foil on the side of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed in the recesses between the plastic foil and the sheet, as desired. The strength of the sheet is preferably such that the tablets or capsules can be removed from the blister pack by applying manual pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through said openings.

[0315]

[0245] A medical document containing information and / or instructions on when to administer the medication, provided by a physician, pharmacist, or It may be desirable to provide a written memory aid directed to the subject. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. If the kit contains separate compositions, the daily dose of one or more compositions of the kit can consist of one tablet or capsule, while the daily dose of one or more other compositions of the kit can consist of several tablets or capsules. The kit can be in the form of a dispenser designed to dispense the daily doses one by one in the order of their intended use. The dispenser can also be equipped with a memory aid to further promote compliance with the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Other examples of such memory aids are a battery-powered microchip memory coupled with a liquid crystal readout, or an audible reminder signal that, for example, reads out the date the last daily dose was taken and / or reminds the patient when the next dose should be taken. [Example]

[0316]

[0246] All references provided in the Examples are incorporated herein by reference. All abbreviations, symbols, and conventions used herein are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd ed., Washington, DC: American Chemical Society, 1997, which is incorporated herein by reference in its entirety.

[0317] Example 1: Synthesis of compounds Intermediate 1a

[0318] [ka]

[0319] 8-(2-Fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (1a) : The title compound was synthesized in two steps according to patent literature procedures (WO2015 / 187470A1) as a yellow solid (0.60 g, 39% yield over two steps). 1 H NMR (500 MHz, methanol-d4) δ (ppm) 9.09 (s, 1 H), 8.14 (s, 1 H), 7.91 (s, 1 H), 7.35 (t, 1 H), 7.28 (m, 1 H), 7.10 (m, 2 H), 4.60 (s, 2 H). The following nitrile intermediates were prepared using a similar synthetic procedure to 1a. Reaction conditions (such as ratios of reagents, temperature and reaction time) were modified as necessary.

[0320] 8-Phenylimidazo[1,2-a]pyrazine-6-carbonitrile; 8-benzylimidazo[1,2-a]pyrazine-6-carbonitrile; 8-(4-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile; 8-(2,3-Difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile; 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile; 8-(3,3,4,4,4-pentafluorobutyl)imidazo[1,2-a]pyrazine-6-carbonitrile, 8-(2-fluorobenzyl)-2-methylimidazo[1,2-a]pyrazine-6-carbonitrile; 8-(3,5-Difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile; 8-(3,5-Difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile.

[0321] Alternatively, intermediate 1a and related analogues (such as intermediate 1b) can be synthesized by the following procedure: Phase 1: Synthesis of 6-bromo-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine A suspension of dry zinc powder (47 g, 720 mmol, dried by heating under reduced pressure) in THF (750 mL) was treated with 1,2-dibromoethane (1 mL), and the resulting mixture was heated to 50 °C. Chlorotrimethylsilane (1 mL) was added. After stirring at 48–50 °C for 30 min, the mixture was cooled to ambient temperature. Dry lithium chloride (30 g, 710 mmol, dried by heating under reduced pressure) was added, followed by the dropwise addition of a solution of 2-fluorobenzyl bromide (74 g, 390 mmol) in THF (100 mL) (CAUTION: exothermic; maintain the reaction temperature below 48 °C). The mixture was stirred at ambient temperature for 1 h. A slurry of 6,8-dibromoimidazo[1,2-a]pyrazine (99 g, 360 mmol) and Pd(PPh3)2Cl2 (7.8 g, 11 mmol) in THF (500 mL) was degassed by bubbling nitrogen through it for 10 minutes and rapidly added to the 2-fluorobenzylzinc bromide reagent with THF (100 mL). The reaction vessel was purged with nitrogen, and the mixture was stirred overnight at ambient temperature until the starting material was completely consumed. The reaction was quenched with saturated NH4Cl solution (800 mL). The brown organic phase was concentrated to dryness, redissolved in DCM (1.3 L), and filtered through a bed of Celite. The organic layer in the filtrate was collected, decolorized with activated carbon (45 g), filtered through Celite, and concentrated to dryness. The crude material was azeotropically dried with toluene (2 × 500 mL) and used in the next step without purification.

[0322] Phase 2: Synthesis of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile A reaction mixture consisting of the crude material from the previous step (360 mmol, theoretical yield), zinc cyanide (35 g, 300 mmol), Pd(dba) (16 g, 18 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf) (14 g, 25 mmol), and zinc powder (1.0 g) in DMF (800 mL) was degassed under nitrogen for 10 minutes and then heated at 85 °C until the starting material was completely consumed. The reaction was cooled to ambient temperature and poured into EtOAc (1.5 L), 10% NH4Cl solution (1.1 L), and 5% NaCl solution (1.0 L). The organic layer was filtered through a bed of Celite and washed with EtOAc (2 × 750 mL). The organic filtrate was washed with 10% NaCl solution (2 × 1.0 L), decolorized with activated carbon (75 g), filtered through Celite, and washed with EtOAc (2 × 300 mL). The filtrate was concentrated to dryness and suspended in a mixture of DCM (150 mL) and MTBE (300 mL). After stirring for 1 h, the product was collected by filtration, washed with MTBE (2 x 100 mL), and dried in an oven at 45 °C under vacuum to give the title compound as a brown solid (52 g, 57% yield). 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.09 (s, 1 H), 8.13 (s, 1 H), 7.91 (s, 1 H), 7.35 (app. t, 1 H), 7.27 (m, 2 H), 7.13 - 7.06 (m, 2 H), 4.60 (s, 2 H). Intermediate 1b

[0323] [ka]

[0324] 8-(3-Fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (1b) : The title compound was synthesized in two steps. Phase 1: Synthesis of 6-bromo-8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine A suspension of dry zinc powder (2.6 g, 40 mmol) in THF (50 mL) was treated with 1,2-dibromoethane (0.3 mL, 3.5 mmol), and the resulting mixture was heated at 50 °C for 5 min. Chlorotrimethylsilane (0.30 mL, 2.4 mmol) was then added, and the mixture was cooled to ambient temperature. Dry lithium chloride (1.7 g, 40 mmol) was added, followed by the dropwise addition of a solution of 3-fluorobenzyl bromide (4.8 g, 26 mmol) in THF (25 mL). (Caution: Exothermic; maintain the reaction temperature below 35 °C.) The mixture was stirred at ambient temperature for 1 h, after which a slurry of 6,8-dibromoimidazo[1,2-a]pyrazine (5.9 g, 21 mmol) and Pd(PPh3)2Cl2 (0.25 g, 0.36 mmol) in THF (75 mL) was added. The reaction mixture was degassed with nitrogen and stirred overnight at ambient temperature until the starting material was completely consumed. The reaction mixture was concentrated and diluted with DCM (100 mL) and 10% NH4Cl solution (100 mL). The thick mixture was filtered through a celite bed, and the organic layer in the filtrate was collected. The organic layer was dried, decolorized with Na2SO4 (10 g) and activated carbon (7 g), filtered through celite, and concentrated to give a crude orange oil (7.1 g), which was used in the next step without purification.

[0325] Phase 2: Synthesis of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile A reaction mixture consisting of the crude material from the previous step (21 mmol, theoretical yield), zinc cyanide (3.0 g, 26 mmol), Pd(dba) (1.9 g, 2.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf) (1.5 g, 2.7 mmol), and zinc powder (0.30 g, 4.6 mmol) in DMF (70 mL) was degassed under nitrogen for 5 min and then heated at 110 °C until the starting material was completely consumed. The reaction was cooled to ambient temperature, diluted with EtOAc (150 mL), and filtered through a bed of Celite. The organic filtrate was washed with 10% NHCl solution (2 × 100 mL), dried over NaSO, filtered, and concentrated to a brown oil, which was purified by column chromatography (15–40% EtOAc / hexane gradient) to give the title compound as an off-white solid (2.4 g, 45% yield). 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 9.37 (s, 1 H), 8.25 (s, 1 H), 7.98 (s, 1 H), 7.29 - 7.39 (m, 1 H), 7.23 (d, 2 H), 6.99 - 7.12 (m, 1 H), 4.45 - 4.56 (m, 2 H). Using a similar synthetic procedure to intermediates 1a and 1b, the following nitrile intermediates were prepared. Reaction conditions (such as ratios of reagents, temperature and reaction time) were modified as necessary.

[0326] 8-(2,6-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile; 8-(3-Fluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile.

[0327] Intermediate 2

[0328] [ka]

[0329] 8-Benzyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile(2): The title compound was synthesized in two steps according to patent literature procedures (WO2016 / 081668A1) as a golden residue (0.12 g, 23% yield over two steps). 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 9.96 (s, 1 H), 8.94 (s, 1 H), 7.39 (d, 2 H) 7.30 (dd, 2 H), 7.23 (t, 1 H), 4.53 (s, 2 H). The following nitrile intermediates were prepared using a synthetic procedure similar to that of 2. Reaction conditions (such as ratio of reagents, temperature and reaction time) were modified as necessary.

[0330] 8-(2-Fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile. 8-(2,3-Difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile; 8-(3-Fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine benzo-6-carbonitrile; 8-(2,5-Difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile; 8-(3,5-Difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile.

[0331] Compound I-1

[0332] [ka]

[0333] General Procedure A: 8-(2-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-1) To a solution of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (1a) (4.0 g, 16 mmol) in methanol (40 mL) was added anhydrous hydrazine (3.1 mL, 100 mmol). After stirring overnight at ambient temperature, complete disappearance of the starting material was observed. The reaction was concentrated under reduced pressure, and residual hydrazine was removed by chasing with methanol and toluene, and the resulting foam was dried under reduced pressure overnight. A brown foam was obtained. The mixture was taken up in DCM (75 mL) and 2,2,2-trifluoroacetic anhydride (3.8 mL, 27 mmol) was added dropwise to prevent a strongly exothermic reaction. The reaction was stirred at ambient temperature until the amidrazone intermediate was completely consumed. The solvent was removed under reduced pressure and dried to yield a yellow residue. The residue was taken up in AcOH (10 mL) and EtOH (100 mL) and heated at 90 °C for 1 h. The reaction mixture was cooled to ambient temperature and concentrated to half its volume. The resulting thick suspension was filtered, and the filtrate was concentrated to yield a brown oil. The crude material was purified using silica gel chromatography (10-100% EtOAc / hexanes gradient) to isolate the title compound (4.0 g, 69% yield) as a tan solid. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.46 (s, 1 H), 9.45 (s, 1 H), 8.26 (s, 1 H), 7.87 (s, 1 H), 7.43 (t, 1 H), 7.22 - 7.32 (m, 1 H), 7.14 - 7.22 (m, 1 H), 7.09 (t, 1 H), 4.60 (s, 2 H). LCMS [M+H] = 363.1 Compound I-2

[0334] [ka]

[0335] 8-(3-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-2) was synthesized as an off-white solid (170 mg, 60% yield) according to general procedure A. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ (ppm) 9.22 (s, 1 H), 8.17 (s, 1 H), 7.87 (s, 1 H) LCMS [M+H] = 363.2 Compound I-3

[0336] [ka]

[0337] 6-(3-(Difluoromethyl)-1H-1,2,4-triazol-5-yl)-8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine (I-3) was synthesized as an off-white solid (160 mg, 55% yield) according to general procedure A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.17 (s, 1 H), 8.17 (s, 1 H), 7.86 (s, 1 H), 7.35-7.25 (m, 3 H), 6.92 (m, 1 H), 6.90 (t, 1 H), 4.61 (s, 2 H). LCMS [M+H] = 345.2 Compound I-17

[0338] [ka]

[0339] 8-(2,3-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-17) was synthesized as a white solid (120 mg, 62% yield) according to general procedure A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.3 (s, 1 H), 9.58 (s, 1 H), 8.83 (s, 1 H), 7.27 - 7.35 (m, 2 H), 7.08 - 7.19 (m, 2 H), 4.69 (s, 2 H). LCMS [M+H] = 364.2 Compound I-19

[0340] [ka]

[0341] 8-(2,6-Difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-19) was synthesized as an off-white solid (300 mg, 87% yield) according to general procedure A. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.3 (s, 1 H), 9.43 (s, 1 H), 8.25 (s, 1 H), 7.85 (s, 1 H), 7.37 (m, 1 H), 7.08 (app. t, 2 H), 4.63 (s, 2 H). LCMS [M+H] = 381.2 Compound I-20

[0342] [ka]

[0343] 8-(2,6-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-20) was synthesized as an off-white solid (240 mg, 72% yield) according to general procedure A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 14.9 (s, 1 H), 9.38 (s, 1 H), 8.24 (s, 1 H), 7.84 (s, 1 H), 7.37 (m, 1 H), 7.13 (t, 1 H), 7.08 (app. t, 2 H), 4.62 (s, 2 H). LCMS [M+H] = 363.2 Compound I-21

[0344] [ka]

[0345] 6-(3-(Difluoromethyl)-1H-1,2,4-triazol-5-yl)-8-(3-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine (I-21) was synthesized as a white solid (110 mg, 29% yield) according to General Procedure A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.3 (s, 1 H), 9.55 (s, 1 H), 8.83 (s, 1 H), 7.30 -7.37 (m, 3 H), 7.19 (t, 1 H), 7.04 - 7.09 (m, 1 H), 4.61 (s, 2 H). LCMS [M+H] = 346.2 Compound I-22

[0346] [ka]

[0347] 8-(3-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-22) was synthesized as an off-white solid (140 mg, 49% yield) according to general procedure A. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.7 (s, 1 H), 9.62 (s, 1 H), 8.85 (s, 1 H), 7.32 -7.36 (m, 3 H), 7.05 - 7.08 (m, 1 H), 4.62 (s, 2 H). LCMS [M+H] = 364.2 Compound I-23

[0348] [ka]

[0349] 8-(2,5-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-23) was synthesized as an off-white solid (120 mg, 72% yield) according to general procedure A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratios of reagents, temperature, and reaction time) were modified as necessary. 1H NMR (500 MHz, methanol-d4) δ(ppm) 9.49 (s, 1 H), 8.65 (s, 1 H), 7.25 (m, 1 H), 7.11 (m, 1 H), 7.01 (m, 1 H), 6.91 (t, 1 H), 4.71 (s, 2 H). LCMS [M+H] = 364.2 Compound I-24

[0350] [ka]

[0351] 8-(3,5-Difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-24) was synthesized as a white solid (120 mg, 42% yield) according to general procedure A. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.7 (s, 1 H), 9.63 (s, 1 H), 8.86 (s, 1 H), 7.23 (d, 2 H), 7.11 (t, 1 H), 4.63 (s, 2 H). LCMS [M+H] = 382.2 Compound I-25

[0352] [ka]

[0353] 8-(3,5-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-25) was synthesized as a white solid (157 mg, 57% yield) according to general procedure A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.2 (s, 1 H), 9.50 (s, 1 H), 8.77 (s, 1 H), 7.16 (d, 2 H), 7.14 (t, 1 H), 7.03 (m, 1 H), 4.55 (s, 2 H). LCMS [M+H] = 364.1 Compound I-4

[0354] [ka]

[0355] General Procedure B: 8-(2-Fluorobenzyl)-6-(3-methyl-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine To a solution of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (1a) (110 mg, 0.45 mmol) in methanol (2.0 mL) was added anhydrous hydrazine (0.08 mL, 2.7 mmol). After stirring at ambient temperature for 40 h, complete disappearance of the starting material was observed. The reaction was concentrated under reduced pressure, and the residue was dried under reduced pressure overnight. The residue was taken up in DCM (6.0 mL), and acetic anhydride (0.09 mL, 0.89 mmol) was added dropwise to prevent a strongly exothermic reaction. The reaction was stirred at ambient temperature until the amidrazone intermediate was completely consumed. The solvent was removed under reduced pressure and dried to yield a yellow residue. The residue was taken up in AcOH (0.2 mL) and EtOH (10 mL) and heated in a microwave oven at 120 °C for 5 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material was purified using silica gel chromatography (gradient of 10-30% acetonitrile / MeOH (7:1) in DCM) to isolate the title compound (85 mg, 62% yield) as an off-white solid. 1H NMR (500 MHz, methanol-d4) δ (ppm) 9.03 (s, 1 H), 8.15 (s, 1 H), 7.81 (s, 1 H), 7.30 (app. t, 1 H), 7.23 (m, 1 H), 7.10-7.02 (m, 2 H), 4.66 (s, 2 H), 2.48 (s, 3 H). LCMS [M+H] = 309.2 Compound I-5

[0356] [ka]

[0357] 8-(2-Fluorobenzyl)-6-(3-(perfluoroethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine was synthesized as a solid (1.5 mg, 1.5% yield) according to General Procedure B, except that 2,2,3,3,3-pentafluoropropanoic anhydride was used as the acylating agent. Reaction conditions (such as ratios of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.26 (s, 1 H), 8.18 (s, 1 H), 7.85 (s, 1 H), 7.34 (t, 1 H), 7.24 (s, 1 H), 7.09 (m, 2 H), 4.69 (s, 2 H). LCMS [M+H] = 413.2 Compound I-6

[0358] [ka]

[0359] 8-Benzyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-6) was synthesized as a white solid (57 mg, 52% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. The reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.09 (s, 1 H), 8.05 (s, 1 H), 7.75 (s, 1 H), 7.41 (d, 2 H), 7.15 (t, 2 H), 7.04 - 7.10 (m, 1 H), 4.50 (s, 2 H). LCMS [M+H] = 345.2 Compound I-7

[0360] [ka]

[0361] 8-Benzyl-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-7) was synthesized as a white solid (15 mg, 16% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.05 (s, 1 H), 8.06 (s, 1 H), 7.75 (s, 1 H), 7.41 (d, 2 H), 7.13 - 7.18 (m, 2 H), 7.05 - 7.10 (m, 1 H), 6.68 - 6.91 (m, 1 H). H), 4.50 (s, 2 H). LCMS [M+H] = 327.2 Compound I-8

[0362] [ka]

[0363] 8-(2,5-Difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-8) was synthesized as a white solid (18 mg, 31% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ (ppm) 9.14 (s, 1 H), 8.09 (s, 1 H), 7.77 (s, 1 H), 7.07 (m, 1 H), 7.00 (m, 1 H), 6.86 - 6.92 (m, 1 H), 4.57 (s, 2 H). LCMS [M+H] = 381.2 Compound I-9

[0364] [ka]

[0365] 8-(2,5-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-9) was synthesized as an off-white solid (32 mg, 36% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.10 (s, 1 H), 8.09 (s, 1 H), 7.76 (s, 1 H), 7.06 (m, 1 H), 7.00 (m, 1 H), 6.87 - 6.92 (m, 1 H), 6.79 (t, 1 H), 4.56 (s, 2 H). LCMS [M+H] = 363.2 Compound I-10

[0366] [ka]

[0367] 8-(2,3-Difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-10) was synthesized as a white solid (110 mg, 39% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.25 (s, 1 H), 8.19 (s, 1 H), 7.86 (s, 1 H), 7.17-7.10 (m, 2H), 7.05 (m, 1 H), 4.72 (s, 2 H). LCMS [M+H] = 381.2 Compound I-11

[0368] [ka]

[0369] 8-(2,3-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-11) was synthesized as an off-white solid (55 mg, 25% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1H NMR (500 MHz, methanol-d4) δ(ppm) 9.21 (s, 1 H), 8.19 (s, 1 H), 7.86 (s, 1 H), 7.17-7.09 (m, 2H), 7.04 (m, 1 H), 6.89 (t, 1 H), 4.71 (s, 2 H). LCMS [M+H] = 363.2 Compound I-12

[0370] [ka]

[0371] 8-(4-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-12) was synthesized as an off-white solid (75 mg, 84% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.50 (s, 1 H), 9.41 (s, 1 H), 8.24 (s, 1 H), 7.88 (s, 1 H) 7.56 (dd, 2 H), 7.10 (dd, 2 H), 4.52 (s, 2 H). [M+H] = 363.2 Compound I-13

[0372] [ka]

[0373] 8-(3,3,4,4,4-Pentafluorobutyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-13) was synthesized as a pale yellow solid (30 mg, 60% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. The reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.24 (s, 1 H), 8.19 (s, 1 H), 7.86 (s, 1 H), 3.59 - 3.66 (m, 2 H), 2.93 - 3.07 (m, 2 H). LCMS [M+H] = 401.2 Compound I-14

[0374] [ka]

[0375] 8-(2-Fluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-14) was synthesized as an off-white solid (46 mg, 56% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.28 (s, 1 H), 8.29 (s, 1 H), 8.00 (s, 1 H), 7.35 (t, 1 H), 7.27 (d, 1 H), 7.09 (m, 2 H), 6.90 (m, 1 H), 4.69 (s, 2 H). LCMS [M+H] = 345.2 Compound I-15

[0376] [ka]

[0377] 8-Benzyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-15) was reacted with This compound was synthesized as a white solid (60 mg, 33% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the silating agent. Reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.72 (s, 1 H), 9.60 (s, 1 H), 8.84 (s, 1 H), 7.50 (d, 2 H) 7.30 (app. t, 2 H), 7.21 (t, 1 H), 4.59 (s, 2 H). LCMS [M+H] = 346.2 Compound I-16

[0378] [ka]

[0379] 8-(2-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-16) was synthesized as an off-white solid (1.2 mg, 10% yield) according to general procedure B. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.51 (s, 1 H), 8.65 (s, 1 H), 7.43 (app. t, 1 H), 7.27 (m, 1 H), 7.10 (t, 2 H), 4.74 (s, 2 H). LCMS [M+H] = 364.1 Compound I-18

[0380] [ka]

[0381] 8-(2,3-Difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-18) was synthesized as a white solid (89 mg, 44% yield) according to general procedure B. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.7 (s, 1 H), 9.64 (s, 1 H), 8.84 (s, 1 H), 7.30 -7.35 (m, 1 H), 7.27 - 7.30 (m, 1 H), 7.12 - 7.15 (m, 1 H), 4.69 (s, 2 H). LCMS [M+H] = 382.2 Compound I-26

[0382] [ka]

[0383] 6-(3-(Difluoromethyl)-1H-1,2,4-triazol-5-yl)-8-(2-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine (I-26) was synthesized as a white solid (180 mg, 88% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.3 (s, 1 H), 9.57 (s, 1 H), 8.81 (s, 1 H), 7.46 (app. t, 1 H), 7.32-7.09 (m, 4 H), 4.64 (s, 2 H). LCMS [M+H] = 346.2 Compound I-27

[0384] [ka]

[0385] 8-(3-Fluoro-4-methylbenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-27) was synthesized as a pale yellow solid (110 mg, 61% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.5 (s, 1 H), 9.41 (s, 1 H), 8.24 (s, 1 H), 7.88 (s, 1 H), 7.30 (d, 1 H), 7.15 - 7.23 (m, 2 H), 4.50 (s, 2 H), 2.15 (s, 3 H). LCMS [M+H] = 377.1 Compound I-28

[0386] [ka]

[0387] 6-(3-(Difluoromethyl)-1H-1,2,4-triazol-5-yl)-8-(3-fluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine (I-28) was synthesized as a pale yellow solid (130 mg, 76% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.1 (s, 1 H), 9.36 (s, 1 H), 8.24 (s, 1 H), 7.87 (s, 1 H), 7.14 - 7.35 (m, 4 H), 4.49 (s, 2 H), 2.15 (s, 3 H). LCMS [M+H] = 359.2 Compound I-29

[0388] [ka]

[0389] 8-(3,5-Difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-29) was synthesized as a pale yellow solid (150 mg, 68% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 15.5 (s, 1 H), 9.43 (s, 1 H), 8.26 (s, 1 H), 7.90 (s, 1 H), 7.23 (d, 2 H), 7.08 (t, 1 H), 4.56 (s, 2 H). LCMS [M+H] = 381.1 Compound I-30

[0390] [ka]

[0391] 8-(3,5-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-30) was synthesized as a pale yellow solid (140 mg, 70% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1H NMR (500 MHz, DMSO-d6)δ(ppm) 15.1 (s, 1 H), 9.38 (s, 1 H), 8.26 (s, 1 H), 7.89 (s, 1 H), 7.04 - 7.29 (m, 4 H), 4.55 (s, 2 H). LCMS [M+H] = 363.1 Compound I-31

[0392] [ka]

[0393] 8-(2-Fluorobenzyl)-2-methyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-31) was synthesized as a white solid (35 mg, 55% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, CDCl3)δ(ppm) 11.6 (br. s, 1 H), 8.88 (s, 1 H), 7.61 (s, 1 H), 7.39 (app. t, 1 H), 7.26-7.32 (m, 1 H), 7.09-7.15 (m, 2 H), 4.69 (s, 2 H), 2.60 (s, 3 H). LCMS [M+H] = 377.3 Compound I-32

[0394] [ka]

[0395] 6-(3-(Difluoromethyl)-1H-1,2,4-triazol-5-yl)-8-(2-fluorobenzyl)-2-methylimidazo[1,2-a]pyrazine (I-32) was synthesized as a white solid (44 mg, 85% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, CDCl3)δ(ppm) 11.5 (br. s, 1 H), 8.89 (s, 1 H), 7.61 (s, 1 H), 7.38 (app. t, 1 H), 7.26-7.34 (m, 1 H), 7.08-7.14 (m, 2 H), 6.77 (t, 1 H), 4.69 (s, 2 H), 2.60 (s, 3 H). LCMS [M+H] = 359.2 Compound I-33

[0396] [ka]

[0397] 8-(2,5-Difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-33) was synthesized as a white solid (72 mg, 41% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. The reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, Methanol-d4)δ(ppm) 9.51 (s, 1 H), 8.66 (s, 1 H), 7.20 - 7.29 (m, 1 H), 7.06 - 7.15 (m, 1 H), 7.01 (m, 1 H), 4.72 (s, 2 H). LCMS [M+H] = 382.2 Compound I-34

[0398] [ka]

[0399] 8-(3,5-Difluoro-4-methylbenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-34) was synthesized as a white solid (81 mg, 65% yield) according to general procedure B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, CDCl3)δ(ppm) 11.9 (br. s, 1 H), 9.02 (s, 1 H), 7.94 (s, 1 H), 7.85 (s, 1 H), 6.95 (d, 2 H), 4.58 (s, 2 H), 2.14 (s, 3 H). LCMS [M+H] = 395.2 Compound I-35

[0400] [ka]

[0401] 8-(3,5-Difluoro-4-methylbenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-35) was synthesized as a white solid (83 mg, 62% yield) according to general procedure B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (such as ratio of reagents, temperature, and reaction time) were modified as necessary. 1H NMR (500 MHz, CDCl3)δ(ppm) 11.7 (br. s, 1 H), 9.02 (s, 1 H), 7.92 (s, 1 H), 7.83 (s, 1 H), 6.98 (d, 2 H), 6.81 (t, 1 H), 4.58 (s, 2 H), 2.15 (s, 3 H). LCMS [M+H] = 377.2 Compound I-36

[0402] [ka]

[0403] 4-(2-Fluorobenzyl)-1-methyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-1H-imidazo[4,5-c]pyridine (I-36) : The title compound was synthesized in three steps.

[0404] Phase 1: Synthesis of 6-chloro-4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine To a mixture containing bis(triphenylphosphine)palladium(II) dichloride (290 mg, 0.42 mmol), lithium chloride (350 mg, 8.3 mmol), and 4,6-dichloro-1-methyl-1H-imidazo[4,5-c]pyridine (840 mg, 4.2 mmol) in THF (2.0 mL) at ambient temperature, (2-fluorobenzyl)zinc(II) chloride (0.5 M solution in THF, 10 mL, 5.0 mmol) was added. The mixture was stirred at ambient temperature for 24 hours. The mixture was taken up in EtOAc (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give an oil. The crude material was purified using silica gel chromatography (0-80% EtOAc / hexanes gradient) to afford 6-chloro-4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine (1.0 g, 70% yield) as a yellow solid. 1 H NMR (500 MHZ, CDCl3)δ(ppm) 7.87 (s, 1 H), 7.63-7.79 (m, 1 H), 7.26 (br. s, 1 H), 7.12-7.19 (m, 1 H), 6.96-7.07 (m, 2 H), 4.60 (br. s, 2 H), 3.80 (s, 3 H). Phase 2: Synthesis of 4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine-6-carbonitrile A mixture containing zinc cyanide (850 mg, 7.3 mmol), tetrakis(triphenylphosphine)palladium(0) (420 mg, 0.36 mmol), and 6-chloro-4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine (1.0 g, 3.6 mmol) in DMF (18 mL) was heated to 100° C. for 24 h. The reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (100 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a solid. The crude material was purified using silica gel chromatography (0-100% EtOAc / hexanes gradient) to afford impure 4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine-6-carbonitrile (130 mg) as a white solid. 1 H NMR (500 MHz, CDCl3)δ(ppm) 8.08 (s, 1 H), 7.72 (s, 1 H), 7.65-7.71 (m, 1 H), 7.32 (m, 1 H), 6.98-7.09 (m, 2 H), 4.64 (s, 2 H), 3.92 (s, 3 H). Phase 3: Synthesis of 4-(2-fluorobenzyl)-1-methyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-1H-imidazo[4,5-c]pyridine (I-36) A mixture containing anhydrous hydrazine (0.092 mL, 2.9 mmol) and 4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine-6-carbonitrile (130 mg) in MeOH (2.5 mL) was stirred at ambient temperature for 24 hours. The mixture was concentrated under reduced pressure and azeotropically dried with MeOH and benzene. The resulting mixture was dissolved in DCM (10 mL) and treated with pyridine (0.24 mL, 2.9 mmol) and 2,2,2-trifluoroacetic anhydride (0.21 mL, 1.5 mmol). After stirring at ambient temperature for 2 hours, the reaction was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to yield an oil. The crude material was purified by preparative HPLC to give 4-(2-fluorobenzyl)-1-methyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-1H-imidazo[4,5-c]pyridine (6.3 mg, 0.47% yield over two steps) as a light brown solid. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 8.57 (s, 1 H), 8.41 (s, 1 H), 7.18-7.28 (m, 2 H), 6.97-7.12 (m, 2 H), 4.67 (s, 2 H), 4.04 (s, 3 H). LCMS [M+H] = 377.1 Compound I-72

[0405] [ka]

[0406] 8-(2-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[4,3-a]pyrazine (I-72) : The title compound was synthesized in three steps.

[0407] Phase 1: Synthesis of 6-bromo-8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine A solution of bis(triphenylphosphine)palladium(II) dichloride (62 mg, 0.088 mmol) and 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (410 mg, 1.8 mmol) in THF (5.9 mL) at ambient temperature was purged with argon for 5 minutes and treated with (2-fluorobenzyl)zinc(II) chloride (0.5 M solution in THF, 5.3 mL, 2.6 mmol). The mixture was stirred at 60 °C for 24 h. The reaction was quenched with saturated NH4Cl solution (15 mL) and extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified using reverse-phase HPLC (5–95% acetonitrile / water gradient with 0.1% formic acid) to afford 6-bromo-8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine (110 mg, 43% purity, contaminated with an undesired regioisomer, 9.1% yield) as a brown solid.

[0408] Phase 2: Synthesis of 8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine-6-carbonitrile A solid mixture containing zinc dust (4.7 mg, 0.072 mmol), zinc cyanide (63 mg, 0.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (29 mg, 0.036 mmol), and 6-bromo-8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine (110 mg, 43% purity, 0.15 mmol of the desired regioisomer and 0.21 mmol of the undesired regioisomer) was purged with nitrogen for 15 minutes and then dissolved in DMF (3 mL). The reaction was heated to 120 °C for 8 hours. The resulting mixture was partitioned between water (10 mL), brine (10 mL), and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified using silica gel chromatography (20-100% EtOAc / hexanes gradient) to afford 8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine-6-carbonitrile (24 mg, 61% yield) as a light tan solid.

[0409] Phase 3: Synthesis of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[4,3-a]pyrazine (I-72) A suspension of 8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine-6-carbonitrile (24 mg, 0.094 mmol) in anhydrous methanol (1.5 mL) was treated with sodium methoxide (19 μL, 9.4 μmol of a 0.50 N solution in methanol). After 3.5 h, anhydrous hydrazine (18 μL, 0.57 mmol) was added, and the reaction was stirred at ambient temperature for 23 h. The resulting mixture was concentrated, dried under reduced pressure, and then redissolved in DCM / THF (2 mL, 3:1 ratio). 2,2,2-trifluoroacetic anhydride (21 μL, 0.15 mmol) was added. After 40 min, the mixture was concentrated, dissolved in EtOH (2 mL) and acetic acid (0.2 mL), and heated at 90 °C for 15 h. The resulting solution was poured into water (10 mL), neutralized to pH 6 with saturated NaHCO3 solution, and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (20–90% EtOAc / hexanes gradient) to afford 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[4,3-a]pyrazine (1.4 mg, 4.1% yield) as a pale yellow film. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.43 (s, 1 H), 9.22 (s, 1 H), 7.47 (app. t, 1 H), 7.29 (m, 1 H), 7.13-7.08 (m, 2 H), 4.76 (s, 2 H). LCMS [M+H] = 364.2 Compound I-37

[0410] [ka]

[0411] 6-(2-Fluorobenzyl)-9-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-9H-purine I-37 : The title compound was synthesized in three steps.

[0412] Step 1: Synthesis of 2-chloro-6-(2-fluorobenzyl)-9-methyl-9H-purine A mixture containing bis(triphenylphosphine)palladium(II) dichloride (240 mg, 0.34 mmol), lithium chloride (290 mg, 6.8 mmol), and 2,6-dichloro-9-methyl-9H-purine (690 mg, 3.4 mmol) in THF (17 mL) at ambient temperature was treated with 2-fluorobenzylzinc(II) chloride (THF A 0.5 M solution in HCl (7.5 mL, 3.7 mmol) was added. The reaction was stirred at ambient temperature for 24 h. The resulting mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was dried over NaSO, filtered, and evaporated to yield an oil. The crude material was purified using silica gel chromatography (0-50% EtOAc / hexanes gradient) to afford 2-chloro-6-(2-fluorobenzyl)-9-methyl-9H-purine (620 mg, 66% yield) as a white solid. 1 H NMR (500 MHz, CDCl3)δ(ppm) 8.02 (s, 1 H), 7.37 (m, 1 H), 7.18-7.25 (m, 1 H), 7.02-7.10 (m, 2 H), 4.54 (s, 2 H), 3.88 (s, 3 H). Phase 2: Synthesis of 6-(2-fluorobenzyl)-9-methyl-9H-purine-2-carbonitrile A mixture containing zinc cyanide (530 mg, 4.5 mmol), tetrakis(triphenylphosphine)palladium(0) (260 mg, 0.22 mmol), and 2-chloro-6-(2-fluorobenzyl)-9-methyl-9H-purine (620 mg, 2.2 mmol) in DMF (12 mL) was heated to 100 °C for 24 h. The mixture was quenched with water (50 mL) and EtOAc (10 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (100 mL). The organic layer was dried over NaSO, filtered, and evaporated to yield an oil. The crude material was purified using silica gel chromatography (0–100% EtOAc / hexane gradient) to afford 6-(2-fluorobenzyl)-9-methyl-9H-purine-2-carbonitrile (490 mg, 82% yield) as a white solid. 1 H NMR (500 MHz, CDCl3)δ(ppm) 8.22 (s, 1 H), 7.39 (t, 1 H), 7.20-7.26 (m, 1 H), 7.01-7.12 (m, 2 H), 4.61 (s, 2 H), 3.95 (s, 3 H). Phase 3: Synthesis of 6-(2-fluorobenzyl)-9-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-9H-purine (I-37) A mixture containing anhydrous hydrazine (0.090 mL, 2.9 mmol) and 6-(2-fluorobenzyl)-9-methyl-9H-purine-2-carbonitrile (130 mg, 0.48 mmol) in MeOH (2.4 mL) was heated at 60° C. for 2 h. The mixture was concentrated under reduced pressure and azeotropically dried with MeOH and benzene. The resulting solid was dissolved in DCM (5.0 mL) and treated with pyridine (0.23 mL, 2.9 mmol) and 2,2,2-trifluoroacetic anhydride (0.20 mL, 1.4 mmol). After stirring at ambient temperature for 24 h, the reaction was diluted with DCM (100 mL) and washed with water (100 mL). The organic layer was dried over NaSO, filtered, and evaporated to yield an oil. The crude material was purified using silica gel chromatography (0-50% EtOAc / hexanes gradient) to recover the 2,2,2-trifluoro-N'-((6-(2-fluorobenzyl)-9-methyl-9H-purin-2-yl)(imino)methyl)acetohydrazide intermediate. The solid was combined with MeOH (1.0 mL) and a few drops of acetic acid. The resulting mixture was heated in a microwave at 120°C for 1 hour. The mixture was cooled to ambient temperature and concentrated under reduced pressure to provide 6-(2-fluorobenzyl)-9-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-9H-purine (25 mg, 14% yield) as a white solid. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 8.50-8.54 (m, 1 H), 7.28-7.41 (m, 1 H), 7.14-7.27 (m, 1 H), 6.97-7.12 (m, 2 H), 4.63 (s, 2 H), 4.01 (s, 3 H). LCMS [M+H] = 378.1 Compound I-38 and Compound I-39

[0413] [ka]

[0414] General procedure C:8-(2-Fluorobenzyl)-6-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyrazine (I-38) and 8-(2-Fluorobenzyl)-6-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-39) To a suspension of 8-(2-fluorobenzyl)-6-(3-methyl-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (69 mg, 0.22 mmol) and potassium carbonate (68 mg, 0.49 mmol) in DMF (3.0 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.050 mL, 0.31 mmol). After stirring at ambient temperature for 15 h, the reaction mixture was poured into a mixture of water and brine (1:2, 20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified using silica gel chromatography (20-100% EtOAc / hexanes gradient) to isolate 8-(2-fluorobenzyl)-6-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyrazine (I-38) (18 mg, 21% yield) as a pale yellow solid and 8-(2-fluorobenzyl)-6-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-39) (52 mg, 60% yield) as a pale yellow solid. Chemical structures are shown below. 1 Identification was performed using H NMR nOe experiments. In this case, a possible third regioisomer (usually only a trace amount) was not observed. Compound I-38: 1H NMR (500 MHz, DMSO-d6)δ(ppm) 9.19 (s, 1 H), 8.23 ​​(s, 1 H), 7.80 (s, 1 H), 7.34 (app. t, 1 H), 7.27 (m, 1 H), 7.17 (app. t, 1 H), 7.08 (app. t, 1 H), 5.34 (q, 2 H), 4.56 (s, 2 H), 2.53 (s, 3 H). LCMS [M+H] = 391.2 Compound I-39: 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 9.39 (s, 1 H), 8.30 (s, 1 H), 7.93 (s, 1 H), 7.48 (app. t, 1 H), 7.35 (m, 1 H), 7.21-7.15 (m, 2 H), 5.41 (q, 2 H), 4.64 (s, 2 H), 2.31 (s, 3 H). LCMS [M+H] = 391.2 Compound I-41 and Compound I-42

[0415] [ka]

[0416] 8-(2-Fluorobenzyl)-6-(1-(4-fluorobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyrazine (I-41) and 8-(2-fluorobenzyl)-6-(1-(4-fluorobenzyl)-3-methyl-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-42) were synthesized as solids (I-41: 1.3 mg, 3.9% yield, and I-42: 2.9 mg, 8.6% yield) according to General Procedure C, except that 1-(bromomethyl)-4-fluorobenzene was used as the alkylating agent. The reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. Compound I-41: 1H NMR (500 MHz, DMSO-d6)δ(ppm) 9.15 (s, 1 H), 8.21 (s, 1 H), 7.79 (s, 1 H), 7.32 (m, 3 H), 7.21 (m, 4 H), 7.08 (app. t, 1 H), 5.44 (s, 2 H), 4.54 (s, 2 H), 2.48 (s, 3 H). LCMS [M+H] = 417.3 Compound I-42: 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 9.34 (s, 1 H), 8.29 (s, 1 H), 7.91 (s, 1 H), 7.37 (app. t, 1 H), 7.20 (m, 1 H), 7.03 (m, 6 H), 5.61 (s, 2 H), 4.63 (s, 2 H), 2.25 (s, 3 H). LCMS [M+H] = 417.4 Compound I-47

[0417] [ka]

[0418] 8-(2-Fluorobenzyl)-6-(1-(3-fluorobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyrazine (I-47) was synthesized as a solid (4.2 mg, 12% yield) according to general procedure C, except that 1-(bromomethyl)-4-fluorobenzene was used as the alkylating agent. The other regioisomer was not isolated. Reaction conditions (such as ratios of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4) δ(ppm) 9.04 (s, 1 H), 8.11 (s, 1 H), 7.78 (s, 1 H), 7.38 (m, 1 H), 7.23 (m, 2 H), 7.06 (m, 5 H), 5.47 (s, 2 H), 4.65 (s, 2 H), 2.51 (s, 3 H). LCMS [M+H] = 417.4 Compound I-48

[0419] [ka]

[0420] 1-(3-(8-(2-Fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-methyl-1H-1,2,4-triazol-1-yl)-3,3-dimethylbutan-2-one was synthesized as a solid (7.6 mg, 23% yield) according to general procedure C, except that 1-bromo-3,3-dimethylbutan-2-one was used as the alkylating agent. The other regioisomer was not isolated. Reaction conditions (such as ratios of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 9.15 (s, 1 H), 8.22 (s, 1 H), 7.79 (s, 1 H), 7.32 (app. t, 1 H), 7.25 (m, 1 H), 7.17 (app. t, 1 H), 7.08 (app. t, 1 H), 5.54 (s, 2 H), 4.54 (s, 2 H), 2.31 (s, 3 H), 1.22 (s, 9 H). LCMS [M+H] = 407.4 Compound I-50

[0421] [ka]

[0422] 8-(2-Fluorobenzyl)-6-(1-(4-fluorobutyl)-5-methyl-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyrazine (I-50) was synthesized as a solid (0.9 mg, 2.8% yield) according to general procedure C, except that 1-bromo-4-fluorobutane was used as the alkylating agent. The other regioisomer was not isolated. Reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4)δ(ppm) 9.03 (s, 1 H), 8.14 (s, 1 H), 7.81 (s, 1 H), 7.26 (m, 2 H), 7.06 (m, 2 H), 4.67 (s, 2 H), 4.55 (t, 1 H), 4.45 (t, 1 H), 4.27 (t, 2 H), 2.56 (s, 3 H), 2.05 (m, 2 H), 1.77 (m, 2 H). LCMS [M+H] = 383.3 Compound I-51

[0423] [ka]

[0424] 3-((3-(8-(2-Fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-methyl-1H-1,2,4-triazol-1-yl)methyl)-5-methylisoxazole (I-51) was synthesized as a solid (4.1 mg, 13% yield) according to general procedure C, except that 3-(bromomethyl)-5-methylisoxazole was used as the alkylating agent. The other regioisomer was not isolated. Reaction conditions (such as ratios of reagents, temperature, and reaction time) were modified as necessary. 1H NMR (500 MHz, methanol-d4)δ(ppm) 9.05 (s, 1 H), 8.13 (s, 1 H), 7.80 (s, 1 H), 7.26 (m, 2 H), 7.08 (m, 1 H), 7.04 (m, 1 H), 6.20 (s, 1 H), 5.50 (s, 2 H), 4.66 (s, 2 H), 2.58 (s, 3 H), 2.42 (s, 3 H). LCMS [M+H] = 404.3 Compound I-53

[0425] [ka]

[0426] 6-(1-Ethyl-5-methyl-1H-1,2,4-triazol-3-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-53) was synthesized as a solid (3.0 mg, 11% yield) according to general procedure C, except that iodoethane was used as the alkylating agent. The other regioisomer was not isolated. Reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4)δ(ppm) 9.02 (s, 1 H), 8.13 (s, 1 H), 7.81 (s, 1 H), 7.25 (m, 2 H), 7.08 (m, 1 H), 7.04 (m, 1 H), 4.67 (s, 2 H), 4.26 (q, 2 H), 2.56 (s, 3 H), 1.50 (t, 3 H). LCMS [M+H] = 337.3 Compound I-54

[0427] [ka]

[0428] 8-(2-Fluorobenzyl)-6-(5-methyl-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyrazine (I-54) was synthesized as a solid (2.9 mg, 8.8% yield) according to general procedure C, except that 3-(bromo)-1,1,1-trifluoropropane was used as the alkylating agent. The other regioisomer was not isolated. Reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1 H NMR (500 MHz, methanol-d4)δ(ppm) 9.06 (s, 1 H), 8.14 (s, 1 H), 7.81 (s, 1 H), 7.25 (m, 2 H), 7.09 (m, 1 H), 7.04 (m, 1 H), 4.67 (s, 2 H), 4.49 (t, 2 H), 2.94 (m, 2 H), 2.57 (s, 3 H). LCMS [M+H] = 405.3 Compound I-56

[0429] [ka]

[0430] 6-(1-Butyl-5-methyl-1H-1,2,4-triazol-3-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-56) was synthesized as a solid (2.0 mg, 6.8% yield) according to general procedure C, except that 1-bromobutane was used as the alkylating agent. The other regioisomer was not isolated. Reaction conditions (e.g., ratio of reagents, temperature, and reaction time) were modified as necessary. 1H NMR (500 MHz, methanol-d4)δ(ppm) 9.02 (s, 1 H), 8.14 (s, 1 H), 7.80 (s, 1 H), 7.26 (m, 2 H), 7.08 (m, 1 H), 7.04 (m, 1 H), 4.67 (s, 2 H), 4.22 (t, 2 H), 2.55 (s, 3 H), 1.90 (app. quin, 2 H), 1.41 (m, 2 H), 1.00 (t, 3 H). LCMS [M+H] = 365.3 Compound I-57

[0431] [ka]

[0432] 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-3-amine (I-57): A suspension of S-methylisothiourea hemisulfate (510 mg, 1.8 mmol), 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboximide hydrazide (520 mg, 1.8 mmol), and sodium hydroxide (73 mg, 1.8 mmol) in water (8 mL) was heated to 120 °C for 60 min in a microwave oven. The reaction mixture was filtered using methanol as the eluent, and the resulting filtrate was concentrated to give the crude product. This material was purified by reverse-phase HPLC (12–37% acetonitrile / water gradient with 0.1% trifluoroacetic acid) to yield an orange oil, which was a mixture of two compounds (360 mg). This product mixture was used in the next reaction without further purification.

[0433] A small sample of this material was purified by reverse-phase HPLC (10–55% acetonitrile / water gradient with 0.1% formic acid) to afford 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-3-amine (I-57) (3.0 mg) as a white solid. 1H NMR (500 MHz, DMSO-d6)δ(ppm) 12.1 (br. s, 1 H), 8.92 (br. s, 1 H), 8.21 (s, 1 H), 7.77 (s, 1 H), 7.35 - 7.40 (m, 1 H), 7.25 - 7.29 (m, 1 H), 7.15 - 7.19 (m, 1 H), 7.06 - 7.11 (m, 1 H), 6.09 (s, 2 H), 4.53 (s, 2 H). LCMS [M+H] = 310.1 Compound I-58

[0434] [ka]

[0435] 1-(3-fluorobenzyl)-3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-5-amine (I-58): To a solution of crude 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-3-amine (360 mg) in DMF (4 mL) was added 1-(bromomethyl)-3-fluorobenzene (0.11 mL, 0.88 mmol), followed by potassium carbonate (210 mg, 1.6 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then heated to 50° C. for 24 h. The reaction mixture was cooled to ambient temperature, diluted with water (50 mL), and extracted with EtOAc (4×30 mL). The combined organic phases were dried over NaSO, filtered, and concentrated to give a brown residue. First pass purification of the crude product by silica gel chromatography yielded a mixture This material was purified by reverse-phase HPLC (10–60% acetonitrile / water gradient with 0.1% trifluoroacetic acid) to afford 1-(3-fluorobenzyl)-3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-5-amine (I-58) (6.9 mg) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6)δ(ppm) 9.01 (s, 1 H), 8.22 (s, 1 H), 7.81 (s, 1 H), 7.40 - 7.44 (m, 1 H), 7.30 - 7.34 (m, 1 H), 7.24 - 7.27 (m, 1 H), 7.12 - 7.18 (m, 2 H), 7.06 - 7.10 (m, 3 H), 6.78 (br. s, 2 H), 5.25 (s, 2 H), 4.52 (s, 2 H). LCMS [M+H] = 418.3 Compound I-59 and Compound I-60

[0436] [ka]

[0437] 3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-amine (I-59) and 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-amine (I-60). A suspension of crude 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-3-amine (550 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.30 mL, 2.2 mmol), and potassium carbonate (540 mg, 3.90 mmol) in DMF (4 mL) was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over NaSO, filtered, and concentrated to give a residue. First-pass purification was achieved by silica gel chromatography (0–100% EtOAc / hexanes gradient). A second purification using silica gel chromatography (0-50% acetonitrile / MeOH (7:1) gradient in DCM) afforded 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-amine (I-60) (40 mg) as a gold solid. Compound I-59 was detected in this campaign but was not isolated.

[0438] In a second campaign, crude 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-3-amine (330 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.18 mL, 1.3 mmol), and potassium carbonate (320 mg, 2.4 mmol) were combined in DMF (4 mL) to yield a similar product mixture. This mixture was purified using reverse-phase HPLC (10–55% acetonitrile / water gradient with 0.1% formic acid) to yield 3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-amine (I-59) (3.5 mg) as a white solid. Compound I-60: 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 9.19 (s, 1 H), 8.31 (d, 1 H), 7.92 (d, 1 H), 7.45 - 7.50 (m, 1 H), 7.30 - 7.36 (m, 1 H), 7.14 - 7.20 (m, 2 H), 5.64 (s, 2 H), 5.21 (q, 2 H), 4.62 (s, 2 H). LCMS [M+H] = 392.2 Compound I-59: 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 8.98 (s, 1 H), 8.22 (s, 1 H), 7.78 (s, 1 H), 7.30 - 7.34 (m, 1 H), 7.24 - 7.29 (m, 1 H), 7.15 - 7.19 (m, 1 H), 7.06 - 7.09 (m, 1 H), 6.76 (s, 2 H), 4.98 (q, 2 H), 4.43 (s, 2 H). The regiochemical assignment is 1 This was confirmed by H NMR nOe experiments (approximately 3% of nOe is C H 2CF3 proton and N H located between the two). LCMS [M+H] = 392.2 Compound I-62 and Compound I-63

[0439] [ka]

[0440] 6-(3-chloro-1H-1,2,4-triazol-5-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-62) and 6-(3-(1H-imidazo-1-yl)-1H-1,2,4-triazol-5-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-63). A solution containing 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboximide hydrazide (140 mg, 0.51 mmol) and 1,1'-carbonyldiimidazole (CDI) (410 mg, 2.5 mmol) in THF (4 mL) was stirred at ambient temperature for 40 hours. A tan suspension was observed. DCM / MeOH (60 mL, 1:1 ratio) was added, and the resulting mixture was slowly warmed to dissolve the solids. The crude mixture was concentrated and dried under reduced pressure. Phosphoryl trichloride (3.0 mL, 32 mmol) was added, and the resulting mixture was heated at 120 °C for 16 hours. The reaction mixture was concentrated, carefully treated with ice, and neutralized with saturated NaHCO solution. The crude mixture was extracted with DCM / isopropanol (5:1 ratio, 3 × 20 mL). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 to 25% acetonitrile / MeOH (7:1) in DCM) afforded the title compound I-62 (23 mg, 14% yield, first eluting product) as an off-white solid and I-63 (18 mg, 9.9% yield, second eluting by-product) as a light tan solid. Compound I-62: 1 H NMR (500 MHz, DMSO-d6)δ(ppm) 14.9 (s, 1 H), 9.31 (s, 1 H), 8.25 (s, 1 H), 7.85 (s, 1 H), 7.43 (app. t, 1 H), 7.27 (m, 1 H), 7.17 (app. t, 1 H), 7.09 (app. t, 1 H), 4.58 (s, 2 H). LCMS [M+H] = 329.2 Compound I-63: 1H NMR (500 MHz, DMSO-d6)δ(ppm) 14.8 (s, 1 H), 9.36 (s, 1 H), 8.32 (m, 2 H), 7. 86 (s, 1 H), 7.76 (s, 1 H), 7.43 (app. t, 1 H), 7.28 (m, 1 H), 7.20-7.15 (m, 2 H), 7.10 (app. t, 1 H), 4.60 (s, 2 H). LCMS [M+H] = 361.3 Compound I-64 and Compound I-65

[0441] [ka]

[0442] rac-6-(3-(2,2-difluorocyclopropyl)-1H-1,2,4-triazol-5-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-64) and 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-N,N-dimethyl-1H-1,2,4-triazol-3-amine (I-65). A solution of rac-2,2-difluorocyclopropane-1-carboxylic acid (89 mg, 0.70 mmol) in DMF (2.0 mL) was treated sequentially with HATU (400 mg, 1.0 mmol) and 4-methylmorpholine (0.23 mL, 2.1 mmol). The amber solution was stirred at ambient temperature for 30 minutes, after which 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboximide hydrazide (200 mg, 0.70 mmol) was added using 0.50 mL of DMF. After 18 hours, the reaction was diluted with EtOAc (100 mL) and water (50 mL). The aqueous layer was back-extracted with EtOAc (25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2,2-difluoro-N'-((8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)(imino)methyl)cyclopropane-1-carbohydrazide (400 mg, >99% yield) as a brown solid, which was used without further treatment. This intermediate was suspended in ethanol (10 mL) and acetic acid (1.0 mL). The reaction was heated at 90°C for 15.5 hours. The contents were concentrated under reduced pressure, and the resulting residue was purified twice by silica gel chromatography (20–10% EtOAc / hexanes gradient and 0–4% acetonitrile / MeOH (7:1) gradient in DCM) and repurified by reverse-phase HPLC (5–95% acetonitrile / water with 0.1% formic acid) to afford the title compound I-64 (51 mg, 19% yield, first eluting product) as a white solid and I-65 (20 mg, 8.5% yield, second eluting byproduct) as an off-white solid. Compound I-64: 1 H NMR (500 MHz, methanol-d4)δ(ppm) 9.12 (s, 1 H), 8.16 (s, 1 H), 7.83 (s, 1 H), 7.32 (m, 1 H), 7.25 (m, 1 H), 7.11-7.02 (m, 2 H), 4.67 (s, 2 H), 2.97 (m, 1 H), 2.17 (m, 1 H), 2.00 (m, 1 H). LCMS [M+H] = 371.2 Compound I-65: 1 H NMR (500 MHz, methanol-d4) δ (ppm) 9.08 and 8.98 (s, 1 H, tautomers), 8.13 and 8.10 (s, 1 H, tautomers), 7.87 and 7.77 (s, 1 H, tautomers), 7.36-7.16 (m, 2 H), 7.13-6.98 (m, 2 H), 4.64 (s, 2 H), 3.09 and 3.03 (s, 6 H, tautomers). LCMS [M+H] = 338.2 Compound I-66

[0443] [ka]

[0444] 8-(2-Fluorobenzyl)-3-iodo-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-66): A solution of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (99 mg, 0.27 mmol) in DMF (2.0 mL) was treated with N-iodosuccinimide (92 mg, 0.41 mmol) and heated at 60 °C for 40 h. The reaction mixture was concentrated and purified by silica gel chromatography (0-5% acetonitrile / MeOH (7:1) gradient in DCM) to afford the title compound (I-66) (130 mg, 96% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6)δ(ppm) 15.6 (s, 1 H), 8.79 (s, 1 H), 8.04 (s, 1 H), 7.41 (app. t, 1 H), 7.27 (m, 1 H), 7.18 (app. t, 1 H), 7.08 (app. t, 1 H), 4.62 (s, 2 H). LCMS [M+H] = 489.2 Compound I-67

[0445] [ka]

[0446] 3-chloro-8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-67): A solution of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (99 mg, 0.27 mmol) in DMF (2.0 mL) was treated with N-chlorosuccinimide (55 mg, 0.41 mmol) and heated at 60 °C for 24 h. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% acetonitrile / MeOH (7:1) gradient in DCM) to afford the title compound (I-67) (56 mg, 51% yield) as a white solid. H NMR (500 MHz, methanol-d) δ (ppm) 9.04 (s, 1 H), 7.88 (s, 1 H), 7.39 (app. t, 1 H), 7.26 (m, 1 H), 7.08 (m, 2 H), 4.70 (s, 2 H). LCMS [M+H] = 397.2 Compound I-68

[0447] [ka]

[0448] 3-Fluoro-8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-68) A solution of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (100 mg, 0.28 mmol) in acetonitrile (3.0 mL) was treated with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) (120 mg, 0.34 mmol) and heated at 70° C. for 6 h. An additional amount of Selectfluor® (60 mg, 0.17 mmol) was added and heating was continued at 70° C. for 3 h. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% acetonitrile / MeOH (7:1) gradient in DCM) to afford the title compound I-68) (10 mg, 9.4% yield) as a white solid. H NMR (500 MHz, methanol-d) δ (ppm) 8.96 (s, 1 H), 7.56 (d, 1 H), 7.39 (app. t, 1 H), 7.25 (m, 1 H), 7.08 (m, 2 H), 4.65 (s, 2 H). LCMS [M+H] = 381.2 Compound I-70

[0449] [ka]

[0450] 8-(2-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine-3-carbonitrile (I-70): A solid mixture consisting of 8-(2-fluorobenzyl)-3-iodo-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (49 mg, 0.10 mmol), zinc cyanide (18 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.7 mg, 5.0 μmol), and zinc powder (1.3 mg, 0.020 mmol) was flushed with nitrogen for 15 minutes. DMF (2 mL) was added, and the reaction was heated in a microwave oven at 120 °C for 7.5 hours, during which time additional amounts of palladium catalyst (3.7 mg) and zinc cyanide (24 mg) were added to drive the reaction. The crude mixture was cooled to ambient temperature, diluted with EtOAc (10 mL), and filtered through a bed of Celite with EtOAc (20 mL). The organic filtrate was washed with water / brine (2 × 10 mL, 10:1 ratio) and brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0–10% acetonitrile / MeOH (7:1) gradient in DCM) afforded the title compound I-70 as an off-white solid (15 mg, 38% yield). 1 H NMR (500 MHz, methanol-d4) δ (ppm) 9.23 (s, 1 H), 8.44 (s, 1 H), 7.41 (app. t, 1 H), 7.26 (m, 1 H), 7.10-7.05 (m, 2 H), 4.74 (s, 2 H). LCMS [M+H] = 388.3 Compound I-71

[0451] [ka]

[0452] 8-(2-Fluorobenzyl)-3-methyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-71): A solid mixture consisting of 8-(2-fluorobenzyl)-3-iodo-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (71 mg, 0.15 mmol), potassium carbonate (60 mg, 0.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) was flushed with nitrogen for 5 minutes. DME (3.5 mL) and water (0.5 mL) were added, followed by trimethylboroxine (37 μL), and the reaction was heated at 120 °C for 40 hours. The crude mixture was cooled to ambient temperature, poured into water (20 mL), and neutralized to pH 7 with 1 N HCl solution. The aqueous mixture was extracted with EtOAc (2 × 20 mL). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-40% EtOAc / hexanes gradient) and reverse-phase HPLC (30-80% acetonitrile / water gradient with 0.1% formic acid) afforded the title compound I-71 as a white solid (16 mg, 29% yield). 1 H NMR (500 MHz, methanol-d4) δ(ppm) 8.99 (s, 1 H), 7.66 (s, 1 H), 7.33 (app. t, 1 H), 7.24 (m, 1 H), 7.11-7.03 (m, 2 H), 4.67 (s, 2 H), 2.63 (s, 3 H) LCMS [M+H] = 377.2 Example 2a: Biological activity measurement with the cGMP GloSensor cell-based assay in a 384-well format

[0247] GloSensor TM 40F cGMP (Product No.: CS182801, Pr The activity of test compounds was evaluated using human embryonic kidney (HEK293) cells expressing omega. A luminescent biosensor (artificial luciferase) incorporated into these cells detects cGMP formed by compounds that stimulate the sGC enzyme, resulting in luminescence. Emits a gas.

[0453] cGMP GloSensor cells were cultured in fetal bovine serum (FBS, final 10 The day before the assay, cells were grown in a 50 μL volume of DMEM containing 10% FBS in a 384-well white flat-bottom plate coated with poly-D-lysine (Corning Cat. No. 35661) at 1.5 × 10 4 The cells were plated at a density of 1000 cells / well. The cells were incubated overnight at 37°C in a humidified chamber containing 5% CO2. The next day, the medium was removed and the cells were resuspended in 40 μL / well of GloSensor TM , and 2 mM (Promega catalog number E1291). Cells were treated at 25°C for 90 minutes to allow the substrate to equilibrate in the cells. Test compounds and diethylenetriamine NONOate (DETA-NONOate) were diluted to 3 mM (20x) in serum-free, CO2-independent medium and serially diluted in 4-fold dilutions to generate a 5-fold dose curve, from which 10 μL was added to the wells (x μM concentration for the test compound solution and 10 μM concentration for the DETA-NONOate solution; x is one of the following final concentrations: 30000 nM, 7500 nM, 1875 nM, 468.8 nM, 117.2 nM, 29.29 nM, 7.320 nM, 1.830 nM, 0.460 nM, 0.114 nM, and 0.029 nM).

[0454] For kinetic studies, Envision (Perkin Elmer) was immediately used. Luminescence was measured for 0.2 seconds per well using a 1000 Hz pulse generator. For endpoint SAR screening, data were collected after 55 minutes of incubation at room temperature.

[0455] Data were normalized to the high control using the following formula: 100×(sample−low control) (control) / (high control-low control), where the low control is the average of 16 samples treated with 1% DMSO and the high control is the average of 16 samples treated with 30 μM of compound Y, as shown below. For all compounds, 4-well plates were measured using GraphPad Prism software v.5. n=2. Data were fitted using a parametric fit (log(agonist) vs. response-variable slope). Absolute (Abs) EC 50 is interpolated from the curve fit and defined as the concentration at which a given compound elicits 50% of the high control response after data normalization as described above. Compounds that fail to elicit a 50% minimum response are reported as >30 μM. For compounds performed in duplicate or n replicates greater than duplicate, the results presented herein are the geometric mean of the several results obtained. Table 2a summarizes the results obtained for selected compounds of the present invention in this assay.

[0456] [ka]

[0457] [Table 8]

[0458] [Table 9]

[0459] Values ​​of sGC enzyme activity in HEK cells determined by GloSensor assay. (~) Code definition for values ​​of sGC enzyme activity, in which sGC enzyme activity is the absolute EC 50 Represented by: Abs EC 50 ≦100nM=A;100nM <Abs EC 50 ≦1000nM=B;1000nM <Abs EC 50= C. Compounds that fail to elicit a 50% minimal response are reported as >30 μM or ND. Example 2b: Biological activity measurement with the cGMP GloSensor cell-based assay in a 384-well format GloSensor TM The synergistic effect of test compounds with NO was evaluated using HEK293 cells expressing 40F cGMP (product number: CS182801, Promega). To determine the synergistic effect of test compounds with NO, multiple assays were performed using varying concentrations of test compounds and diethylenetriamine NONOate (DETA-NONOate). Test compounds and diethylenetriamine NONOate (DETA-NONOate or DETA-NO) were diluted to 3 mM (20x) in serum-free, CO2-independent medium and serially diluted in 4-fold dilutions to generate a 5-fold dose curve, from which 10 μL was added to the wells (x μM concentration for the test compound solution and y μM concentration for the DETA-NO solution; x is one of the following final concentrations: 30000 nM, 7500 nM, 1875 nM, 468.8 nM, 117.2 nM, 29.29 nM, 7.320 nM, 1.830 nM, 0.460 nM, 0.114 nM, and 0.029 nM, and y is final concentrations of: 30 μM, 10 μM, 3.33 μM, 1.11 μM, and 0 μM).

[0460] After analysis as described above, Table 2b summarizes the results obtained for compound I-1 at various DETA-NO amounts in this assay.

[0461] [Table 10]

[0462] Values ​​of sGC enzyme activity in HEK cells determined by GloSensor assay. (~) Code definition for values ​​of sGC enzyme activity, in which sGC enzyme activity is the absolute EC50 Represented by: Abs EC 50 ≦100nM=A;100nM <Abs EC 50 ≦1000nM=B;1000nM <Abs EC 50 = C. Compounds that fail to elicit a 50% minimal response are reported as >30 μM or ND.

[0463] As shown in Table 2b, compound I-1 synergizes with NO to stimulate sGC. Example 3: Biological activity measurement by cGMP neuronal cell-based assay Rat primary neurons were isolated from 18-day-old female Sprague-Dawley fetuses. The fetuses were collected in Hank's balanced salt solution (HBSS), and the brains were rapidly removed. The hippocampi were isolated and mechanically disrupted. Furthermore, the neurons were incubated at 37°C for 15 minutes in a Ca 2+ and Mg 2+ Tissue digestion was performed with a 0.25% (wt / vol) trypsin solution in HBSS without trypsin. After trypsinization, cells were washed and resuspended in neurobasal medium supplemented with 0.5 mM L-glutamine, 12.5 μM glutamic acid, 2% B-27, 100 U / mL penicillin, and 100 μg / mL streptomycin. Cells were plated at 4 × 10 wells in a poly-D-lysine-coated 384-well clear flat-bottom plate (Corning catalog number 354662). 4 The cells were plated at a density of 1000 cells / well. The cells were incubated at 37°C in a humidified chamber containing 5% CO for 6-7 days. The medium was removed and the cells were incubated with Ca 2+ and Mg 2+The cells were washed once with HBSS containing 0.5 mM IBMX and replaced with 40 μL of HBSS containing 0.5 mM IBMX and incubated for 15 minutes at 37°C. 10 μL of a 5x stock solution of test compound, including diethylenetriamine NONOate (DETA-NO), was added. The final concentration of DETA-NO was 30 μM. The cells were incubated for 20 minutes at 37°C. The medium was removed, and 50 μL of ice-cold 10% acetic acid was added and incubated for 60 minutes at 4°C. After centrifugation at 1000 x g for 5 minutes at 4°C to pellet cell debris, the supernatant was aspirated into a clean plate, and the samples were analyzed for cGMP content. The cGMP concentration was determined from each sample using LC-MS / MS.

[0464] Data were normalized to the high control using the following formula: 100×(sample−low control) (control) / (high control - low control), where the low control is the average of 15 samples treated with 1% DMSO and the high control is the average of 15 samples treated with 10 μM of a known sGC stimulator, Compound Y. All compounds were analyzed using GraphPad Prism software v.5. n=2. The data were fitted using a four-parameter fit (log(agonist) vs. response-variable slope). 50 is interpolated from the curve fit to determine whether a given compound is a high control The minimum response is defined as the concentration that elicits 50% of the responses. Compounds that fail to elicit a 50% minimum response are reported as >30 μM. For compounds that were run in duplicate or n replicates greater than two, the results presented herein are the geometric mean of the several results obtained. Table 3 summarizes the results obtained for selected compounds of the invention in this assay.

[0465] [Table 11]

[0466] Neuron-based cell assay: AbsEC 50 ≦100nM=A;100nM <AbsEC 50≦1000nM=B;1000nM <AbsEC 50 = C. Compounds that fail to elicit a 50% minimal response are reported as >30 μM or ND. Example 4: Rat cerebrospinal fluid (CSF) pharmacokinetic properties Protocol: PK in rats was determined after oral administration. Oral (PO) administration experiments Groups of six male Sprague-Dawley rats with indwelling catheters placed in the cisterna magna were used. The PO group received either 10 mg / kg or 1 mg / kg of compound formulated as a solution in PEG 400. The PO dose was administered by oral gavage and delivered to the stomach using a syringe and gavage tube. Following administration of the oral dose, the gavage tube was flushed with approximately 0.5 mL of water to ensure complete delivery of the entire dose.

[0467] Plasma samples were collected as follows: CSF and blood samples were collected 1 hour after dosing. Blood samples were collected after 1 hour, 2 hours, and optionally 4 hours. CSF samples (0.05 mL) were collected via an intracisternal catheter. Blood samples (0.25 mL) were collected via retroorbital sampling. These samples were kept on ice until processed for plasma. Blood samples were centrifuged at 3200 rpm for 5 minutes at approximately 5°C within 1 hour of collection. Plasma was transferred directly to 96-well plate tubes (0.125 mL). Stopper caps were placed on the tubes, and the tubes were frozen at approximately -70°C and stored until analysis. Plasma was collected and analyzed for the presence of compounds.

[0468] Compound Quantitation. The compounds and internal standards were extracted from plasma and CSF by precipitation. The samples were analyzed using liquid chromatography (LC) with tandem mass spectrometry detection (MS / MS) using electrospray ionization. The standard curve range was 1-1000 ng / mL. The results of the compounds described in this example in this assay are shown in Table 4a below (10 mg / kg dose) and in Tables 4b and 4c below (1 mg / kg dose). An example is shown in g).

[0469] Kp,uu is defined as the ratio of the concentrations of unbound drug in CSF to unbound drug in plasma. The unbound drug in plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction, which is determined by plasma protein binding. The CSF concentration is then divided by the free plasma concentration to determine Kp,uu (Di et al., J. Med. Chem., 56,2-12(2013)).

[0470] [Table 12]

[0471] [Table 13]

[0472] [Table 14]

[0473] Example 5: Canine cerebrospinal fluid (CSF) pharmacokinetic properties Protocol. PK in dogs was determined after oral administration. Groups of four male beagle dogs were Dogs were dosed at 1 mg / kg with compound formulated as a suspension in 1% HPMC E5, 0.2% Tween 80, and 0.5% MC in water. PO doses were administered by oral gavage in gelatin capsules and delivered to the stomach using a gavage tube. After administration of the oral dose, the gavage tube was flushed with approximately 10 mL of water to ensure complete delivery of the entire dose.

[0474] Plasma and CSF samples were collected as follows: CSF and blood samples were collected as follows: CSF samples (0.05 mL) were collected from the lumbosacral region (L4 / 5) by direct needle puncture at appropriate time points. Blood samples (0.25 mL) were collected from the cephalic vein. These samples were kept on ice until processed for plasma. Blood samples were centrifuged at 3200 rpm for 5 minutes at approximately 5°C within 1 hour of collection. Plasma was transferred directly to 96-well plate tubes (0.125 mL). Stopper caps were attached to the tubes, and the tubes were frozen at approximately -70°C and stored until analysis. Plasma was collected and analyzed for the presence of compound.

[0475] Compound Quantitation. Compounds of the invention and internal standards were quantified in plasma and CS by precipitation. The assay was performed using a 500-mg / kg aliquot of 1000 mg of ethanol (1 mg / kg) extracted from F. Samples were analyzed using liquid chromatography (LC) with tandem mass spectrometry detection (MS / MS) using electrospray ionization. The standard curve range was 1-1000 ng / mL. The results of the compounds described in this example in this assay are illustrated in Tables 5a and 5b (1 mg / kg) below.

[0476] Kp,uu is defined as the ratio of the concentrations of unbound drug in CSF to unbound drug in plasma. The unbound drug in plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction, which is determined by plasma protein binding. The CSF concentration is then divided by the free plasma concentration to determine Kp,uu (Di et al., J. Med. Chem., 56,2-12(2013)).

[0477]

[0261]

[0478] [Table 15]

[0479] [Table 16]

[0480] Example 6: Non-human primate (NHP) cerebrospinal fluid (CSF) pharmacokinetic properties Protocol: PK in NHPs was determined after intravenous and oral administration. In the (IV) administration experiment, groups of four male cynomolgus monkeys were used. The IV group received 10% P Compounds were administered at 0.3 mg / kg, formulated as solutions in EG-400, 20% Solutol HS 15 in 25% water, and 65% DPBS. IV doses were administered by injection and delivered via a catheter into the cephalic vein. For oral (PO) administration experiments, groups of four male cynomolgus monkeys were used. The PO group received 1% HPMC E5, 0.2% Compounds were administered at 1 mg / kg formulated as a suspension in Tween 80, 0.5% MC. The PO dose was administered by oral gavage and delivered in a gelatin capsule.

[0481] Plasma and CSF samples were collected as follows: CSF and blood samples were collected as follows: CSF samples (0.05 mL) were collected at 1, 4, and 24 hours after IV administration and 2, 8, and 24 hours after PO administration. CSF samples (0.05 mL) were collected from the cisterna magna (major site) or lumbosacral region (L4 / 5) by direct needle puncture at appropriate time points. Blood samples (0.25 mL) were collected from a peripheral vein. These samples were kept on ice until processed for plasma. Blood samples were centrifuged at 3200 rpm for 5 minutes at approximately 5°C within 1 hour of collection. Plasma was transferred directly to 96-well plate tubes (0.125 mL). Stopper caps were attached to the tubes, and the tubes were frozen at approximately -70°C and stored until analysis. Plasma was collected and analyzed for the presence of compound.

[0482] Compound Quantitation. Compounds of the invention and internal standards were quantified in plasma and CS by precipitation. The assay was performed using a 500-mg / mL ELISA kit (Table 1). The assay was performed using a 500-mg / mL ELISA kit (Table 2). The assay was performed using a 500-mg / mL ELISA kit (Table 3). The assay was performed using a 500-mg / mL ELISA kit (Table 4). The assay was performed using a 500-mg / mL ELISA kit (Table 5). The assay was performed using a 500-mg / mL ELISA kit (Table 6 ...

[0483] Kp,uu is defined as the ratio of the concentrations of unbound drug in CSF to unbound drug in plasma. The unbound drug in plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction, which is determined by plasma protein binding. The CSF concentration is then divided by the free plasma concentration to determine Kp,uu (Di et al., J. Med. Chem., 56,2-12(2013)).

[0484] [Table 17]

[0485] [Table 18]

[0486] Example 7: Rat cerebrospinal fluid (CSF) biomarker measurements This experiment measured the cGMP response as well as the compound concentration in rat CSF and rat The purpose was to determine the effect of various doses of a compound of the present invention on the concentration of the compound in plasma.

[0487]

[0268] Protocol. Each rat was treated with either a single dose or multiple doses with at least 3 days between each dose. I sampled it.

[0269] The day before the experiment: Rats were fasted overnight with water available ad libitum.

[0488]

[0270] On the day of the experiment, the compounds and cyclic guanosine monophosphate ( cGMP (cGMP) was determined after oral administration. Male Sprague-Dawley rats with an indwelling catheter placed in the cisterna magna were used. Rats were administered 0 mg / kg (n=15), 3 mg / kg (n=19), and 10 mg / kg (n=20) of a compound of the invention formulated as a suspension in 0.5% methylcellulose, 0.5% Tween 80. PO doses were administered by oral gavage and delivered to the stomach using a syringe and gavage tube. After administration of the oral dose, the gavage tube was flushed with approximately 0.5 mL of water to ensure complete delivery of the entire dose.

[0489] Plasma and CSF samples were collected under isoflurane anesthesia as follows: CS F samples were collected 1 and 6 hours after administration, and blood samples were collected 1 hour after administration. CSF samples were collected via an intracisternal catheter. Approximately 20 μL of CSF and waste (dead volume 14–16 μL) were then aspirated into an Eppendorf tube containing 5 μL of glacial acetic acid. CSF was flash-frozen by immersion in liquid nitrogen. Blood samples (0.25 mL) were collected via retroorbital sampling. These samples were kept on ice until processed for plasma. Blood samples were centrifuged at 3200 rpm for 5 minutes at approximately 5°C within 1 hour of collection. Plasma was transferred directly to 96-well plate tubes (0.125 mL). Stopper caps were attached to the tubes, which were frozen at approximately -70°C and stored until analysis. Plasma was collected and analyzed for the presence of compound.

[0490] Quantitation of Compounds and cGMP. Compounds of the present invention, cGMP and internal standards were determined by Extraction from plasma and CSF was performed by precipitation. Samples were analyzed using liquid chromatography (LC) with tandem mass spectrometry detection (MS / MS) using electrospray ionization. The standard curve range was 1-1000 ng / mL. Results for the compounds described in this example in this assay are illustrated in Table 7 below (3 and 10 mg / kg doses). Statistics were determined by planned comparisons using t-tests.

[0491] Kp,uu is defined as the ratio of the concentrations of unbound drug in CSF to unbound drug in plasma. The unbound drug in plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction, which is determined by plasma protein binding. The CSF concentration is then divided by the free plasma concentration to determine Kp,uu (Di et al., J. Med. Chem., 56,2-12(2013)).

[0492] [Table 19]

[0493] Conclusion: Acute oral administration of 3 mg / kg of compound I-1 in rats resulted in Acute oral administration of 10 mg / kg of compound I-1 to rats caused a significant increase in cGMP in rat CSF 1 and 6 hours after administration. Example 8: Evaluation of compounds of the present invention on impairment of synaptic transmission and plasticity in R6 / 2 mouse hippocampal slices Improved synaptic transmission and plasticity as measured by long-term potentiation (LTP) This is believed to indicate the potential of the compound for memory enhancement. LTP is an electrophysiological phenomenon generally referred to as the cellular phenomenon that drives learning and memory.

[0494]

[0276] Protocol. Preparation of acute mouse hippocampal slices. Experiments were performed at the Jackson Laboratory. The study was performed on 11-12-week-old R6 / 2 and WT mice provided by NIH (USA). Hippocampal slices (350 μm thick) were cut with a MacIlwain tissue chopper in ice-cold oxygenated sucrose solution (in mM: sucrose 250, glucose 11, NaHCO3 26, KCl 2, NaH2PO4 1.2, MgCl2 7, and CaCl2 0.5). The slices were incubated for 1 hour at room temperature in ACFS containing the following composition: glucose 11, NaHCO3 25, NaCl 126, KCl 3.5, NaH2PO4 1.2, MgCl2 1.3, and CaCl2 2. The slices were then allowed to recover for at least 1 hour.

[0495] Slice Perfusion and Temperature Control. During the experiment, slices were perfused at 3 mL / min using a peristaltic pump. The MEA chamber was continuously perfused with ACSF (bubbled with 95% O2-5% CO2) at a rate of 1 mL (MEA chamber volume: approximately 1 mL). Complete exchange of the solution in the MEA chamber was achieved 20 seconds after the solution switch. The perfusion solution was continuously preheated to 37°C just before reaching the MEA using a heated perfusion cannula (PH01, MultiChannel Systems, Reutlingen, Germany). The temperature of the MEA chamber was maintained at 37 ± 1°C with a heating element located in the headstage of the MEA amplifier.

[0496] Stimulation Protocol / Compound Application

[0280] Input / Output (I / O) curve: 100 to 800 μA in 100 μA increments. For short-term and long-term synaptic plasticity measurements, the stimulation intensity was set at a fixed value of 250 μA.

[0497] Short-term plasticity properties: As the interstimulus interval decreases (e.g., 300 ms, 200 Two pulses were administered (100 ms, 100 ms, 50 ms, 25 ms). For: fEPSPs were recorded for 10 min under control conditions (to ensure baseline stability), followed by 15 min of compound exposure (or 25 min of control slices in the presence of vehicle). A second I / O protocol and paired-pulse protocol were applied in the continued presence of compound, as described above.

[0498] Long-term potentiation (LTP): 10 min control period (compound and control slices) After 60 min of treatment (in the presence of vehicle for compound and control slices), LTP was induced with 10× TBS, after which potentiation of synaptic transmission was monitored for another 60 min (in the presence of vehicle for compound and control slices).

[0499]

[0283] Results

[0284] Comparison of R6 / 2 and WT mice. I / O characteristics were significantly different at higher stimulation intensities (700 and At 1000 μA and 800 μA, R6 / 2 hippocampal slices were significantly higher than WT littermates. Paired-pulse characteristics were in the same range in R6 / 2 and WT hippocampal slices, except for the 25 ms interstimulus interval, where facilitation was significantly greater in R6 / 2 mice. Long-term potentiation was significantly worse in hippocampal slices from R6 / 2 mice compared with age-matched WT mice (p<0.0001, two-way ANOVA).

[0500]

[0285] Evaluation of 7 nM compound I-1. In R6 / 2 hippocampal slices, all stimulation intensities However, I / O characteristics were not significantly altered after exposure to 7 nM compound I-1. In R6 / 2 mouse hippocampal slices, paired-pulse characteristics were also within the same range before and after exposure to 7 nM compound I-1, and no significant differences were observed for any of the ISIs. A 15-minute exposure to 7 nM compound I-1 did not alter fEPSP amplitude.

[0501] In WT mouse hippocampal slices (control condition), HFS stabilized at approximately 45%. In R6 / 2 mouse hippocampal slices (control condition), HFS resulted in an enhancement of evoked-response amplitude that stabilized at approximately 15% (fEPSP increased by 16±3% at the end point). After exposure to 7 nM compound I-1, HFS resulted in an enhancement of evoked-response amplitude that stabilized at approximately 25% (fEPSP increased by 26±6% at the end point). The enhancement observed after exposure to 7 nM compound I-1 was not significantly different from that recorded in control R6 / 2 slices (p-value <0.0842, two-way ANOVA) (Figure 1).

[0502]

[0287] Evaluation of Compound I-1 at 46 nm. In R6 / 2 hippocampal slices, all stimulation intensities The I / O characteristics of the fEPSPs were similar before and after exposure to 46 nM compound I-1. In R6 / 2 mouse hippocampal slices, there was no significant increase in paired-pulse characteristics after exposure to 46 nM compound I-1 for all ISIs. A 15-minute exposure to 46 nM compound I-1 did not alter fEPSP amplitude compared to control slices.

[0503] In WT mouse hippocampal slices (control condition), HFS stabilized at approximately 45%. In R6 / 2 mouse hippocampal slices (control condition), HFS resulted in an enhancement of evoked-response amplitude that stabilized at approximately 15% (fEPSP increased by 16±3% at the end point). After exposure to 46 nM compound I-1, HFS resulted in an enhancement of evoked-response amplitude that stabilized at approximately 45% (fEPSP increased by 44±12% at the end point). The enhancement observed after exposure to 46 nM compound I-1 was significantly greater than that recorded in control R6 / 2 slices (p=0.0065, two-way ANOVA) (Figure 2).

[0504] Evaluation of Compound I-1 at 308 nm. I / O characteristics recorded from R6 / 2 hippocampal slices. was not significantly increased after exposure to 308 nM of compound I-1 for all stimulus intensities. Paired-pulse response was significantly reduced in R6 / 2 mouse hippocampal slices after exposure to 308 nM compound I-1 only at an ISI of 50 ms. fEPSP amplitude was slightly increased during 15 min exposure to 308 nM compound I-1 compared with control R6 / 2 slices.

[0505] In WT mouse hippocampal slices (control condition), HFS stabilized at approximately 45%. HFS resulted in an enhancement of evoked-response amplitude (fEPSP increased by 46±5% at the end point). In R6 / 2 mouse hippocampal slices (control condition), HFS resulted in an enhancement of evoked-response amplitude that stabilized at approximately 15% (fEPSP increased by 16±3% at the end point). After exposure to 308 nM compound I-1, HFS resulted in an enhancement of evoked-response amplitude that stabilized at approximately 35% (fEPSP increased by 37±9% at the end point). The enhancement observed after exposure to 308 nM compound I-1 was significantly greater than that recorded in control R6 / 2 slices (p=0.0059, two-way ANOVA) (Figure 3).

[0506] Conclusion: The highest concentration of compound I-1 (308 nM) investigated significantly reduced the evoked response. Although compound I-1 slightly increased the amplitude of short-term plasticity, none of the three concentrations had a significant effect on the overall I / O properties in R6 / 2 mouse hippocampal slices. None of the evaluated compound concentrations (7 nM, 46 nM, or 308 nM) had a significant effect on short-term plasticity properties as measured by paired pulses at ISIs of 25 ms to 300 ms (except for compound I-1 at 308 nM, which significantly reduced paired-pulse facilitation at an ISI of 50 ms). Compound I-1 at 7 nM failed to significantly improve LTP impairment recorded in R6 / 2 mouse hippocampal slices, whereas this compound completely reversed LTP loss at concentrations of 46 nM and 308 nM. Example 9: Compound-induced cGMP in mouse brain Objective: The effect of different doses of the compounds of the present invention on cGMP response and the effect of different doses of the compounds of the present invention on the ... To determine the compound concentrations in various regions of the body (cortex, hippocampus, cerebellum and striatum) and the blood concentrations of the compound.

[0507] Protocol. Mice (n=7-8 per experimental condition) were given vehicle (1% hydrochloride). Mice were orally administered 0.3, 1, 3, or 10 mg / kg of compound I-1 prepared in 0.2% Tween 80, 0.5% methylcellulose (0.2% propyl methylcellulose) or vehicle. Thirty minutes after administration, mice were decapitated under isoflurane anesthesia, and the brains were removed and placed in ice-chilled Petri dishes containing mushy dissection solution (saturated with 95% O2 and 5% CO2). Using an ice-chilled spatula, the brains were transferred to a mouse brain matrix with coronal spaces for slicing at 1 mm intervals, as shown below (for schematic illustration only, not to scale):

[0508] [ka]

[0509] The sliced ​​brains were placed in a thick dissection solution (95 ml) containing 0.5 mM IBMX. The tissue was then placed back into a Petri dish containing 100% ethanol (saturated with 5% O2 / 5% CO2). The dorsal striatum was dissected first, followed by the hippocampus, the medial prefrontal cortex, and finally the cerebellum. After each region was dissected, the tissue was quickly placed in an Eppendorf flask that had been placed on dry ice for 30 minutes. The tissue pieces froze very quickly, within approximately 10 seconds. After all regions were placed in the Eppendorf flask, they were immersed in liquid nitrogen to freeze the tissue. The whole blood samples were then transferred to the trunk using a mitra tip. The tissue samples were stored at -80°C, and the MitraTips were stored at room temperature. cGMP and compound levels in the brain and blood were determined by LC / MS; protein quantification in brain samples was determined using a BCA protein assay kit.

[0510] Conclusion: Acute oral administration of 10 mg / kg of compound I-1 to mice resulted in the Significant increases in cGMP occurred in all mouse brain regions (hippocampus, cerebellum, cortex, and striatum) treated with cerebellar steroids (Table 9a-d).

[0511] [Table 20]

[0512] [Table 21]

[0513] [Table 22]

[0514] [Table 23]

[0515] Example 10. Novel Object Recognition (NOR) Test OBJECTIVE: The efficacy of the present invention in reversing memory impairment caused by MK-801 The efficacy of compounds is assessed using the novel object recognition (NOR) test in male Long Evans rats. The NOR is a test of recognition, learning, and memory retrieval that exploits rodents' spontaneous preference to examine familiar versus novel objects (Ennaceur and Delacour, 1988). Studies have included the NOR procedure in the perirhinal cortex (Ennaceur et al. 1996, 1997 and Aggleton et al. 1997) and hippocampus (Wood et al. 1993 and Clark et al. The NOR test has been shown to involve several brain regions, including the NMDA receptor (McGraw-Hill et al. 2000). The NOR test has been widely adopted to evaluate the potential cognitive-enhancing properties of novel compounds. Because the NOR paradigm does not involve rewarding or aversive stimuli, fewer confounding variables are introduced when translated into analogous tests used in human clinical trials. In this study, novel compounds were tested using a memory retention model—MK-801 (dizocilpine), a noncompetitive antagonist of the NMDA receptor, was used to induce a recognition memory deficit. Compounds of the present invention were evaluated for their efficacy in reversing memory impairment.

[0516]

[0297] Materials and Methods. Animals. Adult male Long-Evans rats (Indianapolis, Indianapolis, IN) were used. Animals weighing 275–299 grams upon arrival from Envigo, Illinois, were used in this study. Rats were placed in the experimental room and assigned unique identification numbers (tail marks). Rats were housed two per cage in polycarbonate cages with filter tops and allowed to acclimate for at least 7 days before testing. The animal room was maintained on a 12 / 12-hour light / dark cycle (lights on at 07:00 EST), at 22 ± 1°C, and approximately 50% relative humidity. Food and water were provided ad libitum. All animals were examined, acclimatized, and weighed prior to testing to ensure adequate health and minimize nonspecific stress associated with the study. Each animal was randomly assigned to a treatment group. Experiments were conducted during the animals' light phase of the cycle.

[0517] Test Compounds. The following compounds were used in this study: MK-80 (0.1 mg / kg; Sigma-Aldrich) in saline and injected intraperitoneally 15 min before NOR training.

[0518] Galantamine (1 mg / kg; Tocris) was dissolved in saline and administered to rats during training. The injection was given intraperitoneally 15 minutes before the administration. Compound I-1 (0.01, 0.1, and 1 mg / kg) was administered intravenously 60 minutes before training. The dose was administered orally at a volume of 4 mL / kg.

[0519]

[0303] Experimental Procedure. The NOR test was conducted in an open-field environment in a dimly lit, soundproof room. Tests were conducted in a door arena (40 x 40 cm). Each rat was tested separately, and care was taken to eliminate olfactory / gustatory cues by cleaning the arena and test objects with 70% alcohol between trials and between rats. All training and testing was videotaped and scored by an observer blinded to treatment.

[0520] On days 1 and 2, rats were left in the arena (object) for a 5-minute habituation period. On the third day (training and testing day), rats were administered vehicle (saline), galantamine, or compound solution, followed by MK-801 or vehicle (saline). After a pretreatment period, each animal was placed in a test arena containing two identical objects. Each rat was placed in the same location within the arena, facing the same direction, and the time spent actively exploring the objects during a 3-minute training period (T1) was recorded. After training, rats were returned to their home cages. The NOR test (T2) was conducted 1 hour after T1. Each rat was returned to the test arena containing one familiar object and one novel object for 5 minutes, and the time spent exploring both objects was recorded during time ranges of 0–1, 0–3, and 0–5 minutes. The presentation order and location (left / right) of the objects in T2 were randomized among rats to prevent bias due to order or location.

[0521] Statistical Analysis. Data from the NOR test (T2) were expressed as a cognitive index. The ratio of time spent exploring the novel object to the total time spent exploring both objects during the test period (novel / (familiar + novel) × 100%) was defined. Data were analyzed using one-way ANOVA followed by Fisher's LSD post hoc test, with significance set at p < 0.05 for the 0-1, 0-3, and 0-5 min time ranges separately. Animals whose overall object exploration time during the 5-min test period was less than 10 s were excluded; rats with a recognition index greater than 90% or less than 30% were also excluded, as this suggests a strong (non-memory) bias between the two objects. Statistical outliers exceeding or less than two standard deviations from the mean were removed from the final analysis. Using these criteria, one to three rats were excluded from each experimental group (N = 15–16) and excluded from statistical analysis for all time ranges (0-1, 0-3...

Claims

1. A compound represented by formula I or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 [In the formula: Substituent (J ｃ ) ｐ The core formed by rings E and A together has the following formula: 【Chemistry 2】 wherein the C atom marked with the symbol * represents the point of attachment to the ring containing G, Z and Q; the C atom marked with the symbol ** represents the point of attachment of the two J's; W is i) not present, J Ｂ is directly attached to a carbon atom bearing two J groups, each J being independently selected from hydrogen or methyl, n is 1, and J Ｂ is C, optionally substituted by up to 9 fluorines; １－７ is an alkyl chain; or ii) Ring B, which is a phenyl, a C 3-7 cycloalkyl ring, or a 5- or 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms; When Ring B is a phenyl, or a 5- or 6-membered heteroaryl ring: each J is independently selected from hydrogen or methyl; n is 0, 2, or 3; and each J Ｂ are independently halogen, -CN, C １－６ an aliphatic group, —OR B , or C ３－８ alicyclic rings; When Ring B is a C 3-7 cycloalkyl ring: each J is hydrogen; n is an integer selected from 0 to 3; and each J B is independently selected from halogen, —CN, a C 1-6 aliphatic group, or —OR B1 ; C １－６ Each J is an aliphatic group. Ｂ , and C ３－８ Each J is an alicyclic ring. Ｂ R ３ may be substituted with; Each R Ｂ is independently １－６ Aliphatic group or C ３－８ alicyclic rings; Ｂ R ３ａ may be substituted with; Each R Ｂ１ are independently hydrogen, C １－６ Aliphatic group or C ３－８ alicyclic rings; １－６ Each of the aliphatic groups, and ３－８ Each alicyclic ring may independently have up to three occurrences of R ３ｂ may be substituted with; Each R ３ , R ３ａ and R ３ｂ is, at each occurrence, independently, a halogen, —CN, C １－４ Alkyl, C １－４ Haloalkyl, —O(C １－４ alkyl) or -O(C １－４ haloalkyl); Each J Ｃ are independently hydrogen, halogen, C １－４ aliphatic group, C １－４ alkoxy or -CN; １－４ Aliphatic groups and C １－４ Alkoxy is independently selected from up to 3 C １－４ Alkoxy, C １－４ optionally substituted with haloalkoxy, -OH or halogen; Q, G and Z are each independently N, S or O, whereby at least two of Q, G and Z are N; q is 0, 1 or 2; R １０ R １５ C optionally substituted with １－６ alkyl, 0 to 3 independently occurring R １５ phenyl, which may be substituted with １５ 5- or 6-membered heteroaryl optionally substituted with １５ C optionally substituted with ３－８ cycloalkyl, or 0 to 3 independently occurring R １５ wherein each of said 5- or 6-membered heteroaryl and each of said 3- to 8-membered heterocyclyl contains up to three ring heteroatoms independently selected from N, O or S; R １１ is H, -NR ａ２ R ｂ２ , -C(O)NR ａ２ R ｂ２ , -C(O)R １５ａ , -SO ２ R ｂ２ , -SR ｂ２ , halo, -OCF ３ , -CN, hydroxyl, R independently present 0 to 2 ｂ２ C optionally substituted with ２－６ alkenyl, independently 0 to 2 R ｂ２ C optionally substituted with ２－６ Alkynyl; R independently occurring 0 to 5 times １５ C optionally substituted with １－６ alkyl, 0 to 5 independently occurring R １５ C optionally substituted with １－６ Alkoxy, R independently occurring 0-3 times １５ phenyl, which may be substituted with １５ 5-6 membered heteroaryl optionally substituted with １５ C optionally substituted with ３－８ cycloalkyl, or 0 to 3 independently occurring R １５ wherein each of said 5- to 6-membered heteroaryls and each of said 3- to 8-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O or S; or R １０ is a substituent of Z, R １０ and R １１ is Z, and R １１ Together with the carbon to which it is attached, there are independently 0 to 3 R １５ wherein each of said 3- to 10-membered heterocyclic rings contains up to three ring heteroatoms independently selected from N, O or S; R １５ is halo, -OR ｂ２ , -SR ｂ２ , -NR ａ２ R ｂ２ , -C(O)R ｂ２ , -C(O)NR ａ２ R ｂ２ , -NR ｂ２ C(O)OR ｂ２ , -OC(O)NR ａ２ R ｂ２ , C ２－４ alkenoxy, R independently occurring 0-3 times １８ C optionally substituted with ３－８ cycloalkyl, 0 to 3 independently occurring R １８ phenyl, which may be substituted with １８ or 0 to 3 independently occurring R １８ wherein each of said 5- or 6-membered heteroaryl rings and each of said 3- to 10-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O or S; R １５ａ R １８ C optionally substituted with ３－８ cycloalkyl, 0 to 3 independently occurring R １８ phenyl, which may be substituted with １８ or 0 to 3 independently occurring R １８ wherein each of said 5- or 6-membered heteroaryl rings and each of said 3- to 10-membered heterocyclyls contains up to three ring heteroatoms independently selected from N, O or S; Each R １８ are independently halo, hydroxyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ haloalkyl or phenyl; R ａ２ is hydrogen, -C(O)R ｂ２ , C １－６ Alkyl or C １－６ haloalkyl; and R ｂ２ is hydrogen, C １－６ Alkyl or C １－６ haloalkyl.

2. W is ring B and the compound has formula IIB: 【Chemistry 3】 [Rings B, G, J, and J in formula IIB] Ｂ , J Ｃ ,n,p,q,Q,R １０ , R １１ , X, Y, and Z are as defined in claim 1.

2. The compound of claim 1, which is represented by: or a pharma- ceutically acceptable salt thereof.

3. n is 2, and each J Ｂ are independently halogen, C １－４ Alkyl, -OR Ｂ Or -OR Ｂ１ 3. The compound of claim 2, selected from:

4. Each J Ｂ 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, wherein: are independently selected from halogen atoms.

5. Each J Ｂ 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from fluoro or chloro.

6. Each J Ｂ 6. The compound of claim 5, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

7. Each J Ｂ C １－４ 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

8. Each J Ｂ 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, wherein is selected from ethyl or methyl.

9. Each J Ｂ 9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

10. 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, wherein Ring B is phenyl.

11. n is 2, J Ｂ is ortho to the attachment of the methylene linker between ring B and the core of the molecule, and J Ｂ 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

12. J Ｂ 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

13. 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, wherein Ring B is a 6-membered heteroaryl ring.

14. 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein Ring B is a pyridyl ring or a pyrimidyl ring.

15. When W is absent, the compound has formula IIA: 【Chemistry 4】 [In the formula, J Ｂ is C, optionally substituted by up to 9 fluorines; １－７ G, J, and J in formula IIA are alkyl chains. Ｃ , p, q, Q, R １０ , R １１ , X, Y, and Z are as defined in claim 1.

2. The compound of claim 1, which is represented by: or a pharma- ceutically acceptable salt thereof.

16. J Ｂ C, optionally substituted by up to five fluorines １－２ 16. The compound of claim 15, or a pharma- ceutically acceptable salt thereof, which is an alkyl chain.

17. 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein G, Z and Q are each N.

18. The compound has the formula III: 【Chemistry 5】 [Rings B, J, and J of Formula III] Ｂ , J Ｃ , n, p, q, R １０ , R １１ , X, and Y are as defined in claim 1. or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 14, which is represented by: or a pharma- ceutically acceptable salt thereof.

19. R １１ But H, NR ａ２ R ｂ２ , -C(O)NR ａ２ R ｂ２ , -C(O)R １５ａ , -SO ２ R ｂ２ , -SR ｂ２ , halo, -OCF ３ , -CN, hydroxyl, R independently present 0 to 2 ｂ２ C optionally substituted with ２－６ alkenyl, independently 0 to 2 R ｂ２ C optionally substituted with ２－６ Alkynyl; R independently occurring 0 to 3 times １５ C optionally substituted with １－６ alkyl, 0 to 3 independently occurring R １５ C optionally substituted with １－６ Alkoxy, R independently occurring 0-3 times １５ phenyl, which may be substituted with １５ 5- or 6-membered heteroaryl optionally substituted with １５ C optionally substituted with ３－８ cycloalkyl, or 0 to 3 independently occurring R １５ 19. The compound according to any one of claims 1 to 18, which is a 3- to 8-membered heterocyclyl optionally substituted by: or a pharma- ceutically acceptable salt thereof.

20. R １１ R exists independently 0 to 3 times １５ C optionally substituted with １－６ 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof, wherein: R is 0 or 1;

21. R １１ R exists independently 0 to 3 times １５ 21. The compound of claim 20, wherein R is methyl, optionally substituted with R; or a pharma- ceutically acceptable salt thereof.

22. In each occurrence R １５ 22. The compound of claim 21 , or a pharma- ceutically acceptable salt thereof, wherein is halo.

23. In each occurrence R １５ 23. The compound of claim 22, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

24. R １１ Ga-CF ２ H; or a pharma- ceutically acceptable salt thereof.

25. R １１ Ga-CF ３ 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

26. 26. The compound of any one of claims 1 to 25, wherein q is 0; or a pharma- ceutically acceptable salt thereof.

27. J of each existence Ｃ The compound or medicament according to any one of claims 1 to 26, wherein is hydrogen. and (b) a commercially acceptable salt thereof.

28. The compound has formula V: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof. The compound of claim 1, [In the formula: Y is N or CH; Each J Ｂ are independently halo or C １－４ alkyl; n is 0, 2 or 3; R １１ is H, halo, -NR ａ２ R ｂ２ , C １－４ Alkyl, 5-6 membered heteroaryl, or C ３－６ Cycloalkyl, in which C １－４ Alkyl, 5-6 membered heteroaryl and C ３－６ Each cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo; R ａ２ is hydrogen or C １－４ is alkyl; and R ｂ２ is hydrogen or C １－４ is alkyl.

29. The compound has formula VI: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof. The compound of claim 1, [In the formula: Each J Ｂ are independently halo or C １－４ alkyl; n is 0, 2, or 3; R １１ is H, halo, -NR ａ２ R ｂ２ , C １－４ Alkyl, 5-6 membered heteroaryl, or C ３－６ Cycloalkyl, in which C １－４ Alkyl, 5-6 membered heteroaryl and C ３－６ Each cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo; R ａ２ is hydrogen or C １－４ is alkyl; and R ｂ２ is hydrogen or C １－４ is alkyl.

30. The compound is one of the following compounds: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 2. The compound of claim 1 selected from:

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient or carrier.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutical acceptable salt thereof, for use in a method of treating a disease, condition or disorder in a subject in need thereof, wherein the disease, condition or disorder is a disease, condition or disorder of the central nervous system (CNS) selected from: thing: Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Down's syndrome, dementia, vascular dementia, vascular cognitive impairment, Binswanger dementia (subcortical arteriosclerotic encephalopathy), autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CADASIL syndrome), frontotemporal lobar degeneration or dementia, HIV-associated dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment, MCI), glaucoma, Huntington's disease (or chorea, HD), multiple sclerosis (MS), multiple system atrophy (MSA), Parkinson's disease, parkinsonism plus, spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD); Neuropathic pain; - a psychiatric, mental, mood or affective disorder selected from bipolar disorder, schizophrenia, general psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depressive disorder, anxiety disorder, panic disorder, and post-traumatic stress disorder (PTSD); - traumatic (closed or open, penetrating head injury) or non-traumatic (stroke, aneurysm, hypoxia) injury to the brain, and cognitive impairment or dysfunction due to brain injury or neurodegenerative disease; -Dystonia and movement disorders; - disorders characterized by a relative decline in synaptic plasticity and synaptic processes, and autism spectrum disorders; and - Chemobrain, levodopa-induced addictive behavior, alcoholism, drug addiction, and substance abuse.

33. 31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutical acceptable salt thereof, for use in a method of treating a disease, condition or disorder in a subject in need thereof, wherein the disease, condition or disorder is selected from: - disorders associated with hypertension and reduced coronary blood flow, acute and chronic elevated coronary blood pressure, arterial hypertension, vascular disorders due to cardiac and renal complications, heart disease, stroke, cerebral ischemia, renal failure, resistant hypertension, diabetic hypertension, congestive heart failure, diastolic or systolic dysfunction, coronary insufficiency, arrhythmias, reduced ventricular preload, cardiac hypertrophy, heart failure / cardiorenal syndrome, portal hypertension, and endothelial dysfunction or damage; - thromboembolic disorders, ischemia, myocardial infarction, stroke, transient ischemic attack (TIA), thromboangiitis obliterans, stable or unstable angina, coronary artery spasm, variant angina, Prinzmetal angina, prevention of restenosis after thrombolytic therapy, and thrombogenic disorders; - a central nervous system disease, condition or disorder selected from the following: Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, dementia, vascular dementia, vascular cognitive impairment, Binswanger dementia, autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, frontotemporal lobar degeneration or dementia, HIV-associated dementia, dementia with Lewy bodies, presenile dementia, glaucoma, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, parkinsonism plus, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, attention deficit disorder and attention deficit hyperactivity disorder, Alzheimer's disease or pre-Alzheimer's disease, mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease, traumatic (closed or open, penetrating head injury) brain injury (TBI), non-traumatic (stroke, aneurysm, hypoxia) injury to the brain, cognitive impairment or dysfunction due to brain injury or neurodegenerative disease, disorders characterized by abnormalities in muscle tone, movement disorders, relative decline in synaptic plasticity and synaptic processes, autism spectrum disorder, neuropathic pain, bipolar disorder, schizophrenia, general psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder, depressive disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, chemobrain, levodopa-induced addictive behaviors, alcoholism, and narcotic dependence or substance abuse; - peripheral arterial disease, peripheral occlusive arterial disease, peripheral vascular disease, hypertonia, Raynaud's syndrome or phenomenon, critical limb ischemia, vasculitis, peripheral embolism, intermittent claudication, vaso-occlusive crisis, Duchenne muscular dystrophy, Becker muscular dystrophy, microcirculatory abnormalities, and control of vascular leakage or permeability; - shock, sepsis, cardiogenic shock, control of leukocyte activation, and inhibition or modulation of platelet aggregation; - pulmonary hypertension, pulmonary arterial hypertension, associated pulmonary vascular remodelling, focal thrombosis, right ventricular hypertrophy, pulmonary hypertonia, primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, multifactorial pulmonary arteriopathy, cystic fibrosis, bronchoconstriction or pulmonary bronchoconstriction, acute respiratory distress syndrome, pulmonary fibrosis, and lung transplantation; Pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, WHO Group I, II, III, IV and V hypertension, mitral valve disease, constrictive pericarditis, aortic valve stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous return, pulmonary veno-occlusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar hypoventilation, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, pulmonary embolism (due to tumor, parasite or foreign body), connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis, histiocytosis X, lymphangiomatosis and compressed pulmonary vessels; - atherosclerosis and inflammation; - metabolic syndrome-related cardiovascular disease, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis, pre-eclampsia, polycystic kidney disease progression, subcutaneous fat, and obesity; - chronic liver disease, liver fibrosis, hepatic stellate cell activation, hepatic fibrocollagen and total collagen accumulation-associated cirrhosis; necroinflammatory and / or immune-driven liver disease; renal fibrosis and failure due to chronic kidney disease or renal insufficiency; prostate hyperplasia; systemic sclerosis; cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; and nonalcoholic steatohepatitis or NASH; - Ischemia, reperfusion injury; ischemia / reperfusion associated with organ transplantation, lung transplantation, heart transplantation; and blood substitute maintenance in trauma patients; - erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction, vaginal atrophy, dyspareunia, atrophic vaginitis; benign prostatic hyperplasia (BPH) or hypertrophy or enlargement; bladder outlet obstruction; bladder pain syndrome (BPS), interstitial cystitis (IC), overactive bladder, neurogenic bladder and incontinence; and diabetic nephropathy; Glaucoma, retinopathy, diabetic retinopathy, blepharitis, dry eye syndrome, and Sjogren's syndrome; - hearing loss, partial or total hearing loss; partial or total deafness; tinnitus; and noise-induced hearing loss; - dermal fibrosis, scleroderma, and dermal fibrosis; - Improved microvascular perfusion, anal fissures, diabetic ulcers; and - Cancer metastasis, osteoporosis, gastroparesis; functional dyspepsia; diabetic complications, diseases associated with endothelial dysfunction, neuropathies associated with decreased nitric oxide production, achalasia or esophageal achalasia.

34. 33. The pharmaceutical composition of claim 32, wherein the dystonia is selected from generalized, focal, segmental, sexual, intermediate, acute dystonia response, and hereditary / primary dystonia; or the movement disorder is selected from acute, chronic / late-onset, and non-motor and levodopa-induced movement disorders (LID).

35. Disorders characterized by a relative decline in synaptic plasticity and synaptic processes 34. The pharmaceutical composition of claim 32 or 33, wherein the disorder is selected from fragile X, Rett syndrome, Williams syndrome, and Rempenning syndrome.

36. 34. The pharmaceutical composition of claim 32 or 33, wherein the autism spectrum disorder is selected from autism, Asperger's syndrome, pervasive developmental disorder and childhood disintegrative disorder.

37. 34. The pharmaceutical composition of claim 32 or 33, wherein the narcotic addiction is selected from amphetamine addiction and opiate addiction.

38. 34. The pharmaceutical composition of claim 33, wherein the atherosclerosis is associated with endothelial injury, platelet or monocyte adhesion or aggregation, smooth muscle proliferation or migration.

39. 34. The pharmaceutical composition according to claim 33, wherein the restenosis is restenosis occurring after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) or bypass surgery.

40. The pharmaceutical composition of claim 33, wherein the cardiovascular disease associated with metabolic syndrome is selected from obesity, dyslipidemia, diabetes, and hypertension.

41. 34. The pharmaceutical composition of claim 33, wherein the renal fibrosis and renal failure resulting from chronic kidney disease or renal insufficiency is due to accumulation / deposition and tissue damage, progressive sclerosis, or glomerulonephritis.

42. 34. The pharmaceutical composition of claim 33, wherein improving microvascular perfusion combats inflammatory responses after injury and in perioperative care.

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