Fused bicyclic sgc stimulators

Abstract

The present invention relates to fused bicyclic sGC stimulators. More specifically, the present invention relates to stimulators of the soluble guanylate cyclase (sGC), pharmaceutical formulations comprising them and their use, alone or in combination with one or more other agents, for the treatment of various diseases, wherein for the treatment of said diseases it is desirable to increase the concentration of nitric oxide (NO) or to increase the concentration of cyclic guanosine monophosphate (cGMP) or to increase the concentration of both or to upregulate the NO-pathway. The compounds have the formula I:

Description

[0001] This application is a divisional application of Chinese invention application (Invention title: SGC stimulant, application date: September 1, 2017; application number: 201780059390.1; international application number: PCT / US2017 / 049834).

[0002] Related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 382,942, filed September 2, 2016; U.S. Provisional Application No. 62 / 423,445, filed November 17, 2016; U.S. Provisional Application No. 62 / 468,598, filed March 8, 2017; and U.S. Provisional Application No. 62 / 482,486, filed April 6, 2017, pursuant to 35 U.S. SC § 119(e). The entire contents of each of the foregoing applications are incorporated herein by reference. Technical Field

[0004] This invention relates to stimulants of soluble guanylate cyclase (sGC), pharmaceutical preparations containing them, and their uses, said stimulants alone or in combination with one or more other pharmaceutical agents for the treatment of a variety of diseases, wherein, in relation to the treatment of the disease, it is desirable that the concentration of nitric oxide (NO) is increased or the concentration of cyclic 3',5'-monophosphate guanosine (cGMP) is increased or both are increased or the NO pathway is upregulated. Background Technology

[0005] Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in the body. sGC can be activated through both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts 5'-guanosine triphosphate (GTP) into a secondary messenger ring GMP (cGMP). The increased cGMP levels subsequently regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels.

[0006] In vivo, NO is synthesized from arginine and oxygen via various nitric oxide synthases (NOS) and through the continuous reduction of inorganic nitrates. Three distinct NOS isoforms have been identified: inducible NOS (iNOS or NOS II) found in activated macrophages; constitutive neuronal NOS (nNOS or NOS I) involved in neurotransmission and long-term enhancement; and constitutive endothelial NOS (eNOS or NOS III) regulating smooth muscle relaxation and blood pressure. Experimental and clinical evidence suggests that reduced concentrations, bioavailability, and / or reactivity of endogenously produced NO contribute to disease progression.

[0007] NO-independent, heme-dependent sGC stimulants possess several important distinguishing features compared to other types of sGC regulators, including their activity being highly dependent on the presence of a reduced heme cofactor, strong coenzyme activation when combined with NO, and stimulation of cGMP synthesis through direct sGC stimulation independent of NO. The benzylindazole compound YC-1 was the first sGC stimulant identified. Subsequently, other sGC stimulants with improved potency and specificity for sGC have been developed.

[0008] Compounds that stimulate sGC in a NO-independent manner offer significant advantages over other current alternative therapies targeting aberrant NO pathways or diseases for which upregulation of the NO pathway is beneficial. There is a need to develop novel sGC stimulators. These compounds could be used to treat a variety of diseases or conditions where sGC stimulation or an increase in the concentration of nitric oxide (NO) or cyclic 3',5'-guanosine monophosphate (cGMP) or both is desired, or where upregulation of the NO pathway is the desired disease or condition. Summary of the Invention

[0009] This invention relates to compounds of formula I or pharmaceutically acceptable salts thereof.

[0010]

[0011] in:

[0012] Rings E and A form the core of the molecule and are aromatic; X and Y are independently selected from N or C each time they appear; at most four of X and Y are N at the same time;

[0013] W is

[0014] i) does not exist, and J B Directly attached to a carbon atom with two J groups, each J independently selected from hydrogen or methyl, where n is 1 and J B C can be substituted with up to 9 fluorine atoms. 1-7 Alkyl chain; or

[0015] ii) Ring B, which is a phenyl group, C 3-7 Cycloalkyl rings or 5- or 6-membered heteroaryl rings containing 1 or 2 cyclic nitrogen atoms;

[0016] Wherein, 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 an integer selected from 0 to 3; and each J B Independently selected from halogens, -CN, C 1-6 aliphatic, -OR B Or C 3-8 Alicyclic rings; and

[0017] Where ring B is C 3-7In the case of cycloalkyl rings, each J represents hydrogen; n is an integer selected from 0 to 3 and each J B Independently selected from halogens, -CN, C 1-6 aliphatic or -OR B1 ;

[0018] Each of them is C 1-6 aliphatic J B and each for C 3-8 J of alicyclic rings B Optional and independently controlled by up to 3 Rs 3 Replaced;

[0019] Each R B Selected independently from C 1-6 aliphatic or C 3-8 Alicyclic ring; the R B Optional and independently controlled by up to 3 Rs 3a Replaced;

[0020] Each R B1 Independently selected from hydrogen, C 1-6 aliphatic or C 3-8 Alicyclic ring; wherein the C 1-6 Each of the aliphatic groups and the C 3-8 Each of the alicyclic rings is arbitrarily and independently bounded by at most 3 Rs. 3b Replaced;

[0021] Each R 3 R 3a and R 3b In each case, it is independently selected from halogen, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, -O(C) 1-4 alkyl) or -O(C 1-4 (Halogenated alkyl);

[0022] p is an integer selected from 1, 2, or 3;

[0023] Each J C Independently selected from hydrogen, halogen, C 1-4 aliphatic, C 1-4 alkoxy or -CN; wherein each of the C 1-4 Aliphatic and C 1-4 The alkoxy group is optionally and independently bound by at most 3 carbon atoms. 1-4 Alkoxy, C 1-4 Substituted with a haloalkoxy group, -OH, or halogen;

[0024] Q, G, and Z are each independently N, S, or O, wherein at least two of Q, G, and Z are N;

[0025] q is 0, 1, or 2;

[0026] R 10 To be arbitrarily and independently controlled by 0-3 R 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 15 The substituted 5 or 6 heteroaryl group is optionally and independently replaced by 0-3 R groups. 15 Replacement C 3-8 Cycloalkyl or optionally and independently marked with 0-3 R 15 Substituted 3-8 membered heterocyclic groups; wherein each of the 5- to 6-membered heteroaryl rings and each of the 3- to 8 membered heterocyclic groups contains up to 3 cyclic heteroatoms independently selected from N, O or S;

[0027] R 11 H, -NR a2 R b2 -C(O)NR a2 R b2 -C(O)R 15a -SO2R b2 -SR b2 Halogen, -OCF3, -CN, hydroxyl, optionally and independently determined by 0-2 R b2 Replacement C 2-6 Alkenyl group, optionally and independently bound by 0-2 R groups b2 Replacement C 2-6 Alkyne group; optionally and independently bounded by 0-3 R groups 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-5 R groups. 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 15 The substituted 5 to 6 heteroaryl groups are optionally and independently replaced by 0 to 3 R groups. 15 Replacement C 3-8 Cycloalkyl or optionally and independently marked with 0-3 R 15 Substituted 3-8 membered heterocyclic groups; wherein each of the 5- to 6-membered heteroaryl groups and each of the 3- to 8-membered heterocyclic groups contains at most 3 independently selected cyclic heteroatoms chosen from N, O, or S; or

[0028] When R 10 When Z is substituent, R 10 and R 11 With Z and R 11 The carbon atoms bonded together form optional and independent groups of 0-3 R atoms. 15Substituted 3-10 membered heterocycles; wherein each of the 3-10 membered heterocycle groups contains at most 3 cyclic heteroatoms independently selected from N, O or S;

[0029] R 15 For halogen, -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 Alkenyl groups, optionally and independently bound by 0-3 R groups 18 Replacement C 3-8 cycloalkyl, optionally and independently bound by 0-3 R 18 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 18 The substituted 5 or 6 heteroaryl group or optionally and independently replaced by 0-3 R groups 18 Substituted 3-10 membered heterocyclic groups; wherein each of the 5- or 6-membered heteroaryl rings and each of the 3- to 10 membered heterocyclic groups contains at most 3 cyclic heteroatoms independently selected from N, O or S;

[0030] R 15a To be arbitrarily and independently controlled by 0-3 R 18 Replacement C 3-8 cycloalkyl, optionally and independently bound by 0-3 R 18 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 18 The substituted 5 or 6 heteroaryl group or optionally and independently replaced by 0-3 R groups 18 Substituted 3-10 membered heterocyclic groups; wherein each of the 5- or 6-membered heteroaryl rings and each of the 3- to 10 membered heterocyclic groups contains at most 3 cyclic heteroatoms independently selected from N, O or S;

[0031] Each R 18 Independently selected from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or phenyl;

[0032] R a2 For hydrogen, -C(O)R b2 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; and

[0033] Rb2 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0034] The present invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient or carrier. The present invention further relates to pharmaceutical formulations or dosage forms comprising the pharmaceutical composition.

[0035] The present invention also provides a method for treating or preventing a disease, health condition or ailment of a subject in need, comprising administering to the subject, alone or in combination therapy, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; wherein the disease is one that benefits from sGC stimulation or from increased concentrations of NO or cGMP or both or from upregulation of the NO pathway. Attached Figure Description

[0036] Figure 1 This is a graph showing the long-term enhancement of hippocampal sections from wild-type (WT) mice (top curve), R6 / 2 mice (bottom curve), and R6 / 2 mice treated with 7 nM compound I-1 (middle curve).

[0037] Figure 2 This is a long-term enhancement graph of hippocampal sections from wild-type (WT) mice (top curve, overlapping with the middle curve), hippocampal sections from R6 / 2 mice (bottom curve), and hippocampal sections from R6 / 2 mice treated with 46 nM compound I-1 (middle curve, overlapping with the top curve).

[0038] Figure 3 This is a long-term enhancement graph of hippocampal sections from wild-type (WT) mice (top curve, overlapping with the middle curve), hippocampal sections from R6 / 2 mice (bottom curve), and hippocampal sections from R6 / 2 mice treated with 308 nM compound I-1 (middle curve, overlapping with the top curve).

[0039] Figure 4 The images show brain images of rats treated with peripherally restricted sGC stimulants (left) and rats treated with the compounds of this invention (right).

[0040] Figure 5 This image shows the brain being transferred to the mouse brain matrix with coronal spacing using an ice-cold scraper, sliced ​​at 1mm intervals. Invention Details

[0041] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the appended structures and formulas. Although the invention will be described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents included within the scope of the invention as defined by the claims. The invention is not limited to the methods and materials described herein, but includes any similar or equivalent methods and materials that can be used in the practice of the invention. If any of the included references, patents, or similar materials differ from or contradict this application (including, but not limited to, defined terminology, usage of terms, described techniques, etc.), this application shall prevail.

[0042] Definitions and General Terms

[0043] For the purposes of this invention, the chemical elements were determined according to the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition. th Ed., Smith, MB and March, J., eds. John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0044] As described herein, compounds of Formula I may optionally be substituted with one or more substituents, as such in the general description below, or as exemplified by the specific categories, subclasses, and species of the invention. The phrase “optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “substituted” means that one or more hydrogen groups in a given structure are substituted with a particular substituent. Unless otherwise stated, an optionally substituted group may have a substituent at each substituted 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 stated. The term “optionally and independently” may be used to describe this situation. As an example, one substituent disclosed herein is R. 10 Among other options, it can be chosen independently by 0-3 R's. 15 Replacement C 1-6 Alkyl group. In this case, C 1-6 Alkyl groups can be "optionally substituted": they may be unsubstituted (i.e., 0 R groups). 15 ) or be replaced (i.e., 1, 2 or 3 Rs)15 When R 15 When it occurs multiple times (e.g., twice), each R 15 These can be the same substituent (e.g., two fluorine atoms) or different substituents (e.g., -OH and chlorine). It will be apparent to those skilled in the art that groups such as -H, halogen, -NO2, -CN, -OH, -NH2, or -OCF3 are not substituted groups.

[0045] As used herein, the phrase "at most" means 0 or any integer value equal to or less than the value following the phrase. For example, "at most 3" means any one of 0, 1, 2, or 3. As described herein, the specified range of the number of atoms includes any integer within this range. For example, a group having 1-4 atoms may have 1, 2, 3, or 4 atoms. A group having 0-3 atoms may have 0, 1, 2, or 3 atoms. When any variable appears more than once in any position, its definition for each occurrence is independent of the other occurrences.

[0046] The selection of substituents and combinations included in this disclosure is limited to those that result in the formation of stable or chemically viable compounds. These selections and combinations are readily apparent to those skilled in the art and can be determined without extensive experimentation. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to the conditions under which it is produced, detected, and, in some embodiments, recovered, purified, and used for one or more purposes disclosed herein. In some embodiments, a stable compound is one that remains substantially unchanged after being kept at 25°C or lower under conditions free from moisture or other chemical reactions for at least one week. A chemically viable compound is one that can be prepared by those skilled in the art based on the disclosure herein and, if necessary, supplemented with relevant knowledge in the art.

[0047] Compounds (such as those of Formula I or Table I disclosed herein, or other compounds) may exist in their free form (e.g., amorphous, crystalline, or polymorphic). Under certain conditions, compounds may also form co-forms. As used herein, the term co-form is synonymous with the term multi-component crystalline form. Salt formation depends on the difference in pKa between the mating bodies forming the mixture. For the purposes of this invention, compounds may include pharmaceutically acceptable salts even if the term "pharmaceutically acceptable salt" is not explicitly stated.

[0048] Unless specifically drawn or named only one isomer, the structures described herein also imply all stereoisomers (e.g., enantiomers, diastereomers, trans-block isomers, and cis-trans isomers) of that structure; for example, R and S configurations for each asymmetry center, Ra and Sa configurations for each asymmetry axis, (Z) and (E) double bond configurations, and cis and trans configuration isomers. Therefore, single stereochemical isomers of the enantiomers, diastereomers, and cis-trans isomers (double bond or conformation) of the compounds of the present invention, as well as racemates and mixtures thereof, are within the scope of the present invention. Unless otherwise stated, all tautomer forms of the compounds of the present invention are also within the scope of the present invention.

[0049] This invention also includes isotopically labeled compounds, which are identical to those described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. All isotopes of any particular atom or element specified are included within the scope of the compounds of this invention and their uses. Exemplary isotopes that may be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, respectively. 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 I. Certain isotope-labeled compounds of the present invention (e.g., using...) 3 H and 14 Those labeled with C can be used in the determination of compound and / or substrate tissue distribution. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are useful due to their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., prolonged half-life or reduced dose requirement) and may therefore be preferred in some cases. Positron-emitting isotopes (e.g.) 15 O、 13 N、 11 C and 18F) These compounds can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of this invention can generally be prepared by replacing the non-isotopically labeled reagents with isotopically labeled reagents, following methods similar to those disclosed in the schemes and / or examples below.

[0050] As used herein, the terms "aliphatic," "aliphatic group," or "aliphatic chain" mean a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units. Unless otherwise specified, an aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-8 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-3 or 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, or ynyl groups. Specific examples of aliphatic groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propynyl, ethynyl, etc. Aliphatic groups will be represented by the term "C". x-y "Aliphatic" means that x and y are the minimum and maximum number of carbon atoms that form an aliphatic chain.

[0051] As used herein, the term "alkyl" (as in "alkyl chain" or "alkyl group") refers to a saturated straight-chain or branched monovalent hydrocarbon group. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl (s-butyl), tert-butyl, pentyl, hexyl, heptyl, octyl, etc. Alkyl groups will be indicated by the term "C". x-y "alkyl" indicates the minimum and maximum number of carbon atoms in the alkyl chain formed by x and y.

[0052] The term "alkenyl" (as in "alkenyl chain" or "alkenyl group") refers to a group having at least one unsaturated site (i.e., carbon-carbon sp). 2Alkenyl groups are straight-chain or branched monovalent hydrocarbon groups (with double bonds), wherein the alkenyl group 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, etc. The term "alkenyl" will be used with respect to the carbon group. x-y "Alkenyl" indicates that x and y are the minimum and maximum number of carbon atoms that form an alkenyl chain.

[0053] The term "alkynyl" (as in "alkynyl chain" or "alkynyl group") refers to a straight-chain or branched monovalent hydrocarbon group having at least one unsaturated site (i.e., a carbon-carbon sp triple bond). Unless otherwise specified, alkynyl 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, ethynyl, propynyl, etc. The alkynyl group will be indicated by the term "C". x-y "Alkyne" indicates that x and y are the minimum and maximum number of carbon atoms that form an alkynyl chain.

[0054] The term "carbocyclic ring" refers to a ring system consisting only of carbon and hydrogen atoms. Unless otherwise stated, throughout this specification, "carbocyclic ring" is used as a synonym for "non-aromatic carbocyclic ring" or "alicyclic ring." In some cases, the term may be used in the phrase "aromatic carbocyclic ring," in which case it will refer to "aryl" as defined below.

[0055] The term "alicyclic" (or "non-aromatic carbocyclic", "non-aromatic carbocyclic group", "non-aromatic carbocyclic", or "alicyclic ring") refers to a cyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, and has a single connection point to the rest of the molecule. In one embodiment, the term "alicyclic" refers to a monocyclic C 3-12 Hydrocarbons. Alicyclic rings will be referred to by the term "C". x-y "Alicyclic" indicates a group of alicyclic compounds; where x and y are the minimum and maximum number of carbon atoms required to form an alicyclic ring. Suitable alicyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of alicyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norcamphenyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

[0056] As used herein, "cycloalkyl" or "cycloalkyl ring" refers to a ring system that is fully saturated and has a single connection point with the rest of the molecule. In one embodiment, the term "cycloalkyl" refers to a monocyclic C16 ring. 3-12Saturated hydrocarbons. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, norcamphenyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The cycloalkyl ring will be indicated by the term "C". x-y "Cycloalkyl" indicates that x and y are the minimum and maximum number of carbon atoms that form a cycloalkyl ring.

[0057] As used herein, a "heterocycle" (or "heterocyclic group," "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 unsaturated units but is not aromatic, and has a single connection point with the rest of the molecule. Unless otherwise stated, through this disclosure, "heterocycle" is used as a synonym for "non-aromatic heterocycle." In some cases, the term may be used in the phrase "aromatic heterocycle," and in this case it will refer to "heteroaryl" as defined below. In some embodiments, the heterocycle has 3-10 ring members, one or more of which are heteroatoms independently selected from oxygen or nitrogen. In other embodiments, the heterocycle may be a monocycle having 3-7 ring members (2-6 carbon atoms and 1-4 heteroatoms).

[0058] Examples of heterocycles include, but are not limited to, the following monocyclic compounds: 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-tetrahydropiperazinyl, 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-thiazolyl, 3-thiazolyl, 4-thiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl.

[0059] The term "heteroaryl" (or "heteroaryl group," "aromatic heterocycle," or "heteroaryl ring"), used alone or as part of a larger portion of "heteroarylalkyl" or "heteroarylalkoxy," refers to an aromatic ring containing one or more heteroatoms, having 5 to 6 ring members, and sharing a single connection point with 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-iso... azole group, 4-iso azole group, 5-iso azole group, 2- azole group, 4- azole, 5- Azolyl, 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- Diazolyl, 1,2,5- Diazolyl, 1,2,4- Diazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl.

[0060] The term "cyclic atom" refers to an atom that is part of an aromatic ring, alicyclic ring, heterocyclic ring, or heteroaryl ring, such as C, N, O, or S. A "substitutable cyclic atom" is a cyclic carbon or nitrogen atom bonded to at least one hydrogen atom. Hydrogen may optionally be substituted with suitable substituents. Therefore, the term "substitutable cyclic atom" does not include cyclic nitrogen or carbon atoms shared when two rings are fused. Additionally, when the structure describes that they are already attached to one or more parts other than hydrogen and no hydrogen is available for substitution, "substitutable cyclic atom" does not include cyclic carbon or nitrogen atoms.

[0061] "Heteroatom" refers to one or more of oxygen, sulfur, and nitrogen, including any oxidized form of nitrogen or sulfur, any quaternized form of basic nitrogen, or substituted nitrogen in a heterocyclic or heteroaryl ring, such as N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrroleyl groups).

[0062] In some embodiments, two independently occurring substituents may form a 5-8 membered aryl or heteroaryl ring or a 3-8 membered alicyclic or heterocyclic ring together with the atom to which each substituent is bonded. Exemplary rings formed when two independently occurring substituents form a ring together with the atom to which each substituent is bonded include, but are not limited to: a) two independently occurring substituents bonded to the same atom and forming a ring together with that atom, wherein the presence of the two substituents together with the atom to which they are bonded forms a heterocyclic, heteroaryl, alicyclic, or aryl ring, wherein the group is connected to the remainder of the molecule via a single connection point; and b) two independently occurring substituents bonded to different atoms and forming a heterocyclic, heteroaryl, alicyclic, or aryl ring together with two of those atoms, wherein the formed ring has two connection points to the remainder of the molecule.

[0063] It should be understood that two independently occurring substituents can form multiple other rings together with the atoms to which each substituent is attached, and the examples detailed above are not limiting.

[0064] As described herein, a bond drawn from the substituent to the center of one ring within a polycyclic system (as shown below) represents the substitution of the substituent at any substituted position in any ring within the polycyclic system. For example, equation D3 represents the possible substitution at any position shown in equation D4:

[0065]

[0066] This also applies to polycyclic systems fused with optional ring systems (which will be indicated by dashed lines). For example, in equation D5, X is an optional substituent for both ring A and ring B.

[0067]

[0068] However, if the two rings in a polycyclic system each have different substituents drawn from the center of each ring, then unless otherwise specified, each substituent represents only the substitution on the ring to which it is attached. For example, in formula D6, Y is only an optional substituent of ring A, and X is only an optional substituent of ring B.

[0069]

[0070] As used herein, the term "alkoxy" refers to an alkyl group as previously defined, which is attached to a molecule or another chain or ring by an oxygen ("alkoxy", i.e., -O-alkyl) atom.

[0071] As used in this article, the terms "halogen" or "halogenated" refer to F, Cl, Br, or I.

[0072] The terms "haloalkyl," "haloalkenyl," "haloaliphatic," and "haloalkoxy" refer to alkyl, alkenyl, aliphatic, or alkoxy groups, which, depending on the case, can be substituted with one or more halogen atoms. For example, C 1-3 The haloalkyl group can be -CFHCH2CHF2, and C 1-2 The haloalkoxy group can be -OC(Br)HCHF2. This term includes perfluorinated alkyl groups, such as -CF3 and -CF2CF3.

[0073] As used in this article, the term "cyano" refers to -CN or -C≡N.

[0074] The terms "cyanoalkyl," "cyanoalkenyl," "cyanoaliphatic," and "cyanoalkoxy" refer to, as the case may be, an alkyl, alkenyl, aliphatic, or alkoxy group that may be substituted with one or more cyano groups. For example, C 1-3 Cyanoalkyl groups can be -C(CN)2CH2CH3, and C 1-2Cyanoolefin can be

[0075] =CHC(CN)H2.

[0076] As used in this article, "amino" refers to -NH2.

[0077] The terms "aminoalkyl," "aminoalkenyl," "aminoaliphatic," and "aminoalkoxy" refer, as the case may be, an alkyl, alkenyl, aliphatic, or alkoxy group that can be substituted with one or more amino groups. For example, C 1-3 The aminoalkyl group can be -CH(NH2)CH2CH2NH2, and C 1-2 The aminoalkoxy group can be -OCH2CH2NH2.

[0078] The term "hydroxyl" or "hydroxyl" refers to -OH.

[0079] The terms "hydroxyalkyl," "hydroxyalkenyl," "hydroxyaliphatic," and "hydroxyalkoxy" refer to alkyl, alkenyl, aliphatic, or alkoxy groups that, depending on the context, can be substituted with one or more -OH groups. For example, C 1-3 The hydroxyalkyl group can be -CH2(CH2OH)CH3, and the C4 hydroxyalkoxy group can be -OCH2C(CH3)(OH)CH3.

[0080] As used herein, “carbonyl”, whether used alone or in combination with another group, refers to -C(O)- or -C(O)H. For example, “alkoxycarbonyl” as used herein refers to a group such as -C(O)O (alkyl).

[0081] As used herein, “oxogroup” refers to =O, where the oxogroup is typically, but not always, attached to a carbon atom (e.g., it may also be attached to a sulfur atom). Aliphatic chains may optionally be interrupted by a carbonyl group or optionally substituted by an oxogroup, and both expressions refer to the same case: e.g., -CH2-C(O)-CH3. When “oxogroup” is listed as a possible substituent on a ring or another part or group (e.g., an alkyl chain), it should be understood that the bond between the oxygen in the oxogroup and the ring or part to which it is attached will be a double bond, even though it may sometimes be drawn with a single line. For example, in the examples described below, the J attached to the ring... D It can be selected from multiple different substituents. When J D When it is an oxygen group, J should be understood. D The bond between the ring and the ring is a double bond. When J D When it is halogen, J should be understood. DThe bond between the oxo group and the ring is a single bond. In some cases, such as when the ring is unsaturated or has aromatic characteristics, the compound can exist in two or more possible tautomer forms. In one, the bond between the oxo group and the ring will be a double bond. In another, hydrogen bonds are exchanged between the atom and the substituent in the ring, such that the oxo group becomes a hydroxyl group and another double bond is formed in the ring. Although the compound is described as D7 or D8, both will be used to represent the set of all possible tautomers of that particular compound.

[0082] For example

[0083] For example

[0084]

[0085] For example

[0086] In all other cases, as used herein, "linking group" refers to a divalent group in which the two free valences are on different atoms (e.g., carbon or heteroatoms) or on the same atom but can be substituted by two different substituents. For example, methylene can be a C1 alkyl linking group (-CH2-) which can be substituted by two different groups, one group replacing one free valence (e.g., in Ph-CH2-Ph, where methylene acts as a linking group between two benzene rings). Ethylene can be a C2 alkyl linking group (-CH2CH2-) in which the two free valences are on different atoms. Acylamino groups can be used as linking groups, for example, 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. When a compound is referred to by both its chemical structure and chemical name and the chemical structure conflicts with the chemical name, the chemical structure determines the properties of the compound.

[0087] Compound implementation plan

[0088] This invention relates to compounds of formula I or pharmaceutically acceptable salts thereof.

[0089]

[0090] in:

[0091] Rings E and A form the core of the molecule and are aromatic; X and Y are independently selected from N or C each time they appear; at most four of X and Y are N at the same time;

[0092] W is

[0093] i) does not exist, and J BDirectly attached to a carbon atom with two J groups, each J independently selected from hydrogen or methyl, where n is 1 and J B C can be substituted with up to 9 fluorine atoms. 1-7 Alkyl chain; or

[0094] ii) Ring B, which is a phenyl group, C 3-7 Cycloalkyl rings or 5- or 6-membered heteroaryl rings containing 1 or 2 cyclic nitrogen atoms;

[0095] Wherein, 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 an integer selected from 0 to 3; and each J B Independently selected from halogens, -CN, C 1-6 aliphatic, -OR B Or C 3-8 Alicyclic rings; and

[0096] Where ring B is C 3-7 Cycloalkyl ring; each J is hydrogen; n is an integer selected from 0 to 3 and each J B Independently selected from halogens, -CN, C 1-6 aliphatic or -OR B1 ;

[0097] Each of them is C 1-6 aliphatic J B and each for C 3-8 J of alicyclic rings B Optional and independently controlled by up to 3 Rs 3 Replaced;

[0098] Each R B Selected independently from C 1-6 aliphatic or C 3-8 Alicyclic ring; the R B Optional and independently controlled by up to 3 Rs 3a Replaced;

[0099] Each R B1 Independently selected from hydrogen, C 1-6 aliphatic or C 3-8 Alicyclic ring; wherein the C 1-6 Each of the aliphatic groups and the C 3-8 Each of the alicyclic rings is arbitrarily and independently bounded by at most 3 Rs. 3b Replaced;

[0100] Each R 3 R 3a and R 3b In each case, it is independently selected from halogen, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, -O(C)1-4 alkyl) or -O(C 1-4 (Halogenated alkyl);

[0101] p is an integer selected from 1, 2, or 3;

[0102] Each J C Independently selected from hydrogen, halogen, C 1-4 aliphatic, C 1-4 alkoxy or -CN; wherein each of the C 1-4 Aliphatic and each of the C 1-4 The alkoxy group is optionally and independently bound by at most 3 carbon atoms. 1-4 Alkoxy, C 1-4 Substituted with a haloalkoxy group, -OH, or halogen;

[0103] Q, G, and Z are each independently N, S, or O, wherein at least two of Q, G, and Z are N;

[0104] q is 0, 1, or 2;

[0105] R 10 To be arbitrarily and independently controlled by 0-3 R 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 15 The substituted 5 or 6 heteroaryl group is optionally and independently replaced by 0-3 R groups. 15 Replacement C 3-8 Cycloalkyl or optionally and independently marked with 0-3 R 15 Substituted 3-8 membered heterocyclic groups; wherein each of the 5- to 6-membered heteroaryl rings and each of the 3- to 8 membered heterocyclic groups contains up to 3 cyclic heteroatoms independently selected from N, O or S;

[0106] R 11 H, -NR a2 R b2 -C(O)NR a2 R b2 -C(O)R 15a -SO2R b2 -SR b2 Halogen, -OCF3, -CN, hydroxyl, optionally and independently determined by 0-2 R b2 Replacement C 2-6 Alkenyl group, optionally and independently bound by 0-2 R groups b2 Replacement C 2-6 Alkyne group; optionally and independently bounded by 0-5 R groups 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 Replacement C1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 15 The substituted 5 or 6 heteroaryl group is optionally and independently replaced by 0-3 R groups. 15 Replacement C 3-8 Cycloalkyl or optionally and independently marked with 0-3 R 15 Substituted 3-8 membered heterocyclic groups; wherein each of the 5- to 6-membered heteroaryl groups and each of the 3- to 8-membered heterocyclic groups contains at most 3 independently selected cyclic heteroatoms chosen from N, O, or S; or

[0107] When R 10 When R is a substituent of Z, 10 and R 11 With Z and R 11 The carbon atoms bonded together form optional and independent groups of 0-3 R atoms. 15 Substituted 3- to 10-membered heterocycles; wherein each of the 3- to 10-membered heterocycle groups contains at most 3 independent cyclic heteroatoms selected from N, O, or S;

[0108] R 15 Halogen, -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 Alkenyl groups, optionally and independently bound by 0-3 R groups 18 Replacement C 3-8 cycloalkyl, optionally and independently bound by 0-3 R 18 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 18 The substituted 5 or 6 heteroaryl group or optionally and independently replaced by 0-3 R groups 18 Substituted 3-10 membered heterocyclic groups; wherein each of the 3-10 membered heterocyclic groups contains at most 3 independent cyclic heteroatoms selected from N, O or S;

[0109] R 15a To be arbitrarily and independently controlled by 0-3 R 18 Replacement C 3-8 cycloalkyl, optionally and independently bound by 0-3 R 18 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 18The substituted 5 or 6 heteroaryl group or optionally and independently replaced by 0-3 R groups 18 Substituted 3-10 membered heterocyclic groups; wherein each of the 5- or 6-membered heteroaryl rings and each of the 3- to 10 membered heterocyclic groups contains at most 3 cyclic heteroatoms independently selected from N, O or S;

[0110] Each R 18 Independently selected from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or phenyl;

[0111] R a2 For hydrogen, -C(O)R b2 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; and

[0112] R b2 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0113] In some embodiments of Formula I, W is absent and the compound is one of Formula IIA or a pharmaceutically acceptable salt thereof:

[0114]

[0115] J B C can be substituted with up to 9 fluorine atoms. 1-7 Alkyl chain. In some embodiments of formula IIA, J B C can be optionally substituted with up to 5 fluorine atoms. 1-4 Alkyl chain. In other embodiments, J B C can be optionally substituted with up to 5 fluorine atoms. 1-2 Alkyl chain. In other cases, J B The ethyl chain is optionally substituted with 3 or 5 fluorine atoms.

[0116] In some embodiments of Formula I, W is ring B and the compound is one of Formula IIB or a pharmaceutically acceptable salt thereof:

[0117]

[0118] In some implementations of Formula IIB, n is an integer selected from 1 or 2, and each J B Independently selected from halogens, C 1-4 Alkyl, -OR B or -OR B1 In other implementations, each J B Independently selected from halogen atoms. In other embodiments, each JB Independently selected from fluorine or chlorine. In other embodiments, each J B It is fluorine.

[0119] In some implementations of Formula IIB, each J B C 1-4 Alkyl. In some of these embodiments, J B It is ethyl or methyl. In some embodiments, J B It is a methyl group.

[0120] In some implementations of Formula IIB, n is 0.

[0121] In some implementations of Formula IIB, n is 1.

[0122] In some implementations of Equation IIB, n is 1 and J B Independently selected from halogens, C 1-4 Alkyl, -OR B or -OR B1 In some of these implementation schemes, J B It is a halogen. In some implementations, J B It is chlorine or fluorine. In other embodiments, J B It is fluorine. In other embodiments, J B C 1-4 Alkyl group. In other embodiments, J B It can be methyl or ethyl.

[0123] In some implementations of Equation IIB, n is 2 and each J B For halogen atoms. In some of these embodiments, each J B Independently selected from chlorine or fluorine. In other embodiments, a J B It is fluorine and another J B For chlorine. In other embodiments, each J B It is fluorine.

[0124] 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 is the number of links between the methylene linker and the molecular core. B In the adjacent position, and J B It is a halogen. In some of these embodiments, J B It is chlorine. In other embodiments, J B It is fluorine.

[0125] 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.

[0126] In some implementations of formula IIB, ring B is C. 3-7 Cycloalkyl rings.

[0127] In some implementations of Formula I, Formula IIA, or Formula IIB, G, Z, and Q are each N.

[0128] In some embodiments of Formula I or Formula IIB, the compound is one of Formula III or a pharmaceutically acceptable salt thereof or any of its tautomers:

[0129]

[0130] In some embodiments of Formulas I, IIA, IIB and III, R 11 For H, NR a2 R b2 -C(O)NR a2 R b2 -C(O)R 15a -SO2R b2 -SR b2 Halogen, -OCF3, -CN, hydroxyl, optionally and independently determined by 0-2 R b2 Replacement C 2-6 Alkenyl group, optionally and independently bound by 0-2 R groups b2 Replacement C 2-6 Alkyne group; optionally and independently bounded by 0-5 R groups 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 Substituted phenyl groups, optionally and independently, are substituted with 0-3 R groups. 15 The 5 or 6 heteroaryl members are replaced, and are optionally and independently replaced by 0-3 R groups. 15 Replacement C 3-8 Cycloalkyl or optionally and independently marked with 0-3 R 15 The 3-8 member heterocyclic group is replaced. In some other embodiments, R 11 H or arbitrarily and independently controlled by 0-5 R 15 Replacement C 1-6 Alkyl group. In some other embodiments, R 11 For any 0-5 R values 15 Replacement C 1-6 Alkyl group. In some other embodiments, R 11For any 0-3 Rs 15 Substituted methyl group. In some other embodiments, R 11 For any 0-3 Rs 15 Substituted methyl group, and R 15 It is a halogen (e.g., fluorine). In some other embodiments, R 11 For any 0-3 Rs 15 Substituted methyl group, and R 15 It is fluorine. In some other embodiments, R 11 The methyl group is unsubstituted. In some other embodiments, R 11 For being 2 R 15 Substituted methyl group. In some other embodiments, R 11 For being 2 R 15 Substituted methyl and R 15 It is a halogen. In some other embodiments, R 11 For -CF2H. In some implementations, R 11 For being 3 R 15 Substituted methyl groups. In some embodiments, R 11 For being 3 R 15 Substituted methyl and R 15 It is a halogen. In some implementations, R 11 It is -CF3.

[0131] In some embodiments of Formulas I, IIA, IIB and III, R 11 For 0-5 R 15 Substituted ethyl group. In some other embodiments, R 11 For being 5 R 15 Substituted ethyl and R 15 It is a halogen. In some other embodiments, R 11 For being 5 R 15 Substituted ethyl and R 15 It is fluorine.

[0132] In some implementations of Equation III, n is an integer selected from 1 or 2, and each J B Independently selected from halogens, C 1-4 Alkyl, -OR B or -OR B1 In other implementations, each J B Independently selected from halogen atoms. In other embodiments, each J B Independently selected from fluorine or chlorine. In other embodiments, each J B It is fluorine.

[0133] In some implementations of Equation III, each JB C 1-4 Alkyl. In some of these embodiments, J B It is ethyl or methyl. In some embodiments, J B It is a methyl group.

[0134] In some implementations of Equation III, n is 0.

[0135] In some implementations of Equation III, n is 1.

[0136] In some implementations of Equation III, n is 1 and each J B Independently selected from halogens, C 1-4 Alkyl, -OR B or -OR B1 In some of these implementation schemes, J B It is a halogen. In some implementations, J B It is chlorine or fluorine. In other embodiments, J B It is fluorine. In other embodiments, J B C 1-4 Alkyl group. In other embodiments, J B It can be methyl or ethyl.

[0137] In some implementations of Equation III, n is 2 and each J B For halogen atoms. In some of these embodiments, each J B Independently selected from chlorine or fluorine. In other embodiments, a J B It is fluorine and another J B For chlorine. In other embodiments, each J B It is fluorine.

[0138] 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 is relative to the methylene linker between ring B and the molecular core. B In the adjacent position, and J B It is a halogen. In some of these embodiments, J B It is chlorine. In other embodiments, J B It is fluorine.

[0139] In some embodiments of Formula III, 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.

[0140] In some embodiments of Equation III, ring B is C. 3-7 Cycloalkyl rings.

[0141] In some embodiments of Equations I, IIA, IIB, and III, q is 0. In some of these embodiments, R... 11 To be arbitrarily and independently controlled by 0-3 R 15 Replacement C 1-6 Alkyl group. In some other embodiments, R 11 To be arbitrarily and independently controlled by 0-3 R 15 Substituted methyl and R 15 It is a halogen (e.g., fluorine). In some other embodiments, R 11 To be independently controlled by 2 R 15 Substituted methyl and R 15 It is a halogen (e.g., fluorine). In some embodiments, R 11 To be independently controlled by 3 R 15 Substituted methyl and R 15 It is a halogen (e.g., fluorine).

[0142] In some embodiments of Formulas I, IIA, IIB, and III, the core formed by rings E and A is selected from:

[0143]

[0144] In this context, C atoms marked with an asterisk (*) represent connection points to rings containing G, Z, and Q, while C atoms marked with a doublet (**) represent connection points with two J atoms. In some of these embodiments, each J... C It is hydrogen.

[0145] In some embodiments of Formulas I, IIA, IIB, and III, the core formed by rings E and A is selected from:

[0146]

[0147] In some of these implementation schemes, J C It is hydrogen each time it appears.

[0148] 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, wherein at least two of Q, G and Z are N or NH.

[0149] In some embodiments of Formula I, the compound is one of Formula IV or a pharmaceutically acceptable salt thereof:

[0150]

[0151] in:

[0152] Each Y is independently selected from N and NJ. c CH or CJc ;

[0153] Each X is N, NJ c CH or CJ c ;

[0154] Among them, at most 3 of X and Y are both N or NJ. c ;

[0155] J c Halogen, CN, or C optionally substituted with 1 to 3 halogens 1-3 alkyl;

[0156] Each J B Independently selected from halogen or C 1-4 alkyl;

[0157] n is 0, 1, 2, or 3;

[0158] R 10 For optional selection by one, two or three independently selected from halogens, -C(O)R b2 C groups substituted with phenyl and 5 or 6 heteroaryl groups 1-4 Alkyl groups, wherein the phenyl group and the 5- or 6-membered heteroaryl group are optionally surrounded by one, two, or three halogens or C-terminals. 1-4 Alkyl substitution, wherein the heteroaryl group comprises one, two, or three heteroatoms independently selected from N, O, and S;

[0159] q is 0 or 1;

[0160] R 11 H, halogen, -NR a2 R b2 C 1-4 Alkyl, 5- to 6-membered heteroaryl or C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, 5- to 6-membered heteroaryl and C 3-6 Each of the cycloalkyl groups is optionally replaced by one, two, or three groups independently selected from halogens, wherein the heteroaryl group includes one, two, or three heteroatoms independently selected from N, O, and S;

[0161] R a2 It is hydrogen or C 1-4 Alkyl; and

[0162] R b2 It is hydrogen or C 1-4 alkyl.

[0163] In some embodiments of Formula I, the compound is one of Formula V or a pharmaceutically acceptable salt thereof:

[0164]

[0165] in:

[0166] Y is either N or CH;

[0167] Each J B Independently selected from halogen or C 1-4 alkyl;

[0168] n is 0, 1, 2, or 3;

[0169] R 11 H, halogen, -NR a2 R b2 C 1-4 Alkyl, 5- to 6-membered heteroaryl or C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, 5- to 6-membered heteroaryl and C 3-6 Each cycloalkyl group may be optionally substituted by one, two, or three independently selected halogen groups;

[0170] R a2 It is hydrogen or C 1-4 Alkyl; and

[0171] R b2 It is hydrogen or C 1-4 alkyl.

[0172] In some embodiments of Formula I, the compound is one of Formula VI or a pharmaceutically acceptable salt thereof:

[0173]

[0174] in:

[0175] Y is either N or CH;

[0176] Each J B Independently selected from halogen or C 1-4 alkyl;

[0177] n is 0, 1, 2, or 3;

[0178] R 11 H, halogen, -NR a2 R b2 C 1-4 Alkyl, 5- to 6-membered heteroaryl or C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, 5- to 6-membered heteroaryl and C 3-6 Each cycloalkyl group may be optionally substituted by one, two, or three independently selected halogen groups;

[0179] R a2 It is hydrogen or C 1-4 Alkyl; and

[0180] R b2 It is hydrogen or C 1-4 alkyl.

[0181] In some implementations of formulas IV, V, and VI, R 11 C is a C that can be substituted with one, two, or three halogens. 1-4 alkyl.

[0182] In some embodiments, the compounds of formula I are selected from those listed in Table I.

[0183] Table I

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] In some implementations, the Formula I compound is in a neutral form or a pharmaceutically acceptable salt form.

[0196] The present invention relates to a pharmaceutically acceptable salt.

[0197] 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 Formula I compounds are used in pharmaceuticals. However, pharmaceutically unacceptable salts can be used to prepare compounds of Formula I or their pharmaceutically acceptable salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion can be any organic or inorganic part that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In cases where multiple charged atoms are part of a pharmaceutically acceptable salt, multiple counterions may be present. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0198] Pharmaceutically acceptable salts of the compounds described herein include those derived from the compounds with inorganic acids, organic acids, or bases. In some embodiments, the salt may be prepared in situ during the final isolation and purification of the compound. In other embodiments, the salt may be prepared from the free form of the compound in a separate synthetic step.

[0199] When the compound of Formula I is acidic or contains sufficiently acidic bioisosteres, a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali (including inorganic and organic bases). Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, and zinc salts. Specific implementation schemes include ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include the following: primary amines, secondary amines, 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, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl reduced glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

[0200] When the compound of Formula I is basic or contains a sufficiently basic bioisostere, the salt can be prepared from a pharmaceutically acceptable non-toxic acid (including inorganic and organic acids). The acid includes acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. Other exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, tartrate, ascorbic acid salts, succinates, maleates, gentisinates, fumarates, gluconates, glucurons, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ates (i.e., 1,1′-methylene-bis(2-hydroxy-3-naphthyl)ates).

[0201] The preparation of pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts described above is more fully described in Berg et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977:66:1-19, the full text of which is incorporated herein by reference.

[0202] In addition to the compounds described herein, their pharmaceutically acceptable salts may also be used in compositions to treat or prevent the conditions identified herein.

[0203] Pharmaceutical Compositions and Administration

[0204] The compounds disclosed herein and their pharmaceutically acceptable salts may be formulated as pharmaceutical compositions or “preparations”.

[0205] Typical formulations are prepared by mixing a Formula I compound or its pharmaceutically acceptable salt 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, etc. The specific carrier, diluent, or excipient used will depend on the manner and purpose of formulating the Formula I compound. Solvents are typically selected based on solvents that are generally considered safe (GRAS - generally considered safe) for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof. The formulation may also include other types of excipients, such as one or more buffers, stabilizers, anti-adhesives, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coatings (e.g., enteric or slow-release), preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, flavorings, and other known additives, to provide an aesthetic presentation of the drug (i.e., a compound of formula I or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (i.e., a pharmaceutical preparation).

[0206] Formulations can be prepared using conventional dissolution and mixing processes. For example, the active pharmaceutical ingredient (i.e., a compound of formula I, a pharmaceutically acceptable salt thereof, or a stable form of the compound, such as 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 aforementioned excipients. The compound, having the desired purity, is optionally mixed with a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer in the form of a lyophilized formulation, a ground powder, or an aqueous solution. Formulations can be prepared by mixing at ambient temperature at a suitable pH and with the desired purity and a physiologically acceptable carrier. The pH of the formulation depends primarily on the specific use and concentration of the compound, but can range from about 3 to about 8. When the pharmaceutical preparations described herein are solid amorphous dispersions formed by solvent methods, additives can be added directly to the spray-drying solution during mixture formation, for example, by dissolving or suspending the additives in a slurry form, which can then be spray-dried. Alternatively, additives can be added after the spray-drying process to facilitate the formation of the final formulated product.

[0207] Compounds of Formula I or their pharmaceutically acceptable salts are typically formulated into pharmaceutical dosage forms to provide easily controlled drug dosages and enable patients to adhere to predetermined regimens. Pharmaceutical formulations of compounds of Formula I or their pharmaceutically acceptable salts can be prepared for various routes and types of administration. Various dosage forms may exist for the same compound because different medical conditions may require different routes of administration.

[0208] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific route of administration. For example, a timed-release formulation intended for oral administration to humans may contain about 1 to 1000 mg of the active substance mixed with a suitable and convenient amount of carrier material, which may comprise about 5% to about 95% (by weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution for intravenous infusion may contain about 3 to 500 μg of the active ingredient per milliliter of solution so that a suitable volume can be infused at a rate of about 30 mL / hr. As a general suggestion, the initial pharmaceutically effective amount of the administered inhibitor will be in the range of about 0.01 to 100 mg / kg / dose, i.e., about 0.1 to 20 mg / kg patient body weight / day, with a typical initial range of 0.3 to 15 mg / kg / day for the compound used.

[0209] As used herein, the term "therapeutic effective amount" means the amount of an active compound or agent that elicits a biological or pharmaceutical response in an tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician. The therapeutic or pharmaceutically effective amount of the compound to be administered will be controlled by these considerations and is the minimum amount required to improve, cure, or treat a disease or condition or one or more of its symptoms.

[0210] The pharmaceutical composition of Formula I will be formulated, administered, and applied in accordance with good medical practice (i.e., dosage, concentration, schedule, process, medium, and route of administration). Factors to be considered in this context include the specific condition being treated, the specific mammal being treated, the individual patient's clinical condition, etiology, delivery site of the drug, method of administration, schedule of administration, and other factors known to the physician, such as the individual patient's age, weight, and response.

[0211] The term "effective preventive measure" refers to the amount that effectively prevents or substantially reduces the chance of acquiring a disease or condition, or reduces the severity of a disease or condition before it develops, or reduces the severity of one or more symptoms before they progress. Broadly speaking, preventive measures are divided into primary prevention (to prevent the development of a disease) and secondary prevention (when the disease has already progressed and the patient is protected to prevent the process from worsening).

[0212] Acceptable diluents, carriers, excipients, and stabilizers are those that are non-toxic to the recipient at the doses and concentrations used, and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride, benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); Proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salts that form counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN. TM PLURONICS TM Alternatively, polyethylene glycol (PEG) may be used. The active pharmaceutical ingredient can also be encapsulated in prepared microcapsules, for example, by coagulation techniques or interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively; said microcapsules are in the form of colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in the form of a crude emulsion. This technique is disclosed in Remington's: The Science and Practice of Pharmacy, 21st edition, edited by the University of the Sciences in Philadelphia, 2005 (hereinafter referred to as "Remington's").

[0213] A "controlled drug delivery system" delivers drugs to the body in a precisely controlled manner to suit the drug and the condition being treated. The primary objective is to achieve therapeutic drug concentrations at the site of action for the desired duration. The term "controlled release" is generally used to refer to various methods of altering the release of a drug from its dosage form. This term includes formulations labeled "extended release," "delayed release," "modified release," or "sustained release." Generally, controlled release of the drugs described herein can be provided through the use of various polymer carriers and controlled-release systems, including permeable and non-permeable matrices, permeation control devices, various reservoir devices, enteric coatings, and multi-particle control devices.

[0214] "Sustained-release formulations" represent the most common application of controlled release. Suitable examples of sustained-release formulations include a semi-permeable matrix of a solid hydrophobic polymer containing the compound, said matrix being in the form of a molded article, such as a membrane or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid (US Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid ester, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.

[0215] "Immediate-release formulations" can also be prepared. These formulations are designed to deliver the drug into the bloodstream and to the site of action as quickly as possible. For example, to facilitate rapid dissolution, most tablets are designed to rapidly disintegrate into particles and subsequently deagglomerate into finer particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.

[0216] The reagents described herein can be incorporated into controlled-release devices using soluble or insoluble polymer matrixes. A soluble matrix refers to a water-soluble, water-swellable, or water-soluble matrix, meaning it is soluble, swellable, or dissolvable in pure water or requires the presence of an acid or base to ionize the polymer matrix sufficiently to cause corrosion or dissolution. Upon contact with an aqueous environment, the soluble polymer matrix absorbs water and forms a water-swellable gel or matrix containing the reagents described herein. The water-swellable matrix gradually erodes, swells, disintegrates, or dissolves in the environment of use, thereby controlling the release of the compounds described herein into the environment of use. A component of this water-swellable matrix is ​​a water-swellable, soluble, or water-soluble polymer, which can generally be described as a permeating polymer, hydrogel, or water-swellable polymer. The polymer can be linear, branched, or cross-linked. The polymer can be a homopolymer or a copolymer. In some embodiments, they may be synthetic polymers derived from vinyl, acrylate, methacrylate, carbamate, ester, and oxide monomers. In other embodiments, they may be derivatives of natural polymers such as: polysaccharides (e.g., chitin, chitosan, dextran, and saccharides; gum agar, gum arabic, gum arvense, bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and stearin), starches (e.g., dextrin and maltodextrin), hydrocolloids (e.g., pectin), phospholipids (e.g., lecithin), alginates (e.g., ammonium alginate, sodium alginate, potassium alginate, or calcium alginate, propylene glycol alginate), gelatin, collagen, and cellulose. Cellulose is a cellulose polymer modified with ester- or ether-linked substituents by reacting with the compound through at least a portion of the hydroxyl groups on the sugar repeating units. For example, cellulose ethyl cellulose has an ether-linked ethyl substituent connected to a sugar repeating unit, while cellulose acetate cellulose has an ester-linked acetate substituent. In some embodiments, the cellulose used for the soluble matrix comprises water-soluble and water-soluble celluloses, which may 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 methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC). In some embodiments, the cellulose comprises various grades of low viscosity (MW less than or equal to 50,000 Daltons), such as Dow Methocel. TMSeries E5, E15LV, E50LV and K100LY) and high viscosity (MW greater than 50,000 Daltons, such as E4MCR, E10MCR, K4M, K15M and K100M and Methocel) TM K-series HPMCs. Other commercially available HPMC types include the Shin Etsu Metolose 90SH series.

[0217] Other materials that can be used as soluble matrix materials include, but are not limited to, saccharides, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethyl acrylic acid or methacrylic acid. Homopolymers and copolymers of Rohm America, Inc., Piscataway, New Jersey and other acrylic acid derivatives, such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, 2-dimethylaminoethyl methacrylate and trimethylaminoethyl methacrylate chlorides.

[0218] Alternatively, the pharmaceutical agent of the present invention can be administered via or contained in an insoluble matrix device. In such a device, the pharmaceutical agent described herein is distributed in an inert matrix. The agent is released through diffusion via the inert matrix. Examples of materials suitable for an inert matrix include insoluble plastics (e.g., methacrylate-methyl methacrylate copolymer, polyvinyl chloride, polyethylene), hydrophilic polymers (e.g., ethyl cellulose, cellulose acetate, cross-linked polyvinylpyrrolidone (also known as crosspovidone)), and aliphatic compounds (e.g., carnauba wax, microcrystalline wax, and triglycerides). The device is further described in Remington: The Science and Practice of Pharmacy, 20th edition (2000).

[0219] As described above, the pharmaceutical agents described herein can also be incorporated into osmotic control devices. Such devices typically include a core containing one or more pharmaceutical agents as described herein and a water-permeable, non-soluble, and non-corrosive coating surrounding the core, which controls the inflow of water from an aqueous use environment into the core to induce drug release by extruding some or all of the core into the use environment. In some embodiments, the coating is polymeric, water-permeable, and has at least one delivery pore. The core of the osmotic device optionally includes an osmotic agent for absorbing water from the surrounding environment through the semi-permeable membrane. The osmotic agent contained in the core of this device may be a water-swellable hydrophilic polymer or may be a proenzyme (also called an osmagent). Pressure is generated within the device, which forces the pharmaceutical agent out of the device through an orifice (the size of which is designed to minimize solute diffusion while preventing hydrostatic head clogging). Non-limiting examples of osmotic control devices are disclosed in U.S. Patent Application No. 09 / 495,061.

[0220] The amount of water-swellable hydrophilic polymer present in the core can range from about 5 to about 80 wt% (including, for example, 10 to 50 wt%). Non-limiting examples of core materials include hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinylpyrrolidone (PVP) and cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers and PVA / PVP copolymers containing hydrophobic monomers (e.g., methyl methacrylate, vinyl acetate, etc.), hydrophilic polyurethanes containing large PEO blocks, cross-linked sodium carboxymethyl cellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate. Other materials include hydrogels containing interpenetrating polymer networks that can be formed by addition or condensation polymerization, the components of which may contain hydrophilic and hydrophobic monomers, such as those just mentioned. Water-swellable hydrophilic polymers include, but are not limited to, PEO, PEG, PVP, crosslinked sodium carboxymethyl cellulose, HPMC, sodium starch glycolate, polyacrylic acid, and their crosslinked forms or mixtures.

[0221] The core may also include a zymogen (or permeabilizer). The amount of zymogen present in the core may range from about 2 to about 70 wt% (including, for example, 10 to 50 wt%). Suitable zymogens of typical classes are water-soluble organic acids, salts, and sugars capable of absorbing water, thereby creating an osmotic pressure gradient across the barrier of the surrounding coating. Typical useful zymogens 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 some embodiments, the zymogen is glucose, lactose, sucrose, mannitol, xylitol, sodium chloride, including combinations thereof.

[0222] The rate of drug delivery is controlled by factors such as the permeability and thickness of the coating, the osmotic pressure of the drug-containing layer, the hydrophilicity of the hydrogel layer, and the surface area of ​​the device. Those skilled in the art will understand that increasing the coating thickness will decrease the release rate, while 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.

[0223] In some embodiments, it is desirable to entrain particles of the pharmaceutical agent described herein in the extrusion fluid during operation of the permeation device. For particles to be sufficiently entrained, the pharmaceutical form of the agent is dispersed in the fluid before the particles may settle in the tablet core. One method to achieve this is to add a disintegrant, which is used to break down the compressed core into its particulate components. Non-limiting examples of standard disintegrants include materials such as 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 And other disintegrants known to those skilled in the art. Depending on the specific formulation, some disintegrants are better than others. Depending on the specific formulation, some disintegrants are more effective than others. Several disintegrants tend to form gels when swelled in water, thus hindering drug delivery from the device. When water enters the core, non-gelling, non-swelling disintegrants allow drug particles to disperse more rapidly within the core. In some embodiments, the non-gelling, non-swelling disintegrant is a resin, such as an ion exchange resin. In one embodiment, the resin is Amberlite. TM IRP 88 (available from Rohm and Haas, Philadelphia, PA). When used, the disintegrant is present in an amount ranging from approximately 1% to 25% of the core formulation.

[0224] Another example of a permeation device is a permeation capsule. The capsule shell or a portion thereof may be semi-permeable. The capsule may be filled with a powder or liquid consisting of the reagents described herein, an excipient that absorbs water to provide osmotic potential, and / or a water-swellable polymer, or optionally a solubilizing excipient. The capsule core may also be made such that it has a bilayer, trilayer, or concentric geometry similar to those described above, consisting of a bilayer or multilayer pharmaceutical agent.

[0225] Another type of permeation device that can be used in this invention comprises coated expandable tablets, such as those described in EP378404. Coated expandable tablets comprise a tablet core containing the pharmaceutical agent described herein and a membrane-coated expandable material, preferably a hydrophilic polymer, containing pores or holes through which the hydrophilic polymer can be extruded and carry the pharmaceutical agent in an aqueous use environment. Alternatively, the membrane may contain a polymeric or low molecular weight water-soluble pore-forming agent. The pore-forming agent is dissolved in an aqueous use environment, thereby providing pores through which the hydrophilic polymer and the pharmaceutical agent can be extruded. Examples of pore-forming agents are water-soluble polymers such as HPMC, 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 methods. In such permeation devices, the membrane material may comprise any membrane-forming polymer, including water-permeable or impermeable polymers, provided that the membrane deposited on the tablet core is porous or contains water-soluble pores or has macropores for water entry and drug release. Such continuous release devices can also be implemented in a multi-layered manner, as described, for example, in EP378404.

[0226] When the pharmaceutical agent described herein is a liquid or oil (e.g., a lipid-mediated formulation, as described in WO05 / 011634), the osmotic controlled release device may comprise a soft gel or gelatin capsule containing the liquid formulation, formed of a composite wall, wherein the wall comprises a barrier layer formed on the outer surface of the capsule, an expandable layer formed on the barrier layer, and a semi-permeable layer formed on the expandable layer. A delivery port connects the liquid formulation to an aqueous application environment. Such devices are described, for example, in US6419952, US6342249, US5324280, US4672850, US4627850, US4203440, and US3995631.

[0227] As further described above, the reagents described herein may be provided in the form of microparticles, typically ranging in size from about 10 μm to about 2 mm (including, for example, diameters from about 100 μm to 1 mm). These microparticles may be packaged, for example, in capsules (e.g., 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 they may be formed into tablets, capsules, or pellets by compression or other methods known in the art. The microparticles may be prepared by any known method such as wet and dry granulation processes, extrusion / spheronization, rolling, melt coagulation, or spray coating of seed cores. For example, in wet and dry granulation processes, the reagents described herein and optional excipients may be granulated to form microparticles of the desired size.

[0228] Pharmaceutical agents can be contained in microemulsions, which are typically thermodynamically stable, isotropic, and clear dispersions of two immiscible liquids (e.g., oil and water) stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology, New York: Marcel Dekker, 1992, Vol. 9). The preparation of microemulsions requires a surfactant (emulsifier), a co-surfactant (co-emulsifier), an oil phase, and an aqueous phase. Suitable surfactants include any surfactant that can be used to prepare emulsions, such as emulsifiers commonly used to prepare creams. Co-surfactants (or "co-emulsifiers") are typically selected from polyglycerol derivatives, glycerol derivatives, and fatty alcohols. Preferred emulsifier / co-emulsifier combinations are typically, but limited to, those selected from: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitoyl stearate; and caprylic and caprylic triglycerides and oleoyl polyethylene glycol glyceride. The aqueous phase includes not only water, but also typically includes buffers, glucose, propylene glycol, polyethylene glycol, preferably lower molecular weight polyethylene glycol (e.g., PEG 300 and PEG 400) and / or glycerol, while the oil phase typically includes, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of monoglycerides, diglycerides and triglycerides, monoesters and diesters of PEG (e.g., oleoyl polyethylene glycol glycerol), etc.

[0229] The compounds described herein can be encapsulated in pharmaceutically acceptable nanoparticle, nanosphere, and nanocapsule formulations (Delie and Blanco-Prieto, 2005, Molecule 10:65-80). Nanocapsules typically encapsulate compounds in a stable and reproducible manner. To avoid side effects due to intracellular polymerization overload, ultrafine particles (approximately 0.1 μm in size) can be designed using in vivo degradable polymers (e.g., biodegradable alkyl cyanoacrylate nanoparticles). These particles are described in the prior art.

[0230] Another embodiment of the invention is an implantable device coated with the compounds of the invention. The compounds may also be coated onto implantable medical devices (e.g., beads) or co-formulated with polymers or other molecules to provide a “drug reservoir,” thereby allowing the release of the drug over a period longer than that of an aqueous solution of the drug. General preparation of suitable coatings and coated implantable devices is described in U.S. Patent 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, or mixtures thereof. The coating may optionally be further coated with a suitable topcoat of fluorosilicone rubber, polysaccharide, polyethylene glycol, phospholipid, or a combination thereof to impart controlled release characteristics to the composition.

[0231] Formulations include those suitable for the routes of administration detailed herein. The formulation may be readily available in a unit dosage form and can be prepared by any method well known in the pharmaceutical field. Techniques and formulations are generally referred to in Remington's. The method includes the step of binding the active ingredient to a carrier constituting one or more minor components. Generally, formulations are prepared by homogenizing and fully binding the active ingredient to a liquid carrier or a fine solid carrier, or both, and then (if necessary) shaping the product.

[0232] The terms “administer,” “administering,” or “administration” when referring to the compounds, compositions, or formulations of the present invention mean the introduction of the compound into the system of an animal requiring treatment. When the compounds of the present invention are provided in combination with one or more other active pharmaceutical agents, “administering” and its variations shall each be understood to include the simultaneous and / or sequential introduction of the compound and the other active agents.

[0233] The compositions described herein can be administered systemically or locally, for example: orally (e.g., using capsules, powders, solutions, suspensions, tablets, sublingual tablets, etc.), by inhalation (e.g., using aerosols, gases, inhalers, nebulizers, etc.), to the ear (e.g., using ear drops), locally (e.g., using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), by the eye (e.g., using eye drops, ophthalmic gels, ophthalmic ointments), by rectum (e.g., using enemas or suppositories), by the nose, by the cheek, by the vagina (e.g., using irrigators, intrauterine contraceptives, vaginal suppositories, vaginal rings, or tablets, etc.), by implantable cassettes, etc., or parenterally, depending on the severity and type of disease being treated. As used herein, the term "parenterally" 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.

[0234] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including 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 may contain inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers commonly used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0235] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In the solid dosage form, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following substances: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetearyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and / or i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or coated using known techniques, including microencapsulation, to mask unpleasant tastes or delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action. For example, delaying materials such as glyceryl monostearate or distearate, alone or in combination with waxes, may be used. Water-soluble taste-masking materials, such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, may also be used.

[0236] Formulations of Formula I compounds suitable for oral administration can be prepared as discrete units, such as tablets, pills, sugar tablets, lozenges, 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 can be prepared according to any method known in the art of manufacturing pharmaceutical compositions.

[0237] Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (e.g., powder or granules) in a suitable machine, the active ingredient optionally being mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine.

[0238] Formulations intended for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin); or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier (e.g., polyethylene glycol) or an oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0239] The active compound may also be in a microencapsulated form having one or more of the above excipients.

[0240] When an aqueous suspension is required for oral use, the active ingredient can be combined with an emulsifier and a suspending agent. Sweeteners and / or flavoring agents may be added if desired. Syrups and elixirs can be formulated using sweeteners (e.g., glycerin, propylene glycol, sorbitol, or sucrose). The formulation may also contain moderating agents, preservatives, flavoring agents, coloring agents, and antioxidants.

[0241] The sterile injectable form of the compositions described herein (e.g., for parenteral administration) may be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are typically used as solvents or suspension media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids (e.g., oleic acid and its glyceride derivatives) may be used to prepare injectable formulations, such as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethyleneized forms. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are commonly used to formulate pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms) may also be used for injectable formulations.

[0242] Oily suspensions can be formulated by suspending a compound of Formula I in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin). The oily suspension may contain a thickener, such as beeswax, hard paraffin, or cetearyl alcohol. Sweeteners (e.g., those described above) and flavoring agents may be added to provide a palatable oral formulation. These compositions may be preserved by adding antioxidants (e.g., butylated hydroxyanisole or α-tocopherol).

[0243] The aqueous suspension of Formula I contains an active substance mixed with excipients suitable for preparing the aqueous suspension. The excipients include suspending agents such as sodium carboxymethyl cellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, and dispersing or wetting agents such as natural phospholipids (e.g., lecithin), condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide and esters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (e.g., ethylparaben or n-propylparaben), one or more colorants, one or more flavoring agents, and one or more sweeteners (e.g., sucrose or saccharin).

[0244] Injectable formulations may be sterilized by, for example, filtering with a bacterial retention filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0245] To prolong the effects of the compounds described herein, it is generally desirable to slow the absorption of the compounds after subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oily medium. Injectable reservoir forms are prepared by forming a microencapsulated matrix of the compound in a biodegradable polymer (e.g., polylactic acid-polyglycolic acid). The rate of compound release can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable reservoir formulations can also be prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0246] The injectable solution or microemulsion can be introduced into the patient's bloodstream via local bolus injection. Alternatively, the solution or microemulsion can be advantageously administered in a manner to maintain a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM Model 5400 intravenous pump.

[0247] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier (e.g., cocoa butter, beeswax, polyethylene glycol, or suppository wax), which is solid at ambient temperature but liquid at body temperature, thereby melting and releasing the active compound within the rectal or vaginal cavity. Other formulations suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams, or sprays.

[0248] The pharmaceutical compositions described herein can also be administered topically, especially when the therapeutic target includes areas or organs that can be easily reached by topical administration (including diseases of the eye, ear, skin, or lower intestine). Suitable topical formulations targeting each of these areas or organs are readily available.

[0249] Dosage forms of the compounds described herein for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient can be mixed under aseptic conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also included within the scope of this invention. Additionally, this invention includes the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. The dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. 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-controlled membrane or by dispersing the compound in a polymer matrix or gel. Local administration to the lower intestine can be achieved through rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0250] For topical administration, the pharmaceutical composition may be formulated in a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, nephrite, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0251] For ocular use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative, such as benzalkonium chloride. Alternatively, for ocular use, the pharmaceutical composition may be formulated in an ointment (e.g., paraffin). For the treatment of the eye or other external tissues (e.g., mouth and skin), the formulation may be applied as a topical ointment or cream containing, for example, 0.075 to 20% w / w of the active ingredient. When formulated as an ointment, the active ingredient may be used with an oil-based paraffin or a water-miscible ointment base.

[0252] Alternatively, an oil-in-water emulsion base can be used to formulate the active ingredients into the cream. If desired, the aqueous phase of the cream base may include polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400) and mixtures thereof. Topical formulations may ideally include compounds that enhance the 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.

[0253] The oil phase of an emulsion prepared using a compound of Formula I can be composed of known components in a known manner. While this phase may contain only an emulsifier (originally referred to as an emulsifier), it ideally includes at least one emulsifier with a fat or oil, or a mixture of both. Hydrophilic emulsifiers and lipophilic emulsifiers used as stabilizers may be included. In some embodiments, the emulsifier includes both oils and fats. The emulsifier, with or without a stabilizer, together constitutes a so-called emulsified wax, and this wax, together with the oil and fat, constitutes a so-called emulsified ointment base, which forms the oily dispersed phase of the ointment formulation. Suitable emulsifiers and emulsion stabilizers for formulating compounds of Formula I include Tween. TM -60, Span TM -80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0254] The pharmaceutical composition may also be administered via nasal aerosol or inhalation. The composition is prepared according to techniques well known in the pharmaceutical formulation field and can be prepared as a saline solution, employing benzyl alcohol or other suitable preservatives, absorption enhancers (for enhancing bioavailability), fluorocarbons, and / or other conventional solubilizers or dispersants. Formulations suitable for intrapulmonary or nasal administration have particle sizes, for example, ranging from 0.1 micrometers to 500 micrometers (including particle sizes between 0.1 and 500 micrometers, in micrometer increments such as 0.5, 1, 30, 35 micrometers, etc.), and are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveolar sacs.

[0255] The pharmaceutical composition (or formulation) used may be packaged in various ways depending on the method of administration. Typically, the dispensing article includes a container in which the pharmaceutical formulation is stored in a suitable form. Suitable containers are known to those skilled in the art and include materials such as bottles (plastic and glass), capsules, ampoules, plastic bags, metal cylinders, etc. Containers may also include tamper-proof assemblies to prevent accidental contact with the contents. Additionally, the container has a label describing its contents. This label may also include appropriate warnings.

[0256] Formulations may be packaged in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier (e.g., water for injection) just before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the types described above. Preferred single-dose formulations are those containing a daily dose or a sub-daily dose (or a suitable fraction thereof) of the active ingredient, as listed above herein.

[0257] In another respect, a compound of formula I or a pharmaceutically acceptable salt thereof may be formulated in a veterinary composition comprising a veterinary carrier. The veterinary carrier is a material suitable for the purpose of administering the composition and may be an inert solid, liquid, or gaseous material. It is compatible with the active ingredient in the veterinary field. These veterinary compositions may be administered parenterally, orally, or via any other desired route of administration.

[0258] Treatment

[0259] In a third aspect, the present invention relates to the treatment of certain conditions by using sGC stimulants alone or in combination with pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them in patients who require such treatment.

[0260] This invention relates to stimulants of soluble guanylate cyclase (sGC), pharmaceutical preparations thereof, and their use, alone or in combination with one or more other pharmaceutical agents, for the treatment and / or prevention of a variety of diseases, where it may be necessary to increase NO concentration or increase cGMP concentration. Treatable diseases include, but are not limited to, pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, renal fibrosis and failure, cirrhosis, erectile dysfunction, female sexual dysfunction, diabetes-related conditions, eye diseases, and other related cardiovascular diseases.

[0261] Increased cGMP concentrations induce vasodilation, inhibit platelet aggregation and adhesion, exert antihypertensive effects, anti-remodeling effects, anti-apoptotic effects, anti-inflammatory effects, and neuronal signaling effects. Therefore, sGC stimulants can be used to treat and / or prevent a range of diseases and conditions, including but not limited to peripheral, pulmonary, hepatic, cardiac, or cerebrovascular / endothelial diseases or conditions, urogenital, gynecological, or sexual dysfunctions or conditions, thromboembolic diseases, ischemic diseases, fibrotic diseases, local or skin diseases, pulmonary or respiratory diseases, renal or hepatic diseases, metabolic disorders, atherosclerosis, or lipid-related diseases.

[0262] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by an undesirable reduction in bioavailability and / or sensitivity to NO, such as those associated with oxidative stress or nitrification stress disorders.

[0263] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by increased neuroinflammation. One embodiment of the invention is a method for reducing neuroinflammation in a subject of need, which is carried out by administering to the subject any one of compounds of formulas 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 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. Specifically, diseases and symptoms are CNS diseases or symptoms described in sections (9)-(16) below.

[0264] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by increased neurotoxicity. One embodiment of the invention is a method for reducing neurotoxicity in a subject in need, which is carried out by administering to the subject any one of compounds of formulas 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 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. Specifically, diseases and symptoms are CNS diseases or symptoms described in sections (9)-(16) below.

[0265] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by impaired nerve regeneration. One embodiment of the invention is a method for restoring nerve regeneration in a subject in need, which is carried out by administering to the subject any one of 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 II-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. Specifically, diseases and symptoms are CNS diseases or symptoms described in sections (9)-(16) below.

[0266] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by impaired synaptic function. One embodiment of the invention is a method for restoring synaptic function in a subject in need, which is carried out by administering to the subject any one of 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. Specifically, diseases and symptoms are CNS diseases or symptoms described in sections (9)-(16) below.

[0267] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by downregulated neurotransmitters. One embodiment of the invention is a method of normalizing neurotransmitters in a subject by administering to a subject any of 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-7, and I-72, or a pharmaceutically acceptable salt thereof. Specifically, the disease and condition are CNS diseases or conditions described in sections (9)-(16) below. In particular, the disease is Alzheimer's Disease. In particular, the disease is mixed dementia.

[0268] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by impaired cerebral blood flow. One embodiment of the invention is a method for restoring cerebral blood flow in a subject in need, which is carried out by administering to the subject any of 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-7, and I-72, or a pharmaceutically acceptable salt thereof. Specifically, the disease and condition are CNS diseases or conditions described in sections (9)-(16) below. In particular, the disease is vascular dementia or Alzheimer's disease. In particular, the disease is mixed dementia. In other embodiments, the CNS condition is selected from traumatic (closed or open, penetrating head injury), traumatic brain injury (TBI), or non-traumatic (stroke, aneurysm, hypoxia) brain injury or cognitive impairment or dysfunction caused by brain injury or neurodegenerative disease.

[0269] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases and conditions characterized by increased neurodegeneration. One embodiment of the invention is a method for reducing neurodegeneration in a subject of need, which is carried out by administering to the subject any one of 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. Specifically, diseases and symptoms are CNS diseases or symptoms described in sections (9)-(16) below.

[0270] In other embodiments, the compounds disclosed herein are neuroprotective sGC stimulants. Specifically, compounds of formulas 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, may be used to protect neurons in subjects of need. Specifically, the disease and condition are CNS diseases or conditions described in sections (9)-(16) below.

[0271] In other embodiments, the compounds disclosed herein are sGC stimulants that can be used for the prevention and / or treatment of orphan pain indications. One embodiment of the invention is a method of treating an orphan pain indication in a subject in need, which is carried out by administering to the subject any one of the compounds of formulas 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. Specifically, the indications for orphan pain are selected from acetazolamide-responsive myotonia, autologous red blood cell sensitization syndrome, and autosomal dominant Charcot-Marie-Tooth disease type 2V. 2V), autosomal dominant intermediate Charcot-Marie-Tuss disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2A, congenital pain insensitivity associated with channel disease, chronic pain requiring intraspinal analgesia, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, congenital pain insensitivity with hyperhidrosis, congenital pain insensitivity with severe intellectual disability, congenital pain insensitivity-hypohidrosis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial paroxysmal pain syndrome, familial paroxysmal pain syndrome mainly involving the lower extremities, familial paroxysmal pain syndrome mainly 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, orbital pain and generalized neurofibromatosis-marfanoid habitus syndrome (Painful orbital and systemic neurofibromas-marfanoid habitus) (Syndrome), paroxysmal severe pain, persistent idiopathic facial pain, qualitative or quantitative calpain deficiency, and Tolosa-Hunt syndrome.

[0272] Throughout this invention, the terms "hypertension," "arterial hypertension," or "high blood pressure (HBP)" are used interchangeably and refer to a very common and 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 diseases. Hypertension can be a primary disease, termed "primary hypertension" or "idiopathic hypertension," or it can be caused by other diseases, in which case it is classified as "secondary hypertension." Primary hypertension accounts for 90%-95% of all cases.

[0273] As used in this article, "refractory hypertension" refers to hypertension that remains above the target blood pressure (usually less than 140 / 90 mmHg, but a lower target of less than 130 / 80 mmHg is recommended for patients with diabetes or kidney disease) despite the simultaneous use of three antihypertensive medications from different classes. Individuals requiring four or more medications to control their blood pressure are also considered to have refractory hypertension. Hypertension is a very common comorbidity of diabetes, affecting approximately 20–60% of people with diabetes, depending on obesity, race, and age. This type of hypertension is referred to as "diabetic hypertension" in this article. In type 2 diabetes, hypertension is often present as part of a metabolic syndrome of insulin resistance (which also includes central obesity and dyslipidemia). In type 1 diabetes, hypertension may reflect the onset of diabetic nephropathy.

[0274] As used in this article, "pulmonary hypertension (PH)" is a disease characterized by persistently elevated blood pressure in the pulmonary vascular system (pulmonary arteries, pulmonary veins, and pulmonary capillaries), causing right ventricular hypertrophy, ultimately leading to right ventricular failure and death. Common symptoms of PH include shortness of breath, dizziness, and syncope, all of which are exacerbated by exertion. Without treatment, the median life expectancy after diagnosis is 2.8 years. PH exists in many different forms, classified according to its etiology. Categories include pulmonary arterial hypertension (PAH), PH with left ventricular disease, PH associated with lung disease and / or hypoxemia, PH due to chronic thrombotic and / or embolic diseases, and other forms of 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, and the association of PH with chronic obstructive pulmonary disease (COPD) is of particular interest. Current treatment for pulmonary hypertension depends on the stage and mechanism of the disease.

[0275] As used in this article, “heart failure” is a progressive condition of left ventricular (LV) myocardial remodeling that ultimately leads to a complex clinical syndrome characterized by impaired cardiac function and circulatory congestion, resulting in insufficient blood and nutrients to be delivered to the body tissues. This condition occurs when the heart is damaged or overworked and unable to pump all the blood returning to the heart from its own circulation. Because less blood is pumped out, blood returning to the heart flows backward and fluid accumulates in other parts of the body. Heart failure also impairs the kidneys' ability to process sodium and water, further contributing to fluid retention. Heart failure is characterized by autonomic dysfunction, neurohormonal activation, and excessive production of cytokines, which contribute to progressive circulatory failure. Symptoms of heart failure include: shortness of breath (dyspnea) due to sudden rapid breathing during exercise or at rest and upon waking at night, both indicating pulmonary edema; general fatigue or weakness; edema of the feet, ankles, and legs; rapid weight gain; and a chronic cough, including one producing mucus or blood. Depending on their clinical presentation, heart failure is classified as de novo, transient, or chronic. Acute heart failure (i.e., symptoms that develop rapidly or gradually and require urgent treatment) may begin atopic or result from decompensation due to chronic heart failure. Diabetes is a common comorbidity in patients with heart failure and is associated with poorer outcomes and potentially impaired treatment efficacy. Other important comorbidities include systemic hypertension, chronic airflow obstruction, sleep apnea, cognitive impairment, anemia, chronic kidney disease, and arthritis. Chronic left ventricular failure is often associated with the development of pulmonary hypertension. The frequency of certain comorbidities varies by sex: in women, hypertension and thyroid disease are more common, while in men, chronic obstructive pulmonary disease (COPD), peripheral vascular disease, coronary artery disease, and renal insufficiency are more common. Depression is a common comorbidity of heart failure, and the two conditions often complicate each other. Cachexia is long recognized as a serious and common comorbidity of heart failure, affecting 15% of all heart failure patients and with a poor prognosis. Cardiac cachexia is defined as non-edema, involuntary loss of at least 6% of body weight over a 6-month period.

[0276] The term "sleep apnea" refers to the most common sleep-related breathing disorder. It is characterized by intermittent, periodic reductions or complete cessation of airflow, with or without upper airway obstruction. There are three types of sleep apnea: obstructive sleep apnea (the most common form), central sleep apnea, and mixed sleep apnea.

[0277] Central sleep apnea (CSA) is caused by a dysfunction of the brain's normal respiratory signals, rather than by a physical blockage of the airway. Lack of respiratory effort can increase carbon dioxide levels in the blood, which can awaken the patient. CSA is relatively rare in the general population, but it occurs more frequently in patients with systolic heart failure.

[0278] As used in this article, “metabolic syndrome,” “insulin resistance 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 high blood pressure (HBP)) that more often occur together than incidentally alone and together contribute to the development of type 2 diabetes and cardiovascular disease. Metabolic syndrome is characterized by specific lipid features such as increased triglycerides, decreased high-density lipoprotein cholesterol (HDL-cholesterol), and in some cases, moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol), and accelerated progression of atherosclerotic disease due to the stress of component risk factors. Several types of dyslipidemia exist: “Hypercholesterolemia” refers to elevated cholesterol levels. Familial hypercholesterolemia is a specific form of hypercholesterolemia caused by a defect on chromosome 19 (19p13.1–13.3). “Hyperglyceridemia” refers to elevated levels of triglycerides (e.g., “hypertriglyceridemia” involves elevated levels of triglycerides). "Hyperlipoproteinemia" refers to an elevated level of lipoproteins (usually LDL unless otherwise specified).

[0279] As used in this article, “peripheral vascular disease (PVD)” (also commonly referred to as “peripheral artery disease (PAD)” or “peripheral artery occlusive disease (PAOD)”) refers to blockages in large arteries not located in the coronary arteries, the aortic arc vascular system, or the brain. PVD can originate from atherosclerosis, inflammatory processes leading to stenosis, embolism, or thrombosis. It causes acute or chronic “ischemia (lack of blood supply).” Typically, PVD is the term used to refer to atherosclerotic blockages found in the lower extremities. PVD also includes a subset of diseases classified as microvascular diseases (i.e., vasospasm) arising from episodic narrowing of arteries (e.g., “Raynaud’s phenomenon”) or widening of them (acromial erythema).

[0280] The term "thrombosis" refers to the formation of a blood clot ("thrombus") within a blood vessel, obstructing blood flow through the circulatory system. When a blood vessel is damaged, the body uses platelets (clotting cells) and fibrin to form a blood clot to prevent blood loss. Alternatively, a blood clot can form in the body even when the blood vessel is not damaged, provided the right conditions are present. If the clot becomes too large and breaks off and becomes free, the mobile clot is now called a "thrombus." The term "thromboembolism" refers to the combination of thrombosis and its major complication, "embolism." When a thrombus occupies more than 75% of the surface area of ​​an arterial lumen, the reduced blood flow to the tissues is sufficient to cause symptoms due to decreased oxygen (hypoxia) and the accumulation of metabolic products such as lactic acid ("gout"). Blockages of more than 90% can cause hypoxia (complete oxygen deprivation) and "infarction" (a pattern of cell death).

[0281] "Embrism" (plural form embolisms) is an event that causes a blockage (vascular obstruction) in the body's distal space by a thrombus (a detached intravascular mass capable of blocking the arterial capillary bed at a site far from its origin) lodged in a narrow capillary within the arterial bed. This should not be confused with a thrombus that blocks at its site of origin.

[0282] A stroke, or cerebrovascular accident (CVA), is a rapid loss of brain function due to disruption of blood supply to the brain. This can be attributed to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism) or hemorrhage (blood leakage). As a result, the affected area of ​​the brain cannot function, which can lead to immobility of one or more limbs on one side of the body, inability to understand or express oneself accurately, or loss of vision on one side of the body. Risk factors for stroke include advanced age, high blood pressure, a previous 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 strokes are sometimes treated in hospitals using thrombolysis (also known as clot dissolving agents), and some hemorrhagic strokes benefit from neurosurgery. Preventing recurrence may involve administering antiplatelet drugs such as aspirin and dipyridamole, controlling and lowering high blood pressure, and using statins. Selected patients can benefit from carotid endarterectomy and the use of anticoagulants.

[0283] "Ischemia" is a condition where blood supply to tissues is restricted, resulting in insufficient oxygen and glucose for cellular metabolism (to keep tissues alive). Ischemia is usually caused by vascular problems and leads to tissue damage or dysfunction. It also refers to localized anemia in a given part of the body, sometimes caused by congestion (such as vasoconstriction, thrombosis, or embolism).

[0284] According to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), the term "sexual dysfunction" includes a range of conditions "characterized by disturbances in libido and psychophysiological changes associated with the sexual response cycle"; although such problems are relatively common, sexual dysfunction is considered only when the problem causes distress to the patient. Sexual dysfunction can have physical or psychological origins. It may often be predisposed to a primary hormonal condition, but most commonly it is secondary to other medical conditions or medications used to treat those conditions. All types of sexual dysfunction can be further classified as permanent, acquired, situational, or generalized (or a combination thereof).

[0285] The DSM-IV-TR specifies five main categories of "female sexual dysfunction": sexual desire / interest disorders; sexual arousal disorders (including reproductive, subjective, and combined disorders); orgasmic disorders; dyspareunia and vaginismus; and persistent sexual arousal disorders.

[0286] Female sexual arousal disorder (FSAD) is defined as a persistent or recurrent inability to achieve or maintain an adequate level of sexual arousal, causing personal distress. FSAD includes both a lack of subjective sensation of arousal (i.e., subjective arousal disorder) and a lack of physical responses (e.g., lubrication and erection) (i.e., genital / physical arousal disorder). FSAD can have strictly psychological origins, but it is usually caused or complicated by medical or physiological factors. Estrogen deficiency is the most common physiological condition associated with FSAD, leading to urogenital atrophy and reduced vaginal lubrication.

[0287] Erectile dysfunction (ED), as used in this article, is characterized by the inability to produce or maintain an erection during sexual intercourse. Penile erection is the hydraulic effect of blood entering and remaining in the corpora cavernosa of the penis. This process is usually initiated by sexual arousal (when signals are transmitted from the brain to the nerves in the penis). Difficulty in achieving an erection indicates erectile dysfunction. The most important organic causes are cardiovascular disease and diabetes, neurological problems (e.g., trauma from prostatectomy), hormone deficiency (hypogonadism), and medication side effects.

[0288] As used in this article, "bronchoconstriction" is defined as the constriction of the airways in the lungs due to the tightening of the surrounding smooth muscle, resulting in cough, wheezing, and shortness of breath. This condition has multiple causes, the most common being asthma. Exercise and allergies can cause symptoms in otherwise asymptomatic subjects. Other conditions such as chronic obstructive pulmonary disease (COPD) can also present with bronchoconstriction.

[0289] Specific diseases that can be treated and / or prevented by administration of the sGC stimulant of the present invention include, but are not limited to: hypertension (e.g., diabetic hypertension, arterial hypertension, pulmonary hypertension, refractory hypertension, peripheral artery 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 diseases (e.g., chronic thromboembolic pulmonary hypertension, thrombosis, stroke (especially ischemic stroke), embolism, pulmonary embolism), Alzheimer's disease, kidney diseases (e.g., renal fibrosis, ischemic nephropathy, renal failure, renal insufficiency, chronic kidney disease), liver diseases (e.g., liver fibrosis or cirrhosis), respiratory diseases (e.g., pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, interstitial lung disease), sexual dysfunction (e.g., erectile dysfunction, male and female sexual dysfunction, vaginal atrophy), sickle cell anemia, neuroinflammatory diseases or conditions, and metabolic disorders (e.g., lipid-related diseases).

[0290] Other specific diseases that can be treated and / or prevented by administering the sGC stimulant of the present invention include, but are not limited to: age-related memory impairment, mixed dementia, sleep-wake disorder, and Sneddon's syndrome.

[0291] Other specific diseases that can be treated and / or prevented by administering the sGC stimulant of the present invention include, but are not limited to: acute pain, central pain syndrome, chemotherapy-induced neuropathy and neuropathic pain, diabetic neuropathy, fibromyalgia, inflammatory pain, neuropathic pain, neuropathic pain associated with CNS diseases, painful diabetic peripheral neuropathy, postoperative pain, rigidity pain, and visceral pain.

[0292] Other specific diseases that can be treated and / or prevented by administering the sGC stimulant of the present invention include, but are not limited to: high altitude (altitude) disease, cerebral small vessel disease, cerebral vasculitis, cerebral vasospasm, diabetic heart failure (diabetic HF), diabetic vascular disease, diabetic macular edema, diabetic microvascular disease, heart failure with preserved ejection fraction (HFpEF), hepatic encephalopathy, moyamoya disease, non-diabetic nephropathy, and Parkinson's dysphagia.

[0293] Other specific diseases that can be treated and / or prevented by administration of the sGC stimulant of the present invention include, but are not limited to: angina pectoris, ataxia-telangiectasia, 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), cognitive impairment associated with sickle cells, concussion, dysphagia, ocular fibrosis, Fabry disease, Gaucher disease, glioblastoma, inflammation caused by cerebral malaria (SoC), inflammation caused by infectious diseases, intellectual disability, microvascular angina, myopic choroidal angiogenesis, neuromyelitis optica, neuropathic pain of multiple sclerosis, neuropathic pain of shingles, neuropathic pain after spinal surgery, and Parkinson's dementia. Dementia, peripheral and autonomic neuropathy, peripheral retinal degeneration, post-traumatic stress disorder, postherpetic neuralgia, postoperative dementia, proliferative vitreoretinopathy, radiation-induced fibrosis, radiculopathy, refractory epilepsy, retinal vein occlusion, Sjögren's syndrome ( Syndrome, spinal cord injury, spinal muscular atrophy, vertebral subluxation, tau protein lesions, ulcers, and wet age-related macular degeneration.

[0294] Compounds of formula I, as sGC stimulants, and their pharmaceutically acceptable salts may be used for the prevention and / or treatment of the following types of diseases, conditions, and symptoms that benefit from sGC stimulation or NO pathway upregulation:

[0295] (1) Peripheral, pulmonary, hepatic, renal, cardiac, or cerebral vascular / endothelial diseases / conditions or other circulatory-related disorders:

[0296] • Conditions associated with hypertension and reduced coronary blood flow, such as increased acute and chronic coronary pressure, arterial hypertension, and vascular conditions resulting from cardiac and renal complications (e.g., heart disease, stroke, cerebral ischemia, renal failure); refractory hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; decreased ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or injury;

[0297] Thromboembolic conditions and ischemia, such as myocardial infarction, stroke (especially ischemic stroke), transient ischemic attack (TIA); obstructive thromboangiitis; stable or unstable angina; coronary artery spasm, variant angina, Prinzmetal's angina; prevention of restenosis after thrombolytic therapy; thrombotic conditions;

[0298] • Peripheral artery disease, peripheral occlusive artery disease; peripheral vascular disease; hypertension; Raynaud's syndrome or phenomenon, borderline limb ischemia, vasculitis; peripheral embolism; intermittent claudication; vascular occlusive crisis; Duchenne and Becker muscular dystrophies; microcirculatory abnormalities; control of vascular leakage or permeability;

[0299] • Shock; sepsis; cardiogenic shock; control of leukocyte activation; inhibition or regulation of platelet aggregation;

[0300] • Lung / respiratory conditions, such as pulmonary hypertension, pulmonary arterial hypertension and related pulmonary vascular remodeling (e.g., localized thrombosis and right cardiac hypertrophy); hypertonic lungs; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, anterior capillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arterial disease, plexogenic pulmonary arterial disease; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis, lung transplantation;

[0301] • Pulmonary hypertension associated with or related to the following: 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 drainage, pulmonary venous occlusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep apnea, sleep apnea, alveolar hypoventilation syndrome, prolonged exposure to high altitude, neopulmonary disease, alveolar capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolism, pulmonary embolism (due to tumors, parasites or foreign bodies), connective tissue diseases, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary angioma; histiocytosis X, lymphangioma, and constricted pulmonary vessels (e.g., due to adenosis, tumors or fibrotic mediastinitis);

[0302] • Arteriosclerotic diseases or conditions, such as atherosclerosis (e.g., associated with endothelial damage, 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;

[0303] • Cardiovascular disease associated with metabolic syndrome (e.g., obesity, dyslipidemia, diabetes, hypertension); lipid-related conditions such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease and hepatitis; preeclampsia; progression of polycystic kidney disease; subcutaneous fat; obesity;

[0304] • Cirrhosis associated with chronic liver disease, liver fibrosis, hepatic stellate cell activation, accumulation of hepatic fibrin and total collagen; necrotizing inflammatory and / or immunogenic liver diseases; and genitourinary disorders, such as renal fibrosis and renal failure due to chronic kidney disease or insufficiency (e.g., due to accumulation / deposition and tissue damage, progressive sclerosis, glomerulonephritis); benign prostatic hyperplasia; systemic sclerosis; interstitial cardiac fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; non-alcoholic steatohepatitis or NASH;

[0305] (2) Ischemia and reperfusion injury; ischemia / reperfusion associated with organ transplantation, lung transplantation, lung transplantation, and heart transplantation; preservation of blood substitutes for trauma patients;

[0306] (3) Sexual, gynecological and urological conditions or disorders: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction (e.g., female sexual arousal disorder, hyporesponsiveness), 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 urinary incontinence; diabetic nephropathy;

[0307] (4) Eye diseases or conditions: glaucoma, retinopathy, diabetic retinopathy (including proliferative and non-proliferative), blepharitis, dry eye syndrome, Sjögren's syndrome;

[0308] (5) Hearing disorders or conditions: hearing loss, partial or complete hearing loss; partial or complete deafness; tinnitus; noise-induced hearing loss;

[0309] (6) Local or skin conditions: dermal fibrosis, scleroderma, skin fibrosis;

[0310] (7) Wound healing: for example in diabetes; microvascular perfusion modification (e.g., after injury to eliminate inflammation in perioperative care), anal fissures, diabetic ulcers;

[0311] (8) Other diseases or conditions: cancer metastasis, osteoporosis, gastroparesis; functional dyspepsia; diabetic complications, diseases related to endothelial dysfunction and neurological disorders related to reduced nitric oxide production; achalasia or esophageal atony.

[0312] (9) Selected from the following CNS diseases, health conditions, or disorders: Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Down syndrome, dementia, vascular dementia, vascular cognitive impairment, mixed dementia, Binswanger's dementia (subcortical arteriosclerotic encephalopathy), CADASIL or CADASIL syndrome with subcortical infarction and leukoencephalopathy, frontotemporal degeneration or dementia, HIV-related dementia (including asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-related dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy), Lewy body dementia, Alzheimer's disease (mild cognitive impairment, MCI), glaucoma, Huntington's disease. Disease (or chorea, HD) or cognitive deficits associated with HD; multiple sclerosis (MS) (including clinical single syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS)), multiple system atrophy (MSA), Parkinson's disease, Parkinson's plus disease, spinocerebellar ataxia, Steel-Richardson-Olszewski disease (progressive supranuclear palsy), attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD);

[0313] (10) Selected from the following CNS conditions or illnesses: Alzheimer's disease or pre-Alzheimer's disease, mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease;

[0314] (11) Selected from the following CNS conditions: traumatic (closed or open, penetrating head injury), traumatic brain injury (TBI, including, for example, concussion and chronic traumatic encephalopathy (CTE)) or non-traumatic (stroke (including ischemic stroke), aneurysm, hypoxia) brain injury or cognitive impairment or dysfunction caused by brain injury or neurodegenerative disease.

[0315] (12) CNS diseases or conditions are selected from dystonia, including, for example, generalized, focal, segmental, sexual, intermediate, acute dystonia response and hereditary / primary dystonia; and movement disorders, including, for example, acute, chronic / tardive movement disorders and non-motor and levodopa-induced movement disorders (LID).

[0316] (13) CNS diseases or conditions are selected from those characterized by synaptic plasticity and relatively shortened synaptic processes, including, for example, fragile X chromosome, Rhett's disorder, Williams syndrome, Renpenning's syndrome, autism spectrum disorders (including autism), Asperger's syndrome, pervasive developmental disorders and childhood disintegration disorder;

[0317] (14) CNS disorders are neuropathic pain;

[0318] (15) CNS disorders are selected from the following psychotic, mental, emotional, or affective disorders: bipolar disorder, schizophrenia, generalized psychosis, drug-induced psychosis, paranoia, affective schizophrenia, obsessive-compulsive disorder (OCD), depression, anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD); or

[0319] (16) CNS disorders are selected from chemotherapy-induced brain, levodopa-induced addictive behavior, alcohol poisoning, narcotic dependence (including but not limited to opioids or other substances) and substance abuse.

[0320] In other embodiments of the invention, compounds of formula I and pharmaceutically acceptable salts thereof can be used to prevent and / or treat diseases, conditions, and symptoms that may benefit from sGC stimulation or NO pathway upregulation:

[0321] Hypertension, refractory hypertension, diabetic hypertension, pulmonary hypertension (PH), pulmonary arterial hypertension, PH associated with COPD, chronic airflow obstruction, asthma or pulmonary fibrosis, thrombosis, embolism, thromboembolic disease, Alzheimer's disease, atherosclerosis, right ventricular hypertrophy, heart failure, diastolic dysfunction, systolic dysfunction, sleep apnea associated with heart failure, cirrhosis, renal fibrosis, renal failure due to chronic kidney disease or insufficiency, metabolic disorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis, erectile dysfunction, female sexual dysfunction, female sexual arousal dysfunction, and vaginal atrophy.

[0322] In some embodiments, the present invention relates to a method of treating a subject’s disease, health condition or ailment, comprising administering to the subject in need of treatment a therapeutically effective amount of a compound of any one of the general formulas described above or a pharmaceutically acceptable salt thereof, wherein the disease, health condition or ailment is selected from one of the diseases listed above.

[0323] In other implementations, the disease, health condition, or ailment is selected from peripheral, pulmonary, hepatic, renal, cardiac, or cerebral vascular / endothelial diseases or conditions or other circulatory-related disorders, selected from: increased acute and chronic coronary artery pressure, arterial hypertension and vascular conditions resulting from cardiac and renal complications, heart disease, stroke (especially ischemic stroke), cerebral ischemia, renal failure; refractory hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; decreased ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or injury; myocardial infarction; stroke or transient ischemic attack (TIA); obstructive thromboangiitis; stable or unstable angina; coronary artery spasm, variant angina, Prinzmoto's angina; restenosis and thrombotic conditions resulting from thrombolytic therapy.

[0324] In other implementations, the disease, health condition, or symptom is selected from peripheral vascular / endothelial diseases or conditions or other circulatory-related diseases, including peripheral artery disease, peripheral occlusive artery disease; peripheral vascular disease; hypertension; Raynaud's syndrome or phenomenon or disease; borderline limb ischemia; vasculitis; peripheral embolism; intermittent claudication; vascular occlusive crisis; Duchenne and Becker muscle dystrophy; microcirculatory abnormalities; and vascular leakage or permeability problems.

[0325] In other implementations, the disease, health condition, or ailment is selected from the following lung conditions or other circulatory-related diseases: pulmonary hypertension; pulmonary hypertension and associated pulmonary vascular remodeling; localized thrombosis; right ventricular hypertrophy; hypertonic lung; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, anterior capillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arterial disease, plexogenic pulmonary arterial disease; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis and lung transplantation. In some of these implementations, pulmonary hypertension is pulmonary hypertension associated with or related to the following: left ventricular dysfunction, hypoxemia, WHO... Hypertension of groups I, II, III, IV, and V; mitral valve disease; constrictive pericarditis; aortic stenosis; cardiomyopathy; mediastinal fibrosis; pulmonary fibrosis; anomalous pulmonary venous drainage; pulmonary venous occlusive disease; pulmonary vasculitis; collagen vascular disease; congenital heart disease; pulmonary venous hypertension; interstitial lung disease; sleep apnea; sleep breathing disorders; alveolar hypoventilation syndrome; prolonged exposure to high altitudes; neopulmonary disease; alveolar capillary dysplasia; sickle cell disease; coagulation disorders; chronic thromboembolism; pulmonary embolism due to tumors, parasites, or foreign bodies; connective tissue diseases; lupus; schistosomiasis; sarcoidosis; chronic obstructive pulmonary disease; asthma; emphysema; chronic bronchitis; pulmonary capillary angioma; histiocytosis X; lymphangioma and pulmonary vessels compressed due to adenosis, tumors, or fibrotic mediastinitis.

[0326] In other implementations, the health condition or disease is selected from the following vascular or endothelial diseases or conditions or other circulatory-related illnesses: atherosclerotic 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 following thrombolytic therapy; restenosis following percutaneous transluminal angioplasty; restenosis following percutaneous transluminal coronary angioplasty and bypass surgery; inflammation; cardiovascular diseases associated with metabolic syndrome, obesity, dyslipidemia, diabetes, or hypertension; lipid-related conditions, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; preeclampsia; progression of polycystic kidney disease; and subcutaneous fat.

[0327] In other implementations, the disease, health condition, or symptom is selected from cirrhosis, cirrhosis associated with chronic liver disease, liver fibrosis, hepatic stellate cell activation, accumulation of hepatic fibrous collagen and total collagen; and necrotizing inflammatory or immunogenic liver disease.

[0328] In other implementations, the disease, health condition, or ailment is selected from the following urogenital system conditions: renal fibrosis; renal failure due to chronic kidney disease or insufficiency; renal failure due to accumulation or deposition and tissue damage, progressive sclerosis, or glomerulonephritis; and benign prostatic hyperplasia.

[0329] In other implementations, the disease, health condition, or symptom is systemic sclerosis.

[0330] In other implementations, the disease, health condition, or symptom is selected from the following cardiac conditions: interstitial cardiac fibrosis; cardiac remodeling and fibrosis; and cardiac hypertrophy.

[0331] In some implementations, the condition is selected from the following CNS diseases, health conditions, or symptoms: Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lugglick's disease), Down syndrome, dementia, vascular dementia, mixed dementia, vascular cognitive impairment, Binswanger dementia (subcortical arteriosclerotic encephalopathy), autosomal dominant arteriosclerosis of the brain with subcortical infarction and leukoencephalopathy (CADASIL or CADASIL syndrome), frontotemporal degeneration or dementia, HIV-related dementia (including asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment), etc. Cognitive impairment (MND) and HIV-associated dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy), Lewy body dementia, Alzheimer's disease (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, Parkinson's plus disease, spinocerebellar ataxia, Triple S-Leigh-Oxley disease (progressive supranuclear palsy), attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD).

[0332] In other implementations, the disease, health condition, or symptom is selected from the following CNS symptoms or conditions: Alzheimer's disease or pre-Alzheimer's disease, mild to moderate Alzheimer's disease, or moderate to severe Alzheimer's disease.

[0333] In other implementations, CNS conditions are selected from traumatic (closed or open, penetrating head injury), traumatic brain injury (TBI), or non-traumatic (stroke (especially ischemic stroke), aneurysm, hypoxia) brain injury or cognitive impairment or dysfunction caused by brain injury or neurodegenerative disease.

[0334] In other implementations, CNS diseases or conditions are selected from dystonia, including, for example, generalized, focal, segmental, sexual, intermediate, acute dystonia response and hereditary / primary dystonia; and movement disorders, including, for example, acute, chronic / delayed and non-motor and levodopa-induced movement disorders (LID).

[0335] In other implementations, CNS diseases or conditions are selected from those characterized by synaptic plasticity and relatively shortened synaptic processes, including, for example, Fragile X syndrome, Rett syndrome, Williams syndrome, René syndrome, autism spectrum disorders (including autism), Asperger syndrome, pervasive developmental disorders, and childhood disintegrative disorders.

[0336] In other implementations, the CNS symptom is neuropathic pain.

[0337] In other implementations, CNS disorders are selected from the following psychosis, mental, mood, or affective disorders: bipolar disorder, schizophrenia, generalized psychosis, drug-induced psychosis, paranoia, affective schizophrenia, obsessive-compulsive disorder (OCD), depression, anxiety disorder, panic disorder, and post-traumatic stress disorder (PTSD).

[0338] In other implementations, CNS symptoms are selected from chemotherapy-induced brain disorders, levodopa-induced addictive behaviors, alcoholism, narcotic dependence (including but not limited to opioids or other substances), and substance abuse.

[0339] In some implementations, the disease or condition is achalasia or esophageal atony.

[0340] In other implementations, the disease or condition is non-alcoholic steatohepatitis or NASH.

[0341] In other implementations, the disease, health condition, or ailment is selected from ischemia-reperfusion injury; ischemia / reperfusion associated with organ transplantation, lung transplantation, lung transplantation, or heart transplantation; and blood substitutes for preserved trauma patients.

[0342] In other implementations, the disease, health condition, or symptom is selected from the following sexual, gynecological, or urological conditions or illnesses: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal dysfunction; hyporesponsiveness 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 urinary incontinence; diabetic nephropathy.

[0343] In other implementations, the disease, health condition, or ailment is selected from vaginal atrophy, dyspareunia, and atrophic vaginitis.

[0344] In other implementations, the disease, health condition, or symptom is selected from benign prostatic hyperplasia (BPH) or hypertrophy or enlargement; bladder outlet obstruction; bladder pain syndrome (BPS); interstitial cystitis (IC); overactive bladder, neurogenic bladder, and urinary incontinence.

[0345] In other implementations, the disease, health condition, or ailment is selected from the following sexually transmitted conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal dysfunction and hyporesponsive arousal disorder.

[0346] In other implementations, the disease or condition is diabetic nephropathy.

[0347] In other implementations, the disease, health condition, or ailment is Duchenne dystrophy and Becker muscle dystrophy.

[0348] In other implementations, the disease is selected from the following eye diseases or conditions: glaucoma, retinopathy, diabetic retinopathy (including proliferative and non-proliferative), blepharitis, dry eye syndrome, and Sjögren's syndrome.

[0349] In other implementations, the disease is selected from the following hearing diseases or conditions: hearing impairment, partial or complete hearing loss; partial or complete deafness; tinnitus; and noise-induced hearing loss.

[0350] In other implementations, the disease is selected from the following local or skin conditions: dermal fibrosis, scleroderma, and skin fibrosis.

[0351] In other implementations, the treatment involves wound healing; wound healing in diabetes; improved microvascular perfusion; improved microvascular perfusion problems after injury; treatment of anal fissures; and treatment of diabetic ulcers.

[0352] In other implementations, the disease or condition is selected from cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; diabetic complications; diseases associated with endothelial dysfunction; and neurological disorders associated with reduced nitric oxide production.

[0353] In other implementations, the disease or condition is selected from age-related memory impairment, mixed dementia, sleep-wake disorder, and Snedden syndrome.

[0354] In other implementations, the disease or condition is selected from acute pain, central pain syndrome, chemotherapy-induced neuropathy and neuropathic pain, diabetic neuropathy, fibromyalgia, inflammatory pain, neuropathic pain, neuropathic pain associated with CNS disease, painful diabetic peripheral neuropathy, postoperative pain, rigidity pain, and visceral pain.

[0355] In other implementations, the disease or condition is selected from high-altitude (altitude) disease, cerebral small vessel disease, cerebral vasculitis, cerebral vasospasm, diabetic heart failure (diabetic HF), diabetic vascular disease, diabetic macular edema, diabetic microvascular disease, heart failure with preserved ejection fraction (HFpEF), hepatic encephalopathy, moyamoya disease, non-diabetic nephropathy, and Parkinson's dysphagia.

[0356] In other implementations, the disease or condition is selected from angina pectoris, ataxia-telangiectasia, 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), cognitive impairment associated with sickle cell disease, concussion, dysphagia, ocular fibrosis, Fabry disease, Gaucher's disease, glioblastoma, cerebral malaria-associated inflammation (SoC), inflammation caused by infectious diseases, intellectual disability, and microvascular disease. Angina pectoris, myopic choroidal neovascularization, neuromyelitis optica, neuropathic pain of multiple sclerosis, neuropathic pain of herpes zoster (shingles), neuropathic pain after spinal surgery, Parkinson's dementia, peripheral and autonomic neuropathy, peripheral retinal degeneration, post-traumatic stress disorder, postherpetic neuralgia, postoperative dementia, proliferative vitreoretinopathy, radiation-induced fibrosis, radiculopathy, refractory epilepsy, retinal vein occlusion, Sjögren's syndrome, spinal cord injury, spinal muscular atrophy, spinal subluxation, tau proteinosis, ulcers, and wet age-related macular degeneration.

[0357] In other implementations, the disease or condition is selected from the orphan pain indication. Specifically, the orphan pain indication is selected from acetazolamide-responsive myotonia, autologous erythrocyte sensitization syndrome, autosomal dominant Charcot-Marie-Tuss disease type 2V, autosomal dominant intermediate Charcot-Marie-Tuss disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2A, congenital pain insensitivity associated with channel disease, chronic pain requiring intraspinal analgesia, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, congenital pain insensitivity with hyperhidrosis, congenital pain insensitivity with severe intellectual disability, and congenital pain insensitivity with few... Hyperhidrosis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial episodic pain syndrome, familial episodic pain syndrome mainly involving the lower extremities, familial episodic pain syndrome mainly 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, orbital pain and generalized neurofibromatosis-Martovian syndrome, paroxysmal severe pain, persistent idiopathic facial pain, qualitative or quantitative calpain deficiency and Tolosa-Hunt syndrome.

[0358] In another embodiment, the compound of the present invention may be delivered in the form of an implantable device (e.g., a stent). A stent is a mesh "tube" inserted into a natural passage / channel in the body to prevent or eliminate localized flow constriction caused by disease. The term may also refer to a tube used to temporarily hold the opening of the natural passage to allow access for surgery.

[0359] Drug-eluting stents (DES) are slow-release drugs placed in narrowed, diseased peripheral or coronary arteries to block cell proliferation, typically smooth muscle cell proliferation. This prevents fibrosis, which would otherwise block the stented artery along with a clot (thrombus) (a process called restenosis). Stents are usually placed in the peripheral or coronary arteries by an interventional cardiologist or interventional radiologist during angioplasty. Drugs commonly used in DES to block cell proliferation include paclitaxel or rapamycin analogs.

[0360] In some embodiments of the invention, the sGC stimulant of the invention can be delivered via a drug-eluting stent coated with the sGC stimulant. Drug-eluting stents coated with the sGC stimulant of the invention can be used to prevent stent restenosis and thrombosis during percutaneous coronary intervention. Drug-eluting stents coated with the sGC stimulant of the invention can prevent smooth cell proliferation and aid in angiogenesis and endothelial tissue regeneration in the artery where the stent is inserted.

[0361] The alternative to percutaneous coronary intervention (PCI) for treating refractory angina caused by coronary artery obstruction is called coronary artery bypass grafting (CABG). CABG only provides relief from the ongoing complications that can arise from rapidly developing graft atherosclerosis. Saphenous vein grafts are the most commonly used conduits in CABG procedures. Long-term clinical success of venous CABG is hampered by three main factors: accelerated graft atherosclerosis, incomplete internalization, and thrombosis.

[0362] In some embodiments, the sGC stimulant of the present invention can be used to prevent saphenous vein graft failure during CABG. The compounds of the present invention can aid in the internalization process and help prevent thrombosis. In this indication, the sGC stimulant is delivered locally in gel form.

[0363] The terms “disease,” “symptom,” and “condition” are used interchangeably here and refer to medical or pathological conditions mediated by sGC, cGMP, and / or NO.

[0364] As used herein, the terms “subject” and “patient” are used interchangeably. The terms “subject” and “patient” refer to an animal (e.g., poultry, such as chickens, quails, or turkeys, or mammals), specifically “mammals,” including non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more specifically, humans. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, cattle, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In some embodiments, the subject is a human.

[0365] The present invention also provides a method for treating a subject with one of the aforementioned diseases, conditions, and symptoms, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject requiring treatment. Alternatively, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating one of the aforementioned diseases, conditions, and symptoms in a subject requiring treatment. The present invention further provides a method for preparing or manufacturing a medicament for treating one of the aforementioned diseases, conditions, and symptoms, comprising using a compound of formula I or a pharmaceutically acceptable salt thereof.

[0366] As used herein, “biological sample” means a living or ex vivo sample, including but not limited to cell cultures or extracts thereof; bioscopy material obtained from mammals or extracts thereof; blood, saliva, urine, feces, semen, tears, lymph, eye fluid, vitreous humor, cerebrospinal fluid (CSF) or other bodily fluids or extracts thereof.

[0367] The terms "treat," "treating," or "treatment" for a condition or disease refer to the mitigation or elimination of the cause and / or effect of the condition or disease. As used herein, the terms "treat," "treatment," and "treating" refer to the reduction or improvement of the progression, severity, and / or duration of a condition mediated by sGC, cGMP, and / or NO, or the improvement of one or more symptoms (preferably one or more identifiable symptoms) of the condition (i.e., "controlling" but not "curing") caused by administration of one or more therapies (e.g., one or more therapeutic agents, such as compounds or compositions of the present invention). In specific embodiments, the terms "treat," "treatment," and "treating" refer to the improvement of at least one measurable physical parameter of a condition mediated by sGC, cGMP, and / or NO. In other implementations, the terms “treat,” “treatment,” and “treating” refer to the suppression of sGC, cGMP, and / or NO-mediated disease progression by means of, for example, stabilizing identifiable symptoms or by means of, for example, stabilizing physical parameters, or both.

[0368] As used herein, the term "prevention" refers to the pre-administration of a medication to prevent or stop the occurrence of one or more symptoms of a disease or condition. Those skilled in the medical field will recognize that the term "prevention" is not an absolute term. In the medical field, it should be understood to mean the prophylactic administration of a medication to substantially reduce the likelihood or severity of a condition or its symptoms, and this is the intended meaning of this invention. The standard text in this field, the Physician's Desk Reference, uses the term "prevention" hundreds of times. As used herein, the terms "prevent," "preventing," and "prevention" refer to preventing the cause, effects, symptoms, or progression of a disease or condition before it fully manifests itself.

[0369] In one embodiment, the method of the present invention is a preventive or "preemptive" measure for patients, specifically humans, with a predisposition (e.g., genetic predisposition) to have sGC, cGMP and / or NO-related diseases, conditions or symptoms.

[0370] In other embodiments, the method of the present invention is a preventative or "preemptive" measure for patients, specifically humans, suffering from diseases, conditions, or illnesses that give them a risk of developing sGC, cGMP, or NO-related diseases, conditions, or symptoms.

[0371] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy to treat or prevent diseases or conditions mediated, regulated, or affected by sGC, cGMP, and / or NO.

[0372] The compounds and compositions disclosed herein may also be used for veterinary treatment of companion animals, wild animals and farm animals, including but not limited to dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.

[0373] In other embodiments, the present invention provides a method for stimulating sGC activity in a biological sample, comprising contacting the biological sample with a compound or composition of the present invention. The use of sGC stimulants in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioanalysis and biosample storage.

[0374] Combination therapy

[0375] The compounds and pharmaceutical compositions described herein may be used in combination with one or more other therapeutic agents. For combination therapy with more than one active agent (wherein the active agent is in a single-dose formulation), the active agent may be administered alone or in combination. Additionally, administration of one element may be before, simultaneously with, or after administration of another agent.

[0376] When co-administered with other medications, such as another analgesic, the “effective dose” of the second medication will depend on the type of medication used. Appropriate doses are known for approved medications and can be adjusted by a technician based on the subject’s condition, the type of condition being treated, and the amount of the compound described herein. Where no dose is explicitly stated, an effective dose should be assumed. For example, the compounds described herein can be administered to subjects at doses ranging from 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.

[0377] When using "combination therapy", an effective dose can be achieved by using a first dose of a compound of formula I or a pharmaceutically acceptable salt thereof and a second dose of another suitable therapeutic agent.

[0378] In one embodiment of the invention, the Formula I compound or a pharmaceutically acceptable salt thereof and the other therapeutic agent are each administered in an effective amount (i.e., each amount is therapeutically effective when administered alone). In another embodiment, the Formula I compound and the other therapeutic agent are each administered in an amount that, on its own, does not provide a therapeutic effect (a subtherapeutic dose). In another embodiment, the Formula I compound may be administered in an effective amount, while the other therapeutic agent is administered in a subtherapeutic dose. In yet another embodiment, the Formula I compound may be administered in a subtherapeutic dose, while the other therapeutic agent (e.g., a suitable cancer therapeutic agent) is administered in an effective amount.

[0379] As used herein, the terms “in combination” or “co-administered” are used interchangeably and refer to the use of more than one therapy (e.g., one or more preventive and / or therapeutic agents). The use of these terms does not limit the order in which therapies (e.g., preventive and / or therapeutic agents) are administered to the subject.

[0380] Co-dosing includes administering a first and a second amount of a compound in a substantially simultaneous manner, for example, in a single pharmaceutical composition (e.g., capsules or tablets having a fixed ratio of first and second amounts) or in a plurality of separate capsules or tablets. Additionally, co-dosing also includes administering each compound in a sequential manner in any order. When co-dosing involves administering a first amount of a Formula I compound and a second amount of another therapeutic agent, the compounds are administered sufficiently close in time to achieve the desired therapeutic effect. For example, the time interval between each administration that produces the desired therapeutic effect can range from several minutes to several hours and can be determined based on the properties of each compound (e.g., efficacy, solubility, bioavailability, plasma half-life, and kinetic characteristics). For example, the Formula I compound and the second therapeutic agent can be administered in any order within approximately 24 hours, approximately 16 hours, approximately 8 hours, approximately 4 hours, approximately 1 hour, or approximately 30 minutes of each other.

[0381] More specifically, the first therapy (e.g., a preventative or therapeutic agent, such as the compound described herein) may be administered to the subject before (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 prior to, during, 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 prior to, during, or after) the administration of the second therapy ...

[0382] Examples of other therapeutic agents that can be administered in combination with, alone or in the same pharmaceutical composition as a compound of formula I or a pharmaceutically acceptable salt thereof include, but are not limited to:

[0383] (1) Endothelial-derived release factor (EDRF) or NO gas.

[0384] (2) NO donors, such as nitrosothiols, nitrites, sydnonimine, NONOate, N-nitrosamines, N-hydroxynitrosamines, nitrosimines, nitrotyrosine, diazacyclobutene dioxide, etc. Triazole 5-imine, oxime, hydroxylamine, N-hydroxyguanidine, hydroxyurea, or furazolidone. Some examples of these types of compounds include: trinitroglycerin ester (also known as GTN, nitroglycerin, nitroglycerin, and trinitroglycerin), which is a nitrate ester of glycerol; sodium nitroprusside (SNP), which is a tetragonal bipyramidal complex in which nitric oxide molecules coordinate with iron metal; 3-morpholino-siderone imine (SIN-1), which is an amphoteric compound formed by the combination of morpholine and siderone imine; S-nitroso-N-acetylpenicillamine (SNAP), which is an N-acetylated amino acid derivative containing a nitrosothiol functional group; diethylenetriamine / NO (DETA / NO), which is a compound in which nitric oxide is covalently linked to diethylenetriamine; and m-nitrooxymethylphenyl ester of acetylsalicylic acid. More specific examples of NO donors in some of these categories include: classic nitro vasodilators, such as organic nitrates and nitrites, including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil; isosorbide ( -SR、 ), 3-morpholino-siderone imine; linsidomine chloride hydrate (“SIN-1”); S-nitroso-N-acetylpenicillamine (“SNAP”); S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione monoethyl ester (GSNO-ester), 6-(2-hydroxy-1-methyl-nitrosohydrazyl)-N-methyl-1-hexylamine or diethylamine NONOate.

[0385] (3) Other substances that enhance cGMP concentration, such as protoporphyrin IX, arachidonic acid and phenylhydrazine derivatives.

[0386] (4) Nitric oxide synthase substrates: e.g., N-hydroxyguanidine-based analogs, such as N[G]-hydroxy-L-arginine (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylamino)-3-hydroxyguanidine and PR5 (1-(3,4-dimethoxy-2-chlorobenzylamino)-3-hydroxyguanidine); L-arginine derivatives (e.g., high-Arg, high-NOHA, N-tert-butoxy- and N-(3-methyl-2-butenyl)oxy- L-arginine, canavanine, ε-guanidinocanoic acid, guanidine, hydroxyguanidine, and L-tyrosyl-L-arginine); N-alkyl-N'-hydroxyguanidine (e.g., N-cyclopropyl-N'-hydroxyguanidine and n-butyl-N'-hydroxyguanidine), N-aryl-N'-hydroxyguanidine (e.g., N-phenyl-N'-hydroxyguanidine and its para-substituted derivatives with -F, -Cl, -methyl, and -OH substituents, respectively); guanidine derivatives, such as 3-(trifluoromethyl)propylguanidine.

[0387] (5) Compounds that enhance eNOS transcription.

[0388] (6) NO-independent heme-independent sGC activators, including but not limited to:

[0389] BAY 58-2667 (described in patent publication DE19943635)

[0390]

[0391] HMR-1766 (Sodium ataciguat, described in patent publication WO2000002851)

[0392]

[0393] S 3448(2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (described in patent publications DE19830430 and WO2000002851)

[0394] and

[0395] HMR-1069 (Sanofi-Aventis).

[0396] (7) Heme-dependent and NO-independent sGC stimulants, including but not limited to:

[0397] YC-1 (see patent publications EP667345 and DE19744026)

[0398]

[0399] Riociguat (BAY 63-2521) (Described in DE19834044)

[0400]

[0401] Neliciguat (BAY 60-4552, described in WO 2003095451)

[0402]

[0403] Vericiguat (BAY 1021189)

[0404]

[0405] BAY 41-2272 (described in DE19834047 and DE19942809)

[0406]

[0407] BAY 41-8543 (described in DE19834044)

[0408]

[0409] Etriciguat (described in WO 2003086407)

[0410]

[0411] CFM-1571 (described in patent publication WO2000027394)

[0412]

[0413] A-344905, its acrylamide analog A-350619 and aminopyrimidine analog A-778935

[0414]

[0415] And other sGC stimulants described in any of the following disclosures:

[0416] US20090209556, US8455638, US20110118282 (WO2009032249), US20100292192, US20110201621 , US7947664, US8053455 (WO2009094242), US20100216764, US8507512, (WO2010099054) US2011 0218202 (WO2010065275), US20130012511 (WO2011119518), US20130072492 (WO2011149921), US20130210798 (WO2012058132), and other compounds described in Tetrahedron Letters (2003), 44(48):8661-8663.

[0417] (8) Compounds that inhibit cGMP degradation, such as:

[0418] PDE5 inhibitors, such as sildenafil. and related medications, such as avanafil, lodenafil, mirodenafil, and sildenafil citrate. Tadalafil (tadalafil) or ), vardenafil And udenafil; alprostadil; dipyridamole and PF-00489791; and

[0419] PDE9 inhibitors, such as PF-04447943, and

[0420] PDE10 inhibitors, such as PF-02545920 (PF-10).

[0421] (9) The following types of calcium channel blockers:

[0422] Dihydropyridine calcium channel blockers, such as asamlodipine. Aranidipine Azelnidipine Barnidipine Benidipine Cinnidipine Clevidipine Diltiazem and efonidipine felodipine Lacidipine Lercanidipine Manidipine nicardipine Nifedipine Nilvadipine Nimodipine Nisoldipine Nitrindyldipine pranidipine isradipine

[0423] Phenylalkylamine calcium channel blockers, such as verapamil.

[0424]

[0425] and gallopamil ( D600);

[0426] Benzothiazazepines, such as diltiazem

[0427] and

[0428] Non-selective calcium channel inhibitors, such as miladil, bepridil, fluspirilene, and fendiline.

[0429] (10) Endothelin receptor antagonists (ERAs), such as dual (ETA) A and ET B Bosentan, an endothelin receptor antagonist Sitaxentan Or ambrisentan

[0430] (11) Prostaglandin derivatives or analogues, such as prostaglandin (prostaglandin I2), epoprostenol (synthetic prostaglandin, ), treprostinil Iloprost Iloprost And oral and inhalation forms currently under development

[0431] (12) Anti-hyperlipidemia drugs, such as the following types:

[0432] Bile acid polychelators, such as cholestyramine, colestipol, colestilan, colesevelam, or sevelamer;

[0433] Statins, such as atorvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin, and pravastatin;

[0434] Cholesterol absorption inhibitors, such as ezetimibe;

[0435] Other lipid-lowering agents include ethyl eicosapentaenoate, ethyl ω-3-acid, and reduceol;

[0436] Fibrates, such as clofibrate, bezafibrate, clinofibrate, gemfibrozil, ronifibrate, binifibrate, fenofibrate, ciprofibrate, and choline fenofibrate;

[0437] Nicotinic acid derivatives, such as acipimox and nicotinic acid;

[0438] A combination of statins, nicotinic acid, and intestinal cholesterol absorption inhibitors (ezetimibe and others) and fibrates; and

[0439] Antiplatelet therapy, such as clopidogrel bisulfate.

[0440] (13) Anticoagulants, such as the following types:

[0441] Coumarin (vitamin K antagonists), such as warfarin. Acenocoumarol, phenylpropanol, and phenindione;

[0442] Heparin and its derivatives, such as low molecular weight heparin, fondaparinux, and idraparinux;

[0443] Direct thrombin inhibitors, such as argatroban, lepirudin, bivalirudin, dabigatran, and ximelagatran. and

[0444] Tissue plasminogen activators, used to dissolve clots and clear arteries, such as alteplase.

[0445] (14) Antiplatelet drugs, such as topidogrel, ticlopidine, dipyridamole and aspirin.

[0446] (15) ACE inhibitors, such as the following types:

[0447] Drugs containing thiol groups, such as captopril. And Zofenopril;

[0448] Drugs containing a dicarboxylic acid group, such as enalapril. Ramipril Quinapril (pentapeptide April) Perindopril Lisinopril And benazepril

[0449] Phosphonate-containing agents, such as fosinopril;

[0450] Natural ACE inhibitors, such as casokinins and lactokinins, are naturally occurring breakdown products of casein and whey after ingesting dairy products, especially cultured milk.

[0451] The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro are produced by the probiotic Lactobacillus helveticus or derived from casein, which also has ACE inhibitory and antihypertensive functions.

[0452] Other ACE inhibitors include alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril, and pirapril.

[0453] (16) Supplemental oxygen therapy.

[0454] (17) β-blockers, such as the following types:

[0455] Non-selective agents, such as alprenolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, oxprenonol, acebutolol, sotalol, mepindolol, celiprolol, arotinolol, tertatolol, amosulalol, nipradilol, propranolol, and timolol;

[0456] β1-selective agents, such as cebutolol, atenolol, betaxolol, bisoprolol, celiprolol, dobutamine hydrochloride, irsogladine maleate, carvedilol, talinolol, esmolol, metoprolol, and nebivolol; and

[0457] β2-selective drugs, such as butaxamine.

[0458] (18) Antiarrhythmic agents, such as the following types:

[0459] Type I (sodium channel blockers), such as quinidine, lidocaine, phenytoin, and propafenone;

[0460] Type III (potassium channel blockers), such as amiodarone, dofetilide, and sotalol; and

[0461] V-type, such as adenosine and digoxin.

[0462] (19) Diuretics, such as thiazide diuretics, such as chlorothiazide, chlorothiazide and hydrochlorothiazide, benzylfluorothiazide, cyclopenthiazine, methazothiazide, quinethazone, xipamide, metolazone, indapamide, cicletanine; loop diuretics, such as furosemide and toresamide; potassium-sparing diuretics, such as amiloride, spironolactone, canileate potassium, eplerenone and triamterene; combinations of these agents; other diuretics, such as acetazolamide and carperitide.

[0463] (20) Direct-acting vasodilators, such as hydralazine hydrochloride, diazine, sodium nitroprusside, cadralazine; other vasodilators, such as isosorbide dinitrate and isosorbide 5-mononitrate.

[0464] (21) Exogenous vasodilators, such as and alpha blockers.

[0465] (22) α-1-adrenergic receptor antagonists, such as prazosin, indoramin, urapidil, bunazosin, terazosin and doxazosin; atrial natriuretic peptide (ANP), ethanol, histamine inducers, tetrahydrocannabinol (THC) and papaverine.

[0466] (23) The following types of bronchodilators:

[0467] Short-acting β2 agonists, such as salbutamol or albuterol. And terbutaline;

[0468] Long-acting β2 agonists (LABAs), such as salmeterol and formoterol;

[0469] Anticholinergic drugs, such as pratropium and tiotropium; and

[0470] Theophylline, bronchodilators, and phosphodiesterase inhibitors.

[0471] (24) Corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, triamcinolone, dexamethasone, fluticasone, flunisolide, hydrocortisone, and corticosteroid analogs (such as budesonide).

[0472] (25) Dietary supplements, such as omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, tribulus terrestris, arginine, oats (Avenasativa), horny goat weed, maca root, muira puama, saw palmetto, and Swedish flower pollen; vitamin C, vitamin E, and vitamin K2; testosterone supplements and transdermal testosterone patches; zoraxel, natroxone, bremelanotide, and melanotan II.

[0473] (26) PGD2 receptor antagonists.

[0474] (27) Immunosuppressants, such as cyclosporine (cyclosporine A, cyclosporine B, cyclosporine C, cyclosporine D, cyclosporine A, cyclosporine B, cyclosporine C, cyclosporine D, cyclosporine D, cyclosporine A, cyclosporine B, cyclosporine D ... ), Tacrolimus (FK-506, ), rapamycin Other FK-506 immunosuppressants such as mycophenolate mofetil

[0475] (28) Nonsteroidal anti-asthmatic drugs, such as β2-agonists, including terbutaline, metaproterenol, fenoterol, isoetharine, salbutamol, salmeterol, bitolterol, and pirbuterol; β2-agonist corticosteroid combinations, such as salmeterol-fluticasone. Formolo-Budinede Theophylline, cromoglycine, sodium cromoglycate, nedocromil, atropine, ipratropium, ipratropium bromide, and leukotriene biosynthesis inhibitors (zileuton, BAY1005).

[0476] (29) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives, such as aminoprofen and benzene. Benoxaprofen, buprofen, carprofen, fenbufen, fenoprofen, fluprofen, flubiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, supraprofen, tiaprofenic acid, and sulfur Tioxaprofen; acetic acid derivatives, such as indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac; fenamic acid derivatives, such as flufenamic acid, meclofenamic acid, mefenamic acid, and niflumic acid. Biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal; oxicam, such as isoxicam, piroxicam, sudoxicam and tenoxicam; salicylates, such as acetylsalicylic acid and sulfasalazine; and pyrazolone, such as apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone.

[0477] (30) Cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib. Rofecoxib 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.

[0478] (31) Antidiabetic agents, such as insulin and insulin analogs; sulfonylureas, such as glyburide, glybenclamide, glipizide, gliclazide, gliquidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, and olazamide; biguanides, such as metformin. Alpha-glucosidase inhibitors, such as acarbose, epalrestat, voglibose, and miglitol; thiazolidinone compounds, such as rosiglitazone. Troglitazone Cycloglitazone and pioglitazone And empaglitazone; insulin sensitizers, such as pioglitazone and rosiglitazone; insulin secretagogues, such as repaglinide, nateglinide and mitiglinide; incretin mimics, such as exanatide and liraglutide; amyloid analogs, such as pramlintide; glucose-lowering agents, such as chromium picolinate optionally in combination with biotin; dipeptidyl peptidase IV inhibitors, such as sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin.

[0479] (32) HDL cholesterol increasers, such as anacetrapib and dalcetrapib.

[0480] (33) Anti-obesity drugs, such as amfepramone hydrochloride. phentermine Benzfetamine hydrochloride phendimetrazine tartrate Mazindol Orlistat Rimonabant Amfepramone, chromium picolinate; combinations, such as fentam / topiramate, bupropion / naltrexone, bupropion SR / zonisamide SR, salmeterol oxaliplatin / fluticasone propionate; lorcaserin hydrochloride. hydrochloride, fentanyl / topiramate, cetilistat, exenatide, liraglutide, metformin hydrochloride, bupropion SR / zonisamide SR, CORT-108297, canagliflozin, chromium pyridinecarboxylate, GSK-1521498, LY-377604, metreleptin, obinepitide, P-57AS3, PSN-821, salmeterol oxadixate / fluticasone propionate, sodium tungstate, growth hormone (recombinant), tesamorelin, tesofensine, velneperitone, zonisamide, beloranib hemioxatate Hemioxalate, insulin-stimulating agents, resveratrol, sobetirome, tetrahydrocannabinol, and lapachone.

[0481] (34) Angiotensin receptor blockers, such as losartan, valsartan, candesartan, cilexetil, eprosartan, irbesartan, telmisartan, olmesartan, mesophosphatil, azilsartan and mesophosphatil.

[0482] (35) Renin inhibitors, such as aliskiren hemifumirate.

[0483] (36) Centrally acting α-2-adrenergic receptor agonists, such as methyldopa, clonidine and guanfacine.

[0484] (37) Adrenergic neuron blocking agents, such as guanethidine and guanadrel.

[0485] (38) I-1 receptor agonists of imidazoline, such as rimenidine dihydrogenphosphate and moxonidine hydrochloride hydrate.

[0486] (39) Aldosterone antagonists, such as spironolactone and eplerenone.

[0487] (40) Potassium channel activators, such as pinacidil.

[0488] (41) Dopamine D1 agonists, such as fenoldopam mesilate; other dopamine agonists, such as ibopamine, dopexamine and docarpamine.

[0489] (42) 5-HT2 antagonists, such as ketanserin.

[0490] (43) Vasopressin antagonists, such as tolvaptan.

[0491] (44) Calcium channel sensitizers (e.g., levosimendan) or activators (e.g., nicoridil).

[0492] (45) PDE-3 inhibitors, such as amrinone, milrinone, enoximone, vesnarinone, pimobendan and olprinone.

[0493] (46) Adenylate cyclase activators, such as colforsin dapropate hydrochloride.

[0494] (47) Positive inotropic agents, such as digoxin and metildigoxin; metabolic cardiotonics, such as ubiquinone; brain natriuretic peptides, such as nesiritide.

[0495] (48) Medications used to treat erectile dysfunction, such as alprostadil, avitadil and phentolamine mesilate.

[0496] (49) Medications used to treat obesity, including but not limited to amfepramone hydrochloride. Fentamin Benzylpheniramine hydrochloride phendimetrazine hydrochloride Morindo and orlistat

[0497] (50) Medications used to treat Alzheimer's disease and dementia, such as the following types:

[0498] Acetylcholinesterase inhibitors, including galantamine. Rivastigmine Donepezil and tacrine

[0499] NMDA receptor antagonists, such as memantine. and

[0500] Oxidoreductase inhibitors, such as idebenone.

[0501] (51) Psychiatric medications, such as the following types:

[0502] Ziprasidone (Geodon) TM ), risperidone (Risperdal) TM Olanzapine (Zyprexa) TM ), valproate;

[0503] Dopamine D4 receptor antagonists, such as clozapine;

[0504] Dopamine D2 receptor antagonists, such as nemonapride;

[0505] Mixed dopamine D1 / D2 receptor antagonists, such as zuclopenthixol;

[0506] GABA A receptor modulators, such as carbamazepine;

[0507] Sodium channel inhibitors, such as lamotrigine;

[0508] Monoamine oxidase inhibitors, such as moclobemide and indeloxazine;

[0509] primavanserin, perospirone; and

[0510] PDE4 inhibitors, such as roflumilast.

[0511] (52) Medications used to treat movement disorders or symptoms, such as the following types:

[0512] Catechol-O-methyltransferase inhibitors, such as entacapone;

[0513] Monoamine oxidase B inhibitors, such as selegiline;

[0514] Dopamine receptor modulators, such as levodopa;

[0515] Dopamine D3 receptor agonists, such as pramipexole;

[0516] Decarboxylase inhibitors, such as carbidopa;

[0517] Other dopamine receptor agonists, such as pergolide, ropinirole, and cabergoline;

[0518] Rtigonide, istradefylline, talipexole; zonisamide and safinamide; and

[0519] Synaptic vesicle amine transporter inhibitors, such as tetrabenazine.

[0520] (53) Medications used to treat mood or affective disorders or OCD, such as the following types

[0521] Tricyclic antidepressants, such as amitriptyline. Desipramine Imipramine Amoxapine Nortriptyline and clomipramine;

[0522] Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine. Fluoxetine Sertraline and citralopram

[0523] Doxepin trazodone and agomelatine;

[0524] Selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, reboxetine, and atomoxetine; dopamine antidepressants, such as bupropion and amineptine.

[0525] (54) Drugs used to enhance synaptic plasticity, such as the following types:

[0526] Nicotine receptor antagonists, such as mecamylamine; and

[0527] A combination of 5-HT, dopamine, and norepinephrine receptor agonists, such as lurasidone.

[0528] (55) Medications used to treat ADHD; 5-HT receptor modulators, such as vortioxetine, and α-2 adrenergic receptor agonists (such as cinetin).

[0529] (56) Neutral endopeptidase (NEP) inhibitors, such as sacubitril and omapatrilat; and

[0530] (57) Methylene Blue (MB).

[0531] Reagent test kit

[0532] The compounds and pharmaceutical compositions described herein may be included in a kit. The kit may include one or more doses of two or more pharmaceutical agents, each individually packaged or formulated, or one or more doses of two or more pharmaceutical agents packaged or formulated in combination. Thus, one or more pharmaceutical agents may be present in a first container, and the kit may optionally include one or more pharmaceutical agents in a second container. One or more containers may be placed within a package, which may optionally include instructions for administration or dosage. The kit may include other components, such as syringes or other devices for administering the pharmaceutical agents and diluents, or other devices for formulation. Therefore, the kit may include: a) a pharmaceutical composition comprising the compounds described herein and a pharmaceutically acceptable carrier, medium, or diluent; and b) a container or package. The kit may optionally include instructions for use describing the method of using the pharmaceutical composition in one or more of the methods described herein (e.g., for the prevention or treatment of one or more of the diseases and conditions described herein). The kit may optionally include a second pharmaceutical composition comprising one or more other pharmaceutical agents, pharmaceutically acceptable carriers, mediums, or diluents described herein for co-therapeutic purposes. Pharmaceutical compositions comprising the compounds described herein and the second pharmaceutical composition contained in the kit may optionally be combined in the same pharmaceutical composition.

[0533] The kit includes containers or packages containing the pharmaceutical composition and may also include separate containers (e.g., separate vials or separate foil packs). Containers may be, for example, paper or cardboard boxes, glass or plastic bottles or jars, resealable bags (e.g., to allow for “refilling” of tablets into different containers), or, depending on the treatment regimen, blister packs for dispensing with individual doses. It is feasible to use more than one container in a single package to market a single dosage form. For example, tablets may be contained in a vial, which in turn may be contained in a box.

[0534] An example of a reagent kit is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packs are known and widely used in the packaging industry for packaging unit dosage forms of pharmaceuticals. A blister pack typically consists of a relatively rigid sheet of material covered with a foil, preferably a transparent plastic material. During the packaging process, grooves are formed in the plastic foil. These grooves are the size and shape of a single tablet or capsule to be packaged, or may be sized and shaped to accommodate multiple tablets and / or capsules to be packaged. The tablets or capsules are then placed accordingly in the grooves, and the relatively rigid sheet of material is sealed relative to the plastic foil on the side of the foil opposite to the direction in which the grooves are formed. Thus, tablets or capsules are individually or collectively sealed in the grooves between the plastic foil and the sheet, as needed. Preferably, the sheet is strong enough that tablets or capsules can be removed from the blister pack by manually applying pressure to the grooves, thereby creating an opening in the grooves of the sheet. The tablets or capsules can then be removed through this opening.

[0535] Written memory aids may be required, containing information and / or instructions from the doctor, pharmacist, or subject regarding when to take the medication. A “daily dose” can be a single tablet or capsule, or several tablets or capsules, to be taken on a given date. When the kit contains individual compositions, the daily dose of one or more compositions of the kit may consist of a single tablet or capsule, while the daily dose of another or more compositions of the kit may consist of several tablets or capsules. The kit may take the form of a dispenser designed to dispense one daily dose at a time, as intended for its purpose. This dispenser may be equipped with a memory aid to further facilitate adherence to the protocol. An example of such a memory aid is a mechanical counter indicating the number of daily doses dispensed. Another example is a battery-powered microchip memory coupled to a liquid crystal reader, or an audible signal reminder device that, for example, reads out the date of the last daily dose and / or reminds the user of the next dose to be taken. Example

[0536] All references provided in the embodiments are incorporated herein by reference. All abbreviations, symbols, and conventions used herein are consistent with those used in current scientific literature. See, for example, Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd edition, Washington, DC: American Chemical Society, 1997, the full text of which is incorporated herein by reference.

[0537] Example 1: Compound Synthesis

[0538] Intermediate 1a

[0539]

[0540] 8-(2-Fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxylonitrile (1a) The title compound was synthesized in two steps as a yellow solid (0.60 g, 39% yield in two steps) according to the process described in the patent document (WO2015 / 187470A1). 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.09 (s, ¹H), 8.14 (s, ¹H), 7.91 (s, ¹H), 7.35 (t, ¹H), 7.28 (m, ¹H), 7.10 (m, 2H), 4.60 (s, 2H).

[0541] The following nitrile intermediates were prepared using a process similar to that used in 1a. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0542] 8-Phenylidene[1,2-a]pyrazine-6-carboxynitrile;

[0543] 8-Benzylimidazo[1,2-a]pyrazine-6-carboxynitrile;

[0544] 8-(4-Fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0545] 8-(2,3-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0546] 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0547] 8-(3,3,4,4,4-pentafluorobutyl)imidazo[1,2-a]pyrazine-6-carboxynitrile,

[0548] 8-(2-Fluorobenzyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxynitrile;

[0549] 8-(3,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0550] 8-(3,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile.

[0551] Alternatively, intermediate 1a and related analogues (e.g., intermediate 1b) can be synthesized through the following process:

[0552] Step 1: Synthesis of 6-bromo-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine

[0553] Treat a suspension of dry zinc powder (47 g, 720 mmol, dried by vacuum heating) in THF (750 mL) with 1,2-dibromoethane (1 mL) and heat the resulting mixture to 50 °C. Then add trichloromethylsilane (1 mL). After stirring at 48–50 °C for 30 minutes, cool the mixture to ambient temperature. Add anhydrous lithium chloride (30 g, 710 mmol, dried by vacuum heating), followed by dropwise addition of a solution of 2-fluorobenzyl bromide (74 g, 390 mmol) in THF (100 mL) (Note: This is exothermic; maintain the reaction temperature below 48 °C). Stir the mixture at ambient temperature for 1 hour. The slurry of 6,8-dibromoimidazolo[1,2-a]pyrazine (99 g, 360 mmol) and Pd(PPh3)2Cl2 (7.8 g, 11 mmol) in THF (500 mL) was degassed for 10 minutes by bubbling with nitrogen and then rapidly added to the 2-fluorobenzyl zinc 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 exhausted. The reactants were quenched with saturated NH4Cl solution (800 mL). The brown organic phase was concentrated to dryness, dissolved in DCM (1.3 L), and filtered through a diatomaceous earth bed. The organic layer in the filtrate was collected, decolorized with activated carbon (45 g), filtered through diatomaceous earth, and concentrated to dryness. The crude material was azeotropically dried with toluene (2 × 500 mL) and used without purification.

[0554] Step 2: Synthesis of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile

[0555] Under nitrogen atmosphere, the reaction mixture containing crude material from the previous step (360 mmol, theoretical yield), zinc cyanide (35 g, 300 mmol), Pd2(dba)3 (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 for 10 minutes and then heated at 85 °C until the starting material was completely consumed. The reaction mixture 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 diatomaceous earth bed 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 diatomaceous earth, 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 hour, the product was collected by filtration, washed with MTBE (2 × 100 mL), and dried in a vacuum oven at 45 °C. The title compound was given as a brown solid (52 g, 57% yield).

[0556] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.09 (s, ¹H), 8.13 (s, ¹H), 7.91 (s, ¹H), 7.35 (apparent .t, ¹H), 7.27 (m, 2H), 7.13–7.06 (m, 2H), 4.60 (s, 2H).

[0557] Intermediate 1b

[0558]

[0559] 8-(3-Fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxylonitrile (1b) The title compound is synthesized in two steps.

[0560] Step 1: Synthesis of 6-bromo-8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine

[0561] Treat a suspension of dry zinc powder (2.6 g, 40 mmol) in THF (50 mL) with 1,2-dibromoethane (0.30 mL, 3.5 mmol) and heat the resulting mixture at 50 °C for 5 minutes. Then add trichloromethylsilane (0.30 mL, 2.4 mmol) and cool the mixture to ambient temperature. Add anhydrous lithium chloride (1.7 g, 40 mmol), followed by dropwise addition of a solution of 3-fluorobenzyl bromide (4.8 g, 26 mmol) in THF (25 mL) (Note: This is exothermic; maintain the reaction temperature below 35 °C). Stir the mixture at ambient temperature for 1 hour, then add a slurry of 6,8-dibromoimidazozolo[1,2-a]pyrazine (5.9 g, 21 mmol) and Pd(PPh3)2Cl2 (0.25 g, 0.36 mmol) in THF (75 mL). Degas the reaction mixture with nitrogen and stir overnight at ambient temperature until the starting material is 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 diatomaceous earth bed, and the organic layer in the filtrate was collected. The organic layer was dried and decolorized with Na2SO4 (10 g) and activated carbon (7 g), filtered through diatomaceous earth, and concentrated to produce an orange crude oil (7.1 g), which was used directly without purification.

[0562] Step 2: Synthesis of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile

[0563] Under nitrogen atmosphere, the reaction mixture containing crude material from the previous step (21 mmol, theoretical yield), zinc cyanide (3.0 g, 26 mmol), Pd2(dba)3 (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 for 5 minutes and then heated at 110 °C until the starting material was completely consumed. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (150 mL), and filtered through a diatomaceous earth bed. The organic filtrate was washed with 10% NH4Cl solution (2 × 100 mL), dried over Na2SO4, filtered, and concentrated to provide a brown oil. This oil was purified by column chromatography (15% to 40% EtOAc / hexane gradient) to provide a grayish-white solid containing the title compound (2.4 g, 45% yield).

[0564] 1H NMR (500MHz, DMSO-d6) δ (ppm) 9.37 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.29-7.39 (m, 1H), 7.23 (d, 2H), 6.99-7.12 (m, 1H), 4.45-4.56 (m, 2H).

[0565] The following nitrile intermediates were prepared using a process similar to that used for the synthesis of intermediates 1a and 1b. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0566] 8-(2,6-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0567] 8-(3-fluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile.

[0568] Intermediate 2

[0569]

[0570] 8-Benzyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylonitrile (2) The title compound was synthesized in two steps as a gold residue (0.12 g, 23% yield in two steps) according to the process described in the patent document (WO2016 / 081668A1).

[0571] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 9.96 (s, 1H), 8.94 (s, 1H), 7.39 (d, 2H) 7.30 (dd, 2H), 7.23 (t, 1H), 4.53 (s, 2H).

[0572] The following nitrile intermediates were prepared using a process similar to that used in step 2. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0573] 8-(2-Fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxynitrile;

[0574] 8-(2,3-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylonitrile;

[0575] 8-(3-Fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxynitrile;

[0576] 8-(2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxynitrile;

[0577] 8-(3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylonitrile.

[0578] Compound I-1

[0579]

[0580] General Process A : 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-1)

[0581] Anhydrous hydrazine (3.1 mL, 100 mmol) was added to a solution of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile (1a) (4.0 g, 16 mmol) in methanol (40 mL). After stirring overnight at ambient temperature, the starting material was observed to have completely disappeared. The reaction mixture was concentrated under vacuum, residual hydrazine was removed by elution with methanol and toluene, and the resulting foam was dried under vacuum overnight. The brown foam was dissolved 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 mixture was stirred at ambient temperature until the amidohydrazone intermediate was completely exhausted. The solvent was removed under vacuum and dried to a yellow residue. The residue was dissolved in AcOH (10 mL) and EtOH (100 mL) and heated at 90 °C for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated to half the reaction volume. The resulting thick suspension was filtered, and the filtrate was concentrated to a brown oil. The crude material was purified by silica gel chromatography (10%–100% EtOAc / hexane gradient) to separate the title compound as a brown solid (4.0 g, 69% yield).

[0582] 1 H NMR(500MHz,DMSO-d6)δ(ppm)15.46(s,1H),9.45(s,1H),8.26(s,1H),7.87(s,1 H),7.43(t,1H),7.22-7.32(m,1H),7.14-7.22(m,1H),7.09(t,1H),4.60(s,2H). LCMS[M+H]=363.1

[0583] Compound I-2

[0584]

[0585] 8-(3-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-2) was synthesized as a grayish-white solid (170 mg, 60% yield) according to general process A. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0586] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.22 (s, ¹H), 8.17 (s, ¹H), 7.87 (s, ¹H), 7.35–7.24 (m, ³H), 6.92 (apparent t, ¹H), 4.61 (s, ²H). LCMS [M+H] = 363.2

[0587] Compound I-3

[0588]

[0589] 6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)-8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine (I-3) was synthesized as a grayish-white solid (160 mg, 55% yield) according to general process A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0590] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.17 (s, ¹H), 8.17 (s, ¹H), 7.86 (s, ¹H), 7.35–7.25 (m, ³H), 6.92 (m, ¹H), 6.90 (t, ¹H), 4.61 (s, ²H). LCMS [M+H] = 345.2

[0591] Compound I-17

[0592]

[0593] 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 process A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0594] 1H NMR (500MHz, DMSO-d6) δ (ppm) 15.3 (s, 1H), 9.58 (s, 1H), 8.83 (s, 1H), 7.27-7.35 (m, 2H), 7.08-7.19 (m, 2H), 4.69 (s, 2H).

[0595] LCMS[M+H]=364.2

[0596] Compound I-19

[0597]

[0598] 8-(2,6-difluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-19) was synthesized as a grayish-white solid (300 mg, 87% yield) according to general procedure A. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0599] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 15.3 (s, 1H), 9.43 (s, 1H), 8.25 (s, 1H), 7.85 (s, 1H), 7.37 (m, 1H), 7.08 (apparent .t, 2H), 4.63 (s, 2H).

[0600] LCMS[M+H]=381.2

[0601] Compound I-20

[0602]

[0603] 8-(2,6-difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-20) was synthesized as a grayish-white solid (240 mg, 72% yield) according to general process A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0604] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 14.9 (s, 1H), 9.38 (s, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 7.37 (m, 1H), 7.13 (t, 1H), 7.08 (apparent t, 2H), 4.62 (s, 2H).

[0605] LCMS[M+H]=363.2

[0606] Compound I-21

[0607]

[0608] 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 process A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0609] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.3 (s, 1H), 9.55 (s, 1H), 8.83 (s, 1H), 7.30 -7.37 (m, 3H), 7.19 (t, 1H), 7.04 - 7.09 (m, 1H), 4.61 (s, 2H).

[0610] LCMS[M+H]=346.2

[0611] Compound I-22

[0612]

[0613] 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 a grayish-white solid (140 mg, 49% yield) according to general process A. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0614] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.7 (s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 7.32 -7.36 (m, 3H), 7.05 - 7.08 (m, 1H), 4.62 (s, 2H).

[0615] LCMS[M+H]=364.2

[0616] Compound I-23

[0617]

[0618] 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 a grayish-white solid (120 mg, 72% yield) according to general process A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0619] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.49 (s, 1H), 8.65 (s, 1H), 7.25 (m, 1H), 7.11 (m, 1H), 7.01 (m, 1H), 6.91 (t, 1H), 4.71 (s, 2H).

[0620] LCMS[M+H]=364.2

[0621] Compound I-24

[0622]

[0623] 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 process A. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0624] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.7 (s, 1H), 9.63 (s, 1H), 8.86 (s, 1H), 7.23 (d, 2H), 7.11 (t, 1H), 4.63 (s, 2H).

[0625] LCMS[M+H]=382.2

[0626] Compound I-25

[0627]

[0628] Compound I-25

[0629] 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 process A, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0630] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.2 (s, 1H), 9.50 (s, 1H), 8.77 (s, 1H), 7.16 (d, 2H), 7.14 (t, 1H), 7.03 (m, 1H), 4.55 (s, 2H).

[0631] LCMS[M+H]=364.1

[0632] Compound I-4

[0633]

[0634] General Process B: 8-(2-Fluorobenzyl)-6-(3-Methyl-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine

[0635] Anhydrous hydrazine (0.08 mL, 2.7 mmol) was added to a solution of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile (1a) (110 mg, 0.45 mmol) in methanol (2.0 mL). After stirring at ambient temperature for 40 hours, the starting material was observed to have completely disappeared. The reaction mixture was concentrated under vacuum and the residue was dried under vacuum overnight. The residue was dissolved 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 mixture was stirred at ambient temperature until the amidohydrazone intermediate was completely depleted. The solvent was removed under vacuum and dried to a yellow residue. The residue was dissolved in AcOH (0.2 mL) and EtOH (10 mL) and heated in a microwave at 120 °C for 5 hours. The reaction mixture was cooled to ambient temperature and concentrated under vacuum. The crude material was purified by silica gel chromatography (10%–30% acetonitrile / MeOH (7:1) gradient in DCM) to separate the title compound as a grayish-white solid (85 mg, 62% yield).

[0636] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.03 (s, ¹H), 8.15 (s, ¹H), 7.81 (s, ¹H), 7.30 (apparent t, ¹H), 7.23 (m, ¹H), 7.10–7.02 (m, 2H), 4.66 (s, 2H), 2.48 (s, 3H). LCMS [M+H] = 309.2

[0637] Compound I-5

[0638]

[0639] 8-(2-fluorobenzyl)-6-(3-(perfluoroethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (compound I-5) was synthesized in solid form (1.5 mg, 1.5% yield) according to general process B, except that 2,2,3,3,3-pentafluoropropionic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0640] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.26 (s, ¹H), 8.18 (s, ¹H), 7.85 (s, ¹H), 7.34 (t, ¹H), 7.24 (s, ¹H), 7.09 (m, 2H), 4.69 (s, 2H). LCMS [M+H] = 413.2

[0641] Compound I-6

[0642]

[0643] 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. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0644] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.09 (s, ¹H), 8.05 (s, ¹H), 7.75 (s, ¹H), 7.41 (d, 2H), 7.15 (t, 2H), 7.04–7.10 (m, ¹H), 4.50 (s, 2H). LCMS [M+H] = 345.2

[0645] Compound I-7

[0646]

[0647] 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 (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0648] 1¹H NMR (500MHz, methanol-d⁴) δ (ppm): 9.05 (s, ¹H), 8.06 (s, ¹H), 7.75 (s, ¹H), 7.41 (d, 2H), 7.13–7.18 (m, 2H), 7.05–7.10 (m, ¹H), 6.68–6.91 (m, 1H), 4.50 (s, 2H). LCMS [M+H] = 327.2

[0649] Compound I-8

[0650]

[0651] 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 (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0652] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.14 (s, ¹H), 8.09 (s, ¹H), 7.77 (s, ¹H), 7.07 (m, ¹H), 7.00 (m, ¹H), 6.86–6.92 (m, ¹H), 4.57 (s, 2H). LCMS [M+H] = 381.2

[0653] Compound I-9

[0654]

[0655] 8-(2,5-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-9) was synthesized as a grayish-white solid (32 mg, 36% yield) according to general process B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0656] 1 H NMR (500MHz, methanol-d4) δ (ppm) 9.10 (s, 1H), 8.09 (s, 1H), 7.76 (s, 1H), 7.06 (m, 1H), 7.00 (m, 1H), 6.87-6.92 (m, 1H), 6.79 (t, 1H), 4.56 (s, 2H). LCMS[M+H]=363.2

[0657] Compound I-10

[0658]

[0659] 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 process B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0660] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.25 (s, ¹H), 8.19 (s, ¹H), 7.86 (s, ¹H), 7.17–7.10 (m, ²H), 7.05 (m, ¹H), 4.72 (s, ²H). LCMS [M+H] = 381.2

[0661] Compound I-11

[0662]

[0663] 8-(2,3-Difluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-11) was synthesized as a grayish-white solid (55 mg, 25% yield) according to general process B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0664] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.21 (s, ¹H), 8.19 (s, ¹H), 7.86 (s, ¹H), 7.17–7.09 (m, ²H), 7.04 (m, ¹H), 6.89 (t, ¹H), 4.71 (s, ²H). LCMS [M+H] = 363.2

[0665] Compound I-12

[0666]

[0667] 8-(4-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-12) was synthesized as a grayish-white solid (75 mg, 84% yield) according to general process B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0668] 1H NMR (500MHz, DMSO-d6) δ (ppm) 15.50 (s, 1H), 9.41 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H) 7.56 (dd, 2H), 7.10 (dd, 2H), 4.52 (s, 2H). LCMS[M+H]=363.2

[0669] Compound I-13

[0670]

[0671] 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 process B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0672] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.24 (s, ¹H), 8.19 (s, ¹H), 7.86 (s, ¹H), 3.59–3.66 (m, ²H), 2.93–3.07 (m, ²H). LCMS [M+H] = 401.2

[0673] Compound I-14

[0674]

[0675] 8-(2-fluorobenzyl)-6-(3-(difluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine (I-14) was synthesized as a grayish-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 (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0676] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.28 (s, ¹H), 8.29 (s, ¹H), 8.00 (s, ¹H), 7.35 (t, ¹H), 7.27 (d, ¹H), 7.09 (m, 2H), 6.90 (m, ¹H), 4.69 (s, 2H). LCMS [M+H] = 345.2

[0677] Compound I-15

[0678]

[0679] 8-Benzyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (I-15) was synthesized as a white solid (60 mg, 33% yield) according to general process B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0680] 1 ¹H NMR (500MHz, DMSO-d⁶) δ (ppm) 15.72 (s, ¹H), 9.60 (s, ¹H), 8.84 (s, ¹H), 7.50 (d, 2H), 7.30 (apparent t, 2H), 7.21 (t, ¹H), 4.59 (s, 2H). LCMS [M+H] = 346.2

[0681] Compound I-16

[0682]

[0683] 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 a grayish-white solid (1.2 mg, 1.0% yield) according to general process B. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0684] 1 ¹H NMR (500 MHz, methanol-d⁴) δ (ppm) 9.51 (s, ¹H), 8.65 (s, ¹H), 7.43 (apparent t, ¹H), 7.27 (m, ¹H), 7.10 (t, 2H), 4.74 (s, 2H). LCMS [M+H] = 364.1

[0685] Compound I-18

[0686]

[0687] 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 process B. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0688] 1H NMR (500MHz, DMSO-d6) δ (ppm) 15.7 (s, 1H), 9.64 (s, 1H), 8.84 (s, 1H), 7.30 -7.35 (m, 1H), 7.27-7.30 (m, 1H), 7.12 - 7.15 (m, 1H), 4.69 (s, 2H).

[0689] LCMS[M+H]=382.2

[0690] Compound I-26

[0691]

[0692] 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 process B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0693] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 15.3 (s, 1H), 9.57 (s, 1H), 8.81 (s, 1H), 7.46 (apparent t, 1H), 7.32–7.09 (m, 4H), 4.64 (s, 2H).

[0694] LCMS[M+H]=346.2

[0695] Compound I-27

[0696]

[0697] 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 process B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0698] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.5 (s, 1H), 9.41 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.30 (d, 1H), 7.15-7.23 (m, 2H), 4.50 (s, 2H), 2.15 (s, 3H).

[0699] LCMS[M+H]=377.1

[0700] Compound I-28

[0701]

[0702] 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 process B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0703] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.1 (s, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 7.87 (s, 1H), 7.14-7.35 (m, 4H), 4.49 (s, 2H), 2.15 (s, 3H).

[0704] LCMS[M+H]=359.2

[0705] Compound I-29

[0706]

[0707] 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 process B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0708] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.5 (s, 1H), 9.43 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.23 (d, 2H), 7.08 (t, 1H), 4.56 (s, 2H).

[0709] LCMS[M+H]=381.1

[0710] Compound I-30

[0711]

[0712] 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 process B, except that 2,2-difluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0713] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 15.1 (s, 1H), 9.38 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.04-7.29 (m, 4H), 4.55 (s, 2H).

[0714] LCMS[M+H]=363.1

[0715] Compound I-31

[0716]

[0717] 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 (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0718] 1 ¹H NMR (500MHz, CDCl₃) δ (ppm) 11.6 (br.s, 1H), 8.88 (s, 1H), 7.61 (s, 1H), 7.39 (apparent .t, 1H), 7.26–7.32 (m, 1H), 7.09–7.15 (m, 2H), 4.69 (s, 2H), 2.60 (s, 3H).

[0719] LCMS[M+H]=377.3

[0720] Compound I-32

[0721]

[0722] 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 (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0723] 1 ¹H NMR (500MHz, CDCl₃) δ (ppm) 11.5 (br.s, 1H), 8.89 (s, 1H), 7.61 (s, 1H), 7.38 (apparent .t, 1H), 7.26–7.34 (m, 1H), 7.08–7.14 (m, 2H), 6.77 (t, 1H), 4.69 (s, 2H), 2.60 (s, 3H).

[0724] LCMS[M+H]=359.2

[0725] Compound I-33

[0726]

[0727] 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 process B, except that 2,2,2-trifluoroacetic anhydride was used as the acylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0728] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.51 (s, 1H), 8.66 (s, 1H), 7.20–7.29 (m, 1H), 7.06–7.15 (m, 1H), 7.01 (m, 1H), 4.72 (s, 2H).

[0729] LCMS[M+H]=382.2

[0730] Compound I-34

[0731]

[0732] 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 (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0733] 1H NMR (500MHz, CDCl3) δ (ppm) 11.9 (br.s, 1H), 9.02 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 6.95 (d, 2H), 4.58 (s, 2H), 2.14 (s, 3H).

[0734] LCMS[M+H]=395.2

[0735] Compound I-35

[0736]

[0737] 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 (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0738] 1 H NMR (500MHz, CDCl3) δ (ppm) 11.7 (br.s, 1H), 9.02 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 6.98 (d, 2H), 6.81 (t, 1H), 4.58 (s, 2H), 2.15 (s, 3H).

[0739] LCMS[M+H]=377.2

[0740] Compound I-36

[0741]

[0742] 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.

[0743] Step 1: Synthesis of 6-chloro-4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine

[0744] At ambient temperature, a solution of (2-fluorobenzyl)zinc(II) chloride (0.5 M in THF, 10 mL, 5.0 mmol) was added 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). The mixture was stirred at ambient temperature for 24 hours. The mixture was then dissolved in EtOAc (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain an oily substance. The crude substance was purified by silica gel chromatography (0-80% EtOAc / hexane gradient) to obtain a yellow solid 6-chloro-4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine (1.0 g, 70% yield).

[0745] 1 H NMR (500MHZ, CDCl3) δ (ppm) 7.87 (s, 1H), 7.63-7.79 (m, 1H), 7.26 (br.s, 1H), 7.12-7.19 (m, 1H), 6.96-7.07 (m, 2H), 4.60 (br.s, 2H), 3.80 (s, 3H).

[0746] Step 2: Synthesis of 4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine-6-carboxynitrile

[0747] A mixture containing zinc cyanide (850 mg, 7.3 mmol), tetra(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 and maintained for 24 hours. The reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain a solid. The crude substance was purified by silica gel chromatography (0-100% EtOAc / hexane gradient) to obtain an impure white solid of 4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine-6-carboxynitrile (130 mg).

[0748] 1H NMR (500MHz, CDCl3) δ (ppm) 8.08 (s, 1H), 7.72 (s, 1H), 7.65-7.71 (m, 1H), 7.32 (m, 1H), 6.98-7.09 (m, 2H), 4.64 (s, 2H), 3.92 (s, 3H).

[0749] Step 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)

[0750] A mixture containing anhydrous hydrazine (0.092 mL, 2.9 mmol) and 4-(2-fluorobenzyl)-1-methyl-1H-imidazo[4,5-c]pyridine-6-carboxynitrile (130 mg) in MeOH (2.5 mL) was stirred for 24 hours at ambient temperature. The mixture was concentrated under vacuum 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 reactants were diluted in EtOAc (100 mL) and washed with saturated NaHCO3 solution (50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain an oil. The crude substance was purified by preparative HPLC to provide a light brown solid 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 in 2 steps).

[0751] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 8.57 (s, 1H), 8.41 (s, 1H), 7.18–7.28 (m, 2H), 6.97–7.12 (m, 2H), 4.67 (s, 2H), 4.04 (s, 3H).

[0752] LCMS[M+H]=377.1

[0753] Compound I-72

[0754]

[0755] 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.

[0756] Step 1: Synthesis of 6-bromo-8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine

[0757] 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) was purged with argon for 5 min and treated with (2-fluorobenzyl)zinc(II) chloride (0.5 M 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 vacuum. The crude material was purified by reversed-phase HPLC (5%–95% acetonitrile / water gradient containing 0.1% formic acid) to obtain a brown solid 6-bromo-8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine (110 mg, 43% pure, contaminated with undesirable regioisomers, 9.1% yield).

[0758] Step 2: Synthesis of 8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxynitrile

[0759] A solid mixture containing zinc powder (4.7 mg, 0.072 mmol), zinc cyanide (63 mg, 0.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(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% pure, 0.15 mmol of desired regioisomer and 0.21 mmol of undesired regioisomer) was purged with nitrogen for 15 min and then dissolved in DMF (3 mL). The reaction mixture was heated to 120 °C and maintained for 8 h. 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 vacuum. The crude substance was purified by silica gel chromatography (20%-100% EtOAc / hexane gradient) to obtain a light brown solid 8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxynitrile (24 mg, 61% yield).

[0760] Step 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)

[0761] The suspension of 8-(2-fluorobenzyl)-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxynitrile (24 mg, 0.094 mmol) in anhydrous methanol (1.5 mL) was treated with sodium methoxide (0.50 N solution in methanol, 19 μL, 9.4 μmol). After 3.5 hours, anhydrous hydrazine (18 μL, 0.57 mmol) was added and the reaction mixture was stirred at ambient temperature for 23 hours. The resulting mixture was concentrated, dried under vacuum, and then dissolved in DCM / THF (2 mL, 3:1 ratio). 2,2,2-trifluoroacetic anhydride (21 μL, 0.15 mmol) was added. After 40 minutes, the mixture was concentrated, dissolved in EtOH (2 mL) and acetic acid (0.2 mL), and heated at 90 °C for 15 hours. 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 vacuum. The crude substance was purified by silica gel chromatography (20%–90% EtOAc / hexane gradient) to provide a pale yellow membrane of 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).

[0762] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.43 (s, 1H), 9.22 (s, 1H), 7.47 (apparent t, 1H), 7.29 (m, 1H), 7.13–7.08 (m, 2H), 4.76 (s, 2H).

[0763] LCMS[M+H]=364.2

[0764] Compound I-37

[0765]

[0766] 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.

[0767] Step 1: Synthesis of 2-chloro-6-(2-fluorobenzyl)-9-methyl-9H-purine

[0768] 2-Fluorobenzylzinc(II) chloride (0.5 M solution in THF, 7.5 mL, 3.7 mmol) was added to 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. The reaction mixture was stirred at ambient temperature for 24 hours. The resulting mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain an oil. The crude substance was purified by silica gel chromatography (0-50% EtOAc / hexane gradient) to provide 2-chloro-6-(2-fluorobenzyl)-9-methyl-9H-purine (620 mg, 66% yield) as a white solid.

[0769] 1 H NMR (500MHz, CDCl3) δ (ppm) 8.02 (s, 1H), 7.37 (m, 1H), 7.18-7.25 (m, 1H), 7.02-7.10 (m, 2H), 4.54 (s, 2H), 3.88 (s, 3H).

[0770] Step 2: Synthesis of 6-(2-fluorobenzyl)-9-methyl-9H-purine-2-carboxynitrile

[0771] A mixture containing zinc cyanide (530 mg, 4.5 mmol), tetra(triphenylphosphine)palladium(O) (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 and maintained for 24 hours. The mixture was quenched with water (50 mL) and EtOAc (10 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain an oil. The crude substance was purified by silica gel chromatography (0-100% EtOAc / hexane gradient) to provide a white solid 6-(2-fluorobenzyl)-9-methyl-9H-purine-2-carboxynitrile (490 mg, 82% yield).

[0772] 1 H NMR (500MHz, CDCl3) δ (ppm) 8.22 (s, 1H), 7.39 (t, 1H), 7.20-7.26 (m, 1H), 7.01-7.12 (m, 2H), 4.61 (s, 2H), 3.95 (s, 3H).

[0773] Step 3: Synthesis of 6-(2-fluorobenzyl)-9-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-9H-purine (I-37)

[0774] A mixture containing anhydrous hydrazine (0.090 mL, 2.9 mmol) and 6-(2-fluorobenzyl)-9-methyl-9H-purine-2-carboxynitrile (130 mg, 0.48 mmol) in MeOH (2.4 mL) was heated to 60 °C and maintained for 2 hours. The mixture was concentrated under vacuum and dried azeotropically 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 hours, the reaction mixture was diluted with DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated to obtain an oil. The crude substance was purified by silica gel chromatography (0-50% EtOAc / hexane gradient) to recover the intermediate 2,2,2-trifluoro-N′-((6-(2-fluorobenzyl)-9-methyl-9H-purin-2-yl)(imino)methyl)acetylhydrazine. 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 vacuum to obtain a white solid of 6-(2-fluorobenzyl)-9-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-9H-purine (25 mg, 14% yield).

[0775] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 8.50-8.54 (m, 1H), 7.28-7.41 (m, 1H), 7.14-7.27 (m, 1H), 6.97-7.12 (m, 2H), 4.63 (s, 2H), 4.01 (s, 3H).

[0776] LCMS[M+H]=378.1

[0777] Compounds I-38 and I-39

[0778]

[0779] General process 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)

[0780] Add 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (0.050 mL, 0.31 mmol) 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). After stirring at ambient temperature for 15 hours, pour the reaction mixture into a mixture of water and brine (1:2, 20 mL) and extract with DCM (2 × 20 mL). Dry the combined organic layers with Na₂SO₄, filter, and concentrate. The crude substance was purified using silica gel chromatography (20%–100% EtOAc / hexane gradient) to separate the pale yellow solid 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) and the pale yellow solid 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). [The last sentence appears to be incomplete and requires further context.] 1 HNMR nOe experiments assigned the chemical structure. In this case, no possible third-region isomers were observed (which are usually minor).

[0781] Compound I-38:

[0782] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 9.19 (s, 1H), 8.23 ​​(s, 1H), 7.80 (s, 1H), 7.34 (apparent .t, 1H), 7.27 (m, 1H), 7.17 (apparent .t, 1H), 7.08 (apparent .t, 1H), 5.34 (q, 2H), 4.56 (s, 2H), 2.53 (s, 3H).

[0783] LCMS[M+H]=391.2

[0784] Compound I-39:

[0785] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 9.39 (s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.48 (apparent t, 1H), 7.35 (m, 1H), 7.21–7.15 (m, 2H), 5.41 (q, 2H), 4.64 (s, 2H), 2.31 (s, 3H).

[0786] LCMS[M+H]=391.2

[0787] Compound I-41 and Compound I-42

[0788]

[0789] 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 in solid form (I-41: 1.3 mg, 3.9% yield and I-42: 2.9 mg, 8.6% yield) according to general process C, except that 1-(bromomethyl)-4-fluorobenzene was used as the alkylating agent. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0790] Compound I-41:

[0791] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 9.15 (s, 1H), 8.21 (s, 1H), 7.79 (s, 1H), 7.32 (m, 3H), 7.21 (m, 4H), 7.08 (apparent t, 1H), 5.44 (s, 2H), 4.54 (s, 2H), 2.48 (s, 3H).

[0792] LCMS[M+H]=417.3

[0793] Compound I-42:

[0794] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 9.34 (s, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.37 (apparent t, 1H), 7.20 (m, 1H), 7.03 (m, 6H), 5.61 (s, 2H), 4.63 (s, 2H), 2.25 (s, 3H).

[0795] LCMS[M+H]=417.4

[0796] Compound I-47

[0797]

[0798] 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 in solid form (4.2 mg, 12% yield) according to general process C, except that 1-(bromomethyl)-3-fluorobenzene was used as the alkylating agent. No other regioisomers were isolated. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0799] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.04 (s, 1H), 8.11 (s, 1H), 7.78 (s, 1H), 7.38 (m, 1H), 7.23 (m, 2H), 7.06 (m, 5H), 5.47 (s, 2H), 4.65 (s, 2H), 2.51 (s, 3H).

[0800] LCMS[M+H]=417.4

[0801] Compound I-48

[0802]

[0803] 1-(3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-methyl-1H-1,2,4-triazol-1-yl)-3,3-dimethylbut-2-one (I-48) was synthesized in solid form (7.6 mg, 23% yield) according to general process C, except that 1-bromo-3,3-dimethylbut-2-one was used as the alkylating agent. No other regioisomers were isolated. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0804] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 9.15 (s, 1H), 8.22 (s, 1H), 7.79 (s, 1H), 7.32 (apparent .t, 1H), 7.25 (m, 1H), 7.17 (apparent .t, 1H), 7.08 (apparent .t, 1H), 5.54 (s, 2H), 4.54 (s, 2H), 2.31 (s, 3H), 1.22 (s, 9H).

[0805] LCMS[M+H]=407.4

[0806] Compound I-50

[0807]

[0808] 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 in solid form (0.9 mg, 2.8% yield) according to general process C, except that 1-bromo-4-fluorobutane was used as the alkylating agent. No other regioisomers were isolated. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0809] 1 H NMR(500MHz, methanol-d4)δ(ppm)9.03(s,1H),8.14(s,1H),7.81(s,1H),7.26(m,2H),7.06(m,2H) ,4.67(s,2H),4.55(t,1H),4.45(t,1H),4.27(t,2H),2.56(s,3H),2.05(m,2H),1.77(m,2H).

[0810] LCMS[M+H]=383.3

[0811] Compound I-51

[0812]

[0813] 3-((3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-methyl-1H-1,2,4-triazol-1-yl)methyl)-5-methyliso I-51 azole (I-51) was synthesized in solid form (4.1 mg, 13% yield) according to the general process C, except that 3-(bromomethyl)-5-methylisocyanate was used. Azole was used as the alkylating agent. No other regioisomers were isolated. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0814] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.05 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.26 (m, 2H), 7.08 (m, 1H), 7.04 (m, 1H), 6.20 (s, 1H), 5.50 (s, 2H), 4.66 (s, 2H), 2.58 (s, 3H), 2.42 (s, 3H).

[0815] LCMS[M+H]=404.3

[0816] Compound I-53

[0817]

[0818] 6-(1-Ethyl-5-methyl-1H-1,2,4-triazol-3-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-53) was synthesized in solid form (3.0 mg, 11% yield) according to general process C, except that iodoethane was used as the alkylating agent. No other regioisomers were isolated. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) may be modified as needed.

[0819] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.02 (s, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 7.25 (m, 2H), 7.08 (m, 1H), 7.04 (m, 1H), 4.67 (s, 2H), 4.26 (q, 2H), 2.56 (s, 3H), 1.50 (t, 3H).

[0820] LCMS[M+H]=337.3

[0821] Compound I-54

[0822]

[0823] 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 in solid form (2.9 mg, 8.8% yield) according to general process C, except that 3-bromo-1,1,1-trifluoropropane was used as the alkylating agent. No other regioisomers were isolated. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0824] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.06 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.25 (m, 2H), 7.09 (m, 1H), 7.04 (m, 1H), 4.67 (s, 2H), 4.49 (t, 2H), 2.94 (m, 2H), 2.57 (s, 3H).

[0825] LCMS[M+H]=405.3

[0826] Compound I-56

[0827]

[0828] 6-(1-Butyl-5-methyl-1H-1,2,4-triazol-3-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-56) was synthesized in solid form (2.0 mg, 6.8% yield) according to general process C, except that 1-bromobutane was used as the alkylating agent. No other regioisomers were isolated. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) were modified as needed.

[0829] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.02 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.26 (m, 2H), 7.08 (m, 1H), 7.04 (m, 1H), 4.67 (s, 2H), 4.22 (t, 2H), 2.55 (s, 3H), 1.90 (apparent quintet, 2H), 1.41 (m, 2H), 1.00 (t, 3H).

[0830] LCMS[M+H]=365.3

[0831] Compound I-57

[0832]

[0833] 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-3-amine (I-57):

[0834] A suspension of S-methylisothiourea hemisulfate (510 mg, 1.8 mmol), 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxylhydrazine (520 mg, 1.8 mmol), and sodium hydroxide (73 mg, 1.8 mmol) in water (8 mL) was heated to 120 °C and maintained for 60 min in a microwave oven. The reaction mixture was filtered using methanol as the eluent, and the resulting filtrate was concentrated to provide the crude product. This substance was purified by reversed-phase HPLC (12%–37% acetonitrile / water gradient containing 0.1% trifluoroacetic acid) to provide an orange oily mixture (360 mg) of the two compounds. This product mixture was used in subsequent reactions without further purification.

[0835] A small sample of this substance was further purified by reversed-phase HPLC (10%–55% acetonitrile / water gradient containing 0.1% formic acid) to provide a white solid 5-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-3-amine (I-57) (3.0 mg).

[0836] 1H NMR(500MHz,DMSO-d6)δ(ppm)12.1(br.s,1H),8.92(br.s,1H),8.21(s,1H),7.77(s,1H),7.35- 7.40(m,1H),7.25-7.29(m,1H),7.15-7.19(m,1H),7.06-7.11(m,1H),6.09(s,2H),4.53(s,2H).

[0837] LCMS[M+H]=310.1

[0838] Compound I-58

[0839]

[0840]

[0841] 1-(3-fluorobenzyl)-3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1H-1,2,4-triazol-5- Amine (I-58):

[0842] 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), 1-(bromomethyl)-3-fluorobenzene (0.11 mL, 0.88 mmol) was added, followed by potassium carbonate (210 mg, 1.6 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then heated to 50 °C and maintained for 24 hours. 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 Na₂SO₄, filtered, and concentrated to provide a brown residue. The crude product was first purified by silica gel chromatography to give a mixture. This substance was further purified by reversed-phase HPLC (10%-60% acetonitrile / water gradient containing 0.1% trifluoroacetic acid) to provide a pale yellow solid 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).

[0843] 1H NMR(500MHz,DMSO-d6)δ(ppm)9.01(s,1H),8.22(s,1H),7.81(s,1H),7.40-7.44(m,1H),7.30-7.34(m,1 H),7.24-7.27(m,1H),7.12-7.18(m,2H),7.06-7.10(m,3H),6.78(br.s,2H),5.25(s,2H),4.52(s,2H).

[0844] LCMS[M+H]=418.3

[0845] Compound I-59 and Compound I-60

[0846]

[0847] 3-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-tri Azolium-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):

[0848] 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 for 16 hours at ambient temperature. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to provide the residue. A first purification was performed by silica gel chromatography (0-100% EtOAc / hexane gradient). Secondary purification was performed using silica gel chromatography (0–50% acetonitrile / MeOH (7:1) gradient in DCM), yielding a gold solid 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). Compound I-59 was detected in this run (campaign) but was not separated.

[0849] In the second run, 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 provide a similar mixture of products. This reaction mixture was purified by reversed-phase HPLC (10%–55% acetonitrile / water gradient containing 0.1% formic acid) to provide a white solid 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).

[0850] Compound I-60:

[0851] 1H NMR(500MHz,DMSO-d6)δ(ppm)9.19(s,1H),8.31(d,1H),7.92(d,1H),7.45-7.50(m ,1H),7.30-7.36(m,1H),7.14-7.20(m,2H),5.64(s,2H),5.21(q,2H),4.62(s,2H).

[0852] LCMS[M+H]=392.2

[0853] Compound I-59:

[0854] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 8.98 (s, ¹H), 8.22 (s, ¹H), 7.78 (s, ¹H), 7.30–7.34 (m, ¹H), 7.24–7.29 (m, ¹H), 7.15–7.19 (m, ¹H), 7.06–7.09 (m, ¹H), 6.76 (s, 2H), 4.98 (q, 2H), 4.43 (s, 2H). (By...) 1 ¹H NMR experiments confirmed the regional chemical distribution of nOe (approximately 3% nOe was present in C). H 2CF3 protons and N H (between 2 groups).

[0855] LCMS[M+H]=392.2

[0856] Compound I-62 and Compound I-63

[0857]

[0858] 6-(3-chloro-1H-1,2,4-triazol-5-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-62) and 6- (3-(1H-imidazol-1-yl)-1H-1,2,4-triazol-5-yl)-8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine (I-63):

[0859] A solution containing 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-methyliminohydrazine (140 mg, 0.51 mmol) and 1,1′-carbonyldiimidazole (CDI) (410 mg, 2.5 mmol) in THF (4 mL) was stirred for 40 hours at ambient temperature. A brown suspension was observed. DCM / MeOH (60 mL, 1:1 ratio) was added and the resulting mixture was gently heated to dissolve the solids. The crude mixture was concentrated and dried under vacuum. Phosphorus oxychloride (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 NaHCO3 solution. The crude mixture was extracted with DCM / isopropanol (5:1 ratio, 3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (0-25% acetonitrile / MeOH (7:1) in DCM) yielded a grayish-white solid, title compound I-62 (23 mg, 14% yield, first elution product) and a light brown solid, I-63 (18 mg, 9.9% yield, second elution byproduct).

[0860] Compound I-62:

[0861] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 14.9 (s, 1H), 9.31 (s, 1H), 8.25 (s, 1H), 7.85 (s, 1H), 7.43 (apparent .t, 1H), 7.27 (m, 1H), 7.17 (apparent .t, 1H), 7.09 (apparent .t, 1H), 4.58 (s, 2H).

[0862] LCMS[M+H]=329.2

[0863] Compound I-63:

[0864] 1 ¹H NMR (500MHz, DMSO-d6) δ (ppm) 14.8 (s, 1H), 9.36 (s, 1H), 8.32 (m, 2H), 7.86 (s, 1H), 7.76 (s, 1H), 7.43 (apparent .t, 1H), 7.28 (m, 1H), 7.20–7.15 (m, 2H), 7.10 (apparent .t, 1H), 4.60 (s, 2H).

[0865] LCMS[M+H]=361.3

[0866] Compound I-64 and Compound I-65

[0867]

[0868]

[0869] 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-trisyl Azolium-3-amine (I-65):

[0870] 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 for 30 minutes at ambient temperature and then added to 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-methyliminohydrazide (200 mg, 0.70 mmol) with 0.50 mL of DMF. After 18 hours, the reaction mixture 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 vacuum to produce a brown solid, 2,2-difluoro-N′-((8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)(imino)methyl)cyclopropane-1-carbazide (400 mg, >99% yield), which was used directly without further processing. This intermediate was suspended in ethanol (10 mL) and acetic acid (1.0 mL). The reaction mixture was heated at 90 °C for 15.5 hours. The contents were concentrated in vacuum and the resulting residues were purified twice by silica gel chromatography (20%–10% EtOAc / hexane gradient and 0–4% acetonitrile / MeOH (7:1) gradient in DCM), and further purified by reversed-phase HPLC (5%–95% acetonitrile / water containing 0.1% formic acid) to provide the title compound I-64 (51 mg, 19% yield, first elution product) as a white solid and I-65 (20 mg, 8.5% yield, second elution byproduct) as a grayish-white solid.

[0871] Compound I-64:

[0872] 1 H NMR(500MHz, methanol-d4)δ(ppm)9.12(s,1H),8.16(s,1H),7.83(s,1H),7.32(m,1H),7. 25(m,1H),7.11-7.02(m,2H),4.67(s,2H),2.97(m,1H),2.17(m,1H),2.00(m,1H).

[0873] LCMS[M+H]=371.2

[0874] Compound I-65:

[0875] 1 ¹H NMR (500 MHz, methanol-d⁴) δ (ppm) 9.08 and 8.98 (s, ¹H, tautomer), 8.13 and 8.10 (s, ¹H, tautomer), 7.87 and 7.77 (s, ¹H, tautomer), 7.36–7.16 (m, 2H), 7.13–6.98 (m, 2H), 4.64 (s, 2H), 3.09 and 3.03 (s, 6H, tautomer).

[0876] LCMS[M+H]=338.2

[0877] Compound I-66

[0878]

[0879] 8-(2-Fluorobenzyl)-3-iodo-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine Azine (I-66):

[0880] 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 to 60 °C and maintained for 40 h. The reaction mixture was concentrated and purified by silica gel chromatography (0–5% acetonitrile / MeOH (7:1) gradient in DCM) to provide the title compound (I-66) as a white solid (130 mg, 96% yield).

[0881] ¹H NMR (500MHz, DMSO-d6) δ (ppm) 15.6 (s, ¹H), 8.79 (s, ¹H), 8.04 (s, ¹H), 7.41 (apparent .t, ¹H), 7.27 (m, ¹H), 7.18 (apparent .t, ¹H), 7.08 (apparent .t, ¹H), 4.62 (s, 2H).

[0882] LCMS[M+H]=489.2

[0883] Compound I-67

[0884]

[0885]

[0886] 3-Chloro-8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine Azine (I-67):

[0887] 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 to 60 °C and maintained for 24 h. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% acetonitrile / MeOH (7:1) gradient in DCM) to provide the title compound (I-67) as a white solid (56 mg, 51% yield).

[0888] 1H NMR (500MHz, methanol-d4) δ (ppm) 9.04 (s, 1H), 7.88 (s, 1H), 7.39 (apparent .t, 1H), 7.26 (m, 1H), 7.08 (m, 2H), 4.70 (s, 2H).

[0889] LCMS[M+H]=397.2

[0890] Compound I-68

[0891]

[0892] 3-Fluoro-8-(2-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine Azine (I-68)

[0893] 1-Chloromethyl-4-fluoro-1,4-diazobridged bicyclo[2.2.2]octanebis(tetrafluoroborate) (120 mg, 0.34 mmol) Treatment of 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 performed by heating to 70 °C and maintaining the temperature for 6 hours. Additional amounts were added. (60 mg, 0.17 mmol) and heated at 70 °C for 3 hours. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% acetonitrile / MeOH (7:1) gradient in DCM) to give the title compound I-68 as a white solid (10 mg, 9.4% yield).

[0894] 1H NMR (500MHz, methanol-d4) δ (ppm) 8.96 (s, 1H), 7.56 (d, 1H), 7.39 (apparent .t, 1H), 7.25 (m, 1H), 7.08 (m, 2H), 4.65 (s, 2H).

[0895] LCMS[M+H]=381.2

[0896] Compound I-70

[0897]

[0898] 8-(2-Fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine-3- Carbonitrile (I-70):

[0899] A solid mixture containing 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(diphenylphosphine)ferrocene]palladium(II) dichloride (3.7 mg, 5.0 μmol), and zinc powder (1.3 mg, 0.020 mmol) was purged with nitrogen for 15 min. DMF (2 mL) was added, and the reaction mixture was heated in a microwave at 120 °C for 7.5 h, during which additional amounts of palladium catalyst (3.7 mg) and zinc cyanide (24 mg) were added to advance the reaction. The crude mixture was cooled to ambient temperature, diluted with EtOAc (10 mL), and filtered through a diatomaceous earth bed using EtOAc (20 mL). The organic filtrate was washed with water / saline (2 × 10 mL, 10:1 ratio) and saline (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification by silica gel chromatography (0–10% acetonitrile / MeOH (7:1) gradient in DCM) yielded the title compound I-70 as a grayish-white solid (15 mg, 38% yield).

[0900] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.23 (s, ¹H), 8.44 (s, ¹H), 7.41 (apparent t, ¹H), 7.26 (m, ¹H), 7.10–7.05 (m, 2H), 4.74 (s, 2H).

[0901] LCMS[M+H]=388.3

[0902] Compound I-71

[0903]

[0904] 8-(2-fluorobenzyl)-3-methyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a] Pyrazine (I-71):

[0905] A solid mixture containing 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 tetra(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) was purged with nitrogen for 5 min. DME (3.5 mL) and water (0.5 mL) were added, followed by trimethylcycloboroxane (37 μL, 0.29 mmol). The reaction mixture was heated at 100 °C for 5 h and then at 120 °C for 1 h. Additional amounts of palladium catalyst (17 mg) and trimethylcycloboroxane (37 μL) were added, and the reaction mixture was heated at 120 °C for 40 h. 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 Na₂SO₄, filtered, and concentrated under vacuum. Purification by silica gel chromatography (0–40% EtOAc / hexane gradient) and reversed-phase HPLC (30%–80% acetonitrile / water gradient containing 0.1% formic acid) provided a white solid, title compound I-71 (16 mg, 29% yield).

[0906] 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 8.99 (s, 1H), 7.66 (s, 1H), 7.33 (apparent t, 1H), 7.24 (m, 1H), 7.11–7.03 (m, 2H), 4.67 (s, 2H), 2.63 (s, 3H).

[0907] LCMS[M+H]=377.2

[0908] Example 2a: Measurement of bioactivity by 384-well cGMP GloSensor-based analysis

[0909] Using the expression GloSensor TM Human embryonic kidney cells (HEK293 cells) containing 40F cGMP (product number: CS182801, Promega) were used to evaluate the activity of the test compound. A luminescent biosensor (modified luciferase) incorporated into the cells detected and emitted cGMP formed by the sGC enzyme stimulated by the compound.

[0910] cGMP GloSensor cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with fetal bovine serum (FBS, final concentration 10%) and hygromycin (200 μg / ml). The day before the assay, cells were cultured in 50 μL at 1.5 × 10⁻⁶ ppm. 4 Cells were seeded at a density of 10% FBS in 384-well white poly-D-lysine-coated DMEM plates (Corning catalog number 35661). Cells were cultured overnight at 37°C in a humidified chamber with 5% CO2. The next day, the culture medium was removed and the cells were replaced with 40 μL / well GloSensor. TM 2 mM (Promega catalog number E1291). Cells were treated at 25°C for 90 minutes to allow the substrate to equilibrate within the cells. The test compound and diethylenetriamine NONOate (DETA-NONOate or DETA-NO) were diluted to 3 mM (20×) in serum-free, CO2-independent medium and serially diluted 4× to generate a 5× dose profile. 10 μL of each solution was added to the wells (the concentration of the test compound solution was x μM and the concentration of the DETA-NONOate solution was 10 μM; where x was 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).

[0911] For kinetic studies, luminescence was immediately measured using an Envision (Perkin Elmer) at 0.2 seconds per well. For endpoint SAR screening, data were collected after 55 minutes of incubation at room temperature.

[0912] Data were standardized to high control using the following equation: 100*(sample - low control) / (high control - low control), where the low control is the mean of 16 samples treated with 1% DMSO, and the high control is the mean of 16 samples treated with 30 μM of compound Y, described below. For all compounds, data were fitted using GraphPad Prism software v.5.n=2 with a 4-parameter fit (log(agonist) vs. response - variable slope). Absolute (Abs) EC 50Interpolation from curve fitting is used, and is defined as the concentration at which a given compound elicits a 50% high control response after data normalization as described above. Compounds failing to elicit a 50% minimum response are reported to be >30 μM or ND. For compounds in duplicate or with n greater than 2, the results presented herein are the geometric mean of several obtained results. Table 2a summarizes the results obtained in this assay for the selected compounds of the invention.

[0913]

[0914] Table 2a. Complete cell viability in GloSensor-based analysis in 384-well format (Example 2a)

[0915]

[0916]

[0917]

[0918] sGC enzyme activity values ​​in HEK cells were measured using GloSensor analysis. The code definition for sGC enzyme activity values ​​(~) is expressed as absolute EC50. 50 It is defined as the concentration at which a given compound elicits a 50% high control response (compound Y) after data standardization: absolute EC50%. 50 ≤100nM=A;100nM<absolute EC 50 ≤1000nM=B;1000nM<absolute EC 50 =C. Compounds that cannot initiate a 50% minimum reaction are reported as >30 μM or ND.

[0919] Example 2b: Measurement of bioactivity by 384-well cGMP GloSensor-based cell analysis

[0920] Performance using GloSensor TMHEK293 cells in 40F cGMP (product number: CS182801, Promega) were used to evaluate the synergistic effect of the test compound with NO. Multiple analyses were performed, in which the concentrations of the test compound and diethylenetriamine NONOate (DETA-NONOate) were varied to determine the synergistic effect of the test compound with NO. The test compound and diethylenetriamine NONOate (DETA-NONOate or DETA-NO) were diluted to 3 mM (20×) in serum-free CO2-independent medium and serially diluted 4× to generate a 5× dose profile. 10 μL of each solution was added to the wells (the concentration of the test compound solution was x μM and the concentration of the DETA-NO solution was y μM; where 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 one of the following final concentrations: 30 μM, 10 μM, 3.33 μM, 1.11 μM, and 0 μM).

[0921] Following the determinations described above, Table 2b summarizes the results for compound I-1 with different amounts of DETA-NO in the determinations.

[0922] Table 2b shows complete cell viability in GloSensor-based analyses in a 384-well format (Example 2b).

[0923] [DETA-NO] 30uM 10uM 3.33uM 1.11uM 0uM <![CDATA[I-1-EC 50 ]]> A B B B B

[0924] sGC enzyme activity values ​​in HEK cells were measured using GloSensor analysis. The code definition for sGC enzyme activity values ​​(~) is expressed as absolute EC50. 50 It is defined as the concentration at which a given compound elicits a 50% high control response (compound Y) after data standardization: absolute EC50%. 50 ≤100nM=A;100nM<absolute EC 50 ≤1000nM=B;1000nM<absolute EC 50 =C. Compounds that cannot initiate a 50% minimum reaction are reported as >30 μM or ND.

[0925] As shown in Table 2b, compound I-1 works synergistically with NO to stimulate sGC.

[0926] Example 3. Bioactivity measured by cGMP-based neuronal cell analysis

[0927] Primary neurons were isolated from fetuses of female Sprague-Dawley rats at 18 days of gestation. The fetuses were collected in Hanks' balanced salt solution (HBSS) and the brains were rapidly removed. The hippocampus was isolated and mechanically fragmented. The neurons were then incubated at 37°C with a calcium-free solution. 2+ and Mg 2+ Further tissue digestion was performed for 15 minutes using 0.25% (wt / vol) trypsin solution in HBSS. After trypsinization, cells were washed and resuspended in neurobasal medium supplemented with 0.5 mM L-glutamine, 12.5 μM glutamate, 2% B-27, and 100 U / mL penicillin and 100 μg / mL streptomycin. Cells were cultured at 4 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of 100 cells / well in 384-well clear plates coated with poly-D-lysine (Corning catalog number 354662). Cells were cultured for 6–7 days in a humidified chamber containing 5% CO2 at 37°C. The culture medium was then removed and replaced with a solution containing Ca. 2+ and Mg 2+ Cells were washed 1× with HBSS and replaced with 40 μL of HBSS containing 0.5 mM IBMX, and cultured at 37 °C for 15 min. 10 μL of 5× stock solution of the test compound and diethylenetriamine NONOate (DETA-NO) was added. The final concentration of DETA-NO was 30 μM. Cells were cultured at 37 °C for 20 min. The culture medium was removed, 50 μL of 10% ice-cold acetic acid was added, and the cells were cultured at 4 °C for 60 min. After centrifugation at 1000×g for 5 min at 4 °C to precipitate cell debris, the supernatant was aspirated to a clear plate, and the cGMP content of the sample was analyzed. The cGMP concentration of each sample was determined using LC-MS / MS.

[0928] Data were standardized to high control using the following equation: 100*(sample - low control) / (high control - low control), where the low control was the mean of 15 samples treated with 1% DMSO, and the high control was the mean of 15 samples treated with 10 μM of the known sGC stimulator compound Y. For all compounds, a 4-parameter fit (log(agonist) vs. response - variable slope) was used with GraphPad Prism software v.5. n=2 to fit the data. Absolute EC 50Interpolation from curve fitting is used, and is defined as the concentration at which a given compound elicits a 50% 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 in duplicate or with n greater than 2, the results presented herein are the geometric mean of several obtained results. Table 3 summarizes the results obtained in this assay for the selected compounds of the invention.

[0929] Table 3. Bioactivity in cGMP-based neuronal cell analysis (Example 3)

[0930]

[0931]

[0932] Neuron-based cell analysis. Absolute EC. 50 ≤100nM=A;100nM<absolute EC 50 ≤1000nM=B;1000nM<absolute EC 50 =C. Compounds that cannot initiate a 50% minimum reaction are reported as >30 μM or ND.

[0933] Example 4: Pharmacokinetic Properties of Rat Cerebrospinal Fluid (CSF)

[0934] Protocol. PK in rats was determined after oral administration. For the oral (PO) assay, a group of six male Sprague-Dawley rats was used, with an indwelling catheter placed in the cerebellomedullary cistern. The PO group was administered 10 mg / kg or 1 mg / kg of the compound formulated as a PEG400 solution. The PO dose was administered via force-feeding and delivered to the stomach using a syringe and gavage tube. After oral administration, the gavage tube was flushed with approximately 0.5 mL of water to ensure complete delivery of the full dose.

[0935] Collect plasma samples as follows: Collect CSF and blood samples at 1 hour, 2 hours, and optionally 4 hours after administration. Collect CSF samples (0.05 mL) via an intracisional catheter. Collect blood samples (0.25 mL) via retro-orbital sampling. Keep these samples on ice until processing to obtain plasma. Centrifuge blood samples at approximately 5°C and 3200 rpm for 5 minutes within 1 hour of collection. Transfer plasma directly to 96-well plate tubes (0.125 mL). Cap the tubes and freeze them at approximately -70°C until analysis. Collect plasma and analyze for the presence of compounds.

[0936] Compound quantification. The compounds and internal standards were extracted from plasma and CSF by precipitation. Samples were analyzed using liquid chromatography (LC) and tandem mass spectrometry (MS / MS) with electrospray ionization. The standard curve ranged from 1 to 1000 ng / mL. The results for the compounds described in this assay are shown in Table 4a (10 mg / kg dose) and Tables 4b and 4c (1 mg / kg) below.

[0937] Kp,uu is defined as the ratio of unbound drug concentration in the CSF to the unbound drug concentration in the plasma. The unbound drug concentration in plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction, as determined by plasma protein binding assays. Kp,uu is then determined by dividing the CSF concentration by the free plasma concentration. (See, for example, Di et al., J. Med. Chem., 56, 2-12 (2013))

[0938] Table 4a: CSF PK properties of the compound selected in this paper (Example 4) at a dose of 10 mg / kg.

[0939]

[0940]

[0941] Table 4b: CSF concentrations of the compounds selected in this paper (Example 4) at a dose of 1 mg / kg.

[0942]

[0943] Table 4c: Kp,uu of the compound selected in this paper (Example 4) at a dose of 1 mg / kg.

[0944]

[0945] Example 5: Pharmacokinetic Properties of Canine Cerebrospinal Fluid (CSF)

[0946] Protocol. PK in dogs was determined after oral administration. A group of four male beagle dogs was used, and the dogs were administered 1 mg / kg of the compound prepared as a suspension in water containing 1% HPMC E5, 0.2% Tween 80, and 0.5% MC. The PO dose was administered orally in gelatin capsules via a gavage tube to the stomach. After oral administration, the gavage tube was flushed with approximately 10 mL of water to ensure complete delivery of the full dose.

[0947] Plasma and CSF samples were collected as follows: CSF and blood samples were collected at 1, 2, 4, and 8 hours after PO administration. CSF samples (0.05 mL) were collected at the appropriate time points via direct needle puncture from the lumbosacral region (L4 / 5). Blood samples (0.25 mL) were collected via the cephalic vein. These samples were kept on ice until plasma processing. Blood samples were centrifuged at approximately 5°C for 5 minutes at 3200 rpm within 1 hour of collection. Plasma was directly transferred to 96-well plate tubes (0.125 mL). The tubes were capped and frozen at approximately -70°C for storage until analysis. Plasma was collected and the presence of compounds was analyzed.

[0948] Quantification of compounds. The compounds of this invention and internal standards were extracted by precipitation from plasma and CSF. Samples were analyzed using electrospray ionization with detection by liquid chromatography (LC) and tandem mass spectrometry (MS / MS). The standard curve ranged from 1 to 1000 ng / mL. The results for the compounds described in this assay are shown in Tables 5a and 5b below (1 mg / kg dose).

[0949] Kp,uu is defined as the ratio of unbound drug concentration in the CSF to the unbound drug concentration in the plasma. The unbound drug concentration in plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction, as determined by plasma protein binding assays. Kp,uu is then determined by dividing the CSF concentration by the free plasma concentration. (See, for example, Di et al., J. Med. Chem., 56, 2-12 (2013))

[0950] Table 5a: CSF concentrations of the compounds selected in this paper (Example 5) at a dose of 1 mg / kg.

[0951]

[0952] Table 5b: Kp,uu of the compound selected in this paper (Example 5) at a dose of 1 mg / kg.

[0953]

[0954] Example 6: Pharmacokinetic Properties of Cerebrospinal Fluid (CSF) in Non-Human Primates (NHP)

[0955] Protocol. PK in NHP was determined after intravenous and oral administration. For the intravenous (IV) test, a group of four male cynomolgus monkeys was used. The IV group was administered 0.3 mg / kg of the compound prepared as a solution of 10% PEG-400, 25% Solutol HS15 in water, and 65% DPBS. The IV dose was administered by injection and delivered via catheter to the cephalic vein. For the oral (PO) test, a group of four male cynomolgus monkeys was used. The PO group was administered 1 mg / kg of the compound prepared as a suspension of 1% HPMC E5, 0.2% Tween 80, and 0.5% MC in water. The PO dose was administered orally via force-feed and delivered via gelatin capsules.

[0956] Plasma and CSF samples were collected as follows: CSF and blood samples were collected at 1 hour, 4 hours, and 24 hours after IV administration and at 2 hours, 8 hours, and 24 hours after PO administration. CSF samples (0.05 mL) were collected by direct needle puncture at the appropriate time points from the cerebellomedullary cistern (primary site) or lumbosacral region (L4 / 5). Blood samples (0.25 mL) were collected from a peripheral vein. These samples were kept on ice until plasma processing. Blood samples were centrifuged at approximately 5°C for 5 minutes at 3200 rpm within 1 hour of collection. Plasma was directly transferred to 96-well plate tubes (0.125 mL). The tubes were capped and frozen at approximately -70°C until analysis. Plasma was collected and the presence of compounds was analyzed.

[0957] Quantification of compounds. The compounds of this invention and internal standards were extracted by precipitation from plasma and CSF. Samples were analyzed by electrospray ionization using liquid chromatography (LC) and tandem mass spectrometry (MS / MS). The standard curve ranged from 1 to 1000 ng / mL. The results of the compounds described in this assay are shown in Tables 6a and 6b below (0.3 mg / kg IV dose, 1 mg / kg PO dose).

[0958] Kp,uu is defined as the ratio of unbound drug concentration in the CSF to the unbound drug concentration in the plasma. The unbound drug concentration in plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction, as determined by plasma protein binding assays. Kp,uu is then determined by dividing the CSF concentration by the free plasma concentration. (See, for example, Di et al., J. Med. Chem., 56, 2-12 (2013))

[0959] Table 6a: CSF concentrations of the compounds selected in this paper (Example 6) at doses of 0.3 mg / kg IV and 1 mg / kg PO.

[0960]

[0961] Table 6b: Kp,uu of the compounds selected in this paper (Example 6) at doses of 0.3 mg / kg IV and 1 mg / kg PO.

[0962]

[0963] Example 7: Measurement of biomarkers in rat cerebrospinal fluid (CSF)

[0964] This experiment was used to determine the effects of different doses of the compound of the present invention on the cGMP response and the concentrations of the compound in rat CSF and rat plasma.

[0965] Protocol: Each rat is sampled once or multiple times, with an interval of 3 days or more between each administration.

[0966] The day before the experiment, the rats were fasted overnight but allowed free access to water.

[0967] Experimental time. The compounds and cyclic guanosine monophosphate (cGMP) in rat CSF were determined after oral administration. Male Sprague-Dawley rats with indwelling catheters placed in the cerebellomedullary cistern were used. Rats were administered 0 mg / kg (n=15), 3 mg / kg (n=19), and 10 mg / kg (n=20) of the compounds of the present invention in suspensions prepared in 0.5% methylcellulose and 0.5% Tween 80. The PO dose was administered orally via forced feeding and delivered to the stomach using a syringe and gavage tube. After oral administration, the gavage tube was flushed with approximately 0.5 mL of water to ensure complete delivery of the full dose.

[0968] Under isoflurane anesthesia, plasma and CSF samples were collected as follows: CSF samples were collected 1 hour and 6 hours after administration, and blood samples were collected 1 hour after administration. CSF samples were collected via an intracisional catheter. Approximately 20 μL of CSF was aspirated and discarded (dead volume 14–16 μL); then approximately 50 μL of CSF was aspirated into an Eppendorf tube containing 5 μL of glacial acetic acid. The CSF was rapidly frozen by immersion in liquid nitrogen. Blood samples (0.25 mL) were collected via retro-orbital sampling. These samples were kept on ice until plasma processing. Blood samples were centrifuged at approximately 5°C for 10 minutes at 3200 rpm for 1 hour within 1 hour of collection. Plasma was directly transferred to 96-well plate tubes (0.125 mL). The tubes were capped and frozen at approximately -70°C for storage until analysis. Plasma was collected and the presence of compounds was analyzed.

[0969] Quantification of compounds and cGMP. The compounds, cGMP, and internal standard of this invention were extracted from plasma and CSF by precipitation. Samples were analyzed using electrospray ionization with detection by liquid chromatography (LC) and tandem mass spectrometry (MS / MS). The standard curve ranged from 1 to 1000 ng / mL. Results for the compounds described in this assay are shown in Table 7 below (3 mg / kg and 10 mg / kg doses). Statistical data were determined by planned comparison t-tests.

[0970] Kp,uu is defined as the ratio of the concentration of unbound drug in the CSF to the concentration of unbound drug in the plasma. The concentration of unbound drug in the plasma (or free plasma concentration) is calculated by multiplying the total plasma concentration by the unbound fraction as determined by plasma protein binding assay. Then, the CSF concentration is divided by the free plasma concentration to determine Kp,uu. (See, for example, Di et al., J. Med. Chem., 56, 2-12 (2013)).

[0971] Table 7: CSF PK properties of the compounds selected in this paper (Example 7) at doses of 3 mg / kg and 10 mg / kg.

[0972]

[0973]

[0974] *Relative to the medium, p < 0.05; **Relative to the medium, p < 0.01

[0975] Conclusion: Acute administration of compound I-1 at 3 mg / kg (PO) to rats significantly increased cGMP in rat CSF 1 h post-administration. Acute administration of compound I-1 at 10 mg / kg (P.O.) to rats significantly increased cGMP in rat CSF 1 h and 6 h post-administration.

[0976] Example 8: Evaluation of the effects of the compounds of the present invention on synaptic transmission and plasticity impairment in hippocampal sections of R6 / 2 mice.

[0977] Improvements in synaptic transmission and plasticity, measured by long-term enhancement (LTP), are considered to indicate the potential of compounds to enhance memory. LTP is an electrophysiological phenomenon commonly referred to as a cellular phenomenon that advances learning and memory.

[0978] plan.

[0979] Preparation of Acute Hippocampal Sections in Mice. Experiments were performed using 11- to 12-week-old R6 / 2 and WT mice provided by Jackson Laboratories (USA). Hippocampal sections (350 μm thickness) were cut using a Macllwain microtome in ice-cold oxygenated sucrose solution (250 mM succharose, 11 mM glucose, 26 mM NaHCO3, 2 mM KCl, 1.2 mM NaH2PO4, 7 mM MgCl2, and 0.5 mM CaCl2). The sections were incubated for 1 hour at room temperature in ACSF with the following composition: 11 mM glucose, 25 mM NaHCO3, 126 mM NaCl, 3.5 mM KCl, 1.2 mM NaH2PO4, 1.3 mM MgCl2, and 2 mM CaCl2. The sections were then allowed to recover for at least 1 hour.

[0980] Section perfusion and temperature control. During the experiment, sections were continuously perfused with ACSF (bubbled with 95% O2-5% CO2) at a rate of 3 mL / min using a peristaltic pump (MEA chamber volume: approximately 1 mL). Complete solution exchange in the MEA chamber was completed 20 seconds after solution switching. The perfusion solution was continuously preheated at 37°C before reaching the MEA chamber using a heated perfusion sleeve (PH01, MultiChannel Systems, Reutlingen, Germany). The temperature of the MEA chamber was maintained at 37 ± 0.1°C using a heating element located in the MEA amplifier probe.

[0981] Stimulation regimen / compound application.

[0982] Input / output (I / O) curves: from 100 μA to 800 μA in 100 μA steps. The stimulation intensity was then set to a fixed value of 250 μA for short-term and long-term synaptic plasticity measurements.

[0983] Short-term plasticity: Apply two pulses with decreasing stimulation intervals (e.g., 300 ms, 200 ms, 100 ms, 50 ms, 25 ms). Compound application: Record fEPSP for 10 minutes under control conditions (to verify baseline stability), then expose to the compound for 15 minutes (or, for control sections only, maintain exposure in the presence of the medium for 25 minutes). Apply the second I / O protocol and the paired pulse protocol in the continuous presence of the compound as previously described.

[0984] Long-term enhancement (LTP): LTP was induced by 10×TBS after a 10-minute control period (in the presence of the compound or medium (for control sections). Enhancement of synaptic transmission was then monitored for an additional 60-minute period of effect (in the continued presence of the compound or medium (for control sections).

[0985] in conclusion

[0986] Comparison between R6 / 2 and WT mice. For higher stimulus intensities (700 μA and 800 μA), the I / O characteristics of hippocampal sections from R6 / 2 mice were significantly higher than those from their WT littermates due to the higher stimulus intensities (700 and 800 μA). Paired pulse properties of hippocampal sections from R6 / 2 and WT mice were within the same range, except for the 25 ms stimulus interval, indicating significantly greater facilitation in R6 / 2 mice. Long-term enhancement of hippocampal sections from R6 / 2 mice was significantly impaired compared to age-matched WT mice (p < 0.0001, two-way ANOVA).

[0987] Evaluation of 7 nM compound I-1: For all stimulus intensities, the I / O characteristics of R6 / 2 hippocampal sections did not change significantly after exposure to 7 nM compound I-1. The paired pulse properties of R6 / 2 mouse hippocampal sections were also within the same range before and after exposure to 7 nM compound I-1, and showed no significant difference for any ISI. Exposure to 7 nM compound I-1 for up to 15 minutes did not change the fEPSP amplitude.

[0988] In WT mouse hippocampal sections (control conditions), HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 45% (with an increase of 46 ± 5% in fEPSP at the endpoint). In R6 / 2 mouse hippocampal sections (control conditions), HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 15% (with an increase of 16 ± 3% in fEPSP at the endpoint). After exposure to 7 nM compound I-1, HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 25% (with an increase of 26 ± 6% in fEPSP at the endpoint). The enhancement observed after exposure to 7 nM compound I-1 was not significantly different from the enhancement recorded in the control R6 / 2 sections (p = 0.0842, two-way ANOVA). Figure 1 ).

[0989] Evaluation of 46 nm compound I-1. For all stimulus intensities, the I / O characteristics of R6 / 2 hippocampal sections were similar before and after exposure to 46 nM compound I-1. For all ISIs, the paired pulse nature of R6 / 2 mouse hippocampal sections did not significantly increase after exposure to 46 nM compound I-1. Exposure to 46 nM compound I-1 for 15 minutes did not alter the fEPSP amplitude compared to control sections.

[0990] In WT mouse hippocampal sections (control conditions), HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 45% (with an increase of 46 ± 5% in fEPSP at the endpoint). In R6 / 2 mouse hippocampal sections (control conditions), HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 15% (with an increase of 16 ± 3% in fEPSP at the endpoint). After exposure to 46 nM compound I-1, HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 45% (with an increase of 44 ± 12% in fEPSP at the endpoint). The increase observed after exposure to 46 nM compound I-1 was significantly greater than the increase recorded in the R6 / 2 sections (p = 0.0065, two-way ANOVA). Figure 2 )

[0991] Evaluation of 308 nm compound I-1: For all stimulus intensities, no significant increase in I / O characteristics was observed in R6 / 2 hippocampal sections after exposure to 308 nM compound I-1. Only for the 50 ms ISI, the paired pulse nature of R6 / 2 mouse hippocampal sections was significantly lower after exposure to 308 nM compound I-1. During the 15-minute exposure to 308 nM compound I-1, the amplitude of fEPSP was slightly increased compared to the control R6 / 2 sections.

[0992] In WT mouse hippocampal sections (control conditions), HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 45% (with an increase of 46 ± 5% in fEPSP at the endpoint). In R6 / 2 mouse hippocampal sections (control conditions), HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 15% (with an increase of 16 ± 3% in fEPSP at the endpoint). After exposure to 308 nM compound I-1, HFS induced an increase in the amplitude of the induced response, stabilizing at approximately 35% (with an increase of 37 ± 9% in fEPSP at the endpoint). The increase observed after exposure to 308 nM compound I-1 was significantly greater than the increase recorded in the R6 / 2 sections (p = 0.0059, two-way ANOVA). Figure 3 )

[0993] Conclusion. In R6 / 2 mouse hippocampal sections, although the highest concentration of the studied compound I-1 (308 nM) slightly increased the amplitude of the induced response, none of the three concentrations showed a significant effect on the overall I / O characteristics. The concentrations of compound I-1 evaluated (7 nM, 46 nM, or 308 nM) did not show a significant effect on short-term plasticity properties, as measured by paired pulses of ISI from 25 ms to 300 ms (except for 308 nM compound I-1, which significantly reduced facilitation using paired pulses applied with 50 ms ISI). 7 nM compound I-1 failed to significantly rescue LTP damage recorded in R6 / 2 mouse hippocampal sections, while this compound completely restored LTP defects at concentrations of 46 nM and 308 nM.

[0994] Example 9: Compound-induced cGMP in mouse brain

[0995] Objective. To determine the effects of different doses of the compound of the present invention on cGMP response and on compound concentrations in different regions of the mouse brain (cortex, hippocampus, cerebellum, and striatum) and in the blood.

[0996] Protocol. Mice (n = 7-8 per experimental condition) were administered compound I-1 in a PO medium (1% hydroxypropyl methylcellulose, 0.2% Tween 80, 0.5% methylcellulose) or in media prepared at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg. Thirty minutes after administration, mice were decapitated and their brains removed under isoflurane anesthesia and placed in ice-cold Petri dishes containing a slurry dissection solution (saturated with 95% O2 and 5% CO2). Using an ice-cold scraper, the brain was transferred to the mouse brain matrix with coronal spacing and sectioned at 1 mm intervals, as shown below (not to scale).

[0997] The dissected brain was transferred back to Piper dishes containing a serous anatomical solution and 0.5 mM IBMX (saturated with 95% O2 / 5% CO2). The dorsal striatum was dissected first, followed by the hippocampus, then the medial prefrontal cortex, and finally the cerebellum. Immediately after dissecting each region, the dissected tissue was placed in Ependorf tubes that had been previously placed on dry ice for 30 minutes. Small pieces of tissue were rapidly frozen over approximately 10 seconds. After placing all regions in Ependorf tubes, the tubes were then rapidly frozen by immersion in liquid nitrogen. Whole blood samples were collected from the trunk region using a mitra tip. Tissue samples were stored at -80°C while the mitra tip was stored at room temperature. The levels of cGMP and compounds in the brain and blood were determined by LC / MS; protein quantification of the brain samples was performed using a BCA protein assay kit.

[0998] Conclusion: Acute administration of compound I-1 (PO) at 10 mg / kg significantly increased cGMP levels in all analyzed mouse brain regions (hippocampus, cerebellum, cortex, and striatum). (Tables 9a-d)

[0999] Table 9a: The concentration of cGMP in the mouse hippocampus is normalized to the protein concentration in the sample.

[1000]

[1001] **Relative to the medium p<0.01

[1002] Table 9b. The concentration of cGMP in the mouse striatum is normalized to the protein concentration in the sample.

[1003]

[1004] *Relative to the medium, p < 0.05;

[1005] Table 9c: The concentration of cGMP in the mouse cerebellum was normalized to the protein concentration in the sample.

[1006]

[1007] ****Relative to medium p < or = 0.0001;

[1008] Table 9d: The concentration of cGMP in mouse cortex was normalized to the protein concentration in the sample.

[1009]

[1010] *Relative to the medium, p < 0.05;

[1011] Example 10. Novel Object Recognition (NOR) Test

[1012] Objective. To evaluate the effect of the compound of the present invention in reversing memory impairment induced by MK-801 using a novel object recognition (NOR) test in male Long Evans rats. NOR is a recognition learning and memory retrieval test that utilizes the spontaneous preference of rodents to study novel objects compared to familiar ones (Ennaceur and Delacour, 1988). Studies have shown that the NOR process involves several brain regions, including the olfactory cortex (Ennaceur et al., 1996, 1997 and Aggleton et al., 1997) and the hippocampus (Wood et al., 1993 and Clark et al., 2000). The NOR test has been widely used to evaluate the potential cognitive-enhancing properties of novel test compounds. Because the NOR paradigm does not involve reward or harmful stimuli, it provides fewer confounding variables when translated into similar tests to be implemented in human clinical trials. In this study, a memory rescue model was used to test the novel compound MK-801 (dizocilpine), using a non-competitive antagonist of the NMDA receptor to induce recognition memory deficits. The compounds of this invention are evaluated based on their effects in reversing memory impairment.

[1013] Materials and methods.

[1014] Animals. Adult male Long Evans rats (obtained from Envigo, Indianapolis, IN, weighing 275–299 g at arrival) were used in this study. Rats were housed in the experimental room and assigned unique identification numbers (tail tags). Rats were housed in polycarbonate cages with filter tops at a rate of 2 rats per cage and acclimatized for at least 7 days prior to testing. The animal room was maintained at a 12 / 12h light / dark cycle (lighting at 07:00 EST), 22 ± 1°C, and approximately 50% relative humidity. Food and water were provided freely. All animals were examined, handled, and weighed prior to the study to ensure adequate health and minimize test-related nonspecific stress. Each animal was randomly assigned to a treatment group. The experiment was conducted during the animals' light cycle.

[1015] Test compounds. The following compounds were used in this study:

[1016] Dissolve MK-801 (0.1 mg / kg; Sigma-Aldrich) in saline and inject via IP 15 minutes before NOR training.

[1017] Dissolve galantamine (1 mg / kg; Tocris) in saline and inject via IP 15 minutes before training.

[1018] Compound I-1 (0.01 mg / kg, 0.1 mg / kg, and 1 mg / kg) was administered orally 60 minutes prior to training. The volumetric dose was 4 ml / kg.

[1019] Experimental Procedure. NOR tests were conducted on an open-air table (40×40cm) in a dimly lit, soundproof room. Each rat was tested individually, and olfactory / gustatory cues were carefully removed between tests by cleaning the table and test objects with 70% alcohol. All training and testing trials were video-recorded and scored by observers unaware of the treatment.

[1020] On days 1 and 2, rats were allowed free exploration of the table (without objects) for 5-minute habituation periods. On day 3 (training and testing day), rats were administered the drug medium (saline), galantamine, or a compound solution, followed by MK-801 or the medium (saline). After the pretreatment time, each animal was placed in a test table containing two identical objects. Each rat was placed in the table, facing the same location in the same direction, and the time spent actively exploring the objects during the 3-minute training period (T1) was recorded. After training, the rats were returned to their cages. A NOR test (T2) was performed 1 hour after T1. Each rat was reset in a test table containing one familiar object and one novel object for 5 minutes, and the time spent exploring both objects was recorded during the 0–1 minute, 0–3 minute, and 0–5 minute time ranges. The presentation order and position (left / right) of the objects in T2 were randomized among the rats to prevent order bias or positional preference.

[1021] Statistical analysis. Data from the NOR test (T2) were expressed as the recognition index, defined as the ratio of the time spent exploring a novel object to the time spent exploring two objects during the test period (novelty / (familiarity + novelty) × 100%). Fisher's LSD post-hoc test was performed using one-way ANOVA, followed by tests in the 0–1, 0–3, and 0–5 minute time ranges, with significance set at P < 0.05. Animals with a total object exploration time of less than 10 seconds during the 5-minute test period were excluded; rats with recognition indices greater than 90% or less than 30% were also excluded, as they indicated a strong (non-memory) bias between the two objects. Statistical outliers above or below two standard deviations from the mean were then removed from the final analysis. Based on these criteria, 1–3 rats (N = 15–16) were eliminated from each experimental group and excluded from statistical analysis in all time ranges (0–1, 0–3, and 0–5 minutes).

[1022] Results. No rats showed significant side effects at any dose in this study. Rats maintained normal levels of alertness, activity, and exploration of objects. ANOVA showed a significant primary therapeutic effect on the recognition index in the 0–1 minute time range [F(8,121)=2.451, P<0.05]. Post-hoc testing showed that MK-801 0.1 mg / kg induced a strong memory deficit with the recognition index approaching the chance level (50%). Galantamine (1 mg / kg) and 1 mg / kg of compound I-1 significantly reversed the memory deficit induced by MK-801 (Ps<0.01 and Ps<0.05, respectively, compared with the mediator / MK-801 group). ANOVA found a significant primary therapeutic effect in the 0–3 minute time range (Table 10) [F(8,121)=3.404, P<0.01]. Post-hoc testing showed that MK-801 0.1 mg / kg induced a strong memory deficit with the recognition index approaching the chance level (50%). Galantamine (1 mg / kg) and compound I-1 (0.1 mg / kg and 1 mg / kg) significantly reversed MK-801-induced memory deficits (Ps<0.001, Ps<0.01, and P<0.05, respectively, compared with the mediator / MK-801 group). Similarly, ANOVA showed significant primary therapeutic effects in the 0–5 minute timeframe [F(8,121)=3.179, P<0.01]. Post-hoc testing showed that MK-801 (0.1 mg / kg) induced strong memory deficits with recognition indices close to the chance level (50%). Galantamine (1 mg / kg) and compound I-1 (1 mg / kg) significantly reversed MK-801-induced memory deficits (P<0.001, P<0.01, and Ps<0.05, respectively, compared with the mediator / MK-801 group).

[1023] Table 10. Summary of Identification Index Measurements (0 to 3 minute timeframe)

[1024]

[1025] Statistical comparisons were per...

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, ###0001### Formula I wherein: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###0304### ###0305### ###0306### ###0307### ###0308### ###0309### ###0310### ###0311### ###0312### ###0313### ###0314### ###0315### ###0316### ###0317### ###0318### ###0319### ###0320### ###0321### ###0322### ###0323### ###0324### ###0325### ###0326### ###0327### ###0328### ###0329### ###0330### ###0331### ###0332### ###0333### ###0334### ###0335### ###0336### ###0337### ###0338### ###0339### ###0340### ###0341### ###0342### ###0343### ​ the core formed by ring E and A together with the substituents (J c ) p together form: ​ ​ i) is absent, and J B directly connected to the carbon atom bearing two J groups, each J is independently selected from hydrogen or methyl, n is 1 and J B C 1-7 alkyl chain; or ​ wherein each J is independently selected from hydrogen or methyl; n is an integer selected from 0, 2 or 3; and each J B independently halogen or C 1-4 alkyl; and each J is independently selected from hydrogen, halogen, C C is independently selected from hydrogen, halogen, C 1-4 aliphatic or -CN; ​ ​ R 10 To be arbitrarily and independently controlled by 0-3 R 15 Replacement C 1-6 alkyl; R 11 is H, -NR a2 R b2 halogen, optionally and independently substituted by 0-5 R 15 substituted C 1-6 alkyl, optionally and independently substituted by 0-3 R 15 substituted 5 to 6 membered heteroaryl, optionally and independently substituted by 0-3 R 15 substituted C 3-8 cycloalkyl; wherein each of said 5 to 6 membered heteroaryl contains up to 3 ring heteroatoms independently selected from N, O or S; R 15 halogen, -C(O)R b2 , phenyl optionally and independently substituted with 0-3 R 18 , or 5 or 6 membered heteroaryl optionally and independently substituted with 0-3 R 18 ; wherein each of said 5 or 6 membered heteroaryl rings contains up to 3 ring heteroatoms independently selected from N, O, or S. each R is independently selected from halo or C 18 independently selected from halo or C 1-6 alkyl; R a2 is hydrogen or C 1-6 alkyl; and R b2 is hydrogen or C 1-6 alkyl. ​ ​ the core formed by ring E and A together with the substituents (J c ) p together form: ​ ​ ​ wherein each J is independently selected from hydrogen or methyl; n is an integer selected from 0-3; and each J B independently halogen or C 1-4 alkyl; each J is independently selected from hydrogen, halogen, C C is independently selected from hydrogen, halogen, C 1-4 aliphatic or -CN; ​ ​ R 10 R 15 substituted C 1-6 alkyl; R 11 H, -NR a2 R b2 Halogen, optional and independently determined by 0-5 R 15 Replacement C 1-6 Alkyl groups, optionally and independently bound by 0-3 R groups 15 The substituted 5 to 6 heteroaryl groups or optionally and independently replaced by 0 to 3 R groups 15 Replacement C 3-8 cycloalkyl; wherein each of the 5 to 6-membered heteroaryl groups contains up to 3 independently selected cyclic heteroatoms chosen from N, O or S; R 15 halogen, -C(O)R b2 , phenyl optionally and independently substituted with 0-3 R 18 , or 5 or 6 membered heteroaryl optionally and independently substituted with 0-3 R 18 ; wherein each of said 5 or 6 membered heteroaryl rings contains up to 3 ring heteroatoms independently selected from N, O, or S. each R is independently selected from halo or C 18 independently selected from halo or C 1-6 alkyl; R a2 is hydrogen or C 1-6 alkyl; and R b2 is hydrogen or C 1-6 alkyl. ​ 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein each J B is independently selected from a halogen atom.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein each J B is independently selected from fluoro or chloro.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein each J B is fluoro.

7. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein each J B is C 1-4 alkyl.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein each J B is selected from ethyl or methyl.

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein each J B is methyl.

10. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein each J B is independently selected from fluoro and methyl. ​ 12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 2, J is located ortho to the methylene linker between ring B and the molecular core, and J is halo. B B is halo.​ 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein J is fluoro. B is fluoro. ​ wherein J B is C 1-4 alkyl chain optionally substituted with up to 5 fluorines.

15. A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein J B is C 1-2 alkyl chain optionally substituted with up to 5 fluorines.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 11 is C 15 alkyl optionally and independently substituted with 0-5 R 1-6 alkyl.

17. A compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 11 is methyl optionally and independently substituted with 0-3 R 15 substituents.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein R 15 In each case is halogen.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R 15 In each case is fluoro.

20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R 11 is -CF2H.

21. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R 11 is -CF3. ​ 23. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein J C at each occurrence is hydrogen. ​ ​ each J is independently selected from halo or C B is independently selected from halo or C 1-4 alkyl; ​ R 11 is H, halogen, -NR a2 R b2 , C 1-4 alkyl, 5- to 6-membered heteroaryl or C 3-6 cycloalkyl, wherein the C 1-4 alkyl, 5- to 6-membered heteroaryl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, or 3 groups independently selected from halogen; R a2 is hydrogen or C 1-4 alkyl; and R b2 is hydrogen or C 1-4 alkyl. ​ ​ each J is independently selected from halo or C B independently selected from halo or C 1-4 alkyl; ​ R 11 H, halogen, -NR a2 R b2 , C 1-4 alkyl, 5- to 6-membered heteroaryl or C 3-6 cycloalkyl, wherein said C 1-4 alkyl, 5- to 6-membered heteroaryl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, or 3 groups independently selected from halogen; R a2 is hydrogen or C 1-4 alkyl; and R b2 is hydrogen or C 1-4 alkyl. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ • dementia is selected from vascular dementia, vascular cognitive impairment, Binswanger's dementia, frontotemporal lobar degeneration or dementia, HIV-associated dementia, Lewy body dementia, or Alzheimer's disease; • Parkinson's disease is Parkinson's plus syndrome; • psychotic, mental, emotional or affective disorder is selected from bipolar disorder, schizophrenia, pervasive psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder, depression, anxiety, panic disorder, or post-traumatic stress disorder; • dystonia is selected from generalized, focal, segmental, torsion, dystonic reaction, and inherited / idiopathic dystonia; and movement disorder; • disorder characterized by relatively shortened synaptic plasticity and synaptic processes is selected from fragile X, Rett syndrome, Williams syndrome, Angelman syndrome, autism spectrum disorder.

30. The use of claim 28, wherein the disease, health condition, or disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, glaucoma, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, attention deficit disorder, or attention deficit hyperactivity disorder.

31. The use of claim 28, wherein the disease, health condition, or disorder is neuropathic pain.

32. The use of claim 28, wherein the disease, health condition, or disorder is selected from bipolar disorder, schizophrenia, pervasive psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder, depression, anxiety, panic disorder, or post-traumatic stress disorder.

33. The use of claim 28, wherein the disease, health condition, or disorder is selected from traumatic or non-traumatic brain injury or cognitive impairment or dysfunction resulting from brain injury or neurodegenerative disease.

34. The use of claim 28, wherein the disease, health condition, or disorder is Alzheimer's disease.

35. The use of claim 28, wherein the disease, health condition, or disorder is dystonia or movement disorder.

36. The use of claim 28, wherein the disease, health condition, or disorder is selected from a disorder characterized by relatively shortened synaptic plasticity and synaptic processes.

37. The use of claim 28, wherein the disease, health condition, or disorder is selected from chemo brain, levodopa-induced addictive behavior, alcoholism, narcotic dependence, and substance abuse.

38. The use of claim 29, wherein the autism spectrum disorder is selected from autism, Asperger's syndrome, pervasive developmental disorder, and childhood disintegrative disorder.

39. The use of claim 29, wherein the movement disorder is selected from acute, chronic / tardive movement disorder, and non-motor and levodopa-induced movement disorder.

40. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, in the manufacture of a medicament for treating a disease, health condition, or disorder in a subject in need of treatment, wherein the disease, health condition, or disorder is selected from: • a disorder associated with hypertension and reduced coronary blood flow, a vascular disorder caused by cardiac and renal complications, heart disease, renal failure, endothelial dysfunction or damage; • a thromboembolic disorder, ischemia, stroke; • a CNS disease, health condition, or disorder selected from Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, glaucoma, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, attention deficit disorder, attention deficit hyperactivity disorder, traumatic brain injury, non-traumatic brain injury, cognitive impairment or dysfunction resulting from brain injury or neurodegenerative disease, dystonia, movement disorder, a disorder characterized by relatively shortened synaptic plasticity and synaptic processes, fragile X, Rett syndrome, Williams syndrome, Angelman syndrome, autism spectrum disorder, neuropathic pain, bipolar disorder, schizophrenia, pervasive psychoses, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, chemo brain, levodopa-induced addictive behavior, alcoholism, narcotic dependence, or substance abuse; • peripheral arterial disease, peripheral occlusive arterial disease, peripheral vascular disease, hypertonus, Raynaud's syndrome or phenomenon, intermittent claudication, Duchenne and Becker muscular dystrophy, microcirculation abnormalities, control of vascular leakage or permeability; • shock, sepsis, control of leukocyte activation, inhibition or modulation of platelet aggregation; • thrombotic pulmonary arterial disease, plexiform pulmonary arterial disease, cystic fibrosis, bronchoconstriction or pulmonary bronchoconstriction, acute respiratory distress syndrome, pulmonary fibrosis; • atherosclerosis, restenosis, and inflammation; • cirrhosis associated with chronic liver disease, liver fibrosis, hepatic stellate cell activation, liver fibrous and total collagen accumulation; immunogenic liver disease, prostatic hypertrophy, systemic sclerosis, nonalcoholic steatohepatitis or NASH; • preservation of blood substitutes in trauma patients; • erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction, vaginal atrophy, dyspareunia, atrophic vaginitis; bladder outlet obstruction; painful bladder syndrome, interstitial cystitis, overactive bladder, neurogenic bladder, and urinary incontinence; • glaucoma, retinopathy, blepharitis, dry eye syndrome, Sjogren's syndrome; • impaired hearing; • dermal fibrosis, scleroderma; • microvascular perfusion improvement, anal fissure; and • cancer metastasis, osteoporosis, gastroparesis; functional dyspepsia; diabetic complications, diseases associated with endothelial dysfunction, neurological conditions associated with reduced nitric oxide production, achalasia or esophageal achalasia.

40. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, in the manufacture of a medicament for treating a disease, health condition, or disorder in a subject in need of treatment, wherein the disease, health condition, or disorder is selected from: • a disorder associated with hypertension and reduced coronary blood flow, a vascular disorder caused by cardiac and renal complications, heart disease, renal failure, endothelial dysfunction or damage; • a thromboembolic disorder, ischemia, stroke; • a CNS disease, health condition, or disorder selected from Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, glaucoma, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, attention deficit disorder, attention deficit hyperactivity disorder, traumatic brain injury, non-traumatic brain injury, cognitive impairment or dysfunction resulting from brain injury or neurodegenerative disease, dystonia, movement disorder, a disorder characterized by relatively shortened synaptic plasticity and synaptic processes, fragile X, Rett syndrome, Williams syndrome, Angelman syndrome, autism spectrum disorder, neuropathic pain, bipolar disorder, schizophrenia, pervasive psychoses, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, chemo brain, levodopa-induced addictive behavior, alcoholism, narcotic dependence, or substance abuse; • peripheral arterial disease, peripheral occlusive arterial disease, peripheral vascular disease, hypertonus, Raynaud's syndrome or phenomenon, intermittent claudication, Duchenne and Becker muscular dystrophy, microcirculation abnormalities, control of vascular leakage or permeability; • shock, sepsis, control of leukocyte activation, inhibition or modulation of platelet aggregation; • thrombotic pulmonary arterial disease, plexiform pulmonary arterial disease, cystic fibrosis, bronchoconstriction or pulmonary bronchoconstriction, acute respiratory distress syndrome, pulmonary fibrosis; • atherosclerosis, restenosis, and inflammation; • cirrhosis associated with chronic liver disease, liver fibrosis, hepatic stellate cell activation, liver fibrous and total collagen accumulation; immunogenic liver disease, prostatic hypertrophy, systemic sclerosis, nonalcoholic steatohepatitis or NASH; • preservation of blood substitutes in trauma patients; • erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction, vaginal atrophy, dyspareunia, atrophic vaginitis; bladder outlet obstruction; painful bladder syndrome, interstitial cystitis, overactive bladder, neurogenic bladder, and urinary incontinence; • glaucoma, retinopathy, blepharitis, dry eye syndrome, Sjogren's syndrome; • impaired hearing; • dermal fibrosis, scleroderma; • microvascular perfusion improvement, anal fissure; and • cancer metastasis, osteoporosis, gastroparesis; functional dyspepsia; diabetic complications, diseases associated with endothelial dysfunction, neurological conditions associated with reduced nitric oxide production, achalasia or esophageal achalasia.

41. Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 27 for the manufacture of a medicament for the treatment of a disease, health condition or disorder in a subject in need of treatment, wherein the disease, health condition or disorder is selected from: • increased acute and chronic coronary artery pressure, stroke, congestive heart failure, diastolic or systolic dysfunction, coronary insufficiency, arrhythmia, reduced ventricular pre-load, associated pulmonary vascular remodeling, localized thrombosis, right heart hypertrophy, pulmonary hypertension; • prodromal Alzheimer's disease, mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease; • autism, Asperger syndrome, pervasive developmental disorder, childhood disintegrative disorder; • cardiogenic shock; • stable or unstable angina pectoris, coronary spasm, variant angina, Prinzmetal's angina, thrombotic disorders, cardiac hypertrophy, heart failure / heart kidney syndrome, myocardial infarction, cardiac interstitial fibrosis, cardiac remodeling and fibrosis, cardiovascular diseases associated with metabolic syndrome; • thrombotic vasculitis, peripheral embolism, vascular occlusion crisis; • vasculitis, necrotizing inflammation-induced liver disease; • renal fibrosis and renal failure resulting from chronic kidney disease or insufficiency; • benign prostatic hyperplasia or hypertrophy or enlargement; • reperfusion injury, ischemia / reperfusion associated with organ transplantation, cerebral ischemia, critical limb ischemia, transient ischemic attack; • prevention of restenosis after thrombolytic therapy; • diabetic retinopathy, diabetic nephropathy, diabetic ulcer; • partial or complete hearing loss and tinnitus; • hepatitis, preeclampsia, polycystic kidney disease progression, subcutaneous fat or obesity; and • skin fibrosis.

42. Use of a compound according to claim 41, wherein: • cardiovascular diseases associated with metabolic syndrome are selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease; • increased acute and chronic coronary artery pressure is selected from arterial hypertension, resistant hypertension, diabetic hypertension and pulmonary hypertension; • partial or complete hearing loss is selected from partial or complete deafness and noise-induced hearing loss.

43. Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 27 for the manufacture of a medicament for the treatment of a disease, health condition or disorder in a subject in need of treatment, wherein the disease, health condition or disorder is selected from: pulmonary hypertension associated with or related to left ventricular dysfunction and WHO group I, II, III, IV, and V hypertensions, hypoxemia, mitral valve disease, mediastinal fibrosis, constrictive pericarditis, aortic stenosis, cardiomyopathy, congenital heart disease, chronic thromboemboli, pulmonary emboli due to tumor, parasites, or foreign material, chronic obstructive pulmonary disease, pulmonary vasculitis, pulmonary fibrosis, anomalous pulmonary venous drainage, pulmonary veno-occlusive disease, collagen vascular disease, interstitial lung disease, sleep-disordered breathing, sleep apnea, alveolar hypoventilation disorders, prolonged exposure to high altitudes, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, connective tissue disease, lupus, schistosomiasis, sarcoid, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis, histiocytosis X, lymphangiomatosis, and compressed pulmonary vessels; dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis, preeclampsia, polycystic kidney disease progression, subcutaneous fat, and obesity.

44. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for the manufacture of a medicament for the treatment or prevention of a disease, health condition, or disorder in a subject in need of treatment thereof, wherein the disease, health condition, or disorder is a disease or disorder that benefits from stimulation of sGC or from an increase in the concentration of NO or cGMP or both or upregulation of the NO pathway.

45. The use according to any one of claims 28-44, further comprising a second amount of a further suitable therapeutic agent.

46. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for the manufacture of a medicament for the treatment of mixed dementia in a subject in need of treatment thereof.

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