sGC stimulators

Abstract

The present invention relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts thereof and pharmaceutical formulations comprising the same as well as their use for the treatment of various diseases alone or in combination with one or more additional drugs, wherein an increase in nitric oxide (NO) concentration and / or an increase in cyclic guanosine monophosphate (cGMP) concentration or both, or an upregulation of the NO-pathway is desirable. In some embodiments, the compounds are those shown in Table I or pharmaceutically acceptable salts thereof.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 177,020, filed April 20, 2021, and U.S. Provisional Application No. 63 / 229,248, filed August 4, 2021. The entire contents of each of the foregoing applications are incorporated herein by reference. Technical Field

[0002] This invention relates to compounds as stimulants of soluble guanylate cyclase (sGC) and their pharmaceutically acceptable salts. It also relates to pharmaceutical preparations and dosage forms comprising the compounds, and their use, alone or in combination with one or more additional drugs, for the treatment of various diseases. These diseases are those that would benefit from sGC stimulation or an increase in nitric oxide (NO) and / or cyclic guanosine monophosphate (cGMP) concentrations. Background Technology

[0003] sGC is the primary receptor for NO in vivo. Upon binding to sGC, NO activates its catalytic domain, leading to the conversion of guanosine-5′-triphosphate (GTP) into the second messenger cGMP. Increased levels of cGMP further regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels. In vivo, NO is synthesized from arginine and oxygen via various nitric oxide synthases (NOS) and through the sequential reduction of inorganic nitrates. Experimental and clinical evidence indicates that decreased NO concentration, reduced NO bioavailability, and / or decreased responsiveness to endogenously produced NO contribute to the development of numerous diseases. sGC stimulators are heme-dependent agonists of sGC enzymes that synergize with varying amounts of NO to enhance the enzymatic conversion of GTP to cGMP. sGC stimulators are distinctly different from and structurally unrelated to another class of known NO-independent, heme-independent sGC agonists, which are sGC activators.

[0004] Therapies that improve or restore sGC function offer significant advantages over existing alternative therapies that target or otherwise benefit from the upregulation of the NO-sGC-cGMP pathway. There is an urgent need to develop novel and safe therapies for patients with dysfunctional NO-sGC-cGMP pathways. Summary of the Invention

[0005] This invention is based on the discovery that the compounds disclosed herein are sGC stimulants. Specifically, compounds with a 4-OH substituent on the pyrimidine ring were previously known only as synthetic intermediates for preparing sGC stimulants with a 4-amino substituent on the pyrimidine ring. Unexpectedly, the compounds of this invention have been found to possess strong sGC stimulating activity. In a first aspect, this invention relates to sGC stimulant compounds of Table I or Formula I and their pharmaceutically acceptable salts.

[0006] Table I. Exemplary sGC stimulants of the present invention.

[0007]

[0008]

[0009]

[0010] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of Table I, Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0011] In a third aspect, the present invention relates to a method of treating a disease in a subject in need, comprising administering, alone or in combination therapy, a therapeutically effective amount of a Table I, Formula I compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the subject; wherein the disease is one that would benefit from sGC stimulation or an increase in NO and / or cGMP concentrations. This application also provides the use of a Table I, Formula I compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for manufacturing a medicament for treating a disease in a subject in need, wherein the disease is one that would benefit from sGC stimulation or an increase in NO and / or cGMP concentrations. In some embodiments, the present invention relates to a Table I compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for treating a disease in a subject in need, wherein the disease is one that would benefit from sGC stimulation or an increase in NO and / or cGMP concentrations. Attached Figure Description

[0012] Figure 1 The effect of compound I-14 on the change in MAP relative to baseline in male normotensive rats (Δ) is shown. B The role of MAP.

[0013] Figure 2 Compound I-20 was shown to have an effect on Δ in male normotensive rats. B The role of MAP. Invention Details

[0015] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it should be understood that it is not intended to limit the invention to these embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. The invention is not limited to the methods and materials described herein, but includes any methods and materials similar to or equivalent to those shown herein that can be used in the practice of the invention. Where one or more of the incorporated references, patents, or similar materials (including, but not limited to, defined terminology, usage of terminology, described techniques, etc.) differ from or conflict with this application, this application shall prevail.

[0016] Definitions and General Terms

[0017] For the purposes of this invention, chemical elements are identified according to the periodic table, CAS edition, and 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, Smith, MB and March, J. (eds.), John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0018] Unless otherwise stated, all tautomer forms of the compounds of this invention are also within the scope of this invention.

[0019] In one embodiment, the invention may include the use of deuterium (i.e., 2 H) replacing hydrogen can yield certain therapeutic advantages due to greater metabolic stability (e.g., prolonged in vivo half-life or reduced dose requirement) and is therefore preferred in some cases. The deuterated compounds of the present invention can generally be prepared by operations similar to those shown in the schemes and / or examples below, by replacing the undeuterated reagent with a deuterated reagent.

[0020] As used herein, the term "halogen" or "halogen group" refers to any one of F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0021] The term "hydroxyl" refers to -OH.

[0022] As used herein, the term "alkyl" refers to a saturated unbranched (e.g., straight-chain) or branched monovalent hydrocarbon group. x An alkyl group is an alkyl chain containing x carbon atoms, where x is a non-zero integer. "C x-y An alkyl group (where x and y are two distinct integers, neither of which is 0) is an alkyl chain containing a number of carbon atoms between x and y (including the endpoints). For example, C 1-6 Alkyl is an alkyl group containing any number of carbon atoms between 1 and 6, as defined above. Examples of alkyl groups include (but are not limited to) methyl (i.e., C1 alkyl), ethyl (i.e., C2 alkyl), n-propyl (C3 alkyl), isopropyl (different C3 alkyl), n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, and the like.

[0023] As used herein, the term "fluoroalkyl" refers to an alkyl group as defined above, wherein one or more of the hydrogen atoms attached to the chain carbon atoms at any one or more carbon atoms of the alkyl group have been replaced by fluorine. For example, a fluoroalkyl group substituted with 1 to 3 fluorine atoms is an alkyl group in which 1 to 3 hydrogen atoms at any position on the same or different carbon atoms of the alkyl chain have been replaced by fluorine atoms.

[0024] The compounds of this invention are defined herein by their chemical structure and / or chemical name. In cases where a compound is mentioned by its chemical structure and chemical name and there is a conflict between the two, the chemical structure determines the compound's identity.

[0025] Compound / Composition Implementation Plan

[0026] The first embodiment of the present invention is a compound listed in Table I or a pharmaceutically acceptable salt thereof.

[0027] The second embodiment of the present invention is a compound of Table II or a pharmaceutically acceptable salt thereof.

[0028] Table II. Exemplary sGC stimulants of the present invention.

[0029]

[0030]

[0031] In the third embodiment, the compounds of the present invention are selected from those shown in Table III below:

[0032] Table III. Exemplary sGC stimulants of the present invention.

[0033]

[0034]

[0035] Or its medically acceptable salt.

[0036] In the fourth embodiment, the compounds of the present invention are selected from those compounds shown in Table IV below:

[0037] Table IV. Exemplary sGC stimulants of the present invention.

[0038]

[0039]

[0040] Or its medically acceptable salt.

[0041] In the fifth embodiment, the compounds of the present invention are selected from those shown in Table V below:

[0042] Table V. Exemplary sGC stimulants of the present invention.

[0043]

[0044] Or its medically acceptable salt.

[0045] In the sixth embodiment, the compounds of the present invention are selected from those shown in Table VI below:

[0046] Table VI. Exemplary sGC stimulants of the present invention.

[0047]

[0048] Or its medically acceptable salt.

[0049] In a seventh embodiment, the compound of the present invention is compound I-14 or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt of compound I-14 is a sodium salt. In another embodiment, the compound of the present invention is a sodium salt of compound I-14 represented by the following formula:

[0050]

[0051] In an eighth embodiment, the compound of the present invention is compound I-20 or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt of compound I-20 is a sodium salt. In another embodiment, the compound of the present invention is a sodium salt of compound I-20 represented by the following formula:

[0052]

[0053] In the ninth embodiment, the compound of the present invention is represented by Formula I:

[0054]

[0055] Or its medically acceptable salt, wherein:

[0056] J C Choose from the following groups: hydrogen, halogens, C 1-6 Alkyl groups and C atoms substituted with 1 to 3 fluorine atoms 1-6 fluoroalkyl;

[0057] X is N or C(J) C1 );

[0058] J C1 Choose from the following groups: hydrogen, halogens, C 1-6 Alkyl groups and C atoms substituted with 1 to 3 fluorine atoms 1-6 fluoroalkyl;

[0059] Each J B Independently select from the following groups: hydrogen, halogens, C 1-6 Alkyl groups and C atoms substituted with 1 to 3 fluorine atoms 1-6 fluoroalkyl;

[0060] J D Choose from the following groups: hydrogen, halogens, C 1-6 Alkyl groups and C atoms substituted with 1 to 3 fluorine atoms 1-6 fluoroalkyl groups; and

[0061] n is an integer selected from 0, 1, 2, 3, or 4, with the constraint that the compound is not one of the following:

[0062] Or its medically acceptable salt.

[0063] In the tenth embodiment, for the compound of formula I described in the ninth embodiment, the variables are defined as follows:

[0064] J C Choose from the following groups: hydrogen, halogens, and C. 1-6 alkyl;

[0065] X is N or C(J) C1 );

[0066] J C1 Choose from the following groups: hydrogen, halogens, and C. 1-6 alkyl;

[0067] Each J B Independently selected from the following groups: hydrogen, halogens, and C 1-6 alkyl;

[0068] J D Choose from the following groups: hydrogen, halogens, and C. 1-6 Alkyl groups; and

[0069] n is an integer selected from 0, 1, 2, 3, or 4, with the constraint that the compound is not one of the following:

[0070]

[0071] It is a medicinally acceptable salt.

[0072] In some implementation schemes, each J B Independent selection of free halogens and C 1-6 A group consisting of alkyl groups.

[0073] In the eleventh embodiment, for compounds of formula I, n is an integer selected from 1, 2, 3, or 4, and each J B Independently select from the following groups: halogens, C 1-6 Alkyl groups and C atoms substituted with 1 to 3 fluorine atoms 1-6 fluoroalkyl, wherein J B All other carbon atoms in the connected benzene ring are unsubstituted, and the remaining variables are as defined above in the ninth embodiment.

[0074] In the twelfth embodiment, the compound of formula I is represented by formula IA:

[0075]

[0076] Or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I in the ninth, tenth, or eleventh embodiments, and the limitation is that the compound is not any of the following:

[0077]

[0078] Or its medically acceptable salt.

[0079] In the thirteenth embodiment, for compounds of formula I or formula IA or their pharmaceutically acceptable salts, J C1 H, F, Cl, C 1-2 Alkyl groups or C atoms substituted with 1 to 3 fluorine atoms 1-2 Fluoroalkyl; and the remaining variables are as defined in any of the ninth, eleventh or twelfth embodiments.

[0080] In the fourteenth embodiment, for compounds of formula I or formula IA, or their pharmaceutically acceptable salts, J C1It is H, F, or Cl; and the remaining variables are defined as in any of the ninth to twelfth embodiments.

[0081] In the fifteenth embodiment, for compounds of formula I or formula IA, or their pharmaceutically acceptable salts, J C1 The variable is H, F, methyl, or a fluoromethyl group substituted with 1 to 3 fluorine atoms (i.e., -CH2F, -CHF2, or CF3); and the remaining variables are as defined in any of the ninth and eleventh to thirteenth embodiments.

[0082] In the sixteenth embodiment, for compounds of formula I or formula IA or their pharmaceutically acceptable salts, J C1 H is defined as H; and the remaining variables are defined as in any of the ninth to fifteenth implementation schemes.

[0083] In the seventeenth embodiment, for compounds of formula I or formula IA, or their pharmaceutically acceptable salts, J C1 It is F, methyl, or fluoromethyl substituted with 1 to 3 fluorine atoms (i.e., -CH2F, -CHF2, or CF3); and the remaining variables are as defined in any of the ninth, eleventh to thirteenth, and fifteenth embodiments.

[0084] In the eighteenth embodiment, for compounds of formula I or formula IA according to the thirteenth, fifteenth, or seventeenth embodiment, C 1-2 Fluoroalkyl or fluoromethyl groups are substituted with one fluorine atom.

[0085] In the nineteenth embodiment, for compounds of formula I or formula IA according to the thirteenth, fifteenth, or seventeenth embodiment, C 1-2 Fluoroalkyl or fluoromethyl groups are substituted with two fluorine atoms.

[0086] In the twentieth embodiment, for compounds of formula I or formula IA according to the thirteenth, fifteenth, or seventeenth embodiment, C 1-2 Fluoroalkyl or fluoromethyl groups are substituted with three fluorine atoms.

[0087] In the twenty-first embodiment, for compounds of formula I or formula IA, or their pharmaceutically acceptable salts, J C1 It is F or H; and the remaining variables are defined as in any of the ninth to twelfth embodiments.

[0088] In the twenty-second embodiment, the compound of formula I is represented by formula IB:

[0089]

[0090] Or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I according to the ninth, tenth, or eleventh embodiment, and the limitation is that the compound is not a Or its medically acceptable salt.

[0091] In the twenty-third embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 2 or 3, and the remaining variables are as described in any of the ninth to twenty-second embodiments. In some embodiments, n is 2. In other embodiments, n is 3.

[0092] In the twenty-fourth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 0 or 1, and the remaining variables are as described in any of the ninth to twenty-second embodiments. In some embodiments, n is 1.

[0093] In the twenty-fifth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, each J B H, F, C independently 1-4 Alkyl groups or C atoms substituted with 1 to 3 fluorine atoms 1-4 Fluoroalkyl; and the remaining variables are as described in any of the ninth to twenty-fourth embodiments.

[0094] In the twenty-sixth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, each J B Independently H, F or C 1-4 Alkyl; and the remaining variables are as described in any of the ninth to twenty-fourth embodiments.

[0095] In the twenty-seventh embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 2 or 3; each J B Independently, it is F, methyl, or fluoromethyl substituted with 1 to 3 fluorine atoms; and the remaining variables are as described in any of the ninth to twenty-third embodiments.

[0096] In the twenty-eighth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 2 or 3; each J B Independently, it is either F or methyl; and the remaining variables are as described in any of the ninth to twenty-third embodiments.

[0097] In the twenty-ninth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 2 or 3; each J B Independently, it is F, ethyl, or a fluoroethyl substituted with 1 to 3 fluorine atoms; and the remaining variables are as described in any of the ninth to twenty-third embodiments.

[0098] In the thirtieth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 2; J B All are F or JB One is F and the other is methyl or a fluoromethyl group substituted with 1 to 3 fluorine atoms; and the remaining variables are as described in any of the embodiments from the ninth to the twenty-third. In some embodiments, a J B One is F and the other is methyl or a fluoromethyl group substituted with 1 to 3 atoms. In other embodiments, a J B One is F and the other is methyl. In additional embodiments, one J B The fluorinated methyl group is F, and the other is fluoromethyl. In some embodiments, the fluoromethyl group is substituted with one fluorine atom (i.e., -CH2F). In other embodiments, the fluoromethyl group is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, the fluoromethyl group is substituted with three fluorine atoms (i.e., -CF3).

[0099] In the thirty-first embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 2; J B All are F or J B One of them is F and the other is an ethyl or a fluoroethyl substituted with 1 to 3 fluorine atoms; and the remaining variables are as described in any of the embodiments from the ninth to the twenty-third. In some embodiments, a J B One is F and the other is an ethyl or a fluoroethyl substituted with 1 to 3 atoms. In other embodiments, a J B One is F and the other is ethyl. In additional embodiments, one J B The first is F, and the second is fluoroethyl. In some embodiments, the fluoroethyl is substituted with one fluorine atom. In other embodiments, the fluoroethyl is substituted with two fluorine atoms, and in still other embodiments, the fluoroethyl is substituted with three fluorine atoms.

[0100] In the thirty-second embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 3; J B The three instances are F or J B Both of the J atoms are F and the other is methyl or fluoromethyl substituted with 1 to 3 fluorine atoms; and the remaining variables are as described in any of the ninth to twenty-third embodiments. In some embodiments, the fluoromethyl group is substituted with one fluorine atom (i.e., -CH2F). In other embodiments, the fluoromethyl group is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, the fluoromethyl group is substituted with three fluorine atoms (i.e., -CF3). In some embodiments, the two J atoms are F. B One is F and the other is methyl.

[0101] In the thirty-third embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 3; J B The three instances are F or J BIn this embodiment, both are F and the other is ethyl or a fluoroethyl substituted with one to three fluorine atoms; and the remaining variables are as described in any of the ninth to twenty-third embodiments. In some embodiments, the fluoroethyl is substituted with one fluorine atom. In other embodiments, the fluoroethyl is substituted with two fluorine atoms, and in still other embodiments, the fluoroethyl is substituted with three fluorine atoms.

[0102] In the thirty-fourth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 1; J B The fluorine methyl group is F, methyl, ethyl, fluoromethyl, or fluoroethyl; and the remaining variables are as described in any of the ninth to twenty-second embodiments. In some embodiments, the fluoromethyl group is substituted with one fluorine atom (i.e., -CH2F). In other embodiments, the fluoromethyl group is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, the fluoromethyl group is substituted with three fluorine atoms (i.e., -CF3). In some embodiments, the fluoroethyl group is substituted with one fluorine atom. In other embodiments, the fluoroethyl group is substituted with two fluorine atoms, and in other embodiments, the fluoroethyl group is substituted with three fluorine atoms.

[0103] In the thirty-fifth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, n is 1; J B F; and the remaining variables are as described in any of the ninth to twenty-second implementation schemes.

[0104] In the thirty-sixth embodiment, n is 0 for compounds of formula I, IA, or IB or their pharmaceutically acceptable salts; and the remaining variables are as described in embodiments nine through twenty-two.

[0105] In the thirty-seventh embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J D The fluorine methyl group is H, F, Cl, methyl, ethyl, or fluoromethyl or fluoroethyl, wherein the fluoromethyl or fluoroethyl group is substituted with one to three fluorine atoms; and the remaining variables are as described in any of the ninth to thirty-sixth embodiments. In some embodiments, the fluoromethyl group is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, the fluoromethyl group is substituted with three fluorine atoms (i.e., -CF3). In other embodiments, the fluoroethyl group is substituted with one fluorine atom. In other embodiments, the fluoroethyl group is substituted with two fluorine atoms, and in other embodiments, the fluoroethyl group is substituted with three fluorine atoms.

[0106] In the thirty-eighth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J D It is H or F, and all other variables are defined as in any of the ninth to thirty-seventh embodiments. In some embodiments, J DFor F. In some implementations, J D For H.

[0107] In the thirty-ninth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J D It is hydrogen; and the remaining variables are as described in any of the ninth to thirty-seventh embodiments.

[0108] In the fortieth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J D F; and the remaining variables are as described in any of the ninth to thirty-seventh implementation schemes.

[0109] In the forty-first embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J C The fluorine methyl group is H, Cl, F, methyl, ethyl, fluoroethyl, or fluoromethyl substituted with one to three fluorine atoms; and the remaining variables are as described in any of the ninth to fortieth embodiments. In some embodiments, the fluoromethyl group is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, the fluoromethyl group is substituted with three fluorine atoms (i.e., -CF3). In other embodiments, the fluoroethyl group is substituted with one fluorine atom. In other embodiments, the fluoroethyl group is substituted with two fluorine atoms, and in other embodiments, the fluoroethyl group is substituted with three fluorine atoms.

[0110] In the forty-second embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J C It is H, Cl, or F; and the remaining variables are as described in any of the ninth to fortieth embodiments.

[0111] In the forty-third embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J C The fluorine methyl group is H, F, methyl, or fluoromethyl; and the remaining variables are as described in any of the ninth to fortieth embodiments. In some embodiments, the fluoromethyl group is substituted with two fluorine atoms (i.e., -CHF2) and in other embodiments, the fluoromethyl group is substituted with three fluorine atoms (i.e., -CF3).

[0112] In the forty-fourth embodiment, for compounds of formula I, IA, or IB, or their pharmaceutically acceptable salts, J C It is H or F; and the remaining variables are as described in any of the ninth to fortieth embodiments. In some embodiments, J C For H.

[0113] In the forty-fifth embodiment, the compound of the present invention is a compound represented by formula IC:

[0114]

[0115] Or a medically acceptable salt thereof, wherein X is N or C (J C1 ), where X is C(J) C1 When ), it is represented by C in the table below; and variables X and J C1 and J B The definitions are described in the table below; in addition, Me represents methyl and Me-F represents fluoromethyl groups substituted with 1 to 3 fluorine atoms (i.e., -CH2F, -CHF2 or CF3):

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] This invention relates to a pharmaceutically acceptable salt.

[0125] The term "pharmaceutical-acceptable salt" for the compounds described herein includes those salts obtained by mixing the compound with an inorganic acid or an organic acid or a base. In some embodiments, the salt may be prepared in situ during the final separation 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. The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, which is incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of any of the compounds in Tables I to VI or Formula I are those salts that can be used in pharmaceuticals. However, pharmaceutically unacceptable salts may be used to prepare compounds in Tables I to VI or Formula I or their pharmaceutically acceptable salts.

[0126] When the compounds described herein (e.g., compounds in Tables I to VI or compounds represented by Formula I) are acidic, a suitable "medically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base, including both inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and similar salts. Specific embodiments include ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N,N1-diphenylmethylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, thiazoline, and their analogues.

[0127] In some embodiments, the compounds of the present invention have an acidic OH group capable of reacting with a base (e.g., a pharmaceutically acceptable non-toxic base) to form a salt (e.g., a pharmaceutically acceptable salt). In some embodiments, the salt is an ammonium salt, calcium salt, magnesium salt, potassium salt, or sodium salt. In some embodiments, the salt is a sodium salt.

[0128] When the compounds described herein (e.g., compounds in Tables I to VI or compounds represented by Formula I) are bases, salts can be prepared from pharmaceutically acceptable, non-toxic acids (including inorganic and organic acids). Such acids include acetate, acetic acid, acid citrate, acid phosphate, ascorbate, benzenesulfonic acid, benzenesulfonate, benzoic acid, benzoate, bromide, hydrogen sulfate, hydrogen tartrate, camphorsulfonic acid, chloride, citrate, citric acid, ethanesulfonate, ethanesulfonic acid, formate, fumarate, fumaric acid, gentianate, glucuronide, gluconic acid, glucuronic acid, glutamate, glutamic acid, hydrobromic acid, hydrochloric acid, iodide, hydroxyethylsulfonic acid, isonicotinic acid, and lactic acid. Radicals, lactic acid, maleate, maleic acid, malic acid, mandelic acid, methanesulfonic acid, methanesulfonate, mucilage, nitrate, nitric acid, oleate, oxalate, pyric acid, dihydroxynaphthate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarboxylate)), pantothenic acid, pantothenic acid, phosphate, phosphoric acid, glucoside, salicylate, succinic acid, succinate, sulfuric acid, sulfate, tannate, tartrate, tartaric acid, p-toluenesulfonate, p-toluenesulfonic acid, and the like. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0129] In addition to the compounds described herein, their pharmaceutically acceptable salts may also be used in the composition to treat or prevent the diseases identified herein.

[0130] Pharmaceutical compositions and methods of administration.

[0131] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound described herein (e.g., a compound of Tables I to VI or a compound represented by Formula I, or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[0132] In some embodiments, the pharmaceutical composition of the present invention comprises a compound or a pharmaceutically acceptable salt thereof as described in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, and twenty-eighth embodiments, and at least one pharmaceutically acceptable excipient or carrier.

[0133] The compounds disclosed herein and their pharmaceutically acceptable salts may be formulated as pharmaceutical compositions or “preparations”.

[0134] Typical formulations are prepared by mixing the compounds described herein (e.g., compounds in Tables I to VI or compounds represented by Formula I or their pharmaceutically acceptable salts) with a carrier, diluent, or excipient. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or expandable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The carriers, diluents, or excipients used will be determined according to the manner and purpose of formulating the compounds described herein (e.g., compounds in Tables I to VI or compounds represented by Formula I or their pharmaceutically acceptable salts). Solvents are generally selected based on those generally considered by those skilled in the art to be safe for administration to mammals (GRAS - Generally Regarded as Safe). Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible 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, light-blocking agents, flow aids, processing aids, colorants, sweeteners, flavorings, and other known additives used to provide a refined appearance for the medicine (i.e., compounds of Tables I to VI, compounds represented by Formula I, or pharmaceutical compositions thereof) or to aid in the manufacture of the pharmaceutical product (i.e., the drug).

[0135] Acceptable diluents, carriers, excipients, and stabilizers are those substances 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 (such as octadecyl dimethylbenzyl ammonium chloride; hexachlorobenzyl quaternary ammonium chloride; benzalkonium chloride, benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl parabens such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-methylparaben). Phenols; 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; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN. TM PLURONICS TMAlternatively, polyethylene glycol (PEG) can be used. Active pharmaceutical ingredients can also be encapsulated in prepared microcapsules, for example, through coagulation techniques or interfacial polymerization, such as encapsulation in hydroxymethyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules; encapsulation in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules); or encapsulation in macroemulsions. Such techniques are disclosed in Remington's: The Science and Practice of Pharmacy, 21st edition, University of the Sciences in Philadelphia, 2005 (hereinafter referred to as "Remington's").

[0136] The formulation can be prepared using conventional dissolution and mixing procedures.

[0137] As used herein, the term "therapeutic effective amount" refers to the amount of an active compound or medicine that elicits a biological or pharmaceutical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, or human. The therapeutic effective amount of a compound to be administered will be determined by such considerations and is the minimum amount required to improve, cure, or treat one or more of a disease or its symptoms.

[0138] The term "administer" in relation to the compounds, compositions, or dosage forms of the present invention means the introduction of the compound, composition, or dosage form into the system of an individual or a patient requiring treatment. When the compounds of the present invention are provided in combination with one or more other active agents, "administer" and its variations are each understood to include the simultaneous and / or sequential introduction of said compound, composition, or dosage form and other active agents.

[0139] Depending on the severity and type of the disease to be treated, the compositions described herein may be administered systemically or topically, such as orally (including, but not limited to, solid dosage forms, including hard or soft capsules (e.g., gelatin capsules), tablets, pills, powders, sublingual tablets, sugar lozenges, tablets, and granules); and liquid dosage forms, including, but not limited to, pharmaceutically acceptable emulsions, microemulsions, aqueous or oily solutions, suspensions, syrups, and elixirs); by inhalation (e.g., using aerosols, gases, inhalers, nebulizers, or the like); by ear (e.g., using ear drops); and topically (e.g., using creams, gels, inhalers, liniments, lotions, ointments, etc.). The composition may be administered via patches, pastes, powders, solutions, sprays, percutaneous patches, etc.; via the eye (e.g., using eye drops, eye gels, eye ointments); via the rectum (e.g., using enemas or suppositories); via the nose; via the cheek; via the vagina (e.g., using irrigators, intrauterine devices, vaginal suppositories, vaginal rings, or tablets, etc.); via ear drops; via implantable reservoirs or the like; or via non-intestinal routes. As used herein, the term "non-intestinal" includes (but is not limited to) subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

[0140] Formulations of compounds intended for oral use may be prepared according to any method known in the field of manufacturing pharmaceutical compositions.

[0141] 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.

[0142] 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 and mixtures thereof of sorbitol. Besides inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0143] Oral compositions (solid or liquid) may also contain excipients and adjuvants such as dispersants 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), condensation products of ethylene oxide and metaesters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate); emulsifiers and suspending agents, such as sodium carboxymethyl cellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragali, and gum arabic; sweeteners, flavoring agents, and aroma agents; and / or one or more preservatives (e.g., ethylparaben or n-propylparaben), one or more coloring agents, one or more flavoring agents, and one or more sweeteners (e.g., sucrose or saccharin).

[0144] 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.

[0145] 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 prepared. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required.

[0146] 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.

[0147] 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.

[0148] The oil phase of an emulsion prepared using compounds from Tables I to VI or 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. Emulsifiers, with or without stabilizers, together constitute 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 from Tables I to VI or Formula I include Tween. TM -60, Span TM -80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0149] Additionally, the present invention includes the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. The dosage form 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.

[0150] 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.

[0151] 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.

[0152] 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 (including those described in the preceding paragraphs) 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 a solution 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 vegetable oils like peanut oil, olive oil, sesame oil, or coconut oil, especially in their polyoxyethyleneized form, or mineral oils (e.g., liquid paraffin). 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 to prepare pharmaceutically acceptable solid, liquid, or other dosage forms) may also be used for injectable formulations. The oily suspensions may contain thickeners, such as beeswax, paraffin wax, or cetearyl alcohol. Sweeteners (e.g., those described above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (e.g., butylated hydroxyanisole or α-tocopherol).

[0153] In another respect, compounds of Tables I to VI or Formula I, or pharmaceutically acceptable salts thereof, may be formulated in veterinary compositions comprising a veterinary carrier. A 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.

[0154] Treatment

[0155] In another aspect, this application of the invention also provides a method for treating a disease in a subject in need, comprising administering, alone or in combination, a therapeutically effective amount of a compound from Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof, to the subject; wherein the disease is a disease induced by sGC stimulation or by an increase in the concentration of NO or cGMP, or both, or a disease induced by upregulation of the NO-sGC-cGMP pathway. The invention also provides a method for treating a disease in a subject in need, comprising administering, alone or in combination, to the subject a pharmaceutical composition or dosage form comprising a compound from Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof, to the subject, wherein the disease is a disease induced by sGC stimulation or by an increase in the concentration of NO or cGMP, or both, or a disease induced by upregulation of the NO-sGC-cGMP pathway.

[0156] The tenth embodiment of the present invention is a method of treating a disease in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound such as any one of the compounds described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the ninth embodiment.

[0157] In some embodiments, the compounds disclosed herein are sGC stimulants that can be used to prevent and / or treat diseases characterized by an undesirable reduction in NO bioavailability and / or sensitivity to NO, such as those associated with oxidative stress or nitrification stress disorders.

[0158] Increased cGMP concentration leads to vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive effects, anti-remodeling effects, anti-apoptotic effects, anti-inflammatory effects, anti-fibrotic effects, metabolic effects, neuronal signaling effects, and mitochondrial effects. Therefore, sGC stimulants can be used to treat and / or prevent a variety of diseases.

[0159] Specific diseases or conditions that can be treated and / or prevented by application of the sGC stimulants of the present invention (e.g., compounds of Tables I to VI or Formula I and their pharmaceutically acceptable salts) include (but are not limited to):

[0160] Abelasmoproteinemia, achalasia (e.g., esophageal achalasia), acute respiratory distress syndrome (ARDS), adhesive bursitis, age-related learning and memory impairment, age-related memory loss, alcoholism, baldness or hair loss, altitude sickness, Alzheimer's disease (including preclinical Alzheimer's disease, mild to moderate Alzheimer's disease, and moderate to severe Alzheimer's disease), amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), anal fissure, aneurysm, angina pectoris (e.g., stable or unstable angina, variant angina, Prinzmetal's angina, microvascular angina), anxiety disorder or anxiety disorder, spermine succinateuria, arterial and venous thrombosis, arthritis, Asperger's syndrome Syndrome, asthma and asthmatic disorders, ataxia, telangiectasia, atherosclerosis (e.g., atherosclerosis associated with endothelial damage, platelet and monocyte adhesion and aggregation, smooth muscle hyperplasia or migration), atrophic vaginitis, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), autism and disorders on the autism spectrum, benign prostatic hyperplasia (BPH) or hypertrophy or enlargement, bipolar disorder, bladder outlet obstruction, bladder pain syndrome (BPS), blepharitis, bone and carbohydrate metabolism disorders, bone healing (e.g., osteoclast remodeling, osteoclast resorption, post-new bone formation bone healing), cerebral aneurysm, cerebral hypoxia, cancer metastasis, cerebral amyloid angiopathy (CAA) or Congo erythrophage (Congophilic angiopathy). Angiopathy), autosomal dominant cerebral arteriosclerosis with subcortical infarction and leukoencephalopathy (CADASIL or CADASIL syndrome), cerebral perfusion, cerebral small vessel disease, cerebral vasospasm, chemotherapy head, childhood disintegrative disorder, chronic bronchitis, chronic fatigue, chronic traumatic brain lesions (CTE), ciliary diseases, cirrhosis (e.g., cirrhosis, cirrhosis associated with chronic liver disease, primary biliary cirrhosis), sexual dysfunction associated with central nervous system diseases, sleep disorders associated with central nervous system diseases, Huntington's disease. Cognitive deficits, cognitive impairments, and cognitive impairments (e.g., vascular cognitive impairment, mild cognitive impairment, diabetes-related cognitive impairment, multiple sclerosis-related cognitive impairment, obstructive sleep apnea-related cognitive impairment, schizophrenia-related cognitive impairment (CIAS), sickle cell disease-related cognitive impairment, concussion, congenital myasthenia gravis syndrome, connective tissue diseases, consequences of cerebral infarction (stroke), preservation of blood substitutes for trauma patients, CREST syndrome, Crohn's disease, cystic fibrosis (CF), paranoia, dementia (e.g.,Vascular dementia, post-stroke dementia, Lewy body dementia, frontal lobe degenerative dementia, frontotemporal degenerative dementia, corticobasal degenerative dementia, Creutzfeldt-Jakob dementia, HIV dementia, multi-infarct dementia, postoperative dementia, vital solitary dementia, HIV-related dementia (including asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), HIV-related dementia (HAD, also known as AIDS dementia complex [ADC] or HIV encephalopathy), Alzheimer's disease (mild cognitive impairment, MCI)). Mixed dementia, Binswanger's dementia (subcortical arteriosclerotic encephalopathy), Parkinson's dementia, demyelinating disorders, depression, depressive disorders, dermatomyositis, diabetic angiopathy, diabetic macular edema, diabetic microangiopathy, diabetic ulcers or wounds (e.g., diabetic foot ulcers), diseases associated with or related to metabolic syndrome (e.g., obesity, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia), and diseases involving neurotransmitter downregulation. Diseases involving impaired cerebral blood flow, diseases involving neurodegenerative disorders, diseases involving impaired synaptic function, diseases involving neuroinflammation, diseases involving neurotoxicity, diseases of the male and female genitourinary organs (benign and malignant), attention deficit disorders in children with learning and memory impairments, Down syndrome, drug addiction, drug-induced psychosis, dry eye syndrome, Duchenne muscular dystrophy, palmar aponeurosis contracture, movement disorders (e.g., acute movement disorders, chronic or tardive movement disorders, non-motor movement disorders, levodopa-induced movement disorders). LID (Lystrophic Idiopathic Disorder), dysmenorrhea (e.g., primary dysmenorrhea, secondary dysmenorrhea), dyspareunia, dysphagia, dystonia (e.g., generalized dystonia, focal dystonia, segmental dystonia, sexual dystonia, moderate dystonia, acute dystonia reaction, hereditary or primary dystonia), edema, electrolyte disturbances (e.g., hyperkalemia, hyponatremia), emphysema, endometriosis, endothelial dysfunction or lesions and diseases associated with endothelial dysfunction, erectile dysfunction, achalasia, Fabry disease, female sexual dysfunction-related disorders (e.g., female sexual arousal disorder), fibromyalgia, fibrosis (e.g.,Endocardial fibrosis, atrial fibrosis, interstitial cardiac fibrosis, cardiac fibrosis, pulmonary fibrosis, ocular fibrosis, skin fibrosis, intestinal fibrosis, renal or kidney fibrosis, interstitial renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, progressive large-scale pulmonary fibrosis, liver fibrosis, mediastinal fibrosis, retroperitoneal fibrosis, joint fibrosis, bone marrow fibrosis, myelofibrosis, myelofibroma, radiation-induced fibrosis, pancreatic cystic fibrosis, fragile X syndrome, functional dyspepsia, gastroparesis, Gaucher disease. Diseases, general attention deficit, general psychosis, glaucoma, glioblastoma, glomerular diseases (e.g., glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis), granulomas, head injury, hearing impairment (e.g., partial hearing loss, total hearing loss, partial deafness, complete deafness, noise-induced hearing loss), heart disease (e.g.,Left ventricular myocardial remodeling, left ventricular systolic dysfunction, ischemic cardiomyopathy, dilated cardiomyopathy, alcoholic cardiomyopathy, storage cardiomyopathy, congenital heart defects, reduced coronary blood flow, diastolic or systolic dysfunction, coronary insufficiency, acute coronary syndrome, coronary artery disease, arrhythmia, reduction of ventricular preload, cardiac hypertrophy, right ventricular hypertrophy, atrial and ventricular rhythm disorders and cardiac conduction disorders, first- to third-degree atrioventricular block (AVB I-III), supraventricular tachyarrhythmias, premature ventricular contractions, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsades de pointes, atrial and ventricular premature contractions, AV junction extrasystoles, sick sinus syndrome, atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome. (syndrome), myocardial insufficiency, chronic, acute or viral myocarditis, cardiogenic shock, cardiac remodeling), heart failure (HF; e.g., heart failure with preserved ejection fraction (HFPEF), heart failure with reduced ejection fraction (HFREF), acute heart failure, chronic heart failure, acute phase of existing chronic heart failure (heart failure worsening), transient heart failure, post-acute heart failure, systolic heart failure, diastolic heart failure, congestive heart failure, acute decompensated heart failure, right ventricular failure, total heart failure, high-output heart failure, heart failure with valvular defects, diabetic heart failure). Heart failure, cardiopulmonary syndrome, right heart failure), high concentrations of plasminogen activator inhibitor 1 (PA-1), high levels of fibrinogen and low-density dysplasia of the lungs (DLD), histiocytosis X, Huntington's disease or chorea (HD), hyperammonemia and related conditions, hypertension (e.g., arterial hypertension, refractory hypertension, diabetic hypertension, idiopathic hypertension, essential hypertension, secondary hypertension, gestational hypertension, portal hypertension, systemic hypertension, preeclampsia, acute and chronic coronary hypertension), hypertonia, hypertrophic scarring, hypoactive sexual arousal disorder (HSA). Sexual arousal disorder), hypoperfusion, impotence, enteritis (e.g., Crohn's disease, ulcerative colitis), inflammation caused by cerebral malaria, inflammation caused by infectious diseases, inflammatory response in perioperative care, platelet aggregation, intellectual disability, intermittent claudication, interstitial cystitis (IC), hypotension during dialysis, ischemia (e.g., cerebral ischemia, myocardial ischemia, thromboembolic ischemia, severe limb ischemia), keloids, kidney disease (e.g.,Chronic kidney disease, acute and chronic renal failure, acute and chronic renal insufficiency, sequelae of renal insufficiency, renal insufficiency associated with pulmonary edema, renal insufficiency associated with heart failure, renal insufficiency associated with uremia or anemia, primary kidney disease, congenital kidney disease, progression of polycystic kidney disease, kidney transplant rejection, immune complex-induced kidney disease, abnormally decreased excretion of creatinine and / or water, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered renal enzyme activity (e.g., gamma-glutamyl synthase), altered urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, renal tubular dilatation, hyperphosphatemia, vascular kidney disease, renal cysts, renal edema due to heart failure, Korsakoff's psychosis. Psychosis), leukocyte activation, levodopa-induced addictive behavior, lichen sclerosis, lipid-related diseases (e.g., excessive obesity, excessive subcutaneous fat, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased high-density lipoprotein cholesterol (HDL-cholesterol), moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol), hypertriglyceridemia, hyperglyceridemia, hyperlipoproteinemia, sitosterolemia, fatty liver disease, hepatic steatosis or abnormal lipid accumulation in the liver, steatosis of the heart, kidneys or muscles, sitosterolemia, xanthomas, Tangier disease), liver diseases (e.g.,Vascular liver disease, hepatic stellate cell activation, accumulation of hepatic fibrin and total collagen, necrotizing inflammatory and / or immune-mediated liver disease, cholestatic liver disease associated with granulomatous liver disease, cholestatic liver disease associated with hepatic malignancies, cholestatic liver disease associated with intrahepatic cholestasis of pregnancy, cholestatic liver disease associated with hepatitis, cholestatic liver disease associated with sepsis, cholestatic liver disease associated with drugs or toxins, cholestatic liver disease associated with graft-versus-host disease, cholestatic liver disease associated with post-liver transplantation, and cholestatic liver disease associated with common bile duct stones. Cholestatic liver disease, cholestatic liver disease associated with bile duct tumors, cholestatic liver disease associated with pancreatic cancer, cholestatic liver disease associated with Mirizzi syndrome, cholestatic liver disease associated with AIDS, bile duct lesions, cholestatic liver disease associated with parasites, cholestatic liver disease associated with schistosomiasis, hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic vascular occlusive disease (VOD), hepatic sinusoidal obstruction syndrome (SOS), hepatic encephalopathy, local thrombosis, lower urinary tract syndrome Lumbar spinal stenosis, lupus nephritis, lupus or systemic lupus erythematosus, microalbuminuria, microcirculatory abnormalities, migraine, mild neurocognitive impairment (MND), scleroderma, moyamoya disease, multiple lacunar infarctions, multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF), multiple sclerosis (MS, including clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS)), multiple system atrophy (MSA), heart disease, etc. Myocardial infarction or heart attack (e.g., ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, old myocardial infarction), myopic choroidal neovascularization, nevi, narcotic dependence, kidney disease (e.g., diabetic nephropathy, non-diabetic nephropathy, nephritis, toxin-induced nephropathy, contrast-induced nephropathy, diabetic or non-diabetic nephrosclerosis, nephrotic syndrome, pyelonephritis, nephrogenic fibrosis), neurodegenerative diseases, neurogenic bladder and urinary incontinence, neuroinflammation, neurological disorders associated with reduced nitric oxide production, neuromuscular diseases (e.g.,Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb girdle muscular dystrophy, distal myopathy, type I and II dystrophy, facial-scapular-peroneal muscular dystrophy, autosomal and X-linked Emery-Dreifuss muscular dystrophy dystrophy), oculopharyngeal dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy (SMA), neuromyelitis optica, neuropathy (e.g., peripheral neuropathy, autonomic neuropathy, central nervous system neuropathy, chemotherapy-induced neuropathy, diabetic neuropathy, painful neuropathy, neuropathic pain, non-painful neuropathy, painful diabetic neuropathy, non-painful diabetic neuropathy, neuropathy associated with central nervous system diseases (e.g., multiple sclerosis, MS), radiation-induced neuropathy), herpes zoster-related neuropathic pain, spinal surgery-related neuropathic pain, obsessive-compulsive disorder (OCD), obstructive thrombotic vasculitis, obstructive urinary tract disease, eosinophilic fasciitis, osteoporosis, overactive bladder, pain (e.g., acute pain, central pain syndrome, inflammatory pain, postoperative pain, persistent pain, visceral pain, claudication pain, orphan pain (e.g.,Acetazolamide-responsive myotonia, autosomal erythrocyte sensitization syndrome, autosomal dominant Charcot-Marie-Tooth disease type 2V, autosomal dominant Charcot-Marie-Tooth disease type 2V with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2A, congenital pain insensitivity associated with ion channel disease, chronic pain requiring spinal 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-hyperhidrosis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial paroxysmal pain syndrome, familial paroxysmal pain syndrome primarily affecting the lower limbs, familial paroxysmal pain syndrome primarily affecting the upper body, hereditary painful calluses. Hereditary sensory and autonomic neuropathy type 4, hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 7, interstitial cystitis, painful orbital and systemic neurofibroma-Marfan habitual syndrome, paroxysmal extreme pain disorder, persistent idiopathic facial pain, qualitative or quantitative deficiency of carboplatin, Tolosa-Hunt syndrome, pancreatitis, panic disorder, Parkinson's disease, Parkinson's plus syndrome, Parkinson's dysphagia, pathological eating disorders, pelvic pain, peripheral vascular disease (e.g., peripheral artery disease, peripheral artery occlusive disease, peripheral thrombosis, peripheral blood perfusion disorder), peritonitis, pervasive developmental disorders, Peroni disease, Pick's syndrome Syndrome, polychondritis, polymyositis, postherpetic neuralgia, post-traumatic brain injury, post-traumatic stress disorder (PTSD), premature ejaculation, progressive nucleus palsy, benign prostatic hyperplasia, lung diseases (e.g., plexiform pulmonary arteriosclerosis, bronchoconstriction or pulmonary bronchoconstriction, pulmonary vascular disease, chronic obstructive pulmonary disease (COPD), pulmonary capillary angioma, lymphangioma and compressive pulmonary vessels (e.g., due to adenosis, tumor or fibrotic mediastinitis), pulmonary vascular remodeling, hypertonic lung disease), pulmonary hypertension (PH, e.g., pulmonary arterial hypertension). PAH, primary PH, secondary PH, sporadic PH, precapillary PH, idiopathic PH, PH associated with left ventricular disease, HIV-related PH, SCD-related PH, thromboembolic PH (chronic thromboembolic PH or CTEPH), sarcoidosis-related PH, chronic obstructive pulmonary disease-related PH, acute respiratory distress syndrome-related PH (ARDS), acute lung injury-related PH, α-1-antitrypsin deficiency-related PH (AATD), emphysema-related PH (e.g.,PH associated with various lung diseases, including emphysema caused by smoking, hypoxemia, scleroderma, cystic fibrosis (CF), left ventricular dysfunction, hypoxemia, PH (WHO group I, II, III, IV, and V), mitral valve disease, pericarditis, constrictive pericarditis, aortic stenosis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, and anomalous pulmonary venous drainage. pH associated with venous occlusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep-disordered breathing, chronic airflow obstruction, obstructive sleep apnea, central sleep apnea, mixed sleep apnea, alveolar hypoventilation, prolonged high-altitude exposure, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, and other coagulation disorders. Related PH, PH associated with chronic thromboembolism, radiculopathy, Raynaud's disease, Raynaud's syndrome (primary or secondary), refractory epilepsy, Renpenning syndrome, reperfusion injury (e.g., ischemia-reperfusion injury, organ transplant-related ischemia-reperfusion), restenosis (e.g., after thrombolytic therapy, after percutaneous transluminal angioplasty (PTA), after transluminal coronary angioplasty (PTCA), after heart transplantation or bypass surgery), retinopathy (e.g., diabetic retinopathy, non-diabetic retinopathy, non-proliferative diabetic retinopathy, proliferative vitreoretinopathy, peripheral retinal degeneration, retinal static Artery occlusion), Rhett's disease, rheumatoid arthritis and rheumatic diseases (e.g., arthritis, rheumatoid arthritis), sarcoidosis, sarcoma, schizophrenia, affective schizophrenia, schizophrenia, schizophrenia with dementia, scleroderma (e.g., focal scleroderma or localized scleroderma, generalized scleroderma), sclerosis (e.g., renal sclerosis, progressive sclerosis, cirrhosis of the liver, primary sclerosing cholangitis, gastrointestinal sclerosis, hippocampal sclerosis, focal sclerosis, primary lateral sclerosis, osteosclerosis, otosclerosis, atherosclerosis, tuberous sclerosis, generalized sclerosis), sepsis or septic shock or anaphylactic shock, sickle cell anemia, sickle cell disease, Sjogren's syndrome, sleep-wake disorder, Sneddon's syndrome, spasms (e.g.,Coronary artery spasm, vasospasm, peripheral artery spasm), spinal cord injury, spinal muscular atrophy, spinal subluxation, spinocerebellar ataxia, Steelee-Richardson-Olszewski disease (progressive supranuclear palsy), stroke, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, syncope, Tau disease, tension, thalamic degeneration, thromboembolic or thrombotic disorders, transient ischemic attack (TIA), traumatic brain injury, tubulointerstitial disease, ulcer, uterine fibroids, vaginal atrophy, valvular defects. (For example, mitral stenosis, mitral regurgitation, mitral atresia or mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, combined valvular defects), cerebrovascular disease, vascular disease due to cardiac and renal complications, vascular leakage or permeability, vasculitis (e.g., thromboangiitis obliterans, Kawasaki disease, arteritis, aortitis), vascular occlusive crisis, transplant failure, wet age-related macular degeneration, and Williams syndrome.

[0161] In a specific embodiment of the present invention, the disease is selected from sickle cell disease (SCD), focal segmental glomerulosclerosis (FSGS), heart disease, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), heart failure, pulmonary hypertension, liver fibrosis, and kidney fibrosis.

[0162] As used herein, the term "disease" refers to any deviation from or disruption of the normal structure or function of any part of the body, organ, or system, characterized by a set of symptoms and signs, and its possible known or unknown etiology, pathology, and prognosis. The term "disease" includes other related terms such as symptoms and ailments (or medical ailments) and syndromes, which are defined as combinations of symptoms caused by a single cause, or combinations of symptoms caused by a single cause that typically occur together to constitute distinct clinical phenomena. In some implementations, the term "disease" refers to a medical or pathological disease mediated by sGC, cGMP, and / or NO.

[0163] "Treatment" for a disorder, disease, condition, symptom, or syndrome means eliminating or improving the cause and / or effects of the disorder, disease, condition, or syndrome (i.e., symptoms, physiological, physical, mental, emotional, or any other clinical manifestation, observation, or measurement, or improvement of pathological assessment).

[0164] As used herein, the term “treatment” also refers to delaying or improving or preventing the progression of a disease (i.e., known or anticipated progression of the disease), its severity and / or duration, or delaying or improving or preventing the progression of one or more symptoms, clinical manifestations, observations or measurements, or preventing or mitigating negative progression of a pathological assessment caused by the application of one or more therapies (i.e., “managing” rather than “curing” the condition).

[0165] As used herein, the terms “subject” and “patient” are used interchangeably. The terms “subject” and “patient” refer to animals (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 companion animal or pet (e.g., a dog, cat, rat, mouse, hamster, gerbil, guinea pig, or rabbit). In some embodiments, the subject is a human.

[0166] The present invention also provides a method for treating one of the aforementioned diseases in a subject, comprising administering to the subject requiring treatment a therapeutically effective amount of a compound of Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof. Alternatively, the present invention provides a compound of Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof, for treating one of the aforementioned diseases in a subject requiring treatment. The present invention also includes the use of a compound of Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating one of the aforementioned diseases in a subject requiring treatment. The present invention further provides a method for preparing or manufacturing a medicament that can be used to treat one of the aforementioned diseases, comprising using a compound of Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof.

[0167] As used herein, “biological sample” means an in vitro or ex vivo sample, including but not limited to cell cultures or extracts thereof; biopsy 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.

[0168] 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 is suitable for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioassays and biological sample storage.

[0169] Combination therapy

[0170] The compounds and pharmaceutical compositions described herein may be used alone or in combination therapy for the treatment of diseases mediated, regulated or affected by sGC, cGMP and / or NO.

[0171] As used herein, the terms “combination” (as in “combination therapy”) or “co-administration” are used interchangeably to refer to the use of more than one therapy. The use of this term does not restrict the order in which the therapy is administered to the subject.

[0172] 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.

[0173] When used in combination therapy with other agents, the “therapeutic effective amount” of the compounds and pharmaceutical compositions described herein, along with one or more other agents, will depend on the type of drug used. Appropriate dosages are known for approved pharmaceutical agents and can be adjusted by a technician based on the condition of the subject, the type of condition being treated, and the amount of the compounds described herein. Where no specific amount is stated, an effective amount should be assumed.

[0174] In some embodiments, co-administration or combination therapy includes administering a first and second amount of the compound in a substantially simultaneous manner, for example, in a single pharmaceutical composition (e.g., a capsule or tablet having a fixed ratio of first and second amounts) or in multiple individual capsules or tablets for each agent. Additionally, co-administration also includes administering each compound in a sequential manner in any order.

[0175] When co-administration involves administering a first amount of a Table I-VI or 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 Table I-VI or Formula I compounds and the second therapeutic agent can be administered in any sequence, approximately 24 hours apart, approximately 16 hours apart, approximately 8 hours apart, approximately 4 hours apart, approximately 1 hour apart, or approximately 30 minutes apart.

[0176] Examples of other therapeutic agents that can be administered, alone or in the same pharmaceutical composition, in combination with compounds in Tables I-VI or Formula I or their pharmaceutically acceptable salts, include, but are not limited to:

[0177] (1) Endothelial-derived release factor (EDRF) or NO gas.

[0178] (2) NO donors, including but not limited to nitrosothiols, nitrites, sydnonimine, NONOate, N-nitrosamines, N-hydroxynitrosamines, nitrosimines, nitrotyrosine, diazacyclobutene dioxide, oxtriazole 5-imine, oximes, hydroxylamines, N-hydroxyguanidines, 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 the aforementioned categories include: classic nitro vasodilators, such as organic nitrates and nitrites, including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil; isosorbide, 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.

[0179] (3) Other substances that enhance cGMP concentration, including but not limited to protoporphyrin IX, arachidonic acid and phenylhydrazine derivatives.

[0180] (4) Nitric oxide synthase substrates, including but not limited to L-arginine, 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-butene)). (e.g., α-guanidinium chloride, β-guanidinium chloride, guanidinium chloride, hydroxyguanidinium chloride 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, -OH substituents respectively); guanidine derivatives, such as 3-(trifluoromethyl)propylguanidine.

[0181] (5) Compounds that enhance eNOS transcription.

[0182] (6) NO-independent heme-independent sGC activators, including but not limited to:

[0183] BAY 58-2667 (described in patent publication DE19943635); HMR-1766 (ataciguat, described in patent publication WO2000002851); S 3448 (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholinothiomorpholino-4-sulfonyl)-phenyl)-benzamide (described in patent publications DE19830430 and WO2000002851); and HMR-1069 (from Sanofi-Aventis).

[0184] (7) Heme-dependent and NO-independent sGC stimulants, including but not limited to:

[0185] YC-1 (see patent publications EP667345 and DE19744026); Riociguat (BAY 63-2521, Described in DE19834044); nelociguat (BAY 60-4552, described in WO 2003095451); vericiguat (BAY 1021189, described in US8420656); BAY 41-2272 (described in DE19834047 and DE19942809); BAY 41-8543 (described in DE19834044); etriciguat (described in WO 2003086407); CFM-1571 (described in patent publication WO2000027394); A-344905, its acrylamide analog A-350619 and aminopyrimidine analog A-778935;

[0186] Other sGC stimulants described in any of the following disclosures: US20090209556, US8455638, US20110118282 (WO2009032249), US20100292192, US20110201621, US7947664, US8053455 (WO2009094242), US20100216764 US8507512, (WO2010099054)US20110218202(WO2010065275), US20130012511(WO2011119518), US20130072492(WO2011149921), US20130210798(WO2012058132), and Tetrahedron Letters (2003), 44(48):8661-8663; as well as IW-1973 (praliciguat), IW1701 (olinciguat) and CY6463 (the former IW-6463).

[0187] (8) Compounds that inhibit the degradation of cGMP and / or cAMP, including but not limited to:

[0188] PDE1 inhibitors, PDE2 inhibitors, PDE-3 inhibitors such as amrinone, milrinone, enoxidone, veslinone, pimobene, and olprerinone, PDE4 inhibitors such as lucimilast, PDE5 inhibitors such as sildenafil and related agents such as avanafil, lodenafil, mirodenafil, sildenafil citrate, tadalafil, vardenafil, and udenafil; alprostadil; dipyridamole and PF-00489791; PDE6 inhibitors, PDE9 inhibitors such as PF-04447943, PDE10 inhibitors such as PF-02545920 (PF-10), and PDE11 inhibitors.

[0189] (10) Anticoagulants, including but not limited to:

[0190] Coumarins (vitamin K antagonists), such as warfarin, acenocoumarol, phenylpropargyl and phenindione;

[0191] Heparin and its derivatives, such as low molecular weight heparin, fondaparinux, and idraparinux;

[0192] Direct thrombin inhibitors, such as argatroban, lepirudin, bivalirudin, dabigatran, and ximelagatran; and

[0193] Tissue plasminogen activators, used to dissolve clots and clear arteries, such as alteplase.

[0194] (10) Antiplatelet drugs, including but not limited to topidogrel, ticlopidine, dipyridamole and aspirin.

[0195] (11) Supplemental oxygen therapy.

[0196] (12) α-1-adrenergic receptor antagonists, including but not limited to prazosin, indoramin, urapidil, bunazosin, terazosin and doxazosin; atrial natriuretic peptide (ANP), ethanol, histamine inducers, tetrahydrocannabinol (THC) and papaverine.

[0197] (13) Bronchodilators, including but not limited to:

[0198] Short-acting β2 agonists, such as salbutamol or albuterol and terbutaline;

[0199] Long-acting β2 agonists (LABAs), such as salmeterol and formoterol;

[0200] Anticholinergic drugs, such as pratropium and tiotropium; and

[0201] Theophylline, bronchodilators, and phosphodiesterase inhibitors.

[0202] (14) Corticosteroids, including but not limited to beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide, hydrocortisone, and corticosteroid analogues (e.g., budesonide).

[0203] (15) Dietary supplements, including but not limited to 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.

[0204] (16) PGD2 receptor antagonists.

[0205] (17) Immunosuppressants, including but not limited to cyclosporine, tacrolimus, rapamycin and other FK-506 immunosuppressants mycophenolate mofetil and mycophenolate mofetil.

[0206] (18) Nonsteroidal anti-asthmatic drugs, including but not limited to:

[0207] β2-agonists, such as terbutaline, metaproterenol, fenoterol, isoetharine, salbutamol, salmeterol, bitolterol, and pirbuterol;

[0208] β2 agonist corticosteroid combinations, such as salmeterol-fluticasone, formoterol-budesonide, theophylline, cromoglycine, sodium cromoglycate, nedocromil, atropine, ipratropium, and ipratropium bromide; and

[0209] Leukotriene biosynthesis inhibitors, such as zileuton or veliflapon.

[0210] (19) Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to:

[0211] Propionic acid derivatives, such as aminoprofen, benoxaprofen, buccolic acid, carprofen, fenbufen, fenoprofen, fluprofen, flubiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprafen, tiaprofenic acid, and tioxaprofen;

[0212] Acetic acid derivatives, such as indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac;

[0213] Fenamic acid derivatives, such as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid;

[0214] Biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal;

[0215] Oxicam, such as isoxicam, piroxicam, sudoxicam, and tenoxicam;

[0216] Salicylic acids, such as acetylsalicylic acid and sulfasalazine; and

[0217] Pyrazolone, including but not limited to apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, and phenylbutazone.

[0218] (20) 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.

[0219] (21) Adrenergic neuron blocking agents, such as guanethidine and guanadrel.

[0220] (22) I-1 receptor agonists of imidazoline, including but not limited to rimenidine dihydrogen phosphate and moxonidine hydrochloride hydrate.

[0221] (23) Potassium channel activators, including but not limited to pinacidil.

[0222] (24) Dopamine D1 agonists, including but not limited to fenoldopam mesilate; other dopamine agonists such as ibopamine, dopexamine and docarpamine.

[0223] (25) 5-HT2 antagonists, including but not limited to ketanserin.

[0224] (26) Vasopressin antagonists, including but not limited to tolvaptan.

[0225] (27) Calcium channel sensitizers, including but not limited to levosimendan or activators (e.g., nicoridil).

[0226] (28) Adenylate cyclase activators, including but not limited to colforsindapropate hydrochloride.

[0227] (29) Positive inotropic agents, including but not limited to digoxin and metildigoxin; metabolic cardiotonics, such as ubiquinone; brain natriuretic peptides, such as nesiritide.

[0228] (30) Medications used to treat erectile dysfunction, including but not limited to alprostadil, avitadil and phentolamine mesilate.

[0229] (31) Medications used to treat Alzheimer's disease and dementia, including but not limited to:

[0230] Acetylcholinesterase inhibitors, such as galantamine, rivastigmine, donepezil, and tacrine; and

[0231] NMDA receptor antagonists, such as memantine; and

[0232] Oxidoreductase inhibitors, such as idebenone.

[0233] (32) Psychiatric medications, including but not limited to:

[0234] Ziprasidone, risperidone, olanzapine, valproate;

[0235] Dopamine D4 receptor antagonists, such as clozapine;

[0236] Dopamine D2 receptor antagonists, such as nemonapride;

[0237] Mixed dopamine D1 / D2 receptor antagonists, such as zuclopenthixol;

[0238] GABA A receptor modulators, such as carbamazepine;

[0239] Sodium channel inhibitors, such as lamotrigine;

[0240] Monoamine oxidase inhibitors, such as moclobemide and indeloxazine; primavanserin and perospirone.

[0241] (33) Medications used to treat movement disorders or symptoms, including but not limited to:

[0242] Catechol-O-methyltransferase inhibitors, such as entacapone;

[0243] Monoamine oxidase B inhibitors, such as selegiline;

[0244] Dopamine receptor modulators, such as levodopa;

[0245] Dopamine D3 receptor agonists, such as pramipexole;

[0246] Decarboxylase inhibitors, such as carbidopa;

[0247] Other dopamine receptor agonists, such as pergolide, ropinirole, and cabergoline;

[0248] Rtigonide, istradefylline, talipexole; zonisamide and safinamide; and

[0249] Synaptic vesicle amine transporter inhibitors, such as tetrabenazine.

[0250] (34) Medications used to treat mood or affective disorders or OCD, such as the following types

[0251] Tricyclic antidepressants, such as amitriptyline, desipramine, imipramine, amoxapine, nortriptyline, doxepin, and clomipramine;

[0252] Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, fluoxetine, sertraline, trazodone, and citralopram;

[0253] Atypical antidepressants, such as agomelatine;

[0254] Selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, reboxetine, and atomoxetine; dopamine antidepressants, such as bupropion and amineptine.

[0255] (35) Drugs used to enhance synaptic plasticity, including but not limited to:

[0256] Nicotine receptor antagonists, such as mecamylamine; and

[0257] A combination of 5-HT, dopamine, and norepinephrine receptor agonists, such as lurasidone.

[0258] (36) Medications used to treat ADHD, such as amphetamines; 5-HT receptor modulators, such as vortioxetine; and α-2 adrenergic receptor agonists (such as cinetin).

[0259] (37) Nitric oxide synthase cofactors, including but not limited to: tetrahydrobiopterin, dihydrobiopterin and sapropterin.

[0260] (38) Blood glucose lowering drugs (also known as blood glucose control drugs or antidiabetic drugs) include, but are not limited to:

[0261] Biguanides, such as metformin;

[0262] Sulfonylureas, such as glyburide, glybenclamide, glipizide, gliclazide, gliquidone, glimepiride, atorvastatin calcium in combination with glimepiride, meglinatide, tolbutamide, chlorpropamide, acesulfame potassium, and tolazimide;

[0263] Alpha-glucosidase inhibitors, such as acarbose, epalrestat, voglibose, and miglitol;

[0264] Insulin secretagogues, such as repaglinide, mitiglinide, and nateglinide;

[0265] Thiazolidinediones, such as rosiglitazone, troglitazone, ciglitazone, pioglitazone, emplitazone, lobeglitazone sulfate, and balaglitazone.

[0266] DPP-4 inhibitors (or DPP-IV inhibitors), such as sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, alogliptin benzoate in combination with metformin or metformin hydrochloride, anagliptin, and tenaliglitin. gliptin), atorvastatin calcium and glimepiride, empagliflozin in combination with linagliptin, gemigliptin, sitagliptin phosphate monohydrate in combination with pioglitazone hydrochloride, sitagliptin in combination with pioglitazone, sitagliptin in combination with atorvastatin calcium and (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidone-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidone-2-carboxynitrile (DBPR-108);

[0267] GLP-1 receptor agonists or incretin mimics, such as exenatide, dulaglutide, liraglutide, semaglutide, lixisenatide, lixisenatide in combination with insulin glargine, albiglutide, and pegapamodutide (TT-401), LY3298176 (a diglucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist);

[0268] SGLT2 inhibitors (SGLT2i), such as empagliflozin, empagliflozin in combination with linagliptin, empagliflozin in combination with metformin, ipragliflozin, ipragliflozin L-proline, tofogliflozin, seragliflozin estacarbonate, regagliflozin estacarbonate, ertugliflozin, ertugliflozin in combination with sitagliptin, ertugliflozin in combination with metformin, sotagliflozin, canagliflozin, canagliflozin in combination with metformin or metformin hydrochloride, dapagliflozin, dapagliflozin in combination with metformin or metformin hydrochloride and luseoglifozin, and dapagliflozin in combination with saxagliptin;

[0269] SGLT1 inhibitors or combinations of SGLT1 and SGLT2 inhibitors, such as soggliflozin;

[0270] Insulin therapy includes many types of insulin, such as insulin lisgludec, insulin degludec, insulin lispro, insulin aspart, insulin glargine, insulin detemir, protamine insulin, insulin mixtard (human insulin containing both rapid-acting (soluble) and long-acting (protamine) insulin), insulin degludec in combination with insulin aspart, human (rDNA-derived) inhaled powder insulin, recombinant human insulin, liver-guided vesicular insulin, insulin tregopi (IN-105), insulin degludec in combination with liraglutide, insulin peglispro (LY-2605541), and nodlin; and

[0271] Tolimidone (lyn kinase activator).

[0272] (39) Antihypertensive drugs (also known as antihypertensive medications), including but not limited to:

[0273] Diuretics, such as thiazide diuretics, chlorothiazide, chlorothiazide, hydrochlorothiazide, benzylfluorothiazide, cyclopenthiazine, methacycline, polythiazide, quinetrazolone, xipamide, metolazone, indapamide, cicletanine, furosemide, toresamide, amiloride, spironolactone, potassium canileate, eplerenone, triamterene, acetazolamide, and carperitide;

[0274] β-blockers, such as acebutolol, atenolol, metoprolol, and nebivolol;

[0275] Angiotensin-converting enzyme (ACE) inhibitors, such as thiol-containing drugs (e.g., captopril, zofenopril), dicarboxylate-containing drugs (e.g., enalapril, quinapril, ramipril, perindopril, lisinopril, and benazepril), phosphonate-containing drugs (e.g., fosinopril), and naturally occurring drugs. ACE inhibitors (e.g., tyrosinase, lactokine, lactotripeptide Val-Pro-Pro and Ile-Pro-Pro), alacepril, delapril, cilazapril, imidapril, temocapril, moexipril, lisinopril, combinations of lisinopril and hydrochlorothiazide, trandolapril, and spirapril;

[0276] Angiotensin II receptor blockers (ARBs), such as candesartan, losartan, losartan potassium-hydrochlorothiazide, valsartan, candesartan cilexetil, eprosartan, irbesartan, telmisartan, olmesartan medumid (or olmesartan), azilsartan medoxomil, azilsartan, and amlodipine besylate in combination with irbesartan. besylate), azisartan in combination with amlodipine besylate, cilnidipine in combination with valsartan, fimasartan, irbesartan in combination with atorvastatin, irbesartan in combination with chlorothiazide, losartan potassium in combination with hydrochlorothiazide and / or amlodipine besylate, pratosartan, atorvastatin calcium in combination with losartan potassium, nifedipine and candesartan medoxomil, sacubitril in combination with valsartan or LCZ-696, angiotensin AT2 antagonists and TAK-591, and olmesartan medumid;

[0277] Endothelin receptor antagonists (ERAs), such as atrasentan, bosentan, sitaxentan, ambrisentan, actelion-1 (macitentan), D-trp-D-asp-L-pro-D-Val-L-leu (BQ-123), sparsentan, and tezosentan disodium.

[0278] Mineralocorticoid receptor antagonists (MRAs), such as spironolactone, ampicillin hydrochloride in combination with spironolactone, apararenone or MT-3995, eplerenone and finerenone (BAY-94-8862);

[0279] Calcium channel blockers, such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, diltiazem, efonidipine, felodipine, lacidipine, lercanidipine, and manidipine. ), nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, isradipine, verapamil, gallopamil, diltiazem, mibefradil, bepridil, fluspirilene, and fendiline;

[0280] Renin inhibitors, such as aliskiren;

[0281] Alpha blockers, such as doxazosin and prazosin;

[0282] α-β blockers, such as carvedilol and labetalol;

[0283] Central nervous system drugs, such as clonidine, guanfacine, and methyldopa;

[0284] Vasodilators, such as nitroglycerin, hydralazine, and minoxidil; and

[0285] Aldosterone antagonists, such as fenestrone, spironolactone, and eplerenone.

[0286] (40) Antilipidemia drugs, including but not limited to:

[0287] Statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin;

[0288] Combinations of statins with another drug, such as amlodipine / atorvastatin, aspirin / pravastatin, ezetimibe / simvastatin, niacin / simvastatin, lovastatin / niacin, simvastatin / sitagliptin, and atorvastatin / ezetimibe;

[0289] Fibrates or fibric acid derivatives. Examples include, but are not limited to, fenofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate, and clofibrate;

[0290] Nicotinic acid (or nicotinic acid);

[0291] Bile acid sequestrants, such as cholestyramine, colesevelam, colestilan, and colestipol;

[0292] Izamab, lomitapide, phytosterols, or orlistat; and

[0293] PCSK9 inhibitors, such as alicurumab and evolocumab;

[0294] (41) Endopeptidase inhibitors (also known as endopeptidase inhibitors or NEP inhibitors or neprilysin inhibitors), including but not limited to sacubitril, or a combination of sacubitril and valsartan; neprilysin inhibitors, TD-1439 or TD-0714 under development.

[0295] (42) Renal protective drugs, including but not limited to:

[0296] Bardoxolone;

[0297] ACE inhibitors, such as captopril;

[0298] ARBs, such as losartan or irbesartan;

[0299] SGLT2 inhibitors, such as canagliflozin,

[0300] GLP1 receptor agonists;

[0301] MRAs, such as fenestrone;

[0302] ERAs, such as atrasentan; and apoptosis signal-regulated kinase 1 (ASK1) inhibitors, such as selonsertib.

[0303] (43) Hydroxyurea (HU, hydroxyurea).

[0304] (44) Anti-sickle cell formation drugs, including but not limited to hydroxyurea, voxelotor or GBT-440.

[0305] (45) Anti-adhesion therapy, including but not limited to blocking antibody adhesion to P-selectin, E-selectin, VLA-4, and VCAM-1.

[0306] (46) Glutamine.

[0307] (47) Erythropoietin (EPO), also known as hematopoietin, includes all its forms, such as exogenous erythropoietin, recombinant human erythropoietin (rhEPO) or other erythropoiesis stimulants (ESAs), two examples being epoetin alfa and epoetin beta.

[0308] (48) Antibiotics, including but not limited to:

[0309] Penicillin and its derivatives, including but not limited to penicillin, amoxicillin, ampicillin, azlocillin, cloxacillin, penicillin G, penicillin V, procaine penicillin, or benzathine penicillin.

[0310] Cephalosporins, such as cephalexin, cefadroxil, cefaclor, cefuroxime, and cefixime;

[0311] Macrolides, such as erythromycin, clarithromycin, azithromycin, and roxithromycin;

[0312] Tetracyclines and their derivatives, such as demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline;

[0313] Sulfonamides, including but not limited to sulfamidoline, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethoxazole, and sulfamethoxazole. azole, sulfasalazine, trimethoprim-sulfamethoxazole Cotrimoxazole (a compound sulfamethoxazole) and sulfamethoxazole azole; and

[0314] Quinolinones, including but not limited to ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, and nalidixic acid.

[0315] (49) FXR agonists, including but not limited to obeticholic acid, cenicriviroc, emricasan, GR-MD-02, selonsertib and elafibranor.

[0316] (50) Thyroid receptor-β agonists, including but not limited to MGL-3196.

[0317] (51) Acetyl-CoA carboxylase inhibitors, including but not limited to GS-0976.

[0318] (52) Treatments for mitochondrial disorders, including but not limited to vitamins and supplements, including coenzyme Q10; B complex vitamins, especially thiamine (B1) and riboflavin (B2); alpha fatty acids; L-carnitine; creatine; citrulline and L-arginine.

[0319] (53) Therapeutic agents for epilepsy or seizures, including but not limited to phenytoin, valproic acid, phenobarbital, lamotrigine, carbamazepine, topiramate, oxcarbazepine, zonisamide, gabapentin, levetiracetam, pregabalin, clonazepam, lacosamide, rufinamide and vigabatrin.

[0320] Packaging and reagent kits

[0321] The pharmaceutical composition (or formulation) used can 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 access to the contents. Additionally, the container has a label describing its contents. This label may also include appropriate warnings.

[0322] 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.

[0323] Example

[0324] All references provided in the examples 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 ACSStyle Guide: A Manual for Authors and Editors, 2nd ed., Washington, DC: American Chemical Society, 1997, which is incorporated herein by reference in its entirety.

[0325] Various embodiments of the present invention are described below.

[0326] The definitions of the abbreviations used in the examples section are provided in the table below.

[0327]

[0328]

[0329] Synthesis section

[0330] Example 1: Synthesis of compounds in Table I

[0331] This application also provides a method for synthesizing the compounds in Table I, representing another embodiment of the invention. The compounds of the invention can be prepared according to the general and specific synthetic methods described herein, synthetic operations reported in the chemical literature, or methods known to those skilled in the art. As will be understood by those skilled in the art, the optimal reaction conditions that can be determined during experiments can be varied based on the type of reaction and the specific reagents used in the reaction. Therefore, unless specifically described, reaction conditions such as pressure, temperature, relative ratios of reagents, solvents, and reaction times can be readily selected and varied by those skilled in the art without excessive experimentation. The compounds and intermediates of the invention can be prepared by purification methods known to those skilled in the art. These methods include, but are not limited to, silica gel chromatography, recrystallization, reversed-phase HPLC (RP-HPLC), and supercritical fluid chromatography (SFC). RP-HPLC purification can be achieved using a suitable gradient selected from 0% to 100% acetonitrile in water containing additives such as 0.1% TFA or FA on a suitable reversed-phase column (e.g., Waters XBridge OBD C18, 5 μm, 19 × 150 mm). Diastereomers can be separated by silica gel chromatography, RP-HPLC, or chiral HPLC. Discrete enantiomers can be obtained by resolving mixtures of enantiomers using chiral HPLC. The reaction progress can be monitored by methods known to those skilled in the art, such as thin-layer chromatography, reversed-phase HPLC, or tandem reversed-phase HPLC-mass spectrometry (LC-MS).

[0332] The starting materials used in the synthesis described herein were purchased from commercial sources or could be prepared by those skilled in the art using methods reported in the chemical literature or mentioned herein.

[0333] The general methods described herein can be used to prepare the compounds in Table I. The general and specific methods described herein are provided as illustrative examples of how to implement this invention. Therefore, they are not intended to impose any limitation on the subject matter of this invention or the scope of the claimed compounds.

[0334] All references provided in the examples are incorporated herein by reference. As used herein, all abbreviations, symbols, and conventions are consistent with those used in contemporary scientific literature. See, for example, G.M. Banik, G. Baysinger, P.V. Kamat, N.P. Ph.T., eds., *The ACS Guide to Scholarly Communication*, Washington, DC: American Chemical Society, 2020 (https: / / pub.acs.org / doi / book / 10.1021 / acsguide), which is incorporated herein by reference in its entirety.

[0335] The compounds disclosed herein can be prepared, for example, from the corresponding nitrile intermediates using the general procedure (General Procedure C) described below:

[0336] General Program C

[0337]

[0338] The compounds of the present invention can be prepared via their corresponding nitriles using procedures similar to those described herein. Nitriles with different substitution modes can be prepared via procedures described in WO2015187470, WO2016081668, WO2017197555, WO2017200825, WO2018 / 045276A1 and WO2019 / 126354A1.

[0339] The following nitrile intermediates were prepared according to the procedures described in WO2018 / 045276A1 and WO2019 / 126354A1. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods may be modified as needed.

[0340] 8-Benzylimidazo[1,2-a]pyrazine-6-carboxynitrile;

[0341] 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0342] 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0343] 8-(2,3-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0344] 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0345] 8-(3-fluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxylonitrile;

[0346] 8-(3,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0347] 8-(3,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile;

[0348] 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxylonitrile;

[0349] 8-(2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylonitrile;

[0350] 8-(3-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxynitrile;

[0351] 8-(3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylonitrile;

[0352] 8-(2,3-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylonitrile;

[0353] 8-(2,5-difluoro-4-methylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylonitrile.

[0354] General procedure A, exemplified for the synthesis of compound I-1

[0355] The title compound was synthesized in two steps:

[0356] Step 1 Synthesis of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate

[0357]

[0358] A solution of 0.50N sodium methoxide in methanol (0.17mL, 0.087mmol, 0.10 equivalent) was added to a solution of 220 mg, 0.87 mmol, 1.0 equivalent) of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile (5.0 mL) in methanol (Note: stoichiometric amounts or excess sodium methoxide may also be used). After stirring at ambient temperature for 6 h, ammonium chloride (280 mg, 5.2 mmol, 6.0 equivalent) was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under vacuum, diluted with 20 mL of semi-saturated NaHCO3 solution, and extracted with 2 × 20 mL CH2Cl2 / iPrOH (5:1). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give crude formamidin as a light brown, foamy solid. It was used in the next step without further purification. LC / MS ES + m / z = 270.2[M+H] + .

[0359] Step 2 Synthesis of 5-fluoro-2-(8-(3-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol

[0360]

[0361] Sodium (Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olide (490 mg, 3.1 mmol, 4.0 equivalent) was added to a suspension of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate (210 mg, 0.79 mmol, 1.0 equivalent) in ethanol (7.0 mL). The reaction mixture was heated in a sealed vial at 90 °C for 2.5 h. After cooling to ambient temperature, 1.0 N HCl aqueous solution (3.1 mL, 3.1 mmol, 4.0 equivalent) was added. The resulting mixture was concentrated under vacuum, diluted with water (50 mL), adjusted to pH 6 with saturated NaHCO3 solution, and extracted with 2 × 50 mL CH2Cl2 / iPrOH (5:1). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by silica gel chromatography (0 to 15% acetonitrile / methanol (7:1) in CH2Cl2) to give the title compound as a light brown solid (180 mg, 64% yield, in 2 steps). 1¹H NMR (500MHz, DMSO-d6) δ (ppm) 13.1–12.5 (single peak pair, ¹H, tautomer), 9.46 (s, ¹H), 8.30 (s, ¹H), 8.26–8.00 (single peak pair, ¹H, tautomer), 7.90 (s, ¹H), 7.50 (m, ¹H), 7.41 (m, ¹H), 7.32 (m, ¹H), 7.02 (app.t, ¹H), 4.53 (s, 2H).

[0362] Compound I-2

[0363]

[0364] 2-(8-benzylimidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (compound 2) (25 mg, 14% gross yield) was synthesized as a white solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.30 (s, 1H), 8.09 (s, 1H), 7.99 (d, 1H), 7.80 (s, 1H), 7.40 (d, 2H), 7.17 (t, 2H), 7.07–7.11 (m, 1H), 4.52 (s, 2H).

[0365] Compound I-4

[0366]

[0367] 2-(8-(2,3-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (compound 4) (150 mg, 67% gross yield) was synthesized as a light brown solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 ¹H NMR (500MHz, acetone-d6) δ (ppm) 10.6 (s, 1H), 9.34 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.20 (t, 1H), 7.09 (q, 1H), 7.00 (q, 1H), 4.60 (s, 2H).

[0368] Compound I-6

[0369]

[0370] 5-Fluoro-2-(8-(3-fluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (compound I-6) (200 mg, 54% gross yield) was synthesized as a pale yellow solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR(500MHz,DMSO-d6)δ(ppm)12.9(br.s,1H),9.44(s,1H),8.29(s,1H),8.16(br.s ,1H),7.89(s,1H),7.39(d,1H),7.27(d,1H),7.17(t,1H),4.48(s,2H),2.14(s,3H).

[0371] Compound I-7

[0372]

[0373] 2-(8-(3,5-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (compound I-7) (190 mg, 57% gross yield) was synthesized as a yellow solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR (500MHz, DMSO-d6) δ (ppm) 13.0 (br.s, 1H), 9.47 (s, 1H), 8.31 (s, 1H), 8.22 (br.s, 1H), 7.91 (s, 1H), 7.36 (br.s, 2H), 7.07 (t, 1H), 4.53 (s, 2H).

[0374] Compound I-3

[0375]

[0376] 5-Fluoro-2-(8-(3,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (compound 3) (67 mg, 34% gross yield) was synthesized as a white solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 ¹H NMR (500MHz, chloroform-d) δ (ppm) 11.1 (br.s, 1H), 9.14 (s, 1H), 8.00-7.91 (m, 2H), 7.87 (s, 1H), 7.00 (d, 2H), 4.56 (s, 2H), 2.14 (s, 3H).

[0377] Compound I-14

[0378] The title compound was synthesized in two steps:

[0379] Step 1: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbamate

[0380]

[0381] A solution of 0.50 N sodium methoxide in methanol (18 mL, 8.9 mmol, 1.0 equivalent) was added to a suspension of 2.5 g (2.5 g, 8.9 mmol, 1.0 equivalent) in 44 mL of methanol. After stirring at ambient temperature for 4 h, a further portion of the 0.50 N sodium methoxide solution in methanol (5.3 mL, 2.7 mmol, 0.3 equivalent) was added, and stirring continued for another 2 h. Ammonium chloride (470 mg, 8.9 mmol, 1.0 equivalent) was then added. After 16 h, the reaction mixture was concentrated under vacuum, suspended in a saturated aqueous solution of NaHCO3, and stirred for 20 min. The solid was collected by filtration and washed with 3 volumes of water and 2 volumes of diethyl ether. The crude product was resuspended in 100 mL of acetonitrile under heating, diluted with diethyl ether, and filtered. The filter cake was washed with 3 volumes of diethyl ether and dried to give a light brown solid (2.2 g, 83% yield). It was used in the next step without further purification. LC / MS ES + m / z = 302.1 [M+H] + .

[0382] Step 2: Synthesis of 5-fluoro-2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol

[0383]

[0384] Sodium (Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olide (2.9 g, 19 mmol, 3.0 equivalent) was added to ethanol (31 mL) containing 1.9 g (2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-formamidinium (1.9 g, 6.2 mmol, 1.0 equivalent). The solution was heated in a sealed container at 90 °C for 18 h. After cooling to ambient temperature, 7.4 mL (19 mmol, 3.0 equivalent) of 2.5 N ethanol-HCl solution was added. The resulting mixture was concentrated under vacuum and suspended in acetonitrile (100 mL) under heating. After slight cooling, 100 mL of diethyl ether was added and the mixture was stirred for 10 min. The solid was collected by filtration and washed with 3 volumes of diethyl ether. The resulting solid was resuspended in water, stirred for 1 h, and filtered. The crude product was purified by preparative reversed-phase HPLC (10% to 70% acetonitrile / water containing 0.1% trifluoroacetic acid as an additive). The impure eluent was further purified by preparative reversed-phase HPLC (10% to 50% acetonitrile / water containing 0.1% trifluoroacetic acid as an additive) to give the title compound (840 mg, 37% yield) as a grayish-white solid. 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.43 (s, 1H), 8.21 (s, 1H), 8.08 (br.s, 1H), 7.89 (s, 1H), 7.09 (m, 1H), 7.00 (m, 1H), 4.63 (s, 2H), 2.23 (s, 3H).

[0385] Na+ salt of compound 14

[0386]

[0387] A solution of 0.50 N sodium methoxide in methanol (54 mL, 27 mmol) was added to a grayish-white suspension of 5-fluoro-2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (compound I-14, 10 g, 27 mmol) in 450 mL of anhydrous MeOH under a nitrogen atmosphere. After simple sonication, the resulting pale yellow solution was stirred at ambient temperature for 15 min and concentrated to dryness under vacuum. The solid was resuspended in 250 mL of ether by sonication and concentrated (twice). The resulting solid was resuspended in 650 mL of diethyl ether and stirred at ambient temperature for 3 h. The solid was collected by vacuum filtration and washed with diethyl ether (3 × 100 mL). After drying on a filter overnight, the product salt was dried in a vacuum oven at 45°C for 4 days to obtain sodium 5-fluoro-2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidine-4-olide (11 g, 99% yield) as a white solid.1 H NMR (500MHz, D2O) δ (ppm) 8.92 (s, 1H), 7.99 (d, 1H), 7.97 (d, 1H), 7.70 (d, 1H), 6.98 (dd, 1H), 6.86 (dd, 1H), 4.48 (s, 2H), 2.14 (s, 3H).

[0388] Compound I-11

[0389]

[0390] 5-Fluoro-2-(8-(3-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)pyrimidin-4-ol (compound I-11) (61 mg, 23% gross yield) was synthesized as a golden solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR (500MHz, DMSO-d6) δ (ppm) 13.3 (br.s, 1H), 9.60 (s, 1H), 8.86 (s, 1H), 8.24-8.27 (m, 1H), 7.32-7.47 (m, 3H), 7.03-7.06 (m, 1H), 4.59 (s, 2H).

[0391] Compound I-13

[0392]

[0393] 2-(8-(3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (compound I-13) (57 mg, 17% gross yield) was synthesized as a brown solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR (500MHz, DMSO-d6) δ (ppm) 13.2 (br.s, 1H), 9.61 (s, 1H), 8.87 (s, 1H), 8.25 (s, 1H), 7.33 (d, 2H), 7.10 (t, 1H), 4.60 (s, 2H).

[0394] Compound I-10

[0395]

[0396] 2-(8-(2,3-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (compound I-10) (85 mg, 16% gross yield) was synthesized as a pale yellow solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR (500MHz, DMSO-d6) δ (ppm) 13.0 (br.s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 8.23 ​​(s, 1H), 7.29-7.37 (m, 2H), 7.09-7.16 (m, 1H), 4.68 (s, 2H).

[0397] Compound I-12

[0398]

[0399] 2-(8-(2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (compound I-12) (75 mg, 57% yield) was synthesized as a grayish-white solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 ¹H NMR (500MHz, methanol-d⁴) δ (ppm) 9.67 (s, 1H), 8.69 (s, 1H), 8.12 (d, 1H), 7.25 (m, 1H), 7.13 (m, 1H), 7.02 (m, 1H), 4.73 (s, 2H).

[0400] Compound I-19

[0401]

[0402] 5-Fluoro-2-(8-(2,5-difluoro-4-methylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)pyrimidin-4-ol (compound I-19) (140 mg, 66% gross yield) was synthesized as a light brown solid according to general procedure A. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR (500MHz, DMSO-d6) δ (ppm) 13.1 (br.s, 1H), 9.61 (s, 1H), 8.83 (s, 1H), 8.26 (br.s, 1H), 7.35 (br.s, 1H), 7.17 (m, 1H), 4.57 (s, 2H), 2.18 (s, 3H).

[0403] General procedure B, exemplified for the synthesis of compound I-16

[0404] The title compound was synthesized in two steps:

[0405] Step 1: Synthesis of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate

[0406]

[0407] A solution of 0.50 N sodium methoxide in methanol (3.6 mL, 1.8 mmol, 1.0 equivalent) was added to a suspension of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile (490 mg, 1.8 mmol, 1.0 equivalent) in methanol (5.0 mL) (Note: catalytic amounts or excess sodium methoxide may also be used). After stirring at ambient temperature for 3 h 45 min, ammonium chloride (970 mg, 18 mmol, 10 equivalent) was added and the reaction mixture was stirred for 20 h. The resulting mixture was concentrated to approximately 2 mL under vacuum and diluted with EtOAc (20 mL) and 10% NaHCO3 aqueous solution (10 mL). After stirring for 15 min, the product was collected by filtration, washed with water (10 mL), and dried under vacuum to give the title compound (420 mg, 80% yield) as a grayish-white solid. LC / MSES + m / z = 287.9 ​​[M+H] + .

[0408] Step 2: Synthesis of 5-chloro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol

[0409]

[0410] A solution of 0.50 N sodium methoxide in methanol (1.4 mL, 0.70 mmol) was added to a suspension of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate (100 mg, 0.35 mmol) and ethyl 2-chloro-3-oxopropionate (110 mg, 0.70 mmol) in methanol (1.7 mL). The reaction mixture was heated in a sealed vial at 65 °C for 2.5 h. After cooling to ambient temperature, the resulting mixture was concentrated under vacuum, diluted with water (10 mL), adjusted to pH 3 with 6.0 N HCl aqueous solution, and extracted with 2 × 15 mL CH₂Cl₂ / iPrOH (8:1). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0% to 20% acetonitrile / methanol (7:1) in CH2Cl2) and further purified by silica gel chromatography (20% to 100% EtOAc / CH2Cl2) to give the title compound (37 mg, 28% yield) as a grayish-white solid.

[0411] 1 H NMR(500MHz,DMSO-d6)δ(ppm)12.6(br.s,1H),9.54(s,1H),8.36(br.s,1H),8. 32(s,1H),7.89(s,1H),7.45(br.s,1H),7.25(m,1H),7.12(m,1H),4.58(s,2H).

[0412] Compound I-17

[0413]

[0414] 5-Chloro-2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (compound I-17) (5.2 mg, 2.2% gross yield) was synthesized as a light brown solid according to general procedure B. Reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR(500MHz,DMSO-d6)δ(ppm)9.47(s,1H),8.45(s,1H),8.22(d,1H),7.94(s,1H),7.23(dd,1H),7.16(dd,1H),6.72(d,1H),4.56(s,2H),2.17(br s,3H).LC / MS ES + m / z = 388.0 [M+H] + .

[0415] Compound I-15

[0416] The title compound was synthesized in two steps:

[0417] Step 1: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbamate

[0418]

[0419] Synthesize 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbamate (840 mg, 76% yield) as a light brown solid according to step 1 of general procedure A or B. Adjust reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods as needed. LC / MS ES + m / z = 302.0 [M+H] + .

[0420] Step 2: Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol

[0421]

[0422] Hunig's base (0.63 mL, 3.6 mmol) was added to a suspension of 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbamate (360 mg, 1.2 mmol) and methyl 3-methoxyacrylate (0.39 mL, 3.6 mmol) in ethanol (6.0 mL). The reaction mixture was heated in a sealed vial at 90 °C for 3 h. After cooling to ambient temperature, the mixture was treated with 2.5 N ethanol-HCl solution (1.4 mL, 3.6 mmol) and concentrated to dryness. The crude product was purified by silica gel chromatography (0% to 20% acetonitrile / methanol (7:1) in CH2Cl2) and further purified by silica gel chromatography (0% to 15% MeOH / CH2Cl2) to give the title compound (120 mg, 28% yield) as a light brown solid. 1 H NMR(500MHz,DMSO-d6)δ(ppm)11.9(br.s,1H),9.52(s,1H),8.31(s,1H),8.07(br.d,1H ),7.89(s,1H),7.37(dd,1H),7.16(dd,1H),6.38(br.d,1H),4.54(s,2H),2.18(s,3H).

[0423] Compound I-8

[0424] The title compound was synthesized in two steps:

[0425] Step 1: Synthesis of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate

[0426]

[0427] Synthesize 5.1 g (91% yield) of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate as a milky-yellow solid according to step 1 of general procedure A or B. Adjust reaction conditions (such as reagent ratios, temperature, and reaction time) and purification methods as needed. LC / MS ES + m / z = 270.2[M+H] + .

[0428] Step 2: Synthesis of 2-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-methylpyrimidin-4-ol

[0429]

[0430] Potassium bicarbonate (220 mg, 2.2 mmol) was added to a solution of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate (400 mg, 1.5 mmol) and ethyl 2-methyl-3-oxopropionate (230 mg, 1.8 mmol) in t-BuOH (9.9 mL). The reaction mixture was heated to reflux for 2 h. After cooling to ambient temperature, water was added, and the product was collected by filtration and dried to give the title compound (410 mg, 82% yield) as a milky yellow solid. 1 H NMR(500MHz,DMSO-d6)δ(ppm)11.6(br.s,1H),9.48(s,1H),8.30(s,1H),7.94(br s,1H),7.88(s,1H),7.48(app.t,1H),7.29(m,1H),7.19(m,1H),7.11(app.t,1H),4.60(s,2H),1.98(s,3H).

[0431] Compound I-9

[0432]

[0433] 9.0 mL of acetonitrile-THF (2:1) containing 5-fluoro-2-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (230 mg, 0.67 mmol) was diluted with sodium bicarbonate (84 mg, 1.0 mmol) and Selectfluor TM (350 mg, 1.0 mmol) was treated and heated at 50 °C. During the experiment, additional portions of sodium bicarbonate (42 + 28 mg) and Selectfluor were added. TM (180 + 120 mg). After a total of 49 h, the reactants were cooled to ambient temperature and 20 mL of water was added. The resulting mixture was acidified to pH 3 with 1.0 N HCl aqueous solution and extracted with 2 × 25 mL of LEtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0% to 20% acetonitrile / methanol (7:1) in CH2Cl2) and further purified by preparative reversed-phase HPLC (15% to 65% acetonitrile / water with 0.1% formic acid as an additive) to give the title compound (23 mg, 9.7% yield) as a light brown solid. 1H NMR(500MHz,DMSO-d6)δ(ppm)12.6(br.s,1H),8.98(s,1H),8.19(br.s,1H),7.74( d,1H),7.48(app.t,1H),7.28(m,1H),7.19(m,1H),7.10(app.t,1H),4.56(s,2H).

[0434] Compound I-5

[0435]

[0436] 10 mL of acetonitrile-THF (1:1) containing 5-fluoro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (200 mg, 0.56 mmol) was diluted with sodium bicarbonate (94 mg, 1.1 mmol) and Selectfluor TM (400 mg, 1.1 mmol) was treated and heated at 50 °C. During the experiment, additional portions of sodium bicarbonate (3 × 47 mg) and Selectfluor were added. TM (3 × 200 mg). After a total of 74 h, the reactants were cooled to ambient temperature and 40 mL of water was added. The resulting mixture was acidified to pH 3 with 1.0 N HCl aqueous solution and extracted with 2 × 40 mL CH₂Cl₂ / iPrOH (6:1). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0 to 20% acetonitrile / methanol (7:1) in CH₂Cl₂), preparative reversed-phase HPLC (10% to 70% acetonitrile / water with 0.1% TFA as an additive), and final column chromatography (20% to 100% EtOAc / hexane) to give the title compound (24 mg, 11% yield) as a white solid. 1 HNMR(500MHz,DMSO-d6)δ(ppm)12.8(br.s,1H),8.99(s,1H),8.20(br.s,1H),7.75(d,1H),7.42(m,1H),7.25(m,1H),7.13(m,1H),4.54(s,2H).

[0437] Compound I-18

[0438] The title compound was synthesized in 5 steps:

[0439] Step 1: Synthesis of 6,8-dibromo-3-fluoroimidazole[1,2-a]pyrazine

[0440]

[0441] 40 mL of acetonitrile containing 2.4 g (8.7 mmol) of 6,8-dibromoimidazolo[1,2-a]pyrazine was fluorinated with Selectfluor. TM (4.6 g, 13 mmol) was treated and heated at 50 °C. After 22 h, the reaction mixture was cooled to ambient temperature, poured into 150 mL of semi-saturated NaHCO3 solution, and extracted with 2×EtOAc (total 400 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0 to 20% EtOAc / hexane) to give the title compound (580 mg, 23% yield) as an orange solid.

[0442] Step 2: Synthesis of 6-bromo-8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine

[0443]

[0444] A suspension of dried zinc powder (240 mg, 3.7 mmol) in THF (3.0 mL) was treated with 1,2-dibromoethane (30 mL, catalyst) and heated to 50 °C to obtain a mixture. Trimethylsilane (30 mL, catalyst) was then added. After 15 min, the mixture was cooled to ambient temperature. Dried lithium chloride (170 mg, 3.9 mmol) was added, followed by dropwise addition of a solution of 1-(bromomethyl)-2,5-difluoro-3-toluene (480 mg, 2.2 mmol) in THF (2.0 mL) (Note: exothermic reaction). The mixture was stirred at ambient temperature for 1 h. Simultaneously, a slurry of 6,8-dibromo-3-fluoroimidazolo[1,2-a]pyrazine (580 mg, 2.0 mmol) and Pd(PPh3)2Cl2 (41 mg, 0.059 mmol) in THF (3.0 mL) was degassed with nitrogen. The newly formed zincate solution was transferred to this slurry via syringe and rinsed with 2 × 0.5 mL THF to ensure complete transfer. The resulting mixture was stirred at ambient temperature for 1 hour and 20 minutes, followed by stirring at 40 °C for 4 hours. After cooling to ambient temperature, the reactants were quenched with 4 mL of saturated NH4Cl solution. The organic layer was concentrated, diluted with CH2Cl2 (10 mL), and filtered through a diatomaceous earth bed. The filtrate was concentrated to give a brown residue, which was purified by silica gel chromatography (with the compound supported on CH2Cl2 and eluted with 0 to 10% EtOAc / hexane) to give the title compound as a yellow solid (440 mg, 63% yield).

[0445] Step 3: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine-6-carboxynitrile

[0446]

[0447] The reaction mixture, consisting of 6-bromo-8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine (440 mmol, 1.2 mmol), zinc cyanide (100 mg, 0.87 mmol), Pd2(dba)3 (46 mg, 0.050 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (41 mg, 0.075 mmol) in anhydrous DMF (5.0 mL), was degassed with nitrogen and then heated at 90 °C for 6 h. The reaction mixture was cooled to ambient temperature and treated with CH2Cl2 (50 mL), water (40 mL), and 28% ammonium hydroxide solution (4.0 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give a brown oil, which was purified by column chromatography (0–20% EtOAc / hexane gradient) to give the title compound (310 mg, 81% yield) as a light brown solid. LC / MS ES + m / z = 302.8 [M+H] + .

[0448] Step 4: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazole[1,2-a]pyrazine-6-formamidin

[0449]

[0450] A solution of 0.50 N sodium methoxide in methanol (1.0 mL, 0.50 mmol) was added to a suspension of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazolo[1,2-a]pyrazine-6-carboxynitrile (150 mg, 0.50 mmol) in methanol (6.0 mL). After stirring at ambient temperature for 4 h 30 min, ammonium chloride (270 mg, 5.0 mmol) was added and the reaction mixture was stirred for 18 h. The resulting mixture was concentrated under vacuum, treated with 10% NaHCO3 aqueous solution (10 mL), and sonicated to obtain a suspension. After stirring for 1 h, the product was collected by filtration, washed with water (10 mL), and dried under vacuum to give the title compound (170 mg, >100% yield) as a light brown solid. It was used in the next step without further purification. LC / MSES + m / z = 319.7 [M+H] + .

[0451] Step 5: Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazin-6-fluoropyrimidine-4-ol

[0452]

[0453] Sodium (Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olide (310 mg, 2.0 mmol) was added to a suspension of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazole[1,2-a]pyrazine-6-formamidinium (0.50 mmol, pyroxene from the previous step) in ethanol (5.0 mL). The reaction mixture was heated in a sealed vial at 90 °C for 16 h. After cooling to ambient temperature, the mixture was diluted with water (7.5 mL) and adjusted to pH 4 with 1 N HCl aqueous solution. The resulting light brown solid was collected by filtration, washed with water (50 mL) and ether (30 mL), and dried to give the title compound (140 mg, 71% yield, in two steps) as a brown solid.

[0454] 1 H NMR (500MHz, DMSO-d6) δ (ppm) 12.8 (br.s, 1H), 8.98 (s, 1H), 8.22 (br.s, 1H), 7.74 (d, 1H), 7.35 (br.s, 1H), 7.15 (m, 1H), 4.50 (s, 2H), 2.18 (s, 3H).

[0455] Compound I-20

[0456] The title compound was synthesized in two steps:

[0457] Step 1: Synthesis of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate

[0458]

[0459] A solution of 25 wt% sodium methoxide in methanol (2.1 mL, 9.3 mmol) was added to a solution of 500 mg (1.9 mmol) of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxynitrile (22 mL) in methanol. After stirring at ambient temperature for 1 h, ammonium chloride (1.0 g, 19 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated under vacuum, diluted with a semi-saturated NaHCO3 solution (20 mL) and a 1.0 N sodium hydroxide solution (2.0 mL), and extracted with 2 × 20 mL EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give a crude product as a brown solid. This crude product was used in the next step without further purification. LC / MS ES + m / z = 288.1 [M+H] + .

[0460] Step 2: Synthesis of 5-fluoro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol

[0461]

[0462] Sodium (Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olide (820 mg, 5.2 mmol) was added to a suspension of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbamate (500 mg, 1.7 mmol) in ethanol (9.0 mL). The reaction mixture was heated in a sealed vial at 90 °C for 2 h. After cooling to ambient temperature, concentrated HCl solution was added dropwise to acidify the mixture to pH 4. The resulting mixture was concentrated under vacuum. Purification by preparative reversed-phase HPLC (acetonitrile-water gradient with 0.1% TFA as an additive) yielded the title compound as a yellow solid (200 mg, 28% yield after two steps). 1 H NMR(500MHz,DMSO-d6)δ(ppm)12.6(br.s,1H),9.49(s,1H),8.32(s,1H),8.19 (br.s,1H),7.89(s,1H),7.43(s,1H),7.25(m,1H),7.13(m,1H),4.58(s,2H).

[0463] Na+ salt of compound I-20

[0464]

[0465] A solution of 0.50 N sodium methoxide in methanol (57 mL, 28 mmol) was added to a light brown suspension of 5-fluoro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (compound I-20, 10 g, 28 mmol) in 450 mL of anhydrous MeOH under a nitrogen atmosphere. After simple sonication, the resulting light orange solution was stirred at ambient temperature for 15 min and concentrated to dryness under vacuum. The solid was resuspended in 200 mL of ether by sonication and concentrated (twice). The resulting solid was resuspended in 500 mL of diethyl ether and stirred at ambient temperature for 3 h. The solid was collected by vacuum filtration and washed with diethyl ether (3 × 100 mL). After drying on a filter overnight, the product salt was dried in a vacuum oven at 45°C for 5 days to obtain sodium 5-fluoro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidine-4-olide (11 g, 99% yield) as a light brown solid. 1H NMR (500MHz, D2O) δ (ppm) 8.90 (s, 1H), 7.98 (d, 1H), 7.95 (d, 1H), 7.70 (d, 1H), 7.10 (m, 1H), 6.98-6.89 (m, 2H), 4.53 (s, 2H).

[0466] Biological section

[0467] Table I. Assessment of the biological characteristics of compounds

[0468] This application also provides an assessment of the biological properties of the compounds in Table I. The representative compounds of this invention were tested in vitro as sGC stimulants in various cells and assays, and their ability to lower blood pressure in animals was tested in vivo. The reduction in blood pressure is used to indicate the compound's ability to engage its target in vivo. These biological properties represent another embodiment of the invention.

[0469] Example 2: Bioactivity measurement using cGMP-based GloSensor cells in a 384-well format.

[0470] Performance GloSensor TM Human embryonic kidney (HEK293) cells containing 40F cGMP (product number: CS182801, Promega) were used to evaluate the activity of the test compounds. A luminescent biosensor (engineered luciferase) incorporated into these cells detected cGMP formed by compounds stimulating the sGC enzyme and emitted fluorescence.

[0471] cGMP GloSensor cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with fetal bovine serum (FBS, 10% final) and hygromycin (200 μg / ml). The day before assay, cells were cultured at 1.5 × 10⁶ cells / mL. 4 Cells were seeded at a density of 10% FBS in 50 μL of DMEM containing 10% FBS in 384-well flat white-bottomed, poly-D-lysine-coated plates (Corning catalog number 35661). Cells were cultured overnight at 37°C in a humidified chamber with 5% CO2. The following day, the medium was removed and the cells were seeded with 40 μL / well of GloSensor. TM，Cells were replaced with 2 mM (Promega, catalog number E1291). Cells were treated at 25°C for 90 min to allow the matrix to equilibrate within the cells. The test compound and diethylenetriamine NONO salt (DETA-NONO salt) were diluted to 3 mM (20×) in serum-free CO2-independent medium and serially diluted with 4× diluent to generate a 5X dose profile. 10 μL of each solution was added to each well (x μM for the test compound solution and 10 μM for the DETA-NONO salt solution; where x is one of the following final concentrations: 30 μM, 7.5 μM, 1.9 μM, 469 nM, 117 nM, 29.3 nM, 7.3 nM, 1.83 nM, 0.46 nM, 0.11 nM, 0.03 nM). For kinetic studies, fluorescence was measured immediately using an Envision (Perkin Elmer) at 0.2 sec / well. For endpoint SAR screening, data were collected after incubation at room temperature for 55 min.

[0472] Concentration-response data were analyzed using a 4-parameter fitting (log (agonist) vs. response-variable slope) method. 50 It is derived from curve fitting and is defined as the concentration at which a compound initiates its maximum reaction at 50%. When multiple experiments are performed on a given compound, the geometric mean of all experiments is reported.

[0473] Table A below summarizes the EC values ​​in the Glo determination of the compounds of the present invention. 50 value:

[0474] Table A.

[0475]

[0476]

[0477] The sGC enzyme activity in HEK cells was determined using GloSensor assay. The sGC enzyme activity value (expressed as EC50) was... 50 The code definition for EC (which is defined as the concentration at which a compound initiates 50% of its maximum reaction) is: EC 50 ≤100nM=A;100nM <EC 50 ≤1000nM=B;1000nM <EC 50 =C. *For compounds I-20 and I-14, both the free acid and the sodium salt were used, and the results here are the average of all experiments run independently of the form.

[0478] Example 3. Bioactivity Measurement via cGMP-Based Neuronal Cell Analysis

[0479] Primary rat neurons were isolated from fetuses of female Sprague-Dawley rats with an 18-day gestation period. The fetuses were collected in Hank's balanced salt solution (HBSS) and rapidly removed from the brain. The hippocampus was isolated and mechanically fragmented. Further tissue digestion was performed at 37°C in Ca2+- and Mg2+-free HBSS with 0.25% (wt / vol) trypsin solution for 15 min. After trypsinization, the cells were washed and resuspended in neurotrophic medium supplemented with 0.5 mM L-glutamine, 12.5 μM glutamate, 2% B-27, 100 U / mL penicillin, and 100 μg / mL streptomycin. The cells were then incubated at 26 × 10⁻⁶ cells / mL. 3 Or 4×10 4 Or 3×10 4 Cells were seeded at a density of 10 cells / well in 384-well flat, clear dishes coated with poly-D-lysine (Corning catalog number 354662). Cells were cultured at 37°C in a humidified chamber with 5% CO2 for 6–7 days. The culture medium was removed, and the cells were washed 1× with HBSS containing Ca2+ and Mg2+, and replaced with 40 μL of HBSS containing 0.5 mM IBMX, and cultured at 37°C for 15 minutes. 10 μL of 5× test compound stock solution containing diethylenetriamine NONO salt (DETA-NO) was added. The final concentration of DETA-NO was 10 μM or 30 μM. Cells were cultured at 37°C for 20 minutes. The culture medium was removed, 50 μL of ice-cold 10% acetic acid was added, and the cells were cultured at 4°C for 60 minutes. After centrifugation at 1000×g for 5 minutes at 4°C to precipitate cell debris, the supernatant was aspirated into a clean dish, and the cGMP contents of the sample were analyzed. cGMP concentration was determined from each sample using LC-MS / MS.

[0480] Concentration-response data were analyzed using a 4-parameter fitting (logarithmic (agonist) vs. response-variable slope). EC50 was derived from curve fitting and defined as the concentration at which a compound initiates its maximum response at 50%. When multiple experiments were performed on a given compound, the geometric mean of all experiments was reported.

[0481] Table B below summarizes the EC values ​​in neuronal assays using the compounds of this invention. 50 value:

[0482] Table B.

[0483]

[0484] Neuron-based cell assays. EC 50 ≤100nM=A;100nM <EC 50 ≤1000nM=B;1000nM <EC 50=C. *For compounds I-20 and I-14, both the free acid and the sodium salt were used, and the results here are the average of all experiments run independently of the form.

[0485] Example 4: Measurement of the bioactivity of human a2b1 sGC isoenzyme stably expressed in CHO-K1 cells

[0486] Dissolve the sGC stimulant in DMSO to obtain a 10 mM solution and store at -20°C. To achieve the desired test concentration, serially dilute the stock solution to DMSO and then to the appropriate concentration in the assay buffer.

[0487] CHO-K1 cells stably transfected with human α2β1s GC isoenzyme (produced by GenScript of Ironwood) were cultured in F-12K medium (ATCC catalog number 30-2004) containing 10% fetal bovine serum, 4 μg / mL puromycin (Gibco catalog number A11138-03), and 0.4 mg / mL genimycin (Gibco catalog number 10131-027) for GC activity assays. For GC activity analysis, cells were cultured at 3 × 10⁻⁶ cells / mL. 4 Cells / well or 15 × 10 3 Cells were seeded at a density of 50 μL or 70 μL of medium in 384-well poly-D-lysine-coated flat-bottomed dishes (Fisher Scientific #08-774-311). Cells were cultured at 37°C in a humidified chamber supplemented with 5% CO2 for 24 hours.

[0488] For each test concentration, the compound was diluted in 100% DMSO to 1% of its final analytical concentration. Just before analysis, the solution was diluted 20-fold in HBSS containing calcium, magnesium, and 50 μM DETA-NONO salt (5 × final analytical concentration). The culture medium was removed and the cells were washed once with 40 μL HBSS. The cells were then cultured at 37°C for 15 min in 40 μL of HBSS containing 0.5 mM IBMX. The cells were then incubated for another 20 min at 37°C with 10 μL of the sGC stimulator / HBSS / DETA-NONO salt pan. The final DMSO concentration was 1%, the final DETA-NONO salt concentration was 10 μM, and the final compound concentrations were 30,000 nM, 6,000 nM, 1,200 nM, 240 nM, 48 nM, 9.6 nM, 1.92 nM, 0.384 nM, 0.077 nM, 0.015 nM, or 0.003 nM.

[0489] After incubation with the compound, remove the assay buffer and add 50 μL of ice-cold 10% acetic acid + 150 ng / mL internal standard (+3 cGMP) to each well. Incubate the samples on ice for 30 to 60 min. Centrifuge at 1000 × g for 5 min at 4 °C to precipitate cell debris, transfer the supernatant to a clean dish, and analyze the cGMP content of the samples.

[0490] Data were analyzed using GraphPad Prism software v.8 with a 4-parameter fitting (log (agonist) vs. response - variable slope). EC50 was derived from curve fitting and defined as the concentration at which a compound initiates its maximum response at 50%. When multiple experiments were performed on a given compound, the geometric mean of all experiments was reported.

[0491] Table C below summarizes the EC values ​​in the CHO determination of the compounds of this invention. 50 value:

[0492] Table C

[0493]

[0494] CHO cell analysis. EC 50 ≤100nM=A;100nM <EC 50 ≤1000nM=B;1000nM <EC 50 =C. *For compounds I-20 and I-14, both the free acid and the sodium salt were used, and the results here are the average of all experiments run independently of the form.

[0495] Example 5: Effects of representative compounds of the present invention on blood pressure in normotensive rats after acute doses at multiple concentrations.

[0496] Compound I-14

[0497] Male Sprague Dawley rats with normal blood pressure were purchased from the Charles River Laboratories. These rats had indwelling femoral artery catheters inserted. Animals were tethered to a tethered system connected to pressure sensors to monitor cardiovascular (CV) parameters, specifically mean arterial pressure (MAP) and heart rate (HR). Animals were acclimatized to the system overnight, and baseline CV parameters were collected. Subsequently, awake, freely moving rats were administered single oral doses of 1, 3, 10, and 30 mg / kg of Milli-Q water containing compound I-14 (dose produced by the sodium salt of compound 14). Blood samples were collected from each animal via the catheter before and 2 hours after administration for compound concentration quantification. Hemodynamic measurements were recorded within 10 hours post-administration. Fifty-four male rats, ranked within the 250–275 g weight range, were used for these studies. According to protocol MIL-110, the animals were individually housed in a controlled environment with temperature (21±1℃) and relative humidity (36±1%) in a SmartLabs housing (21 Erie Street, Cambridge, MA) room with a 12-hour light-dark cycle (lights on at 6:00 AM and off at 6:00 PM). The animals were allowed free access to food (LabDiet Prolab Isopro RMH 3000, St. Louis, MO) and water. Two sets of studies were conducted. For the first set, compound I-14 was prepared in Milli-Q water at concentrations of 0.3 and 1.0 mg / ml and frozen at -20℃. For the second set, the sodium salt of compound I-14 was weighed at Cyclerion Therapeutics and reconstituted at SmartLabs to provide solutions of compound I-14 in Milli-Q water at concentrations of 0.1, 0.3, 1.0, and 3.0 mg / ml. Thaw the prepared formulation within 4 hours before administration and store it at room temperature, or prepare it within 2 hours before administration and store it at room temperature.

[0498] The study was conducted in six independent phases. The total number of subjects and the allocation of treatment agents are listed in the table below. Animals were initially administered the treatment within 3 days of receipt, and if the catheter remained patent, it was administered again 6 to 7 days after cleaning. No animal was administered the treatment more than twice.

[0499] 1 13 Mediator 10mL / kg - 2 9 1 mg / kg of compound I-14 10mL / kg 0.1 mg / mL 3 6 3 mg / kg of compound I-14 10mL / kg 0.3 mg / mL 4 11 10 mg / kg of compound I-14 10mL / kg 1.0 mg / mL 5 6 30 mg / kg of compound I-14 10 mL / kg 30mg / mL

[0500] Blood pressure measurement

[0501] This study used an ADInstruments LabChart (v8) to collect hemodynamic data from awake, freely moving rats tethered to a blood pressure sensor (Harvard Apparatus catalog number APT300). Animals were administered the drug 1 hour after baseline recording following overnight acclimatization to the tether and pressure sensor. A single oral (PO) dose of 10 mL / kg volume of the sodium salt of compound I-14 or its carrier was administered. Data collection continued for 10 hours post-administration.

[0502] Hemodynamic data were monitored and output using ADInstruments LabChart (v8). Blood pressure and heart rate were continuously monitored, and data were collected at 1000 data points / second, then averaged into 10-minute groups for analysis. Microsoft Excel 365 was used to calculate the change in MAP relative to baseline (ΔBMAP) and the change in HR relative to baseline (ΔBHR) using an averaged pre-dose baseline over a 1-hour period prior to administration. The ΔVMAP peak, the time of the ΔVMAP peak, the ΔVHR peak, and the time of the ΔVHR peak were determined using this 10-minute grouped dataset. The datasets were further merged into 1-hour groups for MAP and HR plots and for analysis of ΔBMAP, ΔBMAP, and ΔBHR. Definitions of these terms / abbreviations are summarized below:

[0503] <![CDATA[Δ B HR,dHR]]> Heart rate change relative to baseline <![CDATA[Δ V MAP]]> Mediator-adjusted mean arterial pressure <![CDATA[Δ V MAP]]> Mediator-adjusted heart rate AOC Area on the curve

[0504] Statistical analysis was performed using GraphPad Prism (v8). The significance of ΔBMAP and ΔBHR data compared to catalyzed rats was determined by two-factor repeated measures ANOVA followed by Dunnett's multiple comparison test. For missed data points, mixed-effects analysis was used. Catalyzed-adjusted MAP (ΔVMAP) was calculated by subtracting the ΔBMAP of the catalyzed group from the ΔBMAP of the catalyzed group at each time point. Catalyzed-adjusted HR (ΔVHR) was calculated in a similar manner to ΔVMAP.

[0505] The significance of AOC data compared to the mediator was determined by a single-factor ANOVA followed by a Dunnett multiple comparison test.

[0506] Some study data were removed prior to analysis. Data collected at 130 min and 140 min post-dose administration were removed due to 2-hour blood sample collection. A rat was excluded at several time points at 1 mg / kg due to signal loss during the experiment, which began at 470 min and continued until the end of the study (600 min). The entire time series of five animals was excluded from all datasets for various reasons, including outliers used for specific analyses or signal loss leading to anomalous results.

[0507] Blood pressure changes

[0508] The change in MAP relative to the baseline (ΔBMAP) is displayed graphically. Figure 1 In contrast, rats treated with compound I-14 showed a greater reduction in mean arterial pressure (MAP) compared to mediated rats (as assessed by the change in MAP relative to baseline, ΔBMAP). The ΔBMAP data were significant using a two-factor ANOVA (p < 0.0001 for both treatment dose and time, and p = 0.045 for the treatment dose × time interaction). A Dunnett multiple comparison test of the primary therapeutic effect yielded p = ns for 1 mg / kg, p = 0.0034 for 3 mg / kg, and p < 0.0001 for both 10 and 30 mg / kg doses, compared to mediated rats. Compared to rats treated with the carton, single-action Dunnett multiple comparison tests at various time points and doses showed that ΔBMAP decreased more throughout the 6-hour period after administration in rats treated with 10 and 30 mg / kg compound I-14; decreased more at 1, 2, and 3 hours after administration in rats treated with 3 mg / kg compound I-14; and did not decrease in rats treated with 1 mg / kg compound I-14.

[0509] The maximum effect of compound I-14 on ΔVMAP was calculated using a dataset grouped by 10-minute intervals and is shown in Table D below:

[0510] Table D. Maximum effect of compound I-14 on mediator-adjusted MAP (ΔVMAP)

[0511] 1mg / kg -6.2 90 3mg / kg -10.1 70 10mg / kg -22.3 30 30mg / kg -24.4 30

[0512] Based on main effect analysis, single effect analysis, and AOC assessment, the dose with no effect on ΔBMAP is 1 mg / kg.

[0513] in conclusion

[0514] Compared to baseline and adjusted for self-mediating agents, compound I-14 reduced MAP at 3, 10, and 30 mg / kg.

[0515] b) Compound I-20

[0516] Similar studies to those described above were conducted using compound I-20. Single oral doses of compound I-20 (prepared from the sodium salt of compound I-20) in Milli-Q water were administered to awake, freely moving rats at doses of 1, 3, 10, and 30 mg / kg. Blood samples were collected from each animal via catheter before administration and 2 hours after administration for compound concentration quantification. Hemodynamic measurements were recorded 10 hours after administration.

[0517] Blood pressure changes

[0518] The change in MAP relative to the baseline (ΔBMAP) is displayed graphically. Figure 2 In contrast, rats treated with compound I-20 showed a greater reduction in MAP compared to rats treated with mediators (e.g., by the change in MAP relative to baseline, i.e., Δ). B MAP (to assess). A two-factor ANOVA was used to evaluate Δ. B The MAP data were significant (p < 0.0001 for the therapeutic agent and therapeutic agent × time interaction; and p = 0.022 for time). The Dunnett multiple comparison test for the primary therapeutic effect showed p = 0.055 (ns) for 1 mg / kg, p = 0.0001 for 3 mg / kg, and p < 0.0001 for 10 and 30 mg / kg doses, compared to rats treated with the cartel. In contrast, the single Dunnett multiple comparison test for the single effect at each time point and dose in cartel-treated rats showed a greater reduction in MAP over the entire 6-hour post-dose period in rats treated with 3, 10, and 30 mg / kg of compound I-20; and a greater reduction at 1, 2, 3, 4, and 5 hours post-dose in rats treated with 1 mg / kg of compound I-20.

[0519] The effect of compound I-20 on Δ was calculated using a dataset grouped by 10-minute intervals. V The maximum effect of MAP (modified MAP) is shown in Table E below:

[0520] Table E. Effects of compound I-20 on mediator-adjusted MAP (Δ) V The greatest role of MAP

[0521] 1mg / kg -14.3 20 3mg / kg -19.2 20 10mg / kg -20.2 30 30mg / kg -38.1 30

[0522] in conclusion

[0523] Compared to baseline and adjusted for self-mediating agents, compound I-20 reduced MAP at 1, 3, 10, and 30 mg / kg.

[0524] Other BP measurements

[0525] In studies similar to those described above, compound I-4, formulated in PEG400 and administered at 10 mg / kg, showed a maximum reduction in MAP relative to baseline (Δ) at 50 min post-administration. B The mean MAP (maximum arterial pressure) was 20 mm Hg. In studies similar to those described above, compound I-20, formulated in PEG400 and administered at 10 mg / kg, showed a peak ΔHg at 42 min post-administration. B The mean MAP was -26 mm Hg. In another study where compound I-20 was tested at 1, 3, or 10 mg / kg and formulated in methylcellulose, the compound reduced the mean MAP relative to baseline at all tested doses.

Claims

1. Compounds represented by formula I: ； Or its medically acceptable salt, wherein: J C Choose from the following groups: hydrogen, halogens, and carbon. 1-6 alkyl; X is N or C(J) C1 ); J C1 Choose from the following groups: hydrogen, halogens, and carbon. 1-6 alkyl; Each J B Independently selected from the following groups: hydrogen, halogens, and C. 1-6 alkyl; J D Choose from the following groups: hydrogen, halogens, and carbon. 1-6 Alkyl groups; and n is an integer selected from 0, 1, 2, 3, or 4, with the constraint that the compound is not one of the following: and , Or its medically acceptable salt.

2. The compound of claim 1, wherein the compound is represented by formula IA: ， Or its medically acceptable salt.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein J C1 H, F, Cl or C 1-2 alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein J C1 It can be H or F.

5. The compound of claim 1, wherein the compound is represented by formula IB: ， Or its medically acceptable salt.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each J B Independently H, F or C 1-4 alkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3; and each J B It can be F or methyl on its own.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2; and J B All are F or J B One of them is F and the other is methyl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 3; and J B Two of them are F and the other is methyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein J D It can be H, F, Cl, methyl, or ethyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein J D It can be H or F.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein J C It can be H, Cl, F, methyl, or ethyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein J C It can be H or F.

17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein J C For H.

18. The compound of claim 1, wherein the compound is selected from: Or its medically acceptable salt.

19. The compound of claim 18, wherein the compound is selected from: Or its medically acceptable salt.

20. The compound of claim 18, wherein the compound is selected from: Or its medically acceptable salt.

21. The compound of claim 20, wherein the compound is selected from: Or its medically acceptable salt.

22. The compound of claim 20, wherein the compound is selected from: Or its medically acceptable salt.

23. The compound of claim 18, wherein the compound is selected from: Or its medically acceptable salt.

24. A pharmaceutical composition comprising the compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. A pharmaceutical composition comprising the compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. Use of the compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition that benefits from sGC stimulation or from an increase in NO and / or cGMP concentrations.

27. Use of the pharmaceutical composition of claim 24 or 25 in the preparation of a medicament for treating a disease or condition that benefits from sGC stimulation or from an increase in NO and / or cGMP concentrations.

28. The use as described in claim 26, wherein the medicament further comprises an additional therapeutic agent.

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