sGC stimulant

Abstract

The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharma- ceutical acceptable salts thereof and pharmaceutical formulations comprising them, and uses thereof, alone or in combination with one or more additional agents, for treating various diseases in which increasing the concentration of nitric oxide (NO) and / or increasing the concentration of cyclic guanosine monophosphate (cGMP), or both, or upregulating the NO pathway, is desired. In some embodiments, the compound is one of Table I or a pharma-ceutical acceptable salt thereof.

Description

[Technical Field]

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

[0002] Field of Invention This disclosure relates to compounds that are stimulants of soluble guanylate cyclase (sGC) and pharmaceutically acceptable salts thereof. It also relates to pharmaceutical formulations and dosage forms containing them, either alone or in combination with one or more additional agents, for the treatment of various diseases, which are diseases that benefit from sGC stimulation or from increased concentrations of nitric oxide (NO) and / or cyclic guanosine monophosphate (cGMP). [Background technology]

[0003] sGC is the primary receptor for NO in vivo. Upon binding to sGC, NO activates its catalytic domain, resulting in the conversion of guanosine-5'-triphosphate (GTP) to cGMP, a secondary messenger. The increased level of cGMP then modulates the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels. In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by the sequential reduction of inorganic nitrates. Experimental and clinical evidence indicates that decreased NO concentration, reduced NO bioavailability, and / or reduced responsiveness to endogenously produced NO contribute to the development of many diseases. sGC stimulants are heme-dependent agonists of the sGC enzyme that synergistically act with varying amounts of NO to increase its enzymatic conversion of GTP to cGMP. sGC stimulants are clearly differentiated from and structurally unrelated to NO-independent, heme-independent agonists of another class of sGC known as sGC activators.

[0004] Therapies that improve or restore sGC function offer significant advantages over current alternative therapies, which either target the pathway or benefit from upregulation of the NO-sGC-cGMP pathway. There is an urgent need to develop new and safe therapies for patients with dysfunctional NO-sGC-cGMP pathways. [Overview of the project] [Means for solving the problem]

[0005] The present invention is based on the discovery that the compounds disclosed herein are sGC stimulants. The relevant structural features, particularly the compounds with 4-OH substituents on the pyrimidine ring, were previously known only as synthetic intermediates that could be used for the preparation of sGC stimulants having 4-amino substituents on the pyrimidine ring. It was unexpectedly discovered that the compounds of this disclosure possess potent sGC-promoting activity. In a first aspect, the present invention aims at sGC stimulant compounds of Table I or Formula I and pharmaceutically acceptable salts thereof.

[0006] [Table 1-1]

[0007] [Table 1-2]

[0008] [Table 1-3]

[0009] In a second aspect, the present invention relates to a pharmaceutical composition comprising Table I, a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier. In a third aspect, the present invention relates to a method for treating a disease in a subject requiring the use thereof, comprising the step of administering a therapeutically effective amount of a compound of Table I, Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject, either alone or in combination therapy, wherein the disease benefits from sGC stimulation or from an increase in the concentration of NO and / or cGMP. Also provided is the use of a compound of Table I, Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease in a subject requiring the use thereof, wherein the disease benefits from sGC stimulation or from an increase in the concentration of NO and / or cGMP. In certain embodiments, the present invention relates to a compound of Table I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a disease in a subject requiring the use thereof, wherein the disease benefits from sGC stimulation or from an increase in the concentration of NO and / or cGMP. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows the effect of compound I-14 on the change from baseline in MAP (ΔBMAP) in male normal blood pressure rats. [Figure 2] Figure 2 shows the effect of compound I-20 on ΔBMAP in male normal blood pressure rats. [Modes for carrying out the invention]

[0011] The references herein are made in detail to certain embodiments of the invention, examples of which are shown in the accompanying structures and formulas. While the invention is described in relation to the enumerated embodiments, it will be understood that these are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all substitutes, modifications, and equivalents that may fall 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 that are similar to or equivalent to those described herein and may be used in carrying out the invention. If one or more incorporated references, patents, or similar materials differ from, or contradict, this application, including but not limited to, defined terms, use of terms, or described techniques, this application shall take precedence.

[0012] Definitions and common technical terms For the purposes of this disclosure, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entirety.

[0013] Unless otherwise stated, all tautomer forms of the compounds disclosed herein are also within the scope of the present invention. In one embodiment, the present invention relates to hydrogen and deuterium (i.e. 2This may include substitution with H), which may be preferable in some situations because it can yield certain therapeutic benefits resulting in better metabolic stability (e.g., extended in vivo half-life or reduced required dose). The deuterium-labeled compounds of the present invention can generally be prepared by substituting the deuterated reagent with the undeuterated reagent according to a procedure similar to that disclosed in the following schemes and / or examples herein.

[0014] As used herein, the term "halogen" or "halo" means one of the following: F (fluoro), Cl (chloro), Br (bromo), or I (iodine). The term "hydroxyl" or "hydroxy" refers to the -OH group.

[0015] The term "alkyl," as used herein, refers to a saturated, unbranched (e.g., linear) or branched monovalent hydrocarbon radical. x An alkyl group is an alkyl chain containing x carbon atoms, where x is an integer other than 0. x~y An alkyl group is an alkyl chain in which x and y are two distinct integers, both of which are not 0, and which contains a number of carbon atoms equal to x to y (including both ends). For example, C 1~6 Alkyl is an alkyl group as defined above, containing any number of carbon atoms from 1 to 6. 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, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and others.

[0016] The term "fluoroalkyl," as used herein, refers to the alkyl group as defined above, in which one or more hydrogen atoms bonded to the carbon atoms in the chain are replaced by fluorine at any one or more carbon atoms of the alkyl group. For example, a fluoroalkyl group substituted with 1 to 3 fluorine atoms is an alkyl group in which 1 to 3 hydrogen atoms are replaced by fluorine atoms at any position, either on the same carbon atom or on a different carbon atom of the alkyl chain.

[0017] The compounds of the present invention are defined herein by their chemical structure and / or chemical name. When a compound is referred to by both its chemical structure and chemical name, and the chemical structure and chemical name do not match, the chemical structure is the determinant of the compound's identity.

[0018] Embodiments of Compounds / Compositions A first embodiment of the present invention is the compounds listed in Table I or pharmaceutically acceptable salts thereof. A second embodiment of the present invention is the compounds of Table II or pharmaceutically acceptable salts thereof.

[0019] [Table 2-1]

[0020] [Table 2-2]

[0021] [Table 2-3]

[0022] In the third embodiment, the compounds of the present invention are as follows:

[0023] [Table 3-1]

[0024] [Table 3-2]

[0025] Selected from those listed or pharmaceutically acceptable salts thereof. In the fourth embodiment, the compounds of the present invention are as follows: (See Table IV)

[0026] [Table 4-1]

[0027] [Table 4-2]

[0028] Selected from those listed or pharmaceutically acceptable salts thereof. In the fifth embodiment, the compounds of the present invention are as follows (Table V):

[0029] [Table 5]

[0030] Selected from those listed or pharmaceutically acceptable salts thereof. In the sixth embodiment, the compounds of the present invention are as follows: (See Table VI)

[0031] [Table 6]

[0032] Selected from those listed or pharmaceutically acceptable salts thereof. In the 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 the sodium salt. In another embodiment, the compound of the present invention is of the following formula:

[0033] [Chemical formula]

[0034] It is the sodium salt of compound I-14 represented by In the 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 the sodium salt. In another embodiment, the compound of the present invention has the following formula:

[0035] [Chemical formula]

[0036] It is the sodium salt of compound I-20 represented by In the ninth embodiment, the compound of the present invention has the formula I:

[0037] [Chemical formula]

[0038] [wherein, J C is selected from the group consisting of hydrogen, halogen, C 1~6 alkyl and C 1~6 fluoroalkyl substituted with 1 to 3 fluorine atoms, X is N or C(J C1 ), J C1 is selected from the group consisting of hydrogen, halogen, C 1~6 alkyl and C 1~6 fluoroalkyl substituted with 1 to 3 fluorine atoms, each J B is independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl and C 1~6 fluoroalkyl substituted with 1 to 3 fluorine atoms, J D is hydrogen, halogen, C 1~6 alkyl and C 1~6 フルオロアルキルからなる群から選択され、 R C は、水素、ハロゲン、C 1~6 アルキルおよび1~3個のフッ素原子で置換したC C1 フルオロアルキルからなる群から選択され、 R C1 は、水素、ハロゲン、C 1~6 アルキルおよび1~3個のフッ素原子で置換したC [[ID=***]] B フルオロアルキルからなる群から選択され、 R 1~6 は、水素、ハロゲン、C D アルキルおよび1~3個のフッ素原子で置換したC 1~6 フルオロアルキルからなる群から選択される。

[0039] <001~6 Selected from the group consisting of fluoroalkyl groups, n is an integer selected from 0, 1, 2, 3, or 4. Or represented by its pharmaceutically acceptable salt, however, the compound is as follows:

[0039] [ka]

[0040] Not one of them or a pharmaceutically acceptable salt thereof. In the tenth embodiment, for the compound of formula I described in the ninth embodiment, the variables are as follows: J C Hydrogen, halogens, and C 1~6 Selected from the group consisting of alkyl groups, X is N or C(J C1 ) and J C1 Hydrogen, halogens, and C 1~6 Selected from the group consisting of alkyl groups, each J B Hydrogen, halogens, and C 1~6 Independently selected from the group consisting of alkyls, J D Hydrogen, halogens, and C 1~6 Selected from the group consisting of alkyl groups, n is an integer selected from 0, 1, 2, 3, or 4. It is defined as follows, however, the compounds are as follows:

[0041] [ka]

[0042] Not one of or a pharmaceutically acceptable salt thereof. In some embodiments, each J B is halogen and C 1~6 It is independently selected from the group consisting of alkyl groups. In the 11th embodiment, for a compound of formula I, n is an integer selected from 1, 2, 3, or 4, and each J B is halogen, C 1~6 C substituted with alkyl and 1-3 fluorine atoms 1~6 Independently selected from the group consisting of fluoroalkyls, J B All other carbon atoms of the phenyl ring to which is bonded are unsubstituted, and the remaining variables are as defined in the ninth embodiment above.

[0043] In the twelfth embodiment, the compound of formula I is:

[0044] [ka]

[0045] Or represented by its pharmaceutically acceptable salt, the variables are as described above for formula I in the 9th, 10th or 11th embodiment, except that the compound is as follows:

[0046] [ka]

[0047] or none of the pharmaceutically acceptable salts thereof. In the 13th embodiment, a compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, is treated with J C1 These are H, F, Cl, C 1~2 C substituted with alkyl or 1-3 fluorine atoms 1~2 It is a fluoroalkyl; the remaining variables are as defined in any one embodiment of the 9th, 11th, or 12th embodiment.

[0048] In the 14th embodiment, a compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, is treated with J C1 is H, F, or Cl; the remaining variables are as defined in any one embodiment of the 9th to 12th embodiments.

[0049] In the 15th embodiment, a compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, is treated with J C1 is fluoromethyl (i.e., -CH2F, -CHF2, or CF3) substituted with H, F, methyl, or 1 to 3 fluorine atoms; the remaining variables are defined in any one embodiment of the 9th and 11th to 13th embodiments.

[0050] In the sixteenth embodiment, a compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, is treated with J C1 is H; the remaining variables are defined in any one embodiment of the 9th to 15th embodiments.

[0051] In the 17th embodiment, a compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, is treated with J C1 is fluoromethyl (i.e., -CH2F, -CHF2, or CF3) substituted with F, methyl, or 1 to 3 fluorine atoms; the remaining variables are defined in any one embodiment of the 9th, 11th through 13th, and 15th embodiments.

[0052] In the 18th embodiment, for a compound of formula I or formula IA, according to the 13th, 15th, or 17th embodiment, C 1~2 The fluoroalkyl or fluoromethyl group is substituted with a single fluorine atom.

[0053] In the 19th embodiment, for a compound of formula I or formula IA, according to the 13th, 15th, or 17th embodiment, C 1~2 Fluoroalkyl or fluoromethyl groups are substituted with two fluorine atoms.

[0054] In the 20th embodiment, for a compound of formula I or formula IA, according to the 13th, 15th, or 17th embodiment, C 1~2 The fluoroalkyl or fluoromethyl group is substituted with three fluorine atoms.

[0055] In the 21st embodiment, a compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, is treated with J C1 is F or H; the remaining variables are defined in any one embodiment of the 9th to 12th embodiments.

[0056] In the 22nd embodiment, the compound of formula I is formula IB:

[0057] [ka]

[0058] Or represented by its pharmaceutically acceptable salt, the variables are as described above for formula I according to the 9th, 10th or 11th embodiment, provided that the compound is

[0059] [ka]

[0060] Or not a pharmaceutically acceptable salt of that type. In the 23rd embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2 or 3, and the remaining variables are as described in any one embodiment of the 9th to 22nd embodiments. In some embodiments, n is 2. In other embodiments, n is 3.

[0061] In the 24th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 0 or 1, and the remaining variables are as described in any one embodiment of the 9th to 22nd embodiments. In some embodiments, n is 1.

[0062] In the 25th embodiment, each J is used for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof. B These are H, F, and C, independently. 1~4C substituted with alkyl or 1-3 fluorine atoms 1~4 It is a fluoroalkyl; the remaining variables are as defined in any one embodiment of the 9th to 24th embodiments.

[0063] In the 26th embodiment, each J is used for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof. B These are independently H, F, or C 1~4 It is alkyl; the remaining variables are defined in any one embodiment of the 9th to 24th embodiments.

[0064] In the 27th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2 or 3; each J B This is independently F, methyl, or fluoromethyl substituted with 1 to 3 fluorine atoms; the remaining variables are as described in any one embodiment of the 9th to 23rd embodiments.

[0065] In the 28th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2 or 3; each J B This is independently F or methyl; the remaining variables are as described in any one embodiment of the 9th to 23rd embodiments.

[0066] In the 29th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2 or 3; each J B This is independently F, ethyl, or fluoroethyl substituted with 1 to 3 fluorine atoms; the remaining variables are as defined in any one embodiment of the 9th to 23rd embodiments.

[0067] In the 30th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2; J B Both are F, or J BOne of them is F, and the other is methyl or fluoromethyl substituted with 1 to 3 fluorine atoms; the remaining variables are described in any one embodiment of the 9th to 23rd embodiments. In some embodiments, one J B One is F, and the other is methyl or fluoromethyl substituted with 1 to 3 atoms. In yet another embodiment, one J B One is F, and the other is methyl. In other embodiments, one J B One is F, and the other is fluoromethyl. In some embodiments, fluoromethyl is substituted with one fluorine atom (i.e., -CH2F). In other embodiments, fluoromethyl is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, fluoromethyl is substituted with three fluorine atoms (i.e., -CF3).

[0068] In the 31st embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 2; J B Both are F, or J B One of them is F, and the other is ethyl or fluoroethyl substituted with 1 to 3 fluorine atoms; the remaining variables are as described in any one embodiment of the 9th to 23rd embodiments. In some embodiments, one J B One is F, and the other is ethyl or fluoroethyl substituted with 1 to 3 atoms. In yet another embodiment, one J B One is F, and the other is ethyl. In other embodiments, one J B One is F, and the other is fluoroethyl. In some embodiments, fluoroethyl is substituted with one fluorine atom. In other embodiments, fluoroethyl is substituted with two fluorine atoms, and in still other embodiments, fluoroethyl is substituted with three fluorine atoms.

[0069] In the 32nd embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 3; in the case of J B is F, or J BTwo of them are F, and the other is methyl or fluoromethyl substituted with 1 to 3 fluorine atoms; the remaining variables are as described in any one embodiment of the 9th to 23rd embodiments. In some embodiments, fluoromethyl is substituted with 1 fluorine atom (i.e., -CH2F). In other embodiments, fluoromethyl is substituted with 2 fluorine atoms (i.e., -CHF2), and in other embodiments, fluoromethyl is substituted with 3 fluorine atoms (i.e., -CF3). In some embodiments, two J B One is F, and the other is methyl.

[0070] In the 33rd embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 3; in the case of J B is F, or J B Two of the variables are F, and the other is ethyl or fluoroethyl substituted with 1 to 3 fluorine atoms; the remaining variables are as described in any one embodiment of the 9th to 23rd embodiments. In some embodiments, fluoroethyl is substituted with 1 fluorine atom. In other embodiments, fluoroethyl is substituted with 2 fluorine atoms, and in other embodiments, fluoroethyl is substituted with 3 fluorine atoms.

[0071] In the 34th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 1; J B Fluoromethyl is F, methyl, ethyl, fluoromethyl, or fluoroethyl; the remaining variables are described in any one embodiment of the 9th to 22nd embodiments. In some embodiments, fluoromethyl is substituted with one fluorine atom (i.e., -CH2F). In other embodiments, fluoromethyl is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, fluoromethyl is substituted with three fluorine atoms (i.e., -CF3). In some embodiments, fluoroethyl is substituted with one fluorine atom. In other embodiments, fluoroethyl is substituted with two fluorine atoms, and in other embodiments, fluoroethyl is substituted with three fluorine atoms.

[0072] In the 35th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 1; J B is F; the remaining variables are as described in any one embodiment of the 9th to 22nd embodiments.

[0073] In the 36th embodiment, for a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, n is 0; the remaining variables are as described in the 9th to 22nd embodiments.

[0074] In the 37th embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with J D is H, F, Cl, methyl, ethyl, or fluoromethyl or fluoroethyl, where the fluoromethyl or fluoroethyl is substituted with 1 to 3 fluorine atoms; the remaining variables are as described in any one embodiment of the 9th to 36th embodiments. In some embodiments, fluoromethyl is substituted with 2 fluorine atoms (i.e., -CHF2), and in other embodiments, fluoromethyl is substituted with 3 fluorine atoms (i.e., -CF3). In other embodiments, fluoroethyl is substituted with 1 fluorine atom. In other embodiments, fluoroethyl is substituted with 2 fluorine atoms, and in other embodiments, fluoroethyl is substituted with 3 fluorine atoms.

[0075] In the 38th embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with J D is H or F; all other variables are as defined in any one embodiment of the 9th to 37th embodiments. In some embodiments, J D is F. In some embodiments, J D H is H.

[0076] In the 39th embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with JD is hydrogen; the remaining variables are as described in any one embodiment of the 9th to 37th embodiments.

[0077] In the 40th embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with J D is F; the remaining variables are as described in any one embodiment of the 9th to 37th embodiments.

[0078] In the 41st embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with J C Fluoromethyl is H, Cl, F, methyl, ethyl, or fluoroethyl or fluoromethyl substituted with 1 to 3 fluorine atoms; the remaining variables are as described in any one embodiment of the 9th to 40th embodiments. In some embodiments, fluoromethyl is substituted with 2 fluorine atoms (i.e., -CHF2), and in other embodiments, fluoromethyl is substituted with 3 fluorine atoms (i.e., -CF3). In other embodiments, fluoroethyl is substituted with 1 fluorine atom. In other embodiments, fluoroethyl is substituted with 2 fluorine atoms, and in other embodiments, fluoroethyl is substituted with 3 fluorine atoms.

[0079] In the 42nd embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with J C is H, Cl, or F; the remaining variables are as described in any one embodiment of the 9th to 40th embodiments.

[0080] In the 43rd embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with J Cis H, F, methyl, or fluoromethyl; the remaining variables are as described in any one embodiment of the 9th to 40th embodiments. In some embodiments, fluoromethyl is substituted with two fluorine atoms (i.e., -CHF2), and in other embodiments, fluoromethyl is substituted with three fluorine atoms (i.e., -CF3).

[0081] In the 44th embodiment, a compound of formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, is treated with J C is H or F; the remaining variables are as described in any one embodiment of the 9th to 40th embodiments. In some embodiments, J C H is H.

[0082] In the 45th embodiment, the compound of the present invention is of formula IC:

[0083] [ka]

[0084] A compound represented by or a pharmaceutically acceptable salt thereof, where X is N or C(J C1 ) and X is C(J C1 If this is the case, it will be represented in C in the table below; variables X, J C1 and J B The definitions are listed in the table below; furthermore, Me represents a methyl group, and Me-F represents a methyl fluoride group substituted with 1 to 3 fluorine atoms (i.e., -CH2F, -CHF2, or CF3):

[0085] [Table 7-1]

[0086] [Table 7-2]

[0087] [Table 7-3]

[0088] [Table 7-4]

[0089] [Table 7-5]

[0090] [Table 7-6]

[0091] [Table 7-7]

[0092] The pharmaceutically acceptable salt of the present invention The “pharmaceutically acceptable salts” of the compounds described herein include those derived from the above compounds when mixed with inorganic or organic acids or bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments, the salts can be prepared from the free form of the compounds in a separate synthesis step. The preparations of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts are 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 one of the compounds in Tables I-VI or Formula I are usable in pharmaceuticals. However, unpharmaceutically acceptable salts may be useful in the preparation of the compounds in Tables I-VI or Formula I or their pharmaceutically acceptable salts.

[0093] When the compounds described herein (e.g., compounds in Tables I-VI or compounds represented by Formula I) are acidic, a suitable “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable non-toxic base, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Specific embodiments include salts of ammonium, calcium, magnesium, potassium, and sodium. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N, and N. 1 -Contains salts of dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0094] In some embodiments, the compounds of the present invention have an acidic OH group that can react 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 a salt of ammonium, calcium, magnesium, potassium, or sodium. In some embodiments, the salt is a sodium salt.

[0095] When the compounds described herein (e.g., compounds in Tables I-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 acetates, acetic acid, acid citrates, acid phosphates, ascorbic acid, benzenesulfonic acid, benzenesulfonates, benzoic acid, benzoates, bromides, bisulfates, bistartrates, camphorsulfonic acid, chlorides, citrates, citric acid, ethanesulfonates, ethanesulfonic acid, formates, fumarates, fumaric acid, gentisinates, glucons, gluconic acid, glucuronates, glutamates, glutamic acid, hydrobromic acid, hydrochloric acid, iodide, isethionic acid, iso This includes nicotinates, lactates, lactic acid, maleates, maleic acid, malic acid, mandelic acid, methanesulfonic acid, methanesulfonates, mucinic acid, nitrates, nitrates, oleates, oxalates, pamoic acid, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), pantothenic acid, pantothenate, phosphates, phosphoric acid, sugarates, salicylates, succinic acid, succinate, sulfuric acid, sulfates, tannates, tartrates, tartaric acid, p-toluenesulfonates, p-toluenesulfonic acid, and the like. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0096] In addition to the compounds described herein, their pharmaceutically acceptable salts may also be used in compositions to treat or prevent the diseases identified herein. Pharmaceutical composition and method of administration In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound described herein (for example, 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.

[0097] In some embodiments, the pharmaceutical composition of the present invention comprises a compound comprising any one of the compounds described in Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0098] The compounds disclosed herein and their pharmaceutically acceptable salts can be formulated as pharmaceutical compositions or “formulations.” Typical formulations are prepared by mixing the compounds described herein (e.g., compounds in Tables I-VI or compounds represented by Formula I, or pharmaceutically acceptable salts thereof) with a carrier, diluent, or excipient. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swelling polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water. The specific carrier, diluent, or excipient used depends on the means and purpose for which the compounds described herein (e.g., compounds in Tables I-VI or compounds represented by Formula I, or pharmaceutically acceptable salts thereof) are formulated. Solvents are generally selected based on those recognized by those skilled in the art as safe (GRAS: Generally Regarded as Safe) for administration to mammals. 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 contain other types of excipients, such as one or more buffers, stabilizers, anti-adhesives, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or sustained-release), preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, sweeteners, flavorings, and other known additives, which provide a high-quality presentation of the drug (i.e., compounds of Tables I-VI, compounds represented by Formula I, or their pharmaceutical compositions) or assist in the manufacture of pharmaceuticals (i.e., pharmaceuticals).

[0099] Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to the recipient at the doses and concentrations used, and include buffers, e.g., phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens, e.g., methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and proteins, e.g., serum albumin. The active pharmaceutical ingredient may also be encapsulated in microcapsules prepared by, for example, coacervation technology or interfacial polymerization, 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; counterions that form salts, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG). The active pharmaceutical ingredient may also be encapsulated in microcapsules prepared by, for example, coacervation technology or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively; in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's *The Science and Practice of Pharmacy*, 21st edition, edited by the University of the Sciences in Philadelphia, 2005 (hereinafter referred to as "Remington's").

[0100] The formulation can be prepared using conventional dissolution and mixing procedures. The term “therapeutic dose,” as used herein, means the amount of an active compound or drug that elicits a biological or medical response in a tissue, system, animal, or human, as determined by researchers, veterinarians, physicians, or other clinicians. The therapeutic dose of a compound administered is determined by such considerations and is the minimum amount necessary to improve, cure, or treat one or more of the disease or its symptoms.

[0101] The terms “administer,” “dosage,” or “administer,” as used with reference to the compounds, compositions, or dosage forms of the present invention, mean introducing the compound, composition, or dosage form into the system of a subject or patient requiring treatment. When the compounds of the present invention are provided in combination with one or more other activators, “administer” and its variations are understood to include the simultaneous and / or sequential introduction of the compound, composition, or dosage form and the other activators, respectively.

[0102] The compounds described herein may be administered systemically or topically, depending on the severity and type of the disease being treated, for example, orally (solid dosage forms including hard or soft capsules (e.g., gelatin capsules), tablets, pills, powders, sublingual tablets, lozenges, and granules; as well as by inhalation (e.g., aerosols, gases, inhalers, nebulizers, etc.), in the ear (e.g., using ear drops), topically (e.g., creams, gels, inhalants, liniments, lotions, ointments, patches, pastes, powders, solutions), The compositions may be administered parenterally (including, but not limited to, pharmaceutically acceptable liquid dosage forms such as emulsions, microemulsions, aqueous or oily solutions, suspensions, syrups and elixirs), ophthalmologically (e.g., eye drops, ophthalmic gels and ophthalmic ointments), rectally (e.g., enemas or suppositories), nasally, buccally, transvaginally (e.g., irrigators, intrauterine devices, vaginal suppositories, vaginal rings or tablets), via ear drops, via implantable reservoirs, etc. The term “parenteral” as used herein includes, but is not limited to, techniques of injection or infusion subcutaneously, intravenously, intramuscularly, intra-articularly, intrasynovally, intrasternally, intrastellarly, intrahepatically, intralesionally and intracranially. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0103] Formulations of compounds intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. In solid dosage forms, the active compound is an inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia; c) water-retaining agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, ja The tablets are mixed with potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders, e.g. paraffin, f) absorption enhancers, e.g. quaternary ammonium compounds, g) wetting agents, e.g. cetyl alcohol and glycerol monostearate, h) absorbents, e.g. kaolin and bentonite clay, and i) lubricants, e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. The tablets may be coated by known techniques, including microencapsulation, which can be uncoated or which masks unpleasant flavors or delays decomposition and adsorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying materials, e.g. glyceryl monostearate or glyceryl distearate, may be used alone or with wax. Water-soluble taste-masking materials, e.g. hydroxypropyl methylcellulose or hydroxypropyl cellulose, may be used.

[0104] In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. Besides inert diluents, the oral composition may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and fragrances.

[0105] Oral compositions (either solid or liquid) may also include excipients and adjuvants, such as dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), condensation products of oxidized alkylenes with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrous hexitol (e.g., polyoxyethylene sorbitan monooleate); emulsifiers and suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; sweeteners, flavorings and fragrances; and / or one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavorings and one or more sweeteners, such as sucrose or saccharin.

[0106] Pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to well-known techniques in the field of pharmaceutical formulation and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants. Formulations suitable for intrapulmonary or nasal administration have particle sizes in the range of 0.1 to 500 microns (including particles in the range of 0.1 to 500 microns in incremental microns such as 0.5, 1, 30, 35 microns), and are administered by rapid inhalation through the nasal route or by inhalation through the mouth to reach the alveolar sacs.

[0107] The pharmaceutical compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs that are easily accessible by topical application, such as diseases of the eyes, ears, skin, or lower intestines. Suitable topical formulations are readily prepared for each of these areas or organs. The active components are mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers.

[0108] For topical application, the pharmaceutical composition may be formulated as a suitable ointment containing the active component 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 petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0109] Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. Optionally, the aqueous phase of the cream base may contain polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400), and mixtures thereof. Topical formulations are preferably formulated to 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.

[0110] The oily phase of emulsions prepared using compounds of Tables I-VI or Formula I may consist of known components in a known manner. While the phase may contain only emulsifiers (also known as efflux enhancers), it is desirable to include at least one emulsifier with fat or oil, or a mixture of both fat and oil. Hydrophilic emulsifiers may be included together with lipophilic emulsifiers acting as stabilizers. In some embodiments, the emulsifiers include both oil and fat. Together with stabilizers, emulsifiers with or without stabilizers constitute so-called emulsifying waxes, which, together with oils and fats, constitute so-called emulsifying ointment bases that form the oily dispersion phase of cream formulations. Suitable efflux enhancers and emulsifying stabilizers for use in formulations of compounds of Tables I-VI or Formula I include Tween®-60, Span®-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0111] In addition, the present invention has the further benefit of being intended for use as a transdermal patch, resulting in controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0112] For ophthalmic use, the pharmaceutical composition may be formulated as a finely powdered suspension in pH-adjusted isotonic sterile saline, or preferably as a solution in pH-adjusted isotonic sterile saline, with or without a preservative, such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum. For treatment of the eye or other external tissues, such as the mouth and skin, the formulation may be applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w / w. When formulated as an ointment, the active ingredient may be used with either an oily paraffin or a water-miscible ointment base.

[0113] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers, such as cocoa butter, beeswax, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature, so that they dissolve in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be represented as pessaries, tampons, creams, gels, pastes, foams, or sprays.

[0114] The sterile injectable forms (e.g., for parenteral administration) of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting and suspending agents (including those described in the preceding paragraphs). The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, non-extrointestinal, acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solutions. In addition, sterile fixatives are conventionally used as solvents or suspension media. For this purpose, any non-irritating fixatives containing synthetic monoglycerides or synthetic diglycerides may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in injectable preparations, particularly in their polyoxyethylated versions or mineral oils such as liquid paraffin, which are naturally pharmaceutically acceptable oils, such as vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in formulations of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for the purpose of injectable formulations. Oily suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings, such as those described above, may be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants, such as butylated hydroxyanisole or alpha-tocopherol.

[0115] In another embodiment, compounds of Tables I-VI or Formula I, or pharmaceutically acceptable salts thereof, may be formulated in veterinary compositions comprising a veterinary carrier. The veterinary carrier may be a solid, liquid, or gaseous material that is otherwise inert and is useful for administering the composition. In the field of veterinary medicine, it is compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0116] Treatment method In another aspect, the present invention also provides a method for treating a disease in a subject requiring it, comprising the step of administering a therapeutically effective amount of a compound of Table I-VI or Formula I or a pharmaceutically acceptable salt thereof, either alone or in combination, wherein the disease benefits from sGC stimulation, or from an increase in the concentration of NO or cGMP or both, or from upcontrol of the NO-sGC-cGMP pathway. The present invention also provides a method for treating a disease in a subject requiring it, comprising the step of administering a pharmaceutical composition or dosage form comprising a compound of Table I-VI or Formula I or a pharmaceutically acceptable salt thereof, either alone or in combination, wherein the disease benefits from sGC stimulation, or from an increase in the concentration of NO or cGMP or both, or from upcontrol of the NO-sGC-cGMP pathway.

[0117] A tenth embodiment of the present invention is a method for treating a disease in a subject requiring treatment, comprising the step of administering to the subject requiring treatment a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof from any one embodiment of the compounds described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or a pharmaceutical composition described in the ninth embodiment.

[0118] In some embodiments, the compounds disclosed herein are sGC stimulants that may be useful in preventing and / or treating diseases characterized by an undesirable decrease in the bioavailability and / or sensitivity to NO, such as a state of oxidative stress or nitration stress.

[0119] Increased cGMP concentrations result in 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 may be used to treat and / or prevent a range of diseases.

[0120] Specific diseases or disorders that can be treated and / or prevented by administering the sGC stimulants of the present invention (e.g., compounds of Tables I-VI or Formula I and pharmaceutically acceptable salts thereof) include, but are not limited to: Abetalipoproteinemia, achalasia (e.g., esophageal achalasia), acute respiratory distress syndrome (ARDS), adhesive capsulitis, age-related learning and memory impairment, age-related memory loss, alcoholism, alopecia or hair loss, severe disability, Alzheimer's disease (including pre-symptomatic, mild to moderate Alzheimer's disease, or 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, Prinzmetallic angina, microangina) Small vessel angina), anxiety or anxiety disorders, argininosuccinateuria, arterial and venous thrombosis, arthritis, Asperger's syndrome, asthma and asthmatic disorders, ataxia, telangiectasia, atherosclerosis (e.g., atherosclerosis associated with internal injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration), atrophic vaginitis, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), autism and disorders in the autism spectrum, benign prostatic hyperplasia (BPH) or hypertrophy or dilation of the prostate, bipolar disorder, bladder outlet Obstruction of the cerebral artery, bladder pain syndrome (BPS), blepharitis, bone and carbohydrate metabolism disorders, bone healing (e.g., bone healing following osteoclast bone remodeling, osteoclast bone resorption, bone neoplasia), cerebral aneurysm, cerebral hypoxia, cancer metastasis, cerebral amyloid vascular disease (CAA) or Congo Red affinity vascular disease, autosomal dominant cerebral arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL or CADASIL syndrome), cerebral perfusion, cerebral small vessel disease, cerebral vasospasm, chemobrain, childhood disintegrative disorder, chronic bronchitis, chronic fatigue, chronic traumatic encephalopathy (CTE), ciliopathy, cirrhosis (for example) (e.g., cirrhosis, cirrhosis associated with chronic liver disease, primary biliary cirrhosis), CNS disease-related dysfunction, CNS disease-related sleep disorders, Huntington's disease-related cognitive impairment, cognitive dysfunction, cognitive impairment (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 myasthenic syndrome, connective tissue disease, consequences of cerebral infarction (stroke), blood substituent preservation in trauma patients, CREST syndrome, Crohn's disease, cystic fibrosis (CF),Delusional disorder, dementia (e.g., vascular dementia, post-stroke dementia, Lewy body dementia, dementia with frontal lobar degeneration, dementia with frontotemporal lobar degeneration, dementia with corticobasal degeneration, Creutzfeldt-Jakob dementia, HIV dementia, dementia due to multiple strokes, postoperative dementia, dementia due to a single lesion in a strategic area, HIV-related dementia (asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), HIV-related dementia (HAD, also called AIDS dementia complex [ADC] or HIV encephalopathy), presenile dementia (mild cognitive impairment, MCI), mixed Dementia cerebral malformations (including Binswanger dementia (subcortical arteriosclerotic encephalopathy), Parkinson's dementia), demyelinating diseases, depression, depressive disorders, dermatomyositis, diabetic vascular disease, diabetic macular edema, diabetic microangiopathy, diabetic ulcers or wounds (e.g., diabetic foot ulcers), diseases associated with or related to metabolic syndromes (e.g., obesity, diabetes, insulin resistance, elevated fasting glucose, elevated fasting insulin, elevated lipids), diseases involving downregulated neurotransmitters, diseases involving impaired cerebral blood flow, diseases involving neurodegenerative disorders, diseases involving synaptic dysfunction Diseases involving neuroinflammation, diseases involving neurotoxicity, diseases of the genitourinary organs in men and women (benign and malignant), concentration disorders in children with learning and memory problems, Down syndrome, drug addiction, drug-induced psychosis, dry eye syndrome, Duchenne muscular dystrophy, Dupuytren's contracture, dyskinesia (e.g., acute dyskinesia, chronic or tardive dyskinesia, non-motor dyskinesia, levodopa-induced dyskinesia (LID)), dysmenorrhea (e.g., primary dysmenorrhea, secondary dysmenorrhea), dyspareunia, dysphagia, dystonia (e.g., systemic dysmenorrhea) Dystonia (focal dystonia, segmental dystonia, sexual dystonia, intermediate dystonia, acute dystonic reaction, hereditary or primary dystonia), edema, electrolyte disorders (e.g., hyperkalemia, hyponatremia), emphysema, endometriosis, endothelial dysfunction or injuries and diseases associated with endothelial dysfunction, erectile dysfunction, esophageal achalasia, Fabry disease, female sexual dysfunction (e.g., female sexual arousal disorder), fibromyalgia, fibrosis (e.g., endocardial myocardial fibrosis, atrial fibrosis, interstitial fibrosis, cardiac fibrosis, pulmonary fibrosis, ocular fibrosis, cutaneous fibrosis, intestinal fibrosis,Renal fibrosis or kidney fibrosis (renal fibrosis, kidney fibrosis), interstitial renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, progressive nodular fibrosis of the lung, hepatic fibrosis, mediastinal fibrosis, retroperitoneal fibrosis, articular fibrosis, myelofibrosis, myelofibrosis, osteomyelofibrosis, radiation-induced fibrosis, pancreatic fibrosis), fragile X, functional dyspepsia, gastroparesis, Gaucher disease, systemic disorders of concentration, general psychosis, glaucoma, glioblastoma, glomerulopathy (e.g., glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis), granuloma, head injury, hearing impairment (e.g.) (e.g., partial hearing loss, complete hearing loss, partial hearing loss, complete hearing loss, noise-induced hearing loss), heart disease (e.g., left ventricular myocardial remodeling, left ventricular systolic dysfunction, ischemic cardiomyopathy, dilated cardiomyopathy, alcoholic cardiomyopathy, accumulative cardiomyopathy, congenital cardiac dysfunction, decreased coronary blood flow, diastolic or systolic dysfunction, coronary insufficiency, acute coronary syndrome, coronary artery disease, arrhythmias, decreased ventricular preload, cardiac hypertrophy, right ventricular hypertrophy, atrial and ventricular rhythm disorders and cardiac conduction disorders, grades I-III atrioventricular block (AVB) I-III), supraventricular tachyarrhythmia, ventricular premature contractions, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointe tachycardia, atrial and ventricular premature contractions, AV junction premature contractions, sinoatrial node dysfunction syndrome, AV nodular reentrant tachycardia, Wolff-Parkinson-White syndrome, myocardial failure, 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 pre-existing chronic heart failure (worsening of HF), transient heart failure, acute heart failure Overall, systolic heart failure, diastolic heart failure, congestive heart failure, acute decompensated heart failure, right ventricular failure, complete heart failure, high-output heart failure, heart failure with valve defects, diabetic heart failure, heart failure / cardiorenal syndrome, right heart failure), high concentrations of plasminogen activator inhibitor 1 (PA-1), high levels of fibrinogen and low-density DLD, histiocytosis X, Huntington's disease or chorea (HD), hyperammonemia and related conditions, hypertension (e.g., arterial hypertension, treatment-resistant hypertension, diabetic hypertension, idiopathic hypertension, essential hypertension, secondary hypertension, pre-eclampsia, portal hypertension, systemic hypertension, pre-eclampsia)Acute and chronic elevated coronary blood pressure, hypertonia, hypertrophic scarring, impaired sexual arousal, hypoperfusion, impotence, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), inflammation due to cerebral malaria, inflammation due to infection, inflammatory response in perioperative care, platelet aggregation, intellectual disability, intermittent claudication, interstitial cystitis (IC), dialysis hypotension, ischemia (e.g., cerebral ischemia, myocardial ischemia, thromboembolic ischemia, severe limb ischemia), keloids, renal disease (e.g., chronic kidney disease, acute and chronic renal failure, acute and chronic renal insufficiency, sequelae of renal insufficiency, renal insufficiency related to pulmonary enemas, HF) Renal dysfunction related to uremia or anemia, primary kidney disease, congenital kidney disease, progression of polycystic kidney disease, kidney transplant rejection, immune complex-induced kidney disease, abnormally decreased creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes (e.g., glutamyl synthetase), altered urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilation, hyperphosphatemia, vascular kidney disease, renal cysts, renal edema due to HF ), Korsakoff psychosis, leukocyte activation, levodopa-induced addictive behavior, lichen sclerosing, lipid-related disorders (e.g., hyperlipidemia, hypersubcutaneous fat, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased high-density lipoprotein cholesterol (HDL cholesterol), moderate elevation of low-density lipoprotein cholesterol (LDL cholesterol) levels, hypertriglyceridemia, hyperglyceridemia, hypolipoproteinemia, sitosterolemia, fatty liver disease, fatty degeneration of the liver or abnormal lipid accumulation in the liver, fatty degeneration of the heart, kidney or muscle, sitosterolemia (xanthomatosis, Tangier's disease), liver diseases (e.g., vascular liver disease, hepatic astrocytic cell activity, accumulation of hepatic fibrous collagen and total collagen, necrotizing and / or immunological inflammatory liver disease, cholestatic liver disease associated with granulomatous liver disease, cholestatic liver disease associated with malignant hepatic disease, cholestatic liver disease associated with intrahepatic cholestasis in 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,Cholestatic liver disease associated with common bile duct stones, cholestatic liver disease associated with bile duct tumors, cholestatic liver disease associated with pancreatic cancer, cholestatic liver disease associated with Militzi syndrome, cholestatic liver disease associated with AIDS, cholangiopathies, 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), sinusoidal obstruction syndrome (SOS), hepatic encephalopathy, focal thrombosis, lower urinary tract syndrome (LUTS), lumbar spinal stenosis Diseases, lupus nephritis, lupus or systemic lupus erythematosus, microalbuminuria, microcirculatory disorders, migraine, mild neurocognitive impairment (MND), morphea, moyamoya disease, multiple lacunar infarcts, multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF), multiple sclerosis (including MS, clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS)), multiple system atrophy (MSA), myocardial infarction or heart attack (e.g., ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, old myocardial infarction), Visual choroidal neovascularization, nevi, drug dependence, nephropathy (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 incontinence, neuroinflammation, neurological disorders associated with decreased nitric oxide production, neuromuscular diseases (e.g., Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, peripheral myopathy, type I and type II myotonic dystrophy, facioscapulohumeral muscular dystrophy) Autosomal and X-linked Emery-Dreyfus muscular dystrophy, oculopharyngeal muscular 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 CNS disease (e.g., multiple sclerosis, MS),Radiation-induced neuropathy, neuropathic pain associated with herpes zoster, neuropathic pain associated with spinal surgery, obsessive-compulsive disorder (OCD), thromboangiitis obliterans, urinary tract obstruction, eosinophilic fasciitis, osteoporosis, overactive bladder, pain (e.g., acute pain, central pain syndrome, inflammatory pain, postoperative pain, tension pain, visceral pain, claudication pain), rare pain indications (e.g., acetazolamide-responsive myotonia, autologous erythrocyte sensitization syndrome, erythrocyte sensitization), Chromo-dominant Charcot-Marie-Tooth disease type 2V, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2A, ion channel disorder-related congenital insensitivity to pain, chronic pain requiring intrathecal analgesia, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, congenital insensitivity to pain with hyperhidrosis, congenital insensitivity to pain with severe intellectual disability, congenital insensitivity to pain-hypohiridiasis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial paroxysmal pain syndrome, familial paroxysmal pain syndrome with dominant lower limb involvement, mainly upper Familial paroxysmal pain syndrome with hemiplegic involvement, 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-like syndrome, paroxysmal severe pain, persistent idiopathic facial pain, qualitative or quantitative calpain deficiency, Tolosa-Hunt syndrome), pancreatitis, panic disorder, Parkinson's disease, parkinsonism plus, Parkinsonian dysphagia, pathological feeding disorders, pelvic pain, peripheral vascular disease (e.g., peripheral artery disease, peripheral artery disease) Peripheral artery occlusive disease, peripheral vascular embolism, peripheral perfusion disorder), peritonitis, pervasive developmental disorder, Peyronie's disease, Pick's syndrome, polychondritis, polymyositis, postherpetic neuralgia, traumatic occipital head injury, post-traumatic stress disorder (PTSD), premature ejaculation, progressive nuclear palsy, benign prostatic hyperplasia, lung diseases (e.g., multifactorial pulmonary artery disease, bronchoconstriction or pulmonary bronchoconstriction, pulmonary vascular disease, chronic obstructive pulmonary disease (COPD), pulmonary capillary hemangiomatosis, lymphangiomatosis and compressed pulmonary vessels (e.g., due to adenopathy, tumor or fibrous mediastinitis), pulmonary vascular remodeling, hypertonia), pulmonary hypertension (PH, e.g., For example, pulmonary arterial hypertension (PAH), primary PH, secondary PH, idiopathic PH, precapillary PH, idiopathic PH, PH associated with left ventricular disease, PH associated with HIV, PH associated with SCD, PH associated with thromboembolism (chronic thromboembolic PH or CTEPH), PH associated with sarcoidosis, PH associated with chronic obstructive pulmonary disease, PH associated with acute respiratory distress syndrome (ARDS), PH associated with acute lung injury, PH associated with alpha-1 antitrypsin deficiency (AATD), PH associated with emphysema (e.g., smoking-induced emphysema), PH associated with lung disease,PH associated with hypoxemia, PH associated with scleroderma, PH associated with cystic fibrosis (CF), PH associated with left ventricular dysfunction, PH associated with hypoxemia, PH (WHO groups I, II, III, IV and V), PH associated with mitral valve disease, PH associated with pericarditis, PH associated with constrictive pericarditis, PH associated with aortic stenosis, PH associated with dilated cardiomyopathy, PH associated with hypertrophic cardiomyopathy, PH associated with restrictive cardiomyopathy, PH associated with mediastinal fibrosis, PH associated with pulmonary fibrosis, PH associated with anomalous pulmonary venous return, PH associated with pulmonary veno-occlusive disease, PH associated with pulmonary vasculitis, PH associated with collagen disease vascular disease, PH associated with congenital heart disease, PH associated with pulmonary venous hypertension, interstitial lung Disease-related PH, sleep-disordered breathing-related PH, chronic airflow obstruction-related PH, obstructive sleep apnea-related PH, central sleep apnea-related PH, mixed sleep apnea-related PH, alveolar hypoventilation-related PH, chronic exposure to high altitudes-related PH, neonatal lung disease-related PH, alveolar capillary malformation-related PH, sickle cell disease-related PH, other coagulation disorders-related PH, chronic thromboembolism-related PH), radiculopathy, Raynaud's disease, Raynaud's syndrome (primary or secondary), difficulty Intractable epilepsy, Renpenning syndrome, reperfusion injury (e.g., ischemia-reperfusion injury, ischemia-reperfusion associated with organ transplantation), restenosis (e.g., restenosis occurring after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transcatheter arthropathy (PTCA), heart transplantation, or bypass surgery), retinopathy (e.g., diabetic retinopathy, non-diabetic retinopathy, nonproliferative diabetic retinopathy, proliferative vitreoretinopathy, peripheral retinal degeneration, retinal vein occlusion), Rett syndrome, rheumatoid or rheumatic diseases (e.g., arthritis, rheumatoid arthritis), sarcoidosis, monkey Chondrocystis, schistosomiasis, schizoaffective disorder, schizophrenia, schizophrenia with dementia, scleroderma (e.g., focal scleroderma or localized scleroderma, systemic scleroderma), sclerosis (e.g., nephrosclerosis, progressive sclerosis, hepatosclerosis, primary sclerosing cholangitis, gastrointestinal sclerosis, hippocampal sclerosis, focal segmental sclerosis, primary lateral sclerosis, osteosclerosis, otosclerosis, atherosclerosis, tuberous sclerosis, systemic sclerosis), sepsis or septic shock or anaphylactic shock, sickle cell anemia, sickle cell disease, Sjögren's syndrome, sleep-wake disorders,Sneddon syndrome, spasticity (e.g., coronary vasospasm, vasospasm, peripheral artery spasticity), spinal cord injury, spinal muscular atrophy, spinal subluxation, spinocerebellar ataxia, Steel-Richardson-Olszewski disease (progressive supranuclear palsy), stroke, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, syncope, tauopathy, tension, thalamic degeneration, thromboembolic or thromboplastic disorders, transient ischemic attack (TIA), traumatic brain injury, tubulointerstitial disease, ulcers, uterine fibrosis, vagina Atrophy, valve defects (e.g., mitral stenosis, mitral regurgitation, insufficiency or insufficiency, aortic stenosis, aortic regurgitation, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, mixed valvular heart disease), cerebrovascular disease, vascular disorders resulting from cardiac and renal complications, vascular leakage or permeability, vasculitis (e.g., thromboangiitis, thromboangiitis obliterans, Kawasaki disease, arteritis, aortitis), vascular occlusion attacks, Venus transplant failure, wet age-related macular degeneration, and Williams syndrome.

[0121] In specific embodiments 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, hepatic fibrosis, and renal fibrosis.

[0122] The term “disease,” as used herein, means any deviation from or disruption of the normal structure or function of any part, organ, or system of the body, which is characterized by a distinctive set of symptoms and signs, and whose etiology, pathology, and prognosis may be known or unknown. The term “disease” encompasses disorders and conditions (or medical conditions) as well as other related terms such as syndromes, and is defined as a combination of symptoms resulting from a single cause or from causes that usually occur together to constitute a different clinical picture. In some embodiments, the term “disease” refers to sGC, cGMP, and / or NO-mediated medical or pathological diseases.

[0123] With respect to a disorder, disease, condition, symptom, or syndrome, “to treat,” “to treat,” or “treatment” means to suppress or improve the cause and / or effect of the disorder, disease, condition, or syndrome (i.e., improvement of symptoms, physiological, physical, psychological, emotional, or any other clinical manifestation, observation or measurement, or pathological assessment).

[0124] As used herein, the terms “to treat,” “treatment,” or “to treat” also mean delaying, improving, or preventing progression (i.e., known or expected progression of the disease), the severity and / or duration of the disease, or delaying, improving, or preventing the progression of one or more symptoms, clinical manifestations, observations, or measurements, or preventing or slowing the negative progression of a pathological assessment (i.e., “controlling” the condition without “treating” it).

[0125] As used herein, the terms “subject” and “patient” are interchangeable. The terms “subject” and “patient” refer to animals (e.g., birds such as chickens, quail, or turkeys, or mammals), and more specifically, “mammals” include non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice), as well as 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, mouse, rat, hamster, gerbil, guinea pig, or rabbit). In some embodiments, the subject is a human.

[0126] The present invention also provides a method for treating one of the above-mentioned diseases in a subject, comprising the step of administering a therapeutically effective amount of a compound from Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment. Alternatively, the present invention provides the use of a compound from Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof, in the treatment of one of these diseases in a subject in need of treatment. Also included in the present invention is the use of a compound from Tables I to VI or Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating one of the above-mentioned diseases in a subject in need of treatment. The present invention further provides a method for making or manufacturing a medicament useful for treating one of these diseases, comprising the step of using any one of the compounds from Table VI, or a pharmaceutically acceptable salt thereof.

[0127] The term “biological sample” as used herein 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, ocular fluid, vitreous fluid, cerebrospinal fluid (CSF), or other bodily fluids or extracts thereof.

[0128] In other embodiments, the present invention provides a method for stimulating sGC activity in a biological sample, comprising the step of contacting the biological sample with a compound or composition of the present invention. The use of sGC stimulants in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological assays and the storage of biological specimens.

[0129] Combination therapy The compounds and pharmaceutical compositions described herein may be used alone or in combination therapy for the treatment of diseases mediated, modulated, or affected by sGC, cGMP, and / or NO.

[0130] As used herein, the terms “in combination” (as in the sentence “in combination therapy”) or “co-administration” may be used interchangeably to refer to the use of two or more therapies. The use of the terms does not restrict the order in which the therapies are administered to the subject.

[0131] The compounds and pharmaceutical compositions described herein may be used in combination therapy with one or more additional therapeutic agents. For combination therapy with two or more activators, if the activators are in separate dosage formulations, the activators may be administered separately or in combination. In addition, the administration of one element may occur before, simultaneously with, or after the administration of other agents.

[0132] When used in combination therapy with other drugs, the "therapeutic effective dose" of the compounds and pharmaceutical compositions described herein, as well as one or more other drugs, depends on the type of drug used. Suitable doses are known for approved drugs and can be adjusted by those skilled in the art depending on the condition of the subject, the type of condition being treated, and the amount of the compound described herein used. Where no amount is explicitly stated, an effective dose should be assumed.

[0133] In some embodiments, co-administration or combination therapy involves the administration of first and second amounts of the compound in essentially simultaneous manner, for example, in a single pharmaceutical composition, such as capsules or tablets having first and second amounts in a fixed ratio, or in a number of separate capsules or tablets for each. In addition, such co-administration also involves the use of each compound in a sequential manner, in either order.

[0134] If co-administration involves separate administrations of a first dose of a compound from Tables I-VI or Formula I and a second dose of an additional therapeutic agent, the compounds should be administered within a time interval sufficient to produce the desired therapeutic effect. For example, the interval between each administration that can produce the desired therapeutic effect may range from minutes to hours and can be determined while taking into account the characteristics of each compound, such as efficacy, solubility, bioavailability, plasma half-life, and kinetic profile. For example, the compounds from Tables I-VI or Formula I and the second therapeutic agent may be administered in any order within approximately 24 hours, 16 hours, 8 hours, 4 hours, 1 hour, or 30 minutes from each other.

[0135] Other therapeutic agents that can be administered separately or in the same pharmaceutical composition as the compounds of Tables I-VI or Formula I, or pharmaceutically acceptable salts thereof, include, but are not limited to, the following: (1) Endothelial-derived release factor (EDRF) or NO gas.

[0136] (2) NO donors, including but not limited to nitrosothiols, nitrites, cydnonimines, NONOates, N-nitrosamines, N-hydroxylnitrosamines, nitrocymines, nitrotyrosine, diazetine dioxide, oxatriazole 5-imine, oximes, hydroxylamines, N-hydroxyguanidine, hydroxyureas, or floxanes. Some examples of these types of compounds include glyceryl trinitrate (GTN, also known as nitroglycerin, nitroglycerine, and trinitroglycerin), a nitrate ester of glycerol; sodium nitroprusside (SNP) (a molecule of nitric oxide coordinates to metallic iron to form a tetragonal bipyramidal complex); 3-morpholinosidenonimine (SIN-1), a zwitterionic compound formed by a combination of morpholine and sidenonimine; S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acid derivative with a nitrosothiol functional group; diethylenetriamine / NO (DETA / NO), a compound of nitric oxide covalently bonded to diethylenetriamine; and m-nitroxymethylphenyl ester of acetylsalicylic acid. Some more specific examples of NO donors in these classes include classic nitrovasodilators, such as organic nitrates and nitrite esters including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate and nicorandil; isosorbide; 3-morpholinoside nonimine; lincidomine chlorohydrate ("SIN-1"); S-nitroso-N-acetylpenicillamine ("SNAP"); S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione mono-ethyl ester (GSNO ester), 6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexaneamine or diethylamine NONOate.

[0137] (3) Other substances that improve cGMP concentration, including but not limited to protoporphyrin IX, arachidonic acid, and phenylhydrazine derivatives. (4) Analogues based on L-arginine and n-hydroxyguanidine, e.g., N[G]-hydroxy-L-arginine (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine and PR5(1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine); L-arginine derivatives (e.g., homo-Arg, homo-NOHA, N-tert-butyloxy- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, ipsilonganidine-caproic acid, arg Nitric oxide synthase substrates, including, but not limited to, matine, hydroxyl-agmatine, 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 having -F, -Cl, -methyl, and -OH substituents, respectively); and guanidine derivatives, e.g., 3-(trifluoromethyl)propylguanidine.

[0138] (5) Compounds that improve eNOS transcription. (6) NO-independent, heme-independent sGC activators, including, but not limited to, BAY 58-2667 (described in patent publication DE19943635); HMR-1766 (ataciguat, described in patent publication WO2000002851); S 3448 (2-(4-chlorophenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (described in patent publications DE19830430 and WO2000002851); and HMR-1069 (manufactured by Sanofi-Aventis).

[0139] (7) YC-1 (see Patent Publications EP667345 and DE19744026); Rio Ciguato (BAY 63-2521, Adempas®, DE19834044); Nero Ciguato (BAY 60-4552, WO2003095451); Bel I Ciguato (BAY 1021189, US8420656); BAY 41-2272 (DE19834047 and DE19942809); BAY 41-8543 (described in DE19834044); Etriciguat (described in WO2003086407); CFM-1571 (described in patent publication WO2000027394); A-344905, its acrylamide analog A-350619, and aminopyrimidine analog A-778935; Publications US20090209556, US8455638, US20110118282(WO2009032249), US20100292192, U S20110201621, US7947664, US8053455(WO2009094242), US20100216764, US8507512 (WO2010099054)US20110218202(WO2010065275), US20130012511(WO2011119518), US20130072492(WO2011149921), US20130210798(WO2012058132) and other sGC stimulants described in Tetrahedron Letters (2003), 44(48):8661-8663; as well as IW1973 (praliciguat), IW1701 (olinciguat) and CY6463 (formerly IW-6463) Heme-dependent NO-independent sGC stimulants, including but not limited to those listed.

[0140] (8) Compounds that inhibit the degradation of cGMP and / or cAMP, including but not limited to the following: PDE1 inhibitors, PDE2 inhibitors, PDE-3 inhibitors, e.g., amrinone, milrinone, enoximon, vesnarinone, pimobendan and olprinone; PDE4 inhibitors, e.g., roflumilast; PDE5 inhibitors, e.g., sildenafil and related drugs, e.g., avanafil, rodenafil, mirodenafil, sildenafil citrate, tadalafil, vardenafil and udenafil; alprostadil; dipyridamole and PF-00489791; PDE6 inhibitors, PDE9 inhibitors, e.g., PF-04447943; PDE10 inhibitors, e.g., PF-02545920 (PF-10); and PDE11 inhibitors.

[0141] (9) Anticoagulants, including but not limited to the following: Coumarin (vitamin K antagonist), such as warfarin, asenocumarol, fenprocumone and phenindione, Heparin and its derivatives, such as low molecular weight heparin, fondaparinux and hydraparinux, Direct thrombin inhibitors, such as argatroban, repiridine, bivaliridine, dabigatran and ximelagatran, and Tissue plasminogen activators, such as alteplase, are used to dissolve clots and remove blockages in arteries.

[0142] (10) Antiplatelet agents, including but not limited to clopidogrel, ticlopidine, dipyridamole, and aspirin. (11) Supported oxygen therapy.

[0143] (12) Prazosin, indramin, urapidil, bunazosin, terazosin and doxazosin; alpha-1-adrenergic receptor antagonists, including but not limited to atrial natriuretic peptide (ANP), ethanol, histamine inducers, tetrahydrocannabinol (THC) and papaverine.

[0144] (13) Bronchodilators, including but not limited to the following: Short-acting β2 agonists, such as salbutamol or albuterol and terbutaline, Long-acting β2 agonists (LABAs), such as salmeterol and formoterol, Anticholinergic agents, such as ipratropium and tiotropium; as well as theophylline, bronchodilators, and phosphodiesterase inhibitors.

[0145] (14) Corticosteroids, including but not limited to beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide, hydrocortisone, and corticosteroid analogs, such as budesonide.

[0146] (15) Omega-3 oils; folic acid, niacin, zinc, copper, ginseng root, ginkgo, pine bark, Tribulus terrestris, arginine, oat (Avena sativa), horny goat weed, maca root, muira puama, saw palmetto and Swedish flower pollen; vitamin C, vitamin E, vitamin K2; testosterone supplements, testosterone transdermal patches; dietary supplements containing, but not limited to, zoraxel, naltrexone, bremelanotide and melanotan II.

[0147] (16) PGD2 receptor antagonist. (17) Immunosuppressants including, but not limited to, cyclosporine, tacrolimus, rapamycin, and other FK-506 type immunosuppressants, mycophenolates, and mycophenolate mofetil.

[0148] (18) Nonsteroidal anti-asthmatic agents, including but not limited to the following: Beta-2 agonists such as terbutaline, metaproterenol, fenoterol, isoetaline, albuterol, salmeterol, bitolterol, and pirbuterol, β2 agonist-corticosteroid combinations, such as salmeterol-fluticasone, formoterol-budesonide, theophylline, cromoline, cromoline sodium, nedocromil, atropine, ipratropium, ipratropium bromide, and Leukotriene biosynthesis inhibitors, such as diloiton or beriflapon.

[0149] (19) Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to the following: propionic acid derivatives such as aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and thioxaprofen, Acetate derivatives, such as indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclodic acid, fenthiazac, flofenac, ibufenac, isoxepac, oxypinac, sulindac, thiopinac, tolmetin, didomethacin and zomepirac, Fenamic acid derivatives, such as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid, Biphenylcarboxylic acid derivatives, such as diflunisal and fluphenisal, Oxicam, for example isoxicam, piroxicam, sudoxicam and tenoxicam, Salicylates, such as acetylsalicylic acid and sulfasalazine, and Pyrazolons, such as Apazon, bezpiperylon, feprazon, mofebutazone, oxyfenbutazone, and phenylbutazone.

[0150] (20) Celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib and lumiracoxib; opioid analgesics, including but not limited to codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxifene, buprenorphine, butorphanol, dezosin, nalbuffine and pentazocine, and cyclooxygenase-2 (COX-2) inhibitors.

[0151] (21) Adrenergic neuroleptics, including but not limited to guanethidine and guanadrel. (22) Imidazolin I-1 receptor agonists, including but not limited to rilmenidine dihydrogen phosphate and moxonidine hydrochloride hydrate.

[0152] (23) Potassium channel activators, including but not limited to pinacidyl. (24) Phenoldopam mesylate; other dopamine agonists, including but not limited to ivopamine, dopexamine and docarpamine, dopamine D1 agonists.

[0153] (25) A 5-HT2 antagonist, including but not limited to ketanserine. (26) A vasopressin antagonist, including but not limited to tolvaptan. (27) levocimendan, or a calcium channel sensitizer containing, but not limited to, an activating agent such as nicorandil.

[0154] (28) Adenylyl cyclase activators, including but not limited to colforsin dalopate hydrochloride. (29) Digoxin and methyldigoxin; metabolites of cardiotonic agents, e.g., ubicarenone; brain natriuretic peptides, e.g., nesiritide, including but not limited to these, as positive inotropes.

[0155] (30) Drugs used to treat erectile dysfunction, including but not limited to alprostadil, aviptadil, and phentolamine mesylate. (31) Drugs used to treat Alzheimer's disease and dementia, including but not limited to the following: Acetylcholinesterase inhibitors, such as galantamine, rivastigmine, donepezil and tacrine, and NMDA receptor antagonists, such as memantine, and Oxidolysis inhibitors, such as idebenone.

[0156] (32) Psychiatric drugs, including but not limited to the following: Ziprasidone, risperidone, olanzapine, valproate, Dopamine D4 receptor antagonists, such as clozapine, Dopamine D2 receptor antagonists, such as nemonapride, Mixed dopamine D1 / D2 receptor antagonists, such as zuclopentixol, GABA A receptor modulators, such as carbamazepine, Sodium channel inhibitors, such as lamotrigine, Monoamine oxidase inhibitors, such as moclobemide and inderoxazine, and Pimavanserin and perospirone.

[0157] (33) Drugs used to treat motor disorders or symptoms, including but not limited to the following: Catechol-O-methyltransferase inhibitors, such as entacapone, Monoamine oxidase B inhibitors, such as selegiline, Dopamine receptor modulators, such as levodopa, Dopamine D3 receptor agonists, such as pramipexole, Decarboxylase inhibitors, such as carbidopa, Other dopamine receptor agonists, such as pergolide, ropinirole, cabergoline, Ritigonide, istradefylline, talipexol, zonisamide, and Synaptic vesicle amine transporter inhibitors, such as tetrabenazine.

[0158] (34) Medications used to treat mood or affective disorders or OCD, for example, the following types: Tricyclic antidepressants, such as amitriptyline, desipramine, imipramine, amoxapine, nortriptyline, doxepin, and clomipramine. Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, fluoxetine, sertraline, trazodone, and citalopram, Atypical antidepressants, such as agomelatine, Selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, reboxetine, and atomoxetine; dopaminergic antidepressants, such as bupropion and amineptin.

[0159] (35) Drugs used to improve synaptic plasticity, including but not limited to the following: Nicotinic receptor antagonists, such as mecamylamines, and A mixture of 5-HT, dopamine, and norepinephrine receptor agonists, such as lurasidone.

[0160] (36) Drugs used to treat ADHD, e.g., amphetamines; 5-HT receptor modulators, e.g., vortioxetine and alpha-2 adrenergic receptor agonists, e.g., clonidine.

[0161] (37) Nitric oxide synthase cofactors, including but not limited to tetrahydrobiopterin, dihydrobiopterin, and sapropterin. (38) Blood glucose lowering drugs (also called blood glucose control drugs or antidiabetic drugs), including but not limited to the following: Biguanides, for example, metformin, Sulfonylureas, such as glybrid, glibenclamide, glipizide, glyclazide, glikidone, glimepiride, atorvastatin calcium (a combination of glimepiride), meglinatide, tolbutamide, chlorpropamide, acetohexamide, and trazamide. Alpha-glucosidase inhibitors, such as acarbose, epalrestat, voglibose, and miglitol, Insulin secretagogues, such as repaglinide, mitiglinide, and nateglinide, Thiazolidinediones, such as rosiglitazone, troglitazone, siglitazone, pioglitazone, englitazone, robeglitazone sulfate and paraglitazone, DPP-4 inhibitors (or DPP-IV inhibitors), such as sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, alogliptin benzoate in combination with metformin or metformin hydrochloride, anagliptin, teneligliptin, 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-pyrrolidine-1-yl-propylamino)acetyl]-4-fluoropyrrolidine-2-carbonitrile (DBPR-108), GLP-1 receptor agonists or incretin mimetic, such as exenatide, dulaglutide, liraglutide, semaglutide, lixisenatide, lixisenatide in combination with insulin glargine, albiglutide and pegapamozutide (TT-401), LY3298176 (dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist), SGLT2 inhibitors (SGLT2i), such as empagliflozin, empagliflozin combined with linagliptin, empagliflozin combined with metformin, ipragliflozin, ipragliflozin L - proline, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, ertugliflozin combined with sitagliptin, ertugliflozin combined with metformin, sotagliflozin, canagliflozin, canagliflozin combined with metformin or metformin hydrochloride, dapagliflozin, dapagliflozin combined with metformin or metformin hydrochloride and luseogliflozin, dapagliflozin combined with saxagliptin, SGLT1 inhibitors or combinations of SGLT1 and SGLT2 inhibitors, such as sotagliflozin, Insulin therapy, such as one of many types of insulin, such as insulin glulisine, insulin degludec, insulin lispro, insulin aspart, insulin glargine, insulin detemir, isophane insulin, insulin Mixtard (human insulin containing both rapid - acting (soluble) and long - acting (isophane) insulin), insulin degludec combined with insulin aspart, insulin human (rDNA origin) inhalation powder, recombinant human insulin, liver - directed endoplasmic reticulum insulin, insulin Tregopil (IN - 105), insulin degludec combined with liraglutide, insulin peglispro (LY - 2605541) and noduline, and Trimidone (lyn kinase activator).

[0162] (39) Antihypertensive drugs (also known as antihypertensive agents), including but not limited to: Diuretics, such as thiazide diuretics, chlorothiazide, chlorthalidone, hydrochlorothiazide, bendroflumethiazide, cyclopentiazide, meticlothiazide, polythiazide, quinetazone, xypamide, metrazone, indapamide, cicletanin, furosemide, toresamide, amiloride, spironolactone, potassium canrenoate, eplerenone, triamterene, acetazolamide, and carperitide. Beta-blockers, such as acebutolol, atenolol, metoprolol and nebivolol, Angiotensin-converting enzyme (ACE) inhibitors, such as sulfhydryl-containing drugs (e.g., captopril, zofenopril), dicarboxylate-containing drugs (e.g., enalapril, quinapril, ramipril, perindopril, lisinopril, and benazepril), phosphonate-containing drugs (e.g., hosinopril), naturally occurring ACE inhibitors (e.g., casokinin, lactokinin, lactotripeptides Val-Pro-Pro and Ile-Pro-Pro), alacepril, delapril, cilazapril, imidapril, temocapril, moexipril, lisinopril, lisinopril in combination with hydrochlorothiazide, trandolapril, and spirapril. Angiotensin II receptor blockers (ARBs), such as candesartan, losartan, losartan potassium-hydrochlorothiazide, valsartan, candesartan cilexetil, eprosartan, irbesartan, telmisartan, olmesartan medoxomil (or olmesartan), azilsartan medoxomil, azilsartan, amlodipine besylate in combination with irbesartan, azilsartan in combination with amlodipine besylate, cilnidipine in combination with valsartan, fimasartan, irbesartan in combination with atorvastatin, irbesartan in combination with trichlormethiazide, losartan potassium in combination with hydrochlorothiazide and / or amlodipine besylate, pratosartan, losartan potassium, atorvastatin calcium in combination with nifedipine and candesartan cilexetil, sacubitril in combination with valsartan or LCZ-696, angiotensin AT2 antagonist and TAK-591 and olmesartan medoxomil, Endothelin receptor antagonists (ERAs), such as atrasentan, bosentan, sitaxentan, ambrisentan, Actelion-1 (macitentan), cyclo(D-trp-D-asp-L-pro-D-val-L-leu) (BQ-123), sparsentan and tezosentan disodium, Mineralocorticoid receptor antagonists (MRAs), such as spironolactone, amiloride hydrochloride in combination with spironolactone, apararenone or MT-3995, eplerenone, and finerenone (BAY-94-8862), Calcium channel blockers, such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, diltiazem, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, isradipine, verapamil, gallopamil, diltiazem, mibefradil, bepridil, fluspirilene and fendiline, Renin inhibitors, such as aliskiren, Alpha-blockers, such as doxazosin and prazosin, Alpha-beta blockers, such as carvedilol and labetalol, Central agonists, such as clonidine, guanfacine, and methyldopa, Vasodilators, such as nitroglycerin, hydralazine and minoxidil, and Aldosterone antagonists, such as finerenone, spironolactone, and eplerenone.

[0163] (40) and below, including but not limited to, antihyperlipidemic drugs: Statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, Combinations of statins with other drugs, such as amlodipine / atorvastatin, aspirin / pravastatin, ezetimibe / simvastatin, niacin / simvastatin, lovastatin / niacin, simvastatin / sitagliptin, and atorvastatin / ezetimibe. Fibrate or fibric acid derivatives. Examples include, but are not limited to, fenofibrate, gemfibrozil, bezafibrate, cyprofibrate, clinofibrate, and clofibrate.

[0164] Niacin (or nicotinic acid), Bile acid sequestrants, such as cholestyramine, coleseveram, cholestyrane and colestipol, Ezetimibe, lomitapide, phytosterol or orlistat, and PCSK9 inhibitors, such as alirocumab and evolocumab, (41) Sacubitril, or sacubitril in combination with valsartan; neprilysin inhibitors (also known as endopeptidase inhibitors, NEP inhibitors, or enkephalinase inhibitors), including but not limited to the neprilysin inhibitor TD-1439 or TD-0714, which are currently under investigation.

[0165] (42) Renal protective agents, including but not limited to the following: Bardoxolone, ACE inhibitors, such as captopril, ARBs, for example, losartan or irbesartan, SGLT2 inhibitors, for example, canagliflozin, GLP1 receptor agonist, MRA, for example, finerenone, ERAs, such as atrasentan, and apoptosis signal-regulated kinase 1 (ASK1) inhibitors, such as ceroncertib.

[0166] (43) Hydroxyurea (HU, hydroxycarbamide). (44) Antisickle cell agents comprising, but not limited to, hydroxyurea, boxerotol, or GBT-440.

[0167] (45) Anti-adhesiotherapy, including, but not limited to, inhibitory antibodies against P-selectin, E-selectin, VLA-4, and VCAM-1. (46) Glutamine.

[0168] (47) Erythropoietin (EPO) (also known as hematopoietin or hemopoietin), including all forms thereof, e.g., exogenous erythropoietin, recombinant human erythropoietin (rhEPO) or other erythropoiesis-stimulating agents (ESAs). Two examples are epoetin alpha and epoetin beta.

[0169] (48) Antibiotics, including but not limited to the following: In particular, penicillin and its derivatives, including but not limited to penicillin, amoxicillin, ampicillin, azurocillin, cloxacillin, penicillin G, penicillin V, procainepenicillin, or benzathinepenicillin.

[0170] Cephalosporins, such as cephalexin, cefadroxil, cefaclor, cefuroxime, and cefixime, Macrolides, such as erythromycin, clarithromycin, azithromycin, and roxithromycin, Tetracycline and its derivatives, such as demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline, Sulfonamides, including but not limited to, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfasalazine, trimethoprim-sulfamethoxazole (cotrimoxazole), and sulfisoxazole, and Quinolones, including but not limited to, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, and nalidixic acid.

[0171] (49) FXR agonists, including but not limited to, obeticholic acid, selinivac, emricasan, GR-MD-02, cenicriviroc, and elafibranor. (50) Thyroid receptor-beta agonists, including but not limited to, MGL-3196.

[0172] (51) Acetyl-CoA carboxylase inhibitors, including but not limited to, GS-0976. (52) Vitamins and supplements containing coenzyme Q10; B complex vitamins, especially thiamine (B1) and riboflavin (B2); alpha-lipoic acid; L-carnitine (Carnitor); creatine; citrulline, and L-arginine, for the treatment of mitochondrial disorders.

[0173] (53) Treatments for epilepsy or convulsive seizures, including but not limited to, phenytoin, valproic acid, phenobarbital, lamotrigine, carbamazepine, topiramate, oxcarbazepine, zonisamide, gabapentin, levetiracetam, pregabalin, clonazepam, lacosamide, rufinamide, and vigabatrin.

[0174] Packaging and kits Pharmaceutical compositions (or preparations) for use may be packaged in various ways depending on the method used to administer the drug. Generally, articles for distribution include a container in which the pharmaceutical preparation is contained in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (made of plastic and glass), sachets, ampoules, plastic bags, and metal cylinders. Containers may also include tamper-proof assemblies to prevent unintentional access to the contents of the packaging. In addition, containers have labels thereon indicating the contents of the container. Labels also include appropriate warnings.

[0175] The compounds and pharmaceutical formulations described herein may be contained in a kit. A kit may contain two or more single-dose or multi-dose drugs, each individually packaged or formulated, or two or more single-dose or multi-dose drugs packaged or formulated in combination. Thus, one or more drugs may be present in a first container, and the kit may optionally contain one or more drugs in a second container. One or more containers may be placed in packaging, which may optionally include administration or administration instructions. A kit may include additional components, such as syringes or other means for administering drugs, as well as diluents or other means for formulation. Thus, a kit may include a) a pharmaceutical composition comprising the compounds described herein and pharmaceutically acceptable carriers, vehicles or diluents; and b) containers or packaging. A kit may optionally include instructions describing how to use the pharmaceutical composition in one or more of the methods described herein (e.g., to prevent or treat one or more of the diseases and disorders described herein). The kit may optionally include a second pharmaceutical composition comprising one or more additional agents, pharmaceutically acceptable carriers, vehicles, or diluents described herein for combination therapy. The pharmaceutical composition comprising the compounds described herein and the second pharmaceutical composition contained in the kit may optionally be combined with the same pharmaceutical formulation. [Examples]

[0176] All references provided in the examples are incorporated herein by reference. Where used herein, all abbreviations, symbols, and conventions are consistent with those used in modern scientific literature. For example, refer to Janet S. Dodd, ed., *The ACS Style Guide: A Manual for Authors and Editors*, 2nd edition, Washington, DC: American Chemical Society, 1997, which is incorporated herein by reference in its entirety.

[0177] Various embodiments of the present invention may be described below. The definitions of abbreviations used in the Examples section are provided in the table below.

[0178] [Table 8]

[0179] Synthesis section Example 1 Compound synthesis in Table I The present invention also provides a method for synthesizing the compounds in Table I, which represents another embodiment of the present invention. The compounds of the present invention may be prepared by general and specific synthesis described herein, synthetic procedures reported in the chemical literature, or by methods known to those skilled in the art. As can be understood by those skilled in the art, optimal reaction conditions may be determined during experimentation but may vary depending on the type of reaction and the specific reagents used in the reaction. Thus, unless specifically stated, reaction conditions, such as pressure, temperature, relative ratio of reagents, solvent and reaction time, may be readily selected and modified by those skilled in the art without excessive experimentation. The compounds and intermediates of the present invention may be purified 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). Purification by RP-HPLC may be achieved using a suitable reversed-phase column (e.g., Waters XBridge OBD C18, 5 μm, 19 × 150 mm) with a suitable gradient selected from 0% to 100% acetonitrile in water containing an additive such as 0.1% TFA or FA. Diastereomers can be separated by silica gel chromatography, RP-HPLC, or chiral HPLC. Discrete enantiomers can be obtained from a mixture of enantiomers by decomposition using chiral HPLC. The progress of the reaction 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-MS.

[0180] The starting materials used in the synthesis described herein are available from commercial suppliers, or can be prepared by those skilled in the art using methods reported in the chemical literature or referenced herein.

[0181] The general methods described herein may be used to prepare the compounds in Table I. The general and specific methods described herein are provided as an explanation of the feasibility of the present invention. Therefore, they are not intended to impose any limitations on the subject matter and scope of the claimed compounds of the present invention.

[0182] All references provided in the examples are incorporated herein by reference. Where used herein, all abbreviations, symbols, and conventions are consistent with those used in modern scientific literature. For example, refer to GMBanik, G. Baysinger, PV Kamat, and NJPienta (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.

[0183] The compounds disclosed herein can be prepared, for example, from the corresponding nitrile intermediate using the general procedure (general procedure C) described below. General Procedure C

[0184] [ka]

[0185] The compounds of the present invention can be prepared by following procedures similar to those described herein, via the corresponding nitrile. Nitriles with different patterns of substitution can be prepared by following the procedures described in WO2015187470, WO2016081668, WO2017197555, WO2017200825, WO2018 / 045276A1 and WO2019 / 126354A1.

[0186] The following nitrile intermediates were prepared according to the procedures described in WO2018 / 045276A1 and WO2019 / 126354A1. Reaction conditions (e.g., reagent ratios, temperature, and reaction time) and purification methods were modified as needed.

[0187] 8-benzylimidazo[1,2-a]pyrazine-6-carbonitrile, 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile, 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile, 8-(2,3-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile, 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile, 8-(3-fluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbonitride, 8-(3,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile, 8-(3,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbonitride, 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbonitride, 8-(2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile, 8-(3-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile, 8-(3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile, 8-(2,3-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile, 8-(2,5-difluoro-4-methylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile General procedure A, as illustrated for application to the synthesis of compound I-1. The title compound was synthesized in two steps.

[0188] Step 1: Synthesis of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxyimidoamide

[0189] [ka]

[0190] A solution of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (220 mg, 0.87 mmol, 1.0 equivalent) in methanol (5.0 mL) was added to a solution of 0.50 N sodium methanelate in methanol (0.17 mL, 0.087 mmol, 0.10 equivalent) (Note: Stoichiometric or excess amounts of sodium methanelate can also be used). After stirring at ambient temperature for 6 hours, ammonium chloride (280 mg, 5.2 mmol, 6.0 equivalents) was added, and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under vacuum, diluted with semi-saturated NaHCO3 solution (20 mL), and extracted with 2 × 20 mL CH2Cl2 / iPrOH (5:1). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated to obtain the crude product carboxyimidoamide as a yellowish-brown foamy solid. It was used in the next step without further purification. LC / MS ES + m / z = 270.2 [M + H] + .

[0191] Step 2: Synthesis of 5-fluoro-2-(8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol

[0192] [ka]

[0193] To a suspension of 8-(3-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboximidoamide (210 mg, 0.79 mmol, 1.0 equivalent) in ethanol (7.0 mL), sodium(Z)-3-ethoxy-2-fluoro-3-oxopropa-1-ene-1-oleate (490 mg, 3.1 mmol, 4.0 equivalents) was added. The reaction mixture was heated in a sealed vial at 90°C for 2.5 hours. After cooling to ambient temperature, a 1.0 N aqueous HCl solution (3.1 mL, 3.1 mmol, 4.0 equivalents) 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 of CH2Cl2 / iPrOH (5:1). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated. The crude material was purified via silica gel chromatography (0-15% acetonitrile / methanol (7:1) in CH2Cl2) to deliver the title compound (180 mg, 64% yield over two steps) as a pale yellowish-brown solid. 1 ¹H NMR (500 MHz, DMSO-d6) δ (ppm): 13.1–12.5 (one pair of s, 1H, tautomers), 9.46 (s, 1H), 8.30 (s, 1H), 8.26–8.00 (one pair of s, 1H, tautomers), 7.90 (s, 1H), 7.50 (m, 1H), 7.41 (m, 1H), 7.32 (m, 1H), 7.02 (apparent t, 1H), 4.53 (s, 2H). Compound I-2

[0194] [ka]

[0195] 2-(8-benzylimidazo[1,2-a]pyrazine-6-yl)-5-fluoropyrimidine-4-ol (compound 2) was synthesized as a white solid (25 mg, 14% total yield) according to general procedure A. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. 11H NMR (500 MHz, methanol-d4) δ (ppm) 9.30 (s, 1 H), 8.09 (s, 1 H), 7.99 (d, 1 H), 7.80 (s, 1 H), 7.40 (d, 2 H), 7.17 (t, 2 H), 7.07 - 7.11 (m, 1 H), 4.52 (s, 2 H). Compound I-4

[0196]

Chem.

[0197] 2-(8-(2,3-Difluorobenzyl)imidazo[1,2-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (Compound 4) was synthesized as a pale yellowish brown solid (150 mg, 67% overall yield) by a general procedure A. The reaction conditions (e.g., reagent ratio, temperature and reaction time) and purification methods were changed as necessary. 1 1H NMR (500 MHz, acetone-d6) δ (ppm) 10.6 (s, 1 H), 9.34 (s, 1 H), 8.16 (s, 1 H), 7.92 (s, 1 H), 7.78 (s, 1 H), 7.20 (t, 1 H), 7.09 (q, 1 H), 7.00 (q, 1 H), 4.60 (s, 2 H). Compound I-6

[0198]

Chem.

[0199] 5-Fluoro-2-(8-(3-fluoro-4-methylbenzyl)imidazo[1,2-a]pyrazin-6-yl)pyrimidin-4-ol (Compound I-6) was synthesized as a pale yellow solid (200 mg, 54% overall yield) by a general procedure A. The reaction conditions (e.g., reagent ratio, temperature and reaction time) and purification methods were changed as necessary. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 12.9 (br. s, 1 H), 9.44 (s, 1 H), 8.29 (s, 1 H), 8.16 (br. s, 1 H), 7.89 (s, 1 H), 7.39 (d, 1 H), 7.27 (d, 1 H), 7.17 (t, 1 H), 4.48 (s, 2 H), 2.14 (s, 3 H). Compound I-7

[0200] [ka]

[0201] 2-(8-(3,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)-5-fluoropyrimidine-4-ol (compound I-7) was synthesized as a yellow solid (190 mg, 57% total yield) by general procedure A. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 13.0 (br. s, 1 H), 9.47 (s, 1 H), 8.31 (s, 1 H), 8.22 (br. s, 1 H), 7.91 (s, 1 H), 7.36 (br. s, 2 H), 7.07 (t, 1 H), 4.53 (s, 2 H). Compound I-3

[0202] [ka]

[0203] 5-Fluoro-2-(8-(3,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol (compound 3) was synthesized as a white solid (67 mg, 34% total yield) by general procedure A. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. 1¹H NMR (500 MHz, chloroform-d) δ (ppm): 11.1 (br. s, 1 H), 9.14 (s, 1 H), 8.00-7.91 (m, 2 H), 7.87 (s, 1 H), 7.00 (d, 2 H), 4.56 (s, 2 H), 2.14 (s, 3 H). Compound I-14 The title compound was synthesized in two steps.

[0204] Step 1: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxyimamide

[0205] [ka]

[0206] A suspension of 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (2.5 g, 8.9 mmol, 1.0 equivalent) in methanol (44 mL) was to be supplemented with a solution of 0.50 N sodium methanolate in methanol (18 mL, 8.9 mmol, 1.0 equivalent). After stirring at ambient temperature for 4 hours, the additional portion of 0.50 N sodium methanolate in methanol (5.3 mL, 2.7 mmol, 0.3 equivalent) was added, and stirring continued for a further 2 hours. Next, ammonium chloride (470 mg, 8.9 mmol, 1.0 equivalent) was added. After 16 hours, the reaction mixture was concentrated under vacuum, suspended in saturated NaHCO3 aqueous solution, and stirred for 20 minutes. The solid was collected by filtration and washed with 3 volumes of water and 2 volumes of ether. The crude product was resuspended in 100 mL of heated acetonitrile, diluted with ether, and filtered. The filtered cake was washed with 3 volumes of ether and dried to obtain a yellowish-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] + .

[0207] Step 2: Synthesis of 5-fluoro-2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol

[0208] [ka]

[0209] 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboximidoamide (1.9 g, 6.2 mmol, 1.0 equivalent) was added to ethanol (31 mL) with sodium(Z)-3-ethoxy-2-fluoro-3-oxopropa-1-ene-1-oleate (2.9 g, 19 mmol, 3.0 equivalent). The solution was heated in a sealed container at 90°C for 18 hours. After cooling to ambient temperature, 2.5 N HCl ethanol solution (7.4 mL, 19 mmol, 3.0 equivalent) was added. The resulting mixture was concentrated under vacuum and suspended in acetonitrile (100 mL) while heating. After slight cooling, ether (100 mL) was added and the mixture was stirred for 10 minutes. The solid was collected by filtration and washed with 3 volumes of ether. The resulting solid was resuspended in water, stirred for 1 hour, and filtered. The crude material was purified via preparative reverse-phase HPLC (10-70% acetonitrile / water with 0.1% trifluoroacetic acid as an additive). The impurity fraction was re-purified via preparative reverse-phase HPLC (10-50% acetonitrile / water with 0.1% trifluoroacetic acid as an additive) to deliver the title compound (840 mg, 37% yield) as an off-white solid. 1 ¹H NMR (500 MHz, methanol-d4) δ (ppm): 9.43 (s, 1 H), 8.21 (s, 1 H), 8.08 (br. s, 1 H), 7.89 (s, 1 H), 7.09 (m, 1 H), 7.00 (m, 1 H), 4.63 (s, 2 H), 2.23 (s, 3 H). Na+ salt of compound 14

[0210] [ka]

[0211] To a 450 mL off-white suspension of 5-fluoro-2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol (compound I-14, 10 g, 27 mmol) in anhydrous MeOH, a solution of 0.50 N sodium methanolate in methanol (54 mL, 27 mmol) was added under a nitrogen atmosphere. After brief sonication, the resulting pale yellow solution was stirred at ambient temperature for 15 minutes and concentrated to dryness under vacuum. The solid was resuspended in 250 mL of ether with the help of sonication and concentrated (twice). The resulting solid was resuspended in 650 mL of ether and stirred at ambient temperature for 3 hours. The solid was collected by vacuum filtration and washed with ether (3 × 100 mL). After drying overnight on a filter, 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]pyrazine-6-yl)pyrimidine-4-oleate (11 g, 99% yield) as a white solid. 1 H NMR (500 MHz, D2O) δ (ppm) 8.92 (s, 1 H), 7.99 (d, 1 H), 7.97 (d, 1 H), 7.70 (d, 1 H), 6.98 (dd, 1 H), 6.86 (dd, 1 H), 4.48 (s, 2 H), 2.14 (s, 3 H). Compound I-11

[0212] [ka]

[0213] 5-Fluoro-2-(8-(3-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-yl)pyrimidine-4-ol (compound I-11) was synthesized as a yellow-gold solid (61 mg, 23% total yield) according to general procedure A. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed.1 1H NMR (500 MHz, DMSO-d6) δ (ppm) 13.3 (broad s, 1 H), 9.60 (s, 1 H), 8.86 (s, 1 H), 8.24 - 8.27 (m, 1 H), 7.32 - 7.47 (m, 3 H), 7.03 - 7.06 (m, 1 H), 4.59 (s, 2 H). Compound I-13

[0214]

Chem.

[0215] 2-(8-(3,5-Difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (Compound I-13) was synthesized as a brown solid (57 mg, 17% overall yield) by the general procedure A. The reaction conditions (e.g., reagent ratios, temperature, and reaction time) and purification methods were changed as necessary. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm) 13.2 (broad s, 1 H), 9.61 (s, 1 H), 8.87 (s, 1 H), 8.25 (s, 1 H), 7.33 (d, 2 H), 7.10 (t, 1 H), 4.60 (s, 2 H). Compound I-10

[0216]

Chem.

[0217] 2-(8-(2,3-Difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-fluoropyrimidin-4-ol (Compound I-10) was synthesized as a pale yellow solid (85 mg, 16% overall yield) by the general procedure A. The reaction conditions (e.g., reagent ratios, temperature, and reaction time) and purification methods were changed as necessary. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 13.0 (br. s, 1 H), 9.62 (s, 1 H), 8.85 (s, 1 H), 8.23 ​​(s, 1 H), 7.29 - 7.37 (m, 2 H), 7.09 - 7.16 (m, 1 H), 4.68 (s, 2 H). Compound I-12

[0218] [ka]

[0219] 2-(8-(2,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-yl)-5-fluoropyrimidine-4-ol (compound I-12) was synthesized as an off-white solid (75 mg, 57% yield) according to general procedure A. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. 1 ¹H NMR (500 MHz, methanol-d4) δ (ppm): 9.67 (s, 1 H), 8.69 (s, 1 H), 8.12 (d, 1 H), 7.25 (m, 1 H), 7.13 (m, 1 H), 7.02 (m, 1 H), 4.73 (s, 2 H). Compound I-19

[0220] [ka]

[0221] 5-Fluoro-2-(8-(2,5-difluoro-4-methylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-yl)pyrimidine-4-ol (compound I-19) was synthesized as a yellowish-brown solid (140 mg, 66% total yield) by general procedure A. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 13.1 (br. s, 1 H), 9.61 (s, 1 H), 8.83 (s, 1 H), 8.26 (br. s, 1 H), 7.35 (br. s, 1 H), 7.17 (m, 1 H), 4.57 (s, 2 H), 2.18 (s, 3 H). General procedure B, as exemplified for application to the synthesis of compound I-16. The title compound was synthesized in two steps.

[0222] Step 1: Synthesis of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxyimamide

[0223] [ka]

[0224] A suspension of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (490 mg, 1.8 mmol, 1.0 equivalent) in methanol (5.0 mL) was added to a solution of 0.50 N sodium methanelate in methanol (3.6 mL, 1.8 mmol, 1.0 equivalent) (Note: A catalytic or excess amount of sodium methanelate may also be used). After stirring at ambient temperature for 3 hours and 45 minutes, ammonium chloride (970 mg, 18 mmol, 10 equivalents) was added, and the reaction was stirred for 20 hours. The resulting mixture was concentrated under vacuum to a volume of approximately 2 mL and diluted with siRNA (20 mL) and 10% aqueous NaHCO3 (10 mL). After stirring for 15 minutes, the product was collected by filtration, washed with water (10 mL), and vacuum-dried to obtain the title compound (420 mg, 80% yield) as an off-white solid. LC / MS ES + m / z = 287.9 ​​[M + H] + .

[0225] Step 2: Synthesis of 5-chloro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol

[0226] [ka]

[0227] A suspension of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboximidoamide (100 mg, 0.35 mmol) and ethyl 2-chloro-3-oxopropanoate (110 mg, 0.70 mmol) in methanol (1.7 mL) was added to a solution of 0.50 N sodium methanolate in methanol (1.4 mL, 0.70 mmol). The reaction mixture was heated in a sealed vial at 65 °C for 2.5 hours. 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 aqueous HCl solution, and extracted with 2 × 15 mL CH₂Cl₂ / iPrOH (8:1). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated. The crude material was purified via silica gel chromatography (0-20% acetonitrile / methanol (7:1) in CH2Cl2) and re-purified via silica gel chromatography (20-100% siRNA / CH2Cl2) to deliver the title compound (37 mg, 28% yield) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 12.6 (br. s, 1 H), 9.54 (s, 1 H), 8.36 (br. s, 1 H), 8.32 (s, 1 H), 7.89 (s, 1 H), 7.45 (br. s, 1 H), 7.25 (m, 1 H), 7.12 (m, 1 H), 4.58 (s, 2 H). Compound I-17

[0228] [ka]

[0229] 5-Chloro-2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol (compound I-17) was synthesized as a yellowish-brown solid (5.2 mg, 2.2% total yield) by general procedure B. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 9.47 (s, 1 H), 8.45 (s, 1 H), 8.22 (d, 1 H), 7.94 (s, 1 H), 7.23 (dd, 1 H), 7.16 (dd, 1 H), 6.72 (d, 1 H), 4.56 (s, 2 H), 2.17 (br s, 3 H).LC / MS ES + m / z = 388.0 [M + H] + .

[0230] Compound I-15 The title compound was synthesized in two steps. Step 1: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxyimamide

[0231] [ka]

[0232] 8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-carboxyimidoamide was synthesized as a yellowish-brown solid (840 mg, 76% yield) by step 1 of general procedure A or B. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. LC / MS ES + m / z = 302.0 [M + H] + .

[0233] Step 2: Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol

[0234] [ka]

[0235] Hug 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-carboximidoamide (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 hours. After cooling to ambient temperature, the resulting mixture was treated with a 2.5 N HCl ethanol solution (1.4 mL, 3.6 mmol) and concentrated to dryness. The crude material was purified by silica gel chromatography (0-20% acetonitrile / methanol (7:1) in CH2Cl2) and re-purified by silica gel chromatography (0-15% MeOH / CH2Cl2) to deliver the title compound (120 mg, 28% yield) as a yellowish-brown solid. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 11.9 (br. s, 1 H), 9.52 (s, 1 H), 8.31 (s, 1 H), 8.07 (br. d, 1 H), 7.89 (s, 1 H), 7.37 (dd, 1 H), 7.16 (dd, 1 H), 6.38 (br. d, 1 H), 4.54 (s, 2 H), 2.18 (s, 3 H). Compound I-8 The title compound was synthesized in two steps.

[0236] Step 1: Synthesis of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxyimamide

[0237] [ka]

[0238] 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxyimidoamide was synthesized as a cream-colored solid (5.1 g, 91% yield) by step 1 of general procedure A or B. Reaction conditions (e.g., reagent ratio, temperature, and reaction time) and purification methods were modified as needed. LC / MS ES + m / z = 270.2 [M + H] + .

[0239] Step 2: Synthesis of 2-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)-5-methylpyrimidine-4-ol

[0240] [ka]

[0241] Potassium bicarbonate (220 mg, 2.2 mmol) was added to a solution of 8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-carboximidoamide (400 mg, 1.5 mmol) and ethyl 2-methyl-3-oxopropanoate (230 mg, 1.8 mmol) in t-BuOH (9.9 mL). The reaction mixture was heated under reflux for 2 hours. After cooling to ambient temperature, water was added, and the product was collected by filtration and dried to deliver the title compound as a cream-colored solid (410 mg, 82% yield). 1 ¹H NMR (500 MHz, DMSO-d6) δ (ppm): 11.6 (br. s, 1 H), 9.48 (s, 1 H), 8.30 (s, 1 H), 7.94 (br. s, 1 H), 7.88 (s, 1 H), 7.48 (apparent t, 1 H), 7.29 (m, 1 H), 7.19 (m, 1 H), 7.11 (apparent t, 1 H), 4.60 (s, 2 H), 1.98 (s, 3 H). Compound I-9

[0242] [ka]

[0243] 5-fluoro-2-(8-(2-fluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol (230 mg, 0.67 mmol) in 9.0 mL of acetonitrile-THF (2:1) was treated with sodium bicarbonate (84 mg, 1.0 mmol) and Selectfluor® (350 mg, 1.0 mmol), and heated at 50°C. Additional portions of sodium bicarbonate (42 + 28 mg) and Selectfluor® (180 + 120 mg) were added over the duration of the experiment. After a total of 49 hours, the reaction mixture was cooled to ambient temperature and 20 mL of water was added. The resulting mixture was acidified to pH 3 with 1.0 N aqueous HCl and extracted with 2 × 25 mL of siRNA. The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated. The crude material was purified via silica gel chromatography (0-20% acetonitrile / methanol in CH2Cl2 (7:1)) and re-purified via preparative reverse-phase HPLC (15-65% acetonitrile / water with 0.1% formic acid as an additive) to deliver the title compound (23 mg, 9.7% yield) as a yellowish-brown solid. 1 ¹H NMR (500 MHz, DMSO-d6) δ (ppm): 12.6 (br. s, 1 H), 8.98 (s, 1 H), 8.19 (br. s, 1 H), 7.74 (d, 1 H), 7.48 (apparent t, 1 H), 7.28 (m, 1 H), 7.19 (m, 1 H), 7.10 (apparent t, 1 H), 4.56 (s, 2 H). Compound I-5

[0244] [ka]

[0245] 5-fluoro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol (200 mg, 0.56 mmol) in 10 mL of acetonitrile-THF (1:1) was treated with sodium bicarbonate (94 mg, 1.1 mmol) and Selectfluor® (400 mg, 1.1 mmol), and heated at 50°C. Additional portions of sodium bicarbonate (3 × 47 mg) and Selectfluor® (3 × 200 mg) were added over the duration of the experiment. After a total of 74 hours, the reaction mixture was cooled to ambient temperature and 40 mL of water was added. The resulting mixture was acidified to pH 3 with 1.0 N aqueous HCl and extracted with 2 × 40 mL of CH₂Cl₂ / iPrOH (6:1). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated. Crude materials were purified by silica gel chromatography (0-20% acetonitrile / methanol in CH2Cl2 (7:1)), preparative reverse-phase HPLC (10-70% acetonitrile / water with 0.1% TFA as an additive), and final column chromatography (20-100% butyl / hexane) to deliver the title compound (24 mg, 11% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 12.8 (br. s, 1 H), 8.99 (s, 1 H), 8.20 (br. s, 1 H), 7.75 (d, 1 H), 7.42 (m, 1 H), 7.25 (m, 1 H), 7.13 (m, 1 H), 4.54 (s, 2 H). Compound I-18 The title compound was synthesized in 5 steps.

[0246] Step 1: Synthesis of 6,8-dibromo-3-fluoroimidazo[1,2-a]pyrazine

[0247] [ka]

[0248] 6,8-dibromoimidazo[1,2-a]pyrazine (2.4 g, 8.7 mmol) in 40 mL of acetonitrile was treated with Selectfluor™ (4.6 g, 13 mmol) and heated at 50°C. After 22 hours, the reaction mixture was cooled to ambient temperature and poured into 150 mL of semi-saturated NaHCO3 solution, and extracted with 2 × siRNA (total 400 mL). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-20% siRNA / hexane) to deliver the title compound (580 mg, 23% yield) as an orange solid.

[0249] Step 2: Synthesis of 6-bromo-8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine

[0250] [ka]

[0251] 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 the resulting mixture was heated at 50°C. Chlorotrimethylsilane (30 mL, catalyst) was then added. After 15 minutes, the mixture was cooled to ambient temperature. Dried lithium chloride (170 mg, 3.9 mmol) was added, followed by the dropwise addition of a solution of 1-(bromomethyl)-2,5-difluoro-3-methylbenzene (480 mg, 2.2 mmol) in THF (2.0 mL) (Note: exothermic reaction). The mixture was stirred at ambient temperature for 1 hour. Meanwhile, the slurry of 6,8-dibromo-3-fluoroimidazo[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 the slurry via syringe and rinsed with 2 × 0.5 mL of THF to ensure complete transfer. The resulting mixture was stirred at ambient temperature for 1 hour and 20 minutes, then at 40°C for 4 hours. After cooling to ambient temperature, the reaction was quenched with 4 mL of saturated NH4Cl solution. The organic layer was concentrated, diluted with CH2Cl2 (10 mL), and filtered through a Celite bed. The filtrate was concentrated and purified by silica gel chromatography (compounds eluted with 0-10% siRNA / hexane after loading with CH2Cl2) to obtain a brown residue, from which the title compound (440 mg, 63% yield) was delivered as a yellow solid.

[0252] Step 3: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitride

[0253] [ka]

[0254] A 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 heated at 90°C for 6 hours. The reaction mixture was cooled to ambient temperature and treated with CH2Cl2 (50 mL), water (40 mL), and a 28% ammonium hydroxide solution (4.0 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dehydrated with Na2SO4, filtered, concentrated, and purified by column chromatography (0-20% siRNA / hexane gradient) to obtain a brown oily substance, yielding the title compound as a pale yellowish-brown solid (310 mg, 81% yield). LC / MS ES + m / z = 302.8 [M + H] + .

[0255] Step 4: Synthesis of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine-6-carboxyimamide

[0256] [ka]

[0257] A suspension of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine-6-carbonitrile (150 mg, 0.50 mmol) in methanol (6.0 mL) was added to a solution of 0.50 N sodium methanolate in methanol (1.0 mL, 0.50 mmol). After stirring at ambient temperature for 4 hours and 30 minutes, ammonium chloride (270 mg, 5.0 mmol) was added, and the reaction mixture was stirred for 18 hours. The resulting mixture was concentrated under vacuum, treated with 10% aqueous NaHCO3 (10 mL), and sonicated to obtain a suspension. After stirring for 1 hour, the product was collected by filtration, washed with water (10 mL), and vacuum-dried to obtain the title compound (170 mg, yield over 100%) as a pale yellowish-brown solid. It was used in the next step without further purification. LC / MS ES + m / z = 319.7 [M + H] + .

[0258] Step 5: Synthesis of 2-(8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine-6-fluoropyrimidine-4-ol

[0259] [ka]

[0260] To a suspension of 8-(2,5-difluoro-4-methylbenzyl)-3-fluoroimidazo[1,2-a]pyrazine-6-carboximidoamide (0.50 mmol, theoretical amount from the previous step) in ethanol (5.0 mL), sodium (Z)-3-ethoxy-2-fluoro-3-oxopropa-1-ene-1-oleate (310 mg, 2.0 mmol) was added. The reaction mixture was heated in a sealed vial at 90°C for 16 hours. After cooling to ambient temperature, the mixture was diluted with water (7.5 mL) and adjusted to pH 4 with 1 N aqueous HCl. The resulting yellowish-brown solid was collected by filtration, washed with water (50 mL) and ethyl ether (30 mL), and dried to obtain the title compound (140 mg, 71% yield over two steps) as a brown solid. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 12.8 (br. s, 1 H), 8.98 (s, 1 H), 8.22 (br. s, 1 H), 7.74 (d, 1 H), 7.35 (br. s, 1 H), 7.15 (m, 1 H), 4.50 (s, 2 H), 2.18 (s, 3 H). Compound I-20 The title compound was synthesized in two steps.

[0261] Step 1: Synthesis of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboxyimamide

[0262] [ka]

[0263] A solution of 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carbonitrile (500 mg, 1.9 mmol) in methanol (22 mL) was added to a solution of 25 wt% sodium methanolate in methanol (2.1 mL, 9.3 mmol). After stirring at ambient temperature for 1 hour, 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 semi-saturated NaHCO3 solution (20 mL) and 1.0 N sodium hydroxide solution (2.0 mL), and extracted with 2 × 20 mL of siRNA. The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated to obtain the crude product as a brown solid. This product was used in the next step without further purification. LC / MS ES + m / z = 288.1 [M + H] + .

[0264] Step 2: Synthesis of 5-fluoro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol

[0265] [ka]

[0266] 8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-carboximidoamide (500 mg, 1.7 mmol) was suspended in ethanol (9.0 mL) and sodium-(Z)-3-ethoxy-2-fluoro-3-oxopropa-1-ene-1-oleate (820 mg, 5.2 mmol) was added. The reaction mixture was heated in a sealed vial at 90°C for 2 hours. 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 reverse-phase HPLC (acetonitrile-water gradient with 0.1% TFA as an additive) yielded the title compound (200 mg, 28% yield over two steps) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ (ppm) 12.6 (br. s, 1 H), 9.49 (s, 1 H), 8.32 (s, 1 H), 8.19 (br. s, 1 H), 7.89 (s, 1 H), 7.43 (s, 1 H), 7.25 (m, 1 H), 7.13 (m, 1 H), 4.58 (s, 2 H). Na+ salt of compound I-20

[0267] [ka]

[0268] To a pale yellowish-brown suspension of 5-fluoro-2-(8-(2,5-difluorobenzyl)imidazo[1,2-a]pyrazine-6-yl)pyrimidine-4-ol (compound I-20, 10 g, 28 mmol) in 450 mL of anhydrous MeOH, a solution of 0.50 N sodium methanolate in methanol (57 mL, 28 mmol) was added under a nitrogen atmosphere. After brief sonication, the resulting pale orange solution was stirred at ambient temperature for 15 minutes and concentrated to dryness under vacuum. The solid was resuspended in 200 mL of ether with the help of sonication and concentrated (twice). The resulting solid was resuspended in 500 mL of ether and stirred at ambient temperature for 3 hours. The solid was collected by vacuum filtration and washed with ether (3 × 100 mL). After drying overnight on a filter, 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]pyrazine-6-yl)pyrimidine-4-oleate (11 g, 99% yield) as a pale yellowish-brown solid. 1 H NMR (500 MHz, D2O) δ (ppm) 8.90 (s, 1 H), 7.98 (d, 1 H), 7.95 (d, 1 H), 7.70 (d, 1 H), 7.10 (m, 1 H), 6.98-6.89 (m, 2 H), 4.53 (s, 2 H). Biological section Evaluation of the biological properties of compounds in Table I The present invention also provides evaluation of the biological properties of the compounds listed in Table I. Representative examples of the compounds of the present invention have been tested in vitro for their activity as sGC stimulants in various cells and assays, and in vivo for their ability to lower blood pressure in animals. Blood pressure reduction is used as an indicator of the compound's ability to engage its target in vivo. These biological properties represent another embodiment of the present invention.

[0269] Example 2 cGMP GloSensor cell-based assay, biological activity measurement in 384-well format. The activity of the test compound was evaluated using human fetal kidney cells (HEK293) and cells expressing GloSensor® 40F cGMP (part number: CS182801, Promega). A luminescent biosensor (genetically modified luciferase) incorporated into these cells detects cGMP formed by compounds that stimulate the sGC enzyme and emits luminescence.

[0270] cGMP GloSensor cells were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with fetal bovine serum (FBS, final 10%) and hygromycin (200 ug / ml). The day before the assay, cells were measured in 1.5 × 10⁶ wells on a 384-well white flat-bottom plate coated with poly-D-lysine (Corning catalog no. 35661). 4 Cells were plated in DMEM containing 10% FBS in a volume of 50 μL at a density of 1 cells / well. The cells were incubated overnight at 37°C in a humidified chamber with 5% CO2. The following day, the medium was removed and the cells were replaced with 40 μl / well of GloSensor®, 2 mM (Promega catalog no. E1291). The cells were treated at 25°C for 90 minutes to allow the substrate to equilibrate in the cells. The test compound and diethylenetriamine nono-o-ate (DETA-nono-ate) were diluted to 3 mM (20×) in serum-free CO2-independent medium, and serially diluted 4× times to create a 5× dose curve. 10 μl was added to each well (concentration of x μM relative to the test compound solution and 10 μM relative to the DETA-nono-ate solution; 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, luminescence was measured immediately at 0.2 seconds per well using Envision (Perkin Elmer). For endpoint SAR screening, data were collected after incubation at room temperature for 55 minutes.

[0271] Concentration response data was analyzed using a four-parameter fit (log(agonist) vs. response-variable slope). EC 50 This is interpolated from the curve fitting and defined as the concentration at which the compound elicits a 50% maximum response. If the experiment is performed multiple times for a given compound, the geometric mean of all experiments is reported.

[0272] Table A below shows the results of the Glo assay for the compounds of the present invention in EC 50 Summarize the values.

[0273] [Table 9]

[0274] Example 3 Measurement of biological activity using cGMP neuron cell-based assays Primary rat neurons were isolated from 18-day-old pregnant female Sprague-Dawley fetuses. The fetuses were harvested in Hanks equilibrium salt solution (HBSS), and the brain was rapidly extracted. The hippocampus was isolated and mechanically fragmented. Further tissue sublimation was performed at 37°C for 15 minutes with 0.25% (wt / volume) trypsin solution in Ca2+ and Mg2+-free HBSS. After trypsin treatment, cells were washed and resuspended in Neurobasal medium supplemented with 0.5 mM L-glutamine, 12.5 μM glutamate, 2% B-27, 100 U / mL penicillin, and 100 μg / mL streptomycin. Cells were placed in 26 × 10⁶ wells of a 384-well clear flat-bottom plate coated with poly-D-lysine (Corning catalog no. 354662). 3 or 4 x 10 4 or 3 x 10 4Cells were plated at a density of 10 cells / well. Cells were incubated in a humidified chamber with 5% CO2 at 37°C for 6–7 days. The medium was removed, and the cells were washed 1× with HBSS containing Ca2+ and Mg2+, replaced with 40 μL of HBSS containing 0.5 mM IBMX, and incubated at 37°C for 15 minutes. 10 μL of 5× stock of the test compound containing diethylenetriamine nonoate (DETA-NO) was added. The final concentration of DETA-NO was either 10 μM or 30 μM. Cells were incubated at 37°C for 20 minutes. The medium was removed, and 50 μL of ice-cold 10% acetic acid was added, and incubated at 4°C for 60 minutes. After centrifugation at 1000×g at 4°C for 5 minutes to pellet the cell fragments, the supernatant was aspirated into a clear plate, and the samples were analyzed against cGMP content. cGMP concentration was determined from each sample using LC-MS / MS.

[0275] Concentration response data was analyzed using a four-parameter fit (log(agonist) vs. response-variable slope). EC 50 This is interpolated from the curve fitting and defined as the concentration at which the compound elicits a 50% maximum response. If the experiment is performed multiple times for a given compound, the geometric mean of all experiments is reported.

[0276] Table B below shows the results of neuronal assays for the compounds of the present invention. 50 Summarize the values.

[0277] [Table 10]

[0278] Example 4 Measurement of biological activity of human a2b1 sGC isozymes stably expressed in CHO-K1 cells.

[0279] The sGC stimulant was dissolved in DMSO as a 10 mM solution and stored at -20°C. To achieve the desired test concentration, the stock concentration was sequentially diluted in DMSO, and then diluted to the appropriate concentration with assay buffer.

[0280] CHO-K1 cells stably transfected with human α2β1 sGC isozyme (generated by GenScript for 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 geneticin (Gibco catalog number 10131-027) at 37°C in a 95% humid atmosphere containing 5% CO2 from the air. For GC activity assays, cells were measured at 3 × 10⁶ values ​​each. 4 Individual cells / well or 15 × 10 3 Cells were seeded at a density of 1 cell / well in either 50 μL or 70 μL of medium in a 384-well flat-bottom plate coated with poly-D-lysine (Fisher Scientific No. 08-774-311). The cells were incubated at 37°C for 24 hours in a humidified chamber with 5% CO2 supplementation.

[0281] For each test concentration, the compound was diluted with 100% DMSO up to 100 times its final assay concentration. Immediately before the assay, the solution was diluted 20-fold in HBSS containing calcium, magnesium, and 50 μM DETA-NONOate (5× final assay concentration). The medium was removed, and the cells were washed once with 40 μL of HBSS. The cells were then incubated at 37°C for 15 minutes in 40 μL of a solution containing 0.5 mM IBMX in HBSS. 10 μL from the sGC stimulant / HBSS / DETA-NONOate plate was added to the cells, and this was incubated at 37°C for a further 20 minutes. The final DMSO concentration was 1%, and the final DETA-NONOate concentration was 10 μM; 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.

[0282] Following incubation with the compound, the assay buffer was removed, and 50 μL of ice-cold 10% acetic acid + 150 ng / mL internal standard (+3 cGMP) was added to each well. Samples were incubated on ice for 30–60 minutes. Cell fragments were centrifuged at 1000 × g at 4°C for 5 minutes to pelletize them, and the supernatant was transferred to a clear plate. Samples were analyzed against the cGMP-containing material.

[0283] The data was analyzed using GraphPad Prism software v.8 with a 4-parameter fit (log(agonist) vs. response-variable slope). 50 This is interpolated from the curve fitting and defined as the concentration at which the compound elicits a 50% maximum response. If the experiment is performed multiple times for a given compound, the geometric mean of all experiments is reported.

[0284] Table C below shows the results of the CHO assay for the compounds of the present invention in EC 50 Summarize the values.

[0285] [Table 11]

[0286] Example 5 Effects of acute doses at multiple concentrations of representative compounds of the present invention on blood pressure in normotensive rats. a) Compound I-14 Male Sprague Dawley normotensive rats were purchased from Charles River Laboratories. These rats had implanted indwelling femoral artery catheters. The animals were fixed to a tethering system and connected to a pressure transducer to monitor cardiovascular (CV) parameters, specifically mean arterial pressure (MAP) and heart rate (HR). The animals were adapted to a 24-hour system, and baseline CV parameters were collected. Conscious, freely moving rats were then administered single oral doses of compound I-14 (a dose derived from the sodium salt of compound I-14) in Milli-Q water at 1, 3, 10, and 30 mg / kg. Blood samples were taken from each animal via the catheter line before administration and 2 hours after administration for quantification of compound concentration. Hemodynamic measurements were recorded for 10 hours after administration. Fifty-four male rats were used in these studies and were sequenced to be administered at body weights ranging from 250 to 275 grams. These animals were housed individually under controlled conditions of temperature (21±1℃) and relative humidity (36±1%) and placed in a room with a 12-hour light-dark cycle (lights on at 6:00 AM, lights off at 6:00 PM) at the SmartLabs animal facility (21 Erie Street, Cambridge, MA) under protocol MIL-110. The animals were able to optionally consume food (LabDiet Prolab Isopro RMH 3000, St. Louis, MO) and water. Two sets of studies were performed. For the first set of studies, compound I-14 was formulated in Milli-Q water at 0.3 and 1.0 mg / ml and frozen at -20℃. For the second set of studies, the sodium salt of compound I-14 was weighed using Cyclerion Therapeutics, reconstituted at SmartLabs, and provided solutions of compound I-14 in Milli-Q water at 0.1, 0.3, 1.0, and 3.0 mg / ml. The prepared formulations were either thawed at least 4 hours before administration and stored at room temperature, or prepared at least 2 hours before administration and stored at room temperature.

[0287] The study was conducted over six separate sessions. The total number of subjects and treatment assignments are listed in the table below. Animals were initially used within three days of receiving the catheter, and if any catheter remained in the patent, it was reused once after a 6-7 day washout. No animals were used more than once.

[0288] [Table 12]

[0289] Blood pressure measurement This study collected hemodynamic data from conscious, freely moving rats tethered to a pressure transducer (Harvard Apparatus catalog number APT300) using ADInstruments LabChart(v8). After overnight acclimatization to the tethering and pressure transducer, the animals were administered medication following a 1-hour baseline recording period. The animals received a single oral (PO) dose of compound I-14 in sodium salt form or vehicle form at a dosage volume of 10 mL / kg. Data collection continued for 10 hours after administration.

[0290] ADInstruments LabChart(v8) was used to monitor and export hemodynamic data. Blood pressure and heart rate were continuously monitored, and data was collected at 1000 data points per second, then averaged over a 10-minute range for analysis. Changes from baseline MAP (ΔBMAP) and HR (ΔBHR) were calculated using pre-administration baselines averaged over one hour prior to administration using Microsoft Excel for Microsoft 365. This 10-minute range dataset was used to determine peak ΔVMAP, hourly peak ΔVMAP, peak ΔVHR, and peak ΔVHR times. The dataset was further integrated over a 1-hour range for MAP and HR figures, as well as for the analysis of ΔBMAP, ΔBMAP, and ΔBHR. The definitions of these terms / abbreviations are summarized below.

[0291] [Table 13]

[0292] Statistical analysis was performed using Graphpad Prism (v8). Significance of ΔBMAP and ΔBHR data compared to vehicle-treated rats was determined by two-way repeated-measures ANOVA followed by Dunnett's multiple comparison test. Mixed-effects analysis was used when data points were missing. Vehicle-adjusted MAP (ΔVMAP) was calculated by subtracting the ΔBMAP of the vehicle group from the ΔBMAP of each dose group at each time point. Vehicle-adjusted HR (ΔVHR) was calculated using a similar method to that used for ΔVMAP.

[0293] The significance of the AOC data was determined by one-way ANOVA and subsequent Dunnett's multiple comparison test, compared to the vehicle data. Some test data were removed before analysis. Data collected 130 and 140 minutes after drug administration were removed due to 2-hour blood sample collection. Several time points for one rat at 1 mg / kg were excluded due to signal loss during the experiment, which started at 470 minutes and continued until the end of the study (600 minutes). Five-minute time series were excluded from all datasets for various reasons, including being outliers for specific analyses, or due to signal loss resulting in abnormal outcomes.

[0294] blood pressure changes Figure 1 shows a graph of the change from baseline MAP (ΔBMAP). Rats treated with compound I-14 showed a significantly greater decrease in MAP (assessed by the change from baseline MAP and ΔBMAP) compared to vehicle-treated rats. The ΔBMAP dataset showed significant improvement in two-way ANOVA (p<0.0001 for treatment and time, p=0.045 for treatment × time interaction). Dunnett's multiple comparison test for the primary treatment effect yielded p=ns for the 1 mg / kg dose, p=0.0034 for the 3 mg / kg dose, and p<0.0001 for the 10 and 30 mg / kg doses compared to vehicle-treated rats. Separate Dunnett multiple comparison tests of the simple effect at each time point and dose in vehicle-treated rats showed a significant decrease in ΔBMAP throughout 6 hours after administration in rats treated with 10 and 30 mg / kg of compound I-14; and at 1, 2, and 3 hours after administration in rats treated with 3 mg / kg of compound I-14; but not in rats treated with 1 mg / kg of compound I-14.

[0295] The maximum effect of compound I-14 in ΔVMAP was calculated using a 10-minute range dataset and is shown in Table D below.

[0296] [Table 14]

[0297] There is no effective dose of 1 mg / kg in ΔBMAP as evaluated by major effect analysis, simple effect analysis, and AOC. conclusion Compound I-14 was reduced from baseline to MAP and adjusted from the vehicle at 3, 10, and 30 mg / kg.

[0298] b) Compound I-20 Studies similar to those described above were conducted with compound I-20. Conscious, freely moving rats were administered single oral doses of compound I-20 (prepared from the sodium salt of compound I-20) in Milli-Q water at 1, 3, 10, and 30 mg / kg. Blood samples were collected from each animal via catheter lines before administration and 2 hours after administration to quantify compound concentrations. Hemodynamic measurements were recorded for 10 hours after administration.

[0299] blood pressure changes Baseline MAP(Δ B Figure 2 shows the changes from MAP in a graph. Rats treated with compound I-20 showed a greater change from vehicle-treated rats in MAP (baseline MAP, Δ). B The evaluation (based on changes from MAP) decreased significantly. Δ B The MAP dataset showed significant improvement in two-way ANOVA (p<0.0001 for treatment and treatment × time interaction; p=0.022 for time). Dunnett's multiple comparison test for the primary treatment effect yielded p=0.055(ns) for the 1 mg / kg dose, p=0.0001 for the 3 mg / kg dose, and p<0.0001 for the 10 and 30 mg / kg doses compared to vehicle-treated rats. Separate Dunnett's multiple comparison tests for the simple effect at each time point and dose compared to vehicle-treated rats showed a greater decrease in MAP throughout 6 hours after administration in rats treated with 3, 10 and 30 mg / kg of compound I-20; and at 1, 2, 3, 4 and 5 hours after administration in rats treated with 1 mg / kg of compound I-20.

[0300] Δ V The maximum effect of compound I-20 in MAP (vehicle-controlled MAP) was calculated using a 10-minute range dataset and is shown in Table E below.

[0301] [Table 15]

[0302] conclusion Compound I-20 reduced MAP at 1, 3, 10, and 30 mg / kg, both from baseline and when adjusted from the vehicle.

[0303] Other BP measurements In studies similar to those described above, compound I-4 was formulated with PEG400 and administered at 10 mg / kg, with the maximum MAP reduction from baseline of 20 mmHg occurring 50 minutes after administration (Δ B The MAP was shown. In a study similar to the one described above, compound I-20 was formulated with PEG400 and administered at 10 mg / kg, but a peak Δ of -26 mmHg was observed 42 minutes after administration. B MAP was shown. In another study, compound I-20 was tested at 1, 3, or 10 mg / kg and formulated with methylcellulose, and the compound was able to reduce MAP from baseline at all doses tested. In one embodiment, the present invention may be described as follows. [Aspect 1] Formula I: [ka] [In the formula, J C Hydrogen, halogen, C 1~6 C substituted with alkyl and 1-3 fluorine atoms 1~6 Selected from the group consisting of fluoroalkyl groups, X is N or C(J C1 ) and J C1 Hydrogen, halogen, C 1~6 C substituted with alkyl and 1-3 fluorine atoms 1~6 Selected from the group consisting of fluoroalkyl groups, each J B Hydrogen, halogen, C 1~6 C substituted with alkyl and 1-3 fluorine atoms 1~6 Independently selected from the group consisting of fluoroalkyls, J D Hydrogen, halogen, C 1~6 C substituted with alkyl and 1-3 fluorine atoms1~6 Selected from the group consisting of fluoroalkyl groups, n is an integer selected from 0, 1, 2, 3, or 4. The compound represented by or a pharmaceutically acceptable salt thereof, provided that the compound is as follows: [ka] Not one of or a pharmaceutically acceptable salt thereof A compound or a pharmaceutically acceptable salt thereof. [Aspect 2] The compound is of formula IA: [ka] A compound or a pharmaceutically acceptable salt thereof as described in Embodiment 1. [Aspect 3] J C1 However, H, F, Cl, C 1~2 C substituted with alkyl or 1-3 fluorine atoms 1~2 A fluoroalkyl compound or a pharmaceutically acceptable salt thereof as described in embodiment 1 or 2. [Aspect 4] J C1 The compound or pharmaceutically acceptable salt thereof according to embodiment 3, wherein H or F. [Aspect 5] The compound is of formula IB: [ka] A compound or a pharmaceutically acceptable salt thereof as described in Embodiment 1. [Aspect 6] A compound or pharmaceutically acceptable salt thereof according to any one of aspects 1 to 5, wherein n is 2 or 3. [Aspect 7] A compound or pharmaceutically acceptable salt thereof according to any one of aspects 1 to 5, wherein n is 0. [Aspect 8] A compound or pharmaceutically acceptable salt thereof according to any one of aspects 1 to 5, wherein n is 1. [Aspect 9] Each J B However, independently, H, F, or C 1~4 C substituted with alkyl or 1-3 fluorine atoms 1~4A fluoroalkyl compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8. [Aspect 10] Each J B However, independently, H, F or C 1~4 A compound or pharmaceutically acceptable salt thereof, as described in embodiment 9, which is alkyl. [Aspect 11] n is 2 or 3; each J B The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 5, wherein independently, fluorine, methyl, or fluoromethyl substituted with 1 to 3 fluorine atoms. [Aspect 12] n is 2 or 3; each J B However, independently of F or methyl, the compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 5. [Aspect 13] n is 2; J B If both are F, or J B A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 5, wherein one of the compounds is F and the other is methyl. [Aspect 14] n is 3; two J B A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 5, wherein one is F and the other is methyl. [Aspect 15] J D The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 14, wherein the compound is H, F, Cl, methyl, ethyl, fluoromethyl, or fluoroethyl. [Aspect 16] J D A compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 14, wherein is H or F. [Aspect 17] J C The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 16, wherein the compound is H, Cl, F, methyl, ethyl, fluoromethyl, or fluoroethyl. [Aspect 18] J C The compound or pharmaceutically acceptable salt thereof according to embodiment 17, wherein the compound is H or F. [Aspect 19] J C A compound or pharmaceutically acceptable salt thereof according to embodiment 17, wherein is H. [Aspect 20] The compound is [Table 16-1-1] [Table 16-1-2] [Table 16-1-3] A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in Embodiment 1. [Aspect 21] The compound is [Table 16-2-1] [Table 16-2-2] [Table 16-2-3] A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in embodiment 20. [Aspect 22] The compound is [Table 16-3-1] [Table 16-3-2] A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in embodiment 20. [Aspect 23] The compound is [Table 16-4-1] [Table 16-4-2] A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in embodiment 22. [Aspect 24] The compound is [Table 16-5] A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in embodiment 22. [Aspect 25] The compound is [Table 16-6] A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in embodiment 20. [Aspect 26] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 25, and a pharmaceutically acceptable excipient or carrier. [Aspect 27] A method for treating a disease in a subject requiring treatment, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of aspects 1 to 25, or a pharmaceutical composition described in aspect 26, to the subject, either alone or in combination, wherein the disease or disorder benefits from sGC stimulation or from an increase in the concentration of NO and / or cGMP. [Aspect 28] The method according to aspect 27, further comprising the step of administering an additional therapeutic agent to the subject.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, J Ｃ is hydrogen, halogen, C １～６ C substituted with alkyl and 1-3 fluorine atoms １～６ Selected from the group consisting of fluoroalkyl groups, X is N or C (J Ｃ１ ) and J Ｃ１ is hydrogen, halogen, C １～６ C substituted with alkyl and 1-3 fluorine atoms １～６ Selected from the group consisting of fluoroalkyl groups, Each J Ｂ is independently selected from the group consisting of hydrogen, halogen, C １～６ alkyl and C substituted with 1 to 3 fluorine atoms １～６ fluoroalkyl, J Ｄ is hydrogen, halogen, C １～６ C substituted with alkyl and 1-3 fluorine atoms １～６ Selected from the group consisting of fluoroalkyl groups, n is an integer selected from 0, 1, 2, 3, or 4. The compound represented by or a pharmaceutically acceptable salt thereof, provided that the compound is as follows: 【Chemistry 2】 Neither the compound nor any pharmaceutically acceptable salt thereof, A compound or a pharmaceutically acceptable salt thereof.

2. The compound is given by formula IA: 【Transformation 3】 [In the formula, J Ｃ J Ｃ１ , each J Ｂ J Ｄ , and n are as defined in claim 1. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, represented by [formula].

3. J Ｃ１ However, H, F, Cl, C １～２ C substituted with alkyl or 1-3 fluorine atoms １～２ A fluoroalkyl compound or a pharmaceutically acceptable salt thereof as described in claim 1.

4. J Ｃ１ The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein the compound is H or F.

5. The compound is of formula IB: 【Chemistry 4】 [In the formula, J Ｃ , each J Ｂ J Ｄ , and n are as defined in claim 1. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, represented by [formula].

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

7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0.

8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

9. Each J Ｂ However, independently, H, F, or C １～４ C substituted with alkyl or 1-3 fluorine atoms １～４ A fluoroalkyl compound or a pharmaceutically acceptable salt thereof as described in claim 1.

10. Each J Ｂ However, independently, H, F, or C １～４ The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

11. n is 2 or 3; each J Ｂ The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein independently, it is fluorine, methyl, or fluoromethyl substituted with one to three fluorine atoms.

12. n is 2 or 3; each J Ｂ The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein independently, F or methyl.

13. n is 2; J Ｂ If both F, or J Ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the compounds is F and the other is methyl.

14. n is 3; two J Ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one is F and the other is methyl.

15. J Ｄ The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is H, F, Cl, methyl, ethyl, fluoromethyl, or fluoroethyl.

16. J Ｄ The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein is H or F.

17. J Ｃ The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is H, Cl, F, methyl, ethyl, fluoromethyl, or fluoroethyl.

18. J Ｃ However, the compound according to claim 17 or the pharmaceutically acceptable compound is H or F. salt.

19. J Ｃ The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein is H.

20. The compound is represented by the following formula: Table 1-1 Table 1-2 Table 1-3 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

21. The compound is represented by the following formula: Table 2-1 Table 2-2 Table 2-3 A compound according to claim 20 or a pharmaceutically acceptable salt thereof, selected from the above.

22. The compound is represented by the following formula: Table 3-1 Table 3-2 A compound according to claim 20 or a pharmaceutically acceptable salt thereof, selected from the above.

23. The compound is represented by the following formula: Table 4-1 Table 4-2 A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in claim 22.

24. The compound is represented by the following formula: Table 5 A compound or a pharmaceutically acceptable salt thereof, selected from the compounds described in claim 22.

25. The compound is represented by the following formula: Table 6 A compound according to claim 20 or a pharmaceutically acceptable salt thereof, selected from the above.

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

27. A pharmaceutical composition for treating a disease in a subject, comprising a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 25, The disease includes abetalipoproteinemia, achalasia, esophageal achalasia, acute respiratory distress syndrome (ARDS), adhesive capsulitis, age-related learning and memory impairment, age-related memory loss, alcoholism, alopecia or hair loss, severe disability, Alzheimer's disease, pre-symptomatic Alzheimer's disease, mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), anal fissure, aneurysm, angina pectoris, stable or unstable angina, variant angina, Prinzmetallic angina, Microvascular angina, anxiety or anxiety disorders, argininosuccinateuria, arterial and venous thrombosis, arthritis, Asperger's syndrome, asthma and asthmatic disorders, ataxia, telangiectasia, atherosclerosis, atherosclerosis associated with internal injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration, atrophic vaginitis, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), autism and disorders in the autism spectrum, benign prostatic hyperplasia (BPH) or hypertrophy or dilation of the prostate, bipolar disorder, bladder Outlet obstruction, bladder pain syndrome (BPS), blepharitis, bone and carbohydrate metabolism disorders, bone healing, bone healing following osteoclast bone remodeling, osteoclast bone resorption, osteoneoplasia, cerebral aneurysm, cerebral hypoxia, cancer metastasis, cerebral amyloid vascular disease (CAA) or Congo Red affinity vascular disease, autosomal dominant cerebral arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL or CADASIL syndrome), cerebral perfusion, cerebral small vessel disease, cerebral vasospasm, chemobrain, childhood disintegrative disorder, chronic bronchitis, chronic fatigue, chronic traumatic encephalopathy (CTE), cirrhosis, liver Cirrhosis, cirrhosis associated with chronic liver disease, primary biliary cirrhosis, CNS disease-related dysfunction, CNS disease-related sleep disorders, cognitive impairment associated with Huntington's disease, cognitive impairment, cognitive impairment, vascular cognitive impairment, mild cognitive impairment, cognitive impairment associated with diabetes, cognitive impairment associated with multiple sclerosis, cognitive impairment associated with obstructive sleep apnea, cognitive impairment associated with schizophrenia (CIAS), cognitive impairment associated with sickle cell disease, concussion, congenital myasthenic syndrome, connective tissue disease, consequences of cerebral infarction (stroke), blood substitute storage in trauma patients, CREST syndrome, Crohn's disease, cystic fibrosis (CF), delusional disorder, dementia, vascular dementia, post-stroke dementia,Lewy body dementia, dementia with frontal lobar degeneration, dementia with frontotemporal lobar degeneration, dementia with corticobasal degeneration, Creutzfeldt-Jakob dementia, HIV dementia, dementia due to multiple strokes, postoperative dementia, dementia due to a single lesion in a strategic area, HIV-related dementia, asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), HIV-related dementia (HAD, also called AIDS-dementia complex [ADC] or HIV encephalopathy), presenile dementia (mild cognitive impairment, MCI), mixed dementia, Binswanger dementia ( Subcortical arteriosclerotic encephalopathy, Parkinson's dementia, demyelinating diseases, depression, depressive disorders, dermatomyositis, diabetic vascular disease, diabetic macular edema, diabetic microangiopathy, diabetic ulcers or wounds, diabetic foot ulcers, diseases associated with or related to metabolic syndromes, obesity, diabetes, insulin resistance, elevated fasting glucose, elevated fasting insulin, elevated lipids, diseases involving downregulated neurotransmitters, diseases involving impaired cerebral blood flow, diseases involving neurodegenerative disorders, diseases involving synaptic dysfunction, diseases involving neuroinflammation, neurotoxicity Sexual disorders, diseases of the genitourinary organs in men and women (benign and malignant), concentration disorders in children with learning and memory problems, Down syndrome, drug addiction, drug-induced psychosis, dry eye syndrome, Duchenne muscular dystrophy, Dupuytren's contracture, dyskinesia, acute dyskinesia, chronic or tardive dyskinesia, non-motor dyskinesia, levodopa-induced dyskinesia (LID), dysmenorrhea, primary dysmenorrhea, secondary dysmenorrhea, dyspareunia, dysphagia, dystonia, generalized dystonia, focal dystonia, segmental dystonia Sexual dystonia, dystonia, intermediate dystonia, acute dystonic reaction, hereditary or primary dystonia, edema, electrolyte disorders, hyperkalemia, hyponatremia, emphysema, endometriosis, endothelial dysfunction or injuries and diseases associated with endothelial dysfunction, erectile dysfunction, esophageal achalasia, Fabry disease, female sexual dysfunction, female sexual arousal dysfunction, fibromyalgia, fibrosis, endocardial cardiomyopathy, atrial fibrosis, cardiac interstitial fibrosis, cardiac fibrosis, pulmonary fibrosis, ocular fibrosis, cutaneous fibrosis, intestinal fibrosis, renal fibrosis or kidney fibrosis, interstitial renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, hepatic fibrosis,Mediastinal fibrosis, retroperitoneal fibrosis, articular fibrosis, myelofibrosis, myelofibrosis, osteomyelofibrosis, radiation-induced fibrosis, pancreatic fibrosis, fragile X, functional dyspepsia, gastroparesis, Gaucher disease, systemic disorders of concentration, general psychosis, glaucoma, glioblastoma, glomerulosis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis, granuloma, head injury, hearing impairment, partial hearing loss, complete hearing loss, partial hearing loss, complete hearing loss Loss of hearing, noise-induced hearing loss, heart disease, left ventricular myocardial remodeling, left ventricular systolic dysfunction, ischemic cardiomyopathy, dilated cardiomyopathy, alcoholic cardiomyopathy, accumulative cardiomyopathy, congenital cardiac dysfunction, decreased coronary blood flow, diastolic or systolic dysfunction, coronary insufficiency, acute coronary syndrome, coronary artery disease, arrhythmia, decreased ventricular preload, cardiac hypertrophy, right ventricular hypertrophy, atrial and ventricular rhythm disorders and cardiac conduction disorders, Class I-III atrioventricular block (AVB) I-III), supraventricular tachyarrhythmia, ventricular premature contractions, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointe tachycardia, atrial and ventricular premature contractions, AV junction premature contractions, sinoatrial node dysfunction syndrome, AV nodular reentrant tachycardia, Wolff-Parkinson-White syndrome, myocardial failure, chronic, acute or viral myocarditis, cardiogenic shock, cardiac remodeling, heart failure (HF), heart failure with preserved ejection fraction (HFPEF), heart failure with reduced ejection fraction (HFREF), acute heart failure, chronic heart failure, acute phase of pre-existing chronic heart failure (worsening of HF), transient heart failure, post-acute heart failure, systolic heart failure, diastolic heart failure, congestive heart failure, acute decompensated heart failure, right ventricular failure, complete heart failure, high-output heart failure, valve deficient Heart failure with impairment, diabetic heart failure, heart failure / cardiorenal syndrome, right heart failure, high concentrations of plasminogen activator 1 (PA-1), high levels of fibrinogen and low-density DLD, histiocytosis X, Huntington's disease or chorea (HD), hyperammonemia and related conditions, hypertension, arterial hypertension, treatment-resistant hypertension, diabetic hypertension, idiopathic hypertension, essential hypertension, secondary hypertension, pre-eclampsia, portal hypertension, systemic hypertension, pre-eclampsia, acute and chronic elevated coronary blood pressure, hypertonia, hypertrophic scarring, sexual arousal impairment, hypoperfusion, impotence, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammation due to cerebral malaria, inflammation due to infection, inflammatory response in perioperative care, platelet aggregation,Intellectual disability, intermittent claudication, interstitial cystitis (IC), dialysis hypotension, ischemia, cerebral ischemia, myocardial ischemia, thromboembolic ischemia, severe limb ischemia, keloids, kidney disease, chronic kidney disease, acute and chronic renal failure, acute and chronic renal dysfunction, sequelae of renal dysfunction, renal dysfunction related to pulmonary enema, renal dysfunction related to HF, renal dysfunction related to uremia or anemia, primary kidney disease, congenital kidney disease, progression of polycystic kidney disease, kidney transplant rejection, immune complex-induced kidney disease, abnormal decrease in creatinine and / or fluid excretion, abnormal blood concentrations of urea, nitrogen, potassium and / or creatinine. Constant increase, altered activity of renal enzymes, altered activity of glutamyl synthetase, altered urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilation, hyperphosphatemia, vascular kidney disease, renal cysts, renal edema due to HF, Korsakoff psychosis, leukocyte activation, levodopa-induced addictive behavior, lichen sclerosing, lipid-related disorders, hyperlipidemia, hypersubcutaneous fat, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased high-density lipoprotein cholesterol (HDL cholesterol), low-density lipoprotein cholesterol (L) Moderate elevation of DL cholesterol levels, hypertriglyceridemia, hyperglyceridemia, hypolipoproteinemia, sitosterolemia, fatty liver disease, fatty degeneration of the liver or abnormal lipid accumulation in the liver, fatty degeneration of the heart, kidney or muscle, sitosterolemia, xanthomatous tumors, Tangier's disease, liver disease, vascular liver disease, hepatic astrocytic cell activity, accumulation of hepatic fibrous collagen and total collagen, necrotizing and / or immunological inflammatory liver disease, cholestatic liver disease associated with granulomatous liver disease, cholestatic liver disease associated with malignant liver disease, cholestasis associated with intrahepatic cholestasis in pregnancy Cholestatic liver disease, 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, cholestatic liver disease associated with common bile duct stones, cholestatic liver disease associated with bile duct tumors, cholestatic liver disease associated with pancreatic cancer, cholestatic liver disease associated with Militzi syndrome, cholestatic liver disease associated with AIDS, cholangiopathies, 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 encephalopathy, focal thrombosis, lower urinary tract syndrome (LUTS), lumbar spinal stenosis, lupus nephritis, lupus or systemic lupus erythematosus, microalbuminuria, microcirculatory disorders, migraine, morphea, moyamoya disease, multiple lacunar infarcts, multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF), multiple sclerosis (MS), clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), multiple system atrophy (MSA), myocardial infarction or heart attack, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, old myocardial infarction, myopic choroidal neovascularization, nevus, drug dependence, nephropathy, 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 incontinence, neuroinflammation, neurological disorders associated with decreased nitric oxide production, neuromuscular diseases, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, peripheral muscle disorders, type I and type II myotonic dystrophy, facioscapulohumeral muscular dystrophy, autosomal and X-linked Emery-Dreyfus muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy (SMA), neuromyelitis optica, neuropathy, peripheral neuropathy, autonomic neuropathy, central nervous system neuropathy, chemotherapy-induced neuropathy, diabetic neuropathy, painful neuropathy, neuropathic pain, non-painful neuropathy, painful diabetic neuropathy Pathy, non-painful diabetic neuropathy, neuropathy associated with CNS disease, multiple sclerosis (MS), radiation-induced neuropathy, neuropathic pain associated with herpes zoster, neuropathic pain associated with spinal surgery, obsessive-compulsive disorder (OCD), thromboangiitis obliterans, urinary tract obstruction, eosinophilic fasciitis, osteoporosis, overactive bladder, pain, acute pain, central pain syndrome, inflammatory pain, postoperative pain, tension pain, visceral pain, claudication pain, rare pain indications, acetazolamide-responsive myotonia, autologous erythrocyte sensitization syndrome, autosomal dominant Charcot-Marie-Tooth disease type 2VAutosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, autosomal recessive limb-girdle muscular dystrophy type 2A, ion channel disorder-related congenital insensitivity to pain, chronic pain requiring intrathecal analgesia, complex regional pain syndrome, complex regional pain syndrome type 1, complex regional pain syndrome type 2, and hyperhidrosis. Congenital insensitivity to pain, congenital insensitivity to pain with severe intellectual disability, congenital insensitivity to pain-hypohiridiasis syndrome, diffuse palmoplantar keratoderma with painful fissures, familial paroxysmal pain syndrome, familial paroxysmal pain syndrome with dominant lower limb involvement, familial paroxysmal pain syndrome with mainly upper body involvement, 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-type syndrome, paroxysmal severe pain Symptoms include persistent idiopathic facial pain, qualitative or quantitative calpain deficiency, Tolosa-Hunt syndrome, pancreatitis, panic disorder, Parkinson's disease, parkinsonism plus, Parkinsonian dysphagia, pathological feeding disorders, pelvic pain, peripheral vascular disease, peripheral artery disease, peripheral arterial occlusive disease, peripheral vascular embolism, peripheral perfusion disorder, peritonitis, pervasive developmental disorder, Peyronie's disease, Pick's syndrome, polychondritis, polymyositis, postherpetic neuralgia, occipital trauma, post-traumatic stress disorder (PTSD), premature ejaculation, progressive nuclear palsy, benign prostatic hyperplasia, and lung disease. , multifactorial pulmonary arterial disease, bronchoconstriction or pulmonary bronchoconstriction, pulmonary vascular disease, chronic obstructive pulmonary disease (COPD), pulmonary capillary hemangioma, lymphangiomatosis and compressed pulmonary vessels, adenopathy, lymphangiomatosis and compressed pulmonary vessels due to tumor or fibrous mediastinitis, pulmonary vascular remodeling, hypertonia, pulmonary hypertonia (PH), pulmonary arterial hypertension (PAH), primary PH, secondary PH, idiopathic PH, precapillary PH, idiopathic PH, PH associated with left ventricular disease, HIV-related PH, SCD-related PH, thromboembolism-related Related PH (chronic thromboembolic PH or CTEPH), PH associated with sarcoidosis, PH associated with chronic obstructive pulmonary disease, PH associated with acute respiratory distress syndrome (ARDS), PH associated with acute lung injury, PH associated with alpha-1 antitrypsin deficiency (AATD), PH associated with emphysema, smoking-induced emphysema, PH associated with lung disease, PH associated with hypoxemia, PH associated with scleroderma, PH associated with cystic fibrosis (CF), PH associated with left ventricular dysfunction, PH associated with hypoxemia, PH (WHO groups I, II, III, IV and V), PH associated with mitral valve disease, PH associated with pericarditis, PH associated with constrictive pericarditis, PH associated with aortic stenosis, PH associated with dilated cardiomyopathy,PH associated with hypertrophic cardiomyopathy, PH associated with restrictive cardiomyopathy, PH associated with mediastinal fibrosis, PH associated with pulmonary fibrosis, PH associated with anomalous pulmonary venous return, PH associated with pulmonary veno-occlusive disease, PH associated with pulmonary vasculitis, PH associated with collagen disease-related vascular disease, PH associated with congenital heart disease, PH associated with pulmonary venous hypertension, PH associated with interstitial lung disease, PH associated with sleep-disordered breathing, PH associated with chronic airflow obstruction, PH associated with obstructive sleep apnea, PH associated with central sleep apnea, PH associated with mixed sleep apnea, PH associated with alveolar hypoventilation impairment H, PH associated with chronic exposure to high altitudes, PH associated with neonatal lung disease, PH associated with alveolar capillary malformation, PH associated with sickle cell disease, PH associated with other coagulation disorders, PH associated with chronic thromboembolism, radiculopathy, Raynaud's disease, Raynaud's syndrome (primary or secondary), refractory epilepsy, Renpenning's syndrome, reperfusion injury, ischemia-reperfusion injury, ischemia-reperfusion associated with organ transplantation, restenosis, restenosis occurring after thrombolytic therapy, after percutaneous transluminal angioplasty (PTA), after transcatheter arterial angioplasty (PTCA), after heart transplantation or bypass surgery, retinopathy, diabetes. Retinopathy, non-diabetic retinopathy, nonproliferative diabetic retinopathy, proliferative vitreoretinopathy, peripheral retinal degeneration, retinal vein occlusion, Rett syndrome, rheumatoid or rheumatic disease, rheumatoid arthritis, sarcoidosis, sarcoid, schistosomiasis, schizoaffective disorder, schizophrenia, schizophrenia with dementia, scleroderma, focal scleroderma or localized scleroderma, systemic scleroderma, sclerosis, nephrosclerosis, progressive sclerosis, hepatosclerosis, primary sclerosing cholangitis, sclerosis of the gastrointestinal tract, hippocampal sclerosis, focal segmental sclerosis, primary lateral sclerosis, osteosclerosis, otosclerosis, atherosclerosis, tuberous sclerosis, systemic sclerosis, Sepsis or septic shock or anaphylactic shock, sickle cell anemia, sickle cell disease, Sjögren's syndrome, sleep-wake disorder, Sneddon syndrome, spasticity, coronary vasospasm, vasospasm, peripheral artery spasticity, spinal cord injury, spinal muscular atrophy, spinal subluxation, spinocerebellar ataxia, Steel-Richardson-Olszewski disease (progressive supranuclear palsy), stroke, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, syncope, tauopathy, tension, thalamic degeneration, thromboembolic or thromboplastic disorders, transient ischemic attack (TIA), traumatic brain injury, tubulointerstitial disease, ulcers,Uterine fibroid, vaginal atrophy, valve defect, mitral stenosis, mitral regurgitation, insufficiency or insufficiency, aortic stenosis, aortic regurgitation, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, mixed valvular disease, cerebrovascular disease, vascular disorders resulting from cardiovascular and renal complications, vascular leakage or permeability, vasculitis, thromboangiitis, thromboangiitis obliterans, Kawasaki disease, arteritis, aortitis, vascular occlusion attacks, Venus transplant failure, wet age-related macular degeneration, or Williams syndrome. The above-mentioned pharmaceutical composition.

28. The pharmaceutical composition according to claim 27, wherein an additional therapeutic agent is administered to the target.

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