MXPA00008400A

MXPA00008400A - N-[(substituted five-membered di- or triaza diunsaturated ring)carbonyl]guanidine derivatives for the treatment of ischemia

Info

Publication number: MXPA00008400A
Application number: MXPA/A/2000/008400A
Authority: MX
Inventors: Ernest S Hamanaka; Angel Guzmanperez; Roger B Ruggeri; Ronald T Wester; Christian J Mularski
Original assignee: Angel Guzmanperez; Ernest S Hamanaka; Christian J Mularski; Pfizer Products Inc; Roger B Ruggeri; Ronald T Wester
Priority date: 1998-02-27
Filing date: 2000-08-25
Publication date: 2001-07-09

Abstract

NHE-1 inhibitors, methods of using such NHE-1 inhibitors and pharmaceutical compositions containing such NHE-1 inhibitors. The NHE-1 inhibitors are useful for the reduction of tissue damage resulting from tissue ischemia.

Description

DERIVATIVES OF GUANIDINE N-FCARBONILCANILLO DHNSATURADO TRIAZA OR DITRIAZA OF FIVE MEMBERS REPLACED)! FOR THE TREATMENT OF ISCHEMIA This invention relates to inhibitors of the sodium-hydrogen exchanger type 1 (NHE-1), to pharmaceutical compositions containing said inhibitors and to the use of said inhibitors for the treatment, for example, of ischemia, especially ischemic injury Perioperative myocardial in mammals, including man. Myocardial ischemic injury may occur in outpatients, as well as in the perioperative setting, which may result in sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to avoid or minimize myocardial ischemic injury, especially perioperative myocardial infarction. It is anticipated that such a therapy will save lives and reduce the number of hospitalizations, improve the quality of life and reduce the overall health costs of high-risk patients. Cardiac pharmacology protection could reduce the incidence and progression of myocardial infarction and the dysfunction that occurs in this surgical (perioperative) setting. In addition to reducing myocardial damage and improving postischemic myocardial function in patients with ischemic heart disease, cardiac protection should also reduce the incidence of cardiac morbidity and mortality due to myocardial infarction and dysfunction in "at-risk" patients (such as older than 65 years, who can not exercise, with coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery. The mechanism (s) responsible for the myocardial injury observed after ischemia and reperfusion is not completely known. In several publications the use of guanidine derivatives has been described as being useful for the treatment of for example arrhythmias. US Patent No. 5,698,581, issued December 16, 1997 (EP 676395 A2, published in 1995) describes certain substituted N-heteroarylguanidines as inhibitors of the exchange transport system (Na + / H +) useful for the treatment for example arrhythmias. In EP 803 501 A1, published on October 10, 1997, certain substituted guanidine variants useful as exchange inhibitors (Na + / H +) are described. In WO 94/26709 guanidine derivatives are disclosed as inhibitors of exchange (NA + / H +) in cells. PCT / JP97 / 04650 published on June 25, 1998 discloses N - [(substituted five-membered heterocycle) carbonyl] guanidine compounds which are said to be useful as exchange inhibitors (Na + / H +) and thus effective for the treatment of various diseases, such as hypertension, arrhythmia, angina pectoris, myocardial infarction, arteriosclerosis and complications of diabetes.

Therefore, there is a clear need and a continuous search in this field for the treatment technique for perioperative myocardial ischemia.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a compound of formula I Formula I to a prodrug thereof, or to a pharmaceutically acceptable salt of said compound or of said prodrug wherein Z is bonded to a carbon and is a di-saturated diaza ring of five links having two contiguous nitrogens, said ring being optionally mono-, di- - or trisubstituted with up to three substituents independently selected from R1, R2 and R3; or Z is bonded to a carbon and is a diaza ring of five links, said ring being optionally mono- or di-substituted with up to two substituents independently selected from R4, and R5; wherein R1, R2, R3, R4 and R5 are each independently hydrogen, hydroxy alkyl (C? -C), alkyl (C -? - C), alkyl (C1-C4) uncle, cycloalkyl (C3-) C4), cycloalkyl (C3-C7) alkyl (C1-C4), alkoxy (C4), alkoxy (C1-C4) alkyl (C1-C4), mono-N- or di-N, N-alkyl (C1- C4), carbamoyl, M or M-alkyl (C-1-C4), said alkyl moieties (C1.-C4) having from one to nine fluorine atoms optionally.; said (C1-C4) alkyl or (C3-C4) cycloalkyl optionally independently mono or disubstituted with hydroxy, alkoxy (C?), alkyl (C4) thio, alkyl (C1-C4) sulfinyl, alkyl (Cr C4) sulfonyl, (C 1 -C 4) alkyl, mono-N- or di-N, N-C 1 -C 4 alkyl, carbamoyl or mono-N- or di-N, N-(C 1 -C 4) alkyl aminosulfonyl and having said cycloalkyl (C3-C4) optionally from one to seven fluorine atoms; wherein M is a partially saturated, fully saturated or fully unsaturated ring of between five and eight links, optionally having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two partially saturated condensed rings , fully saturated or totally unsaturated of three to six links, considered independently, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; said M being optionally substituted, on a ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three independent substituents selected from R6, R7 and R8, where one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three or seven links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with (C-1-C4) alkyl and additionally R6, R7 and R8 are optionally hydroxy, nitro, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbino, (C1-C4) alkyl, formyl, (C1-C4) alkanoyl, (C1-C4) alkanoyloxy, alkanoyl (C C4) amino, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono-N- or di-N, N-C 1 -C 4 alkylamino, carbamoyl, mono-N - or di-N, N-C 1 -C 4 alkylcarbamoyl, cyano, thiol, alkyl (C 1 -C 4) thio, alkyl (C 1 -C 4) sulfinyl, alkyl (^ -04) sulfonyl, mono-N- or di-N, N-C 1 -C 4 alkylaminosulfonyl, (C 2 -C 4) alkenyl, (C 2 -C 4) alkynyl or (C 5 -C 7) cycloalkenyl, said substituent R6, R7 and R8 (C1-C4) alkoxy, alkyl (Cr C4), alkanoyl (C? -C7), alkyl (C1-C4) thio, mono-N- or di-N, N-alkyl (C1- C4) amino or (C3-C7) cycloalkyl optionally monosubstituted independently with hydroxy, (C1-C4) alkoxycarbonyl, cycloalkyl (C3-C7), alkanoyl (C1-C4), alkanoyl (04.04) amino, alkanoyloxy (C1- C4) C4), (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkyl sulfonamido, amino, mono-N- or di-N, N-alkyl (C1-C4) amino, carbomoyl, mono-N- or di- -N, N-C 1 -C 4 alkylcarbamoyl, cyano, thiol, nitro, alkyl (C 1 -C) thio, alkyl (C 1 -C 4) sulfinyl, alkyl (C 1 -C 4) sulfonyl or mono-N- or di- -N, N-C 1 -C 4 alkylaminosulfonyl or optionally substituted with one to nine fluorine atoms. A preferred group of compounds, designated as group A, contains those compounds having the formula I as shown above where Z is R1 and R3 are each independently hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or (C1-C4) phenylalkyl, said (C1-C4) alkyl being optionally substituted with one of nine fluorine atoms, said substituents R1 and R3 being optionally mono or disubstituted independently with hydroxy, (C1-C4) alkoxy, alkyl (C? -C) thio, alkyl (C1-C4) sulfinyl or (C1-C4) alkylsulfonyl; and R2 is unsubstituted (C1-C4) alkyl or (C3-C7) cycloalkyl; or R2 is phenyl, phenyl (C1-C4) alkyl, pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, considered independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen said R2 substituent optionally being mono-, di or trisubstituted independently with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, (C-1-C4) alkoxycarbonyl, mono-N- or di-N , N-alkyl (C-1-C4) carbamoyl, mono-No di-N, N-C 1 -C 4 alkyl, amino (C 1 -C 4) alkylsulfonyl or sulfonamido, said (C 1 -C 4) alkyl or alkoxy being (C1-C4) optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof.

A group of preferred compounds among group A of, compounds, designated as group B, contains those compounds wherein R 1 is (C -? - C4) alkyl or (C3-C) cycloalkyl; R2 is phenyl, optionally mono- or disubstituted; and R3 is hydrogen or the pharmaceutically acceptable salts thereof. Especially preferred compounds of formula I are the compounds: [1- (2-chlorophenyl) -5-methyl-1 H-pyrazol-4-carbonyl] guanidine; [5-methyl-1- (2-trifluoromethylphenyl) -1 H-pyrrazol-4-carbonyl] guanidine; [5-ethyl-1-phenyl-1 H-pyrazole-4-carbonyl] guanidine; [5-cyclopropyl-1- (2-trifluoromethylphenyl) -1 H-pyrrazol-4-carbonyl] guanidine; [5-cyclopropyl-1-phenyl-1 H-pyrazole-4-carbonyl] guanidine; [5-Cyclopropyl] -1- (2,6-dichlorophen-I) -1 H-pyrrazol-4-carbonyl] guanidine and the pharmaceutically acceptable salts thereof. Especially preferred compounds within group B of the compounds are compounds wherein: a. R2 is 2-chlorophenyl; and R1 is methyl; b. R 2 is 2-trifluoromethylphenyl; and R is methyl; c. R2 is phenyl; and R1 is ethyl; d. R2 is 2-trifluoromethylphenyl; and R1 is cyclopropyl; and. R2 is phenyl; and R1 cyclopropyl; and f. R2 is 2,6-dichlorophenyl; and R is cyclopropyl or the pharmaceutically acceptable salts thereof. A group of preferred compounds among group A of compounds, designated as group C, contains those compounds wherein R 1 is (C 1 -C 4) alkyl or (C 3 -C 7) cycloalkyl; R 2 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said substituent being R2 optionally monosubstituted; R is hydrogen or pharmaceutically acceptable salts thereof. Especially preferred compounds of formula I are the compounds [5-methyl-1 - (quinolin-6-yl) -1H-pyrazole-4-carbonyl] guanidine; [5-methyl-1- (naphthalen-1-yl) -1 H-pyrazole-4-carbonyl] guanidine; [5-cyclopropyl-1- (quinolin-5-yl) -1 H-pyrazole-4-carbonyl] guanidine; [5-cyclopropyl-1 - (quinolin-8-yl) -1H-pyrazole-4-carbonyl] guanidine; and the pharmaceutically acceptable salts thereof. Especially preferred compounds within group C of the compounds are compounds wherein: a. R2 is 1-naphthalenyl; and R1 is methyl; b. R2 is 5-quinolinyl; and R1 is cyclopropyl; c. R2 is 8-quinolinyl; and R1 is cyclopropyl; d. R 2 is 6-quinoline, and R 1 is methyl or the pharmaceutically acceptable salts thereof. A group of preferred compounds within group A of compounds, designated as group D, contains those compounds wherein R 1 is hydrogen; R2 is phenyl, optionally mono- or disubstituted; and R3 is (C1-C4) alkyl or (C3-C7) cycloalkyl or the pharmaceutically acceptable salts thereof The especially preferred compounds of formula I are the compounds [3-methyl-1-phenyl-1 H-pyrazole-4- carbonyl] guanidine; [3-methyl-1 - (naphthalene-1-yl) -1 H-pyrazole-4-carbonyl] guanidine; [3-methyl-1- (isoquinolin-5-yl) -1 H-pyrazole-4-carbonyl] guanidine; and the pharmaceutically acceptable salts thereof. An especially preferred compound within group D of compounds is the compound wherein R 2 is phenyl; and R3 is methyl or the pharmaceutically acceptable salts thereof. A group of preferred compounds within group A of compounds, designated as group E, contains those compounds wherein R 1 is hydrogen; R2 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said substituent R2 being optionally monosubstituted; Y R3 is (C1-C4) alkyl or (C3-C7) cycloalkyl or the pharmaceutically acceptable salts thereof. Especially preferred compounds within the group E of compounds are the compounds in which a. R2 is 1-naphthalenyl; and R3 is methyl; and b. R2 is 5-isoquinolyl; and R > 3 is methyl or the pharmaceutically acceptable salts thereof. A preferred group of compounds, designated as group F, contains those compounds having the formula I as shown above in which Z is R1 is hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or phenylalkyl (Cr C4), said (C1-C4) alkyl being optionally substituted with one to nine fluorine atoms, said substituents R1 being optionally mono or disubstituted independently with hydroxy, alkoxy, (C 1 -C 4), alkyl (dC 4) thio, alkyl (4 ^ 4) sulfinyl or C 1 -C 4 alkylsulfonyl and R 2 and R 3 are each independently alkyl ( C1-C4) or unsubstituted (C3-C7) cycloalkyl; or R2 and R3 are each independently phenyl or phenyl (C1-C4) alkyl, pyridyl or pyrimidinyl or a bicyclic ring consisting of two fused rings of five and / or six independently considered, optionally having from one to four independently selected heteroatoms between nitrogen, sulfur and oxygen, said substituents R2 and R3 being optionally mono-, di- or trisubstituted independently with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, trifluoromethoxy, (C1-C4) alkoxy, carbonyl , mono-N- or di-N, N-alkyl (C1.-C4) carbamoyl, mono-N- or di-N, N-(C1-C4) alkylamino, (C1-C4) alkylsulphonyl or sulfonamido, said (C-1-C4) alkyl or (C 1 -C 4) alkoxy optionally being substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. An especially preferred compound of formula I is: [4-methyl-1-phenyl-1 H-pyrazole-3-carbonyl] guanidine and a pharmaceutically acceptable salt thereof. An especially preferred compound within the group F of compounds is a compound wherein R3 is phenyl; R1 is methyl; and R2 is H or the pharmaceutically acceptable salts thereof. A preferred group of compounds, designated as group G, contains those compounds having the formula I as shown above in which Z is R1 and R3 are each independently hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or (C1-C4) phenylalkyl, said (C1-C4) being optionally substituted with from one to nine carbon atoms; fluorine, said substituents R1 and R3 being optionally mono or independently substituted with hydroxy, (C1-C4) alkoxy, (C- | -C4) alkyl, alkyl (C-1-C4) sulfinyl or alkyl (Cr C4) sulfonyl; and R2 is unsubstituted (C1-C4) alkyl or (C3-C7) cycloalkyl; or R2 is phenyl, phenyl (C1-C4) alkyl, pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen , said substituent R2 being optionally mono-, di or tri substituted independently with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, (C-1-C4) alkoxycarbonyl, mono-N- or di- N, N-C 1 -C 4 alkylcarbamoyl, mono-No di-N, N-C 1 -C 4 alkyl, amino (C 1 -C 4) alkylsulfonyl or sulfonamido, said (C 1 -C 4) alkyl or alkoxy ( C1-C4) optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. A preferred compound group among the group G of compounds, designated as group H, contains those compounds wherein R 1 is (C 1 -C 4) alkyl or (C 3 -C 7) cycloalkyl; R2 is phenyl, optionally mono- or disubstituted; and R3 is hydrogen or the pharmaceutically acceptable salts thereof. A group of preferred compounds among the group G of compounds, designated as group 1, contains those compounds wherein R 1 is (C 1 -C 4) alkyl or cycloalkyl (C 3 -C); R 2 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said R 2 being optionally monosubstituted; and R3 is hydrogen. A group of preferred compounds among the group G of compounds, designated as group J, contain those compounds in which R1 is hydrogen; R2 is phenyl, optionally mono- or disubstituted; and R3 is (C1-C4) alkyl or (C3-C7) cycloalkyl. Especially preferred compounds of formula I are the compounds: [2-methyl-5-phenyl-2H-pyrazole-3-carbonyl] guanidine; [2-methyl-5- (naphthalen-1-yl) -2H-pyrazole-3-carbonyl] guanidine and the pharmaceutically acceptable salts thereof. An especially preferred compound within group J of compounds is the compound wherein R 2 is phenyl; and R3 is methyl or the pharmaceutically acceptable salts thereof.

A group of preferred compounds within group G of compounds, designated as group K, contains those compounds in which R1 is hydrogen; R 2 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinium, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said R 2 being optionally monosubstituted; and R3 is (C1.-C4) alkyl or (C-C) cycloalkyl or the pharmaceutically acceptable salts thereof. An especially preferred compound within the K group of compounds is the compound wherein R 2 is 1-naphthalenyl; and R3 is methyl and the pharmaceutically acceptable salts thereof. A preferred group of compounds, designated as group L, contains those compounds having the formula I as shown above in which Z is R 4 is hydrogen, (C 1 -C 4) alkyl, (C 3 -C 7) cycloalkyl, phenyl or phenylalkyl (Ci-C 4), said (C 1 -C 4) alkyl being optionally substituted as one to nine fluorine atoms, said R substituent being optionally mono- or disubstituted independently with hydroxy, (C 1 -C 4) alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl, sulfinyl or C 1 -C 4 alkylsulfonyl and R 5 is (C 1 -C 4) alkyl or cycloalkyl (C3-C) unsubstituted; or R5 is phenyl or phenyl (C1-C4) alkyl, pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said substituent R5 being optionally mono-, di- or trisubstituted independently with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, (C1-C4) alkoxycarbonyl, mono-N- or di-N, N -alkyl (C1-C4) carbamoyl, mono-N- or di-N, N-(C1-C4) alkyl amino, (C1-C4) alkylsulfonyl or sulfonamido, said (C1-C4) alkyl or alkoxy (C1) -C4) optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. A group of preferred compounds, designated as group M, contains those compounds having the formula I, as shown above in which Z is R is hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or phenylalkyl (Ci-), said alkyl (CrC) being optionally substituted with one to nine fluorine atoms, said substituent R4 being optionally mono - or independently disubstituted with hydroxy, (C1-C4) alkoxy, (C-? - C4) thio alkyl, (C1-C4) alkylsulfinyl or (C1-C4) alkylsulfonyl and R5 is (C1-C4) alkyl or cycloalkyl (C3-C7) unsubstituted; or R5 is phenyl or (C1-C4) phenylalkyl, pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen , said substituent R5 being optionally mono-, di- or trisustitide independently with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, (C1-C4) alkoxycarbonyl, mono-N- or di-N, N-C 1 -C 4 alkylcarbamoyl, mono-N- or di-N, N-C 1 -C 4 alkylamino, C 1 -C 4 alkylsulfonyl or sulfonamido, said (C 1 -C 4) alkyl or alkoxy being ( C1-C4) optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. A group of preferred compounds, designated as group N, contains those compounds having the formula I as shown above in which Z is R 4 is hydrogen, (C 1 -C 4) alkyl, (C 3 -C 7) cycloalkyl, phenyl or phenylalkyl (Cr C), said (C 1 -C 4) alkyl being optionally substituted with one to nine fluorine atoms, said substituent being R 4 optionally mono- or disubstituted independently with hydroxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, C 1 -C 4 alkylsulfinyl or C 1 -C 4 alkylsulfonyl and R 5 is (C 1 -C 4) alkyl or unsubstituted (C3-C7) cycloalkyl; or R5 is phenyl or phenylalkyl (C1-C4), pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said substituent R5 being optionally mono-, di- or trisubstituted independently with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, (C1-C4) alkoxycarbonyl, mono-N- or di-N, N-alkyl (C-1-C4) carbamoyl, mono-N- or di-N, N-alkyl (C? -C4) amino , (C 1 -C 4) alkylsulfonyl or sulfonamido, said (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy optionally substituted by one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. A group of preferred compounds, designated as group O, contains those compounds having the formula I as shown above in which Z is R4 is hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or phenylalkyl (Cr C4), said alkyl (CrC) being optionally substituted with one to nine fluorine atoms, said substituent R4 being optionally mono- or independently disubstituted with hydroxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, C 1 -C 4 alkyl, sulfinyl or C 1 -C 4 alkylsulfonyl and R 5 is (C 1 -C 4) alkyl or cycloalkyl (C 3) -C) not substituted; or R5 is phenyl or phenyl (C1-C4) alkyl, pyridyl or pyrimidinyl or a bicyclic ring consisting of two fused rings of five and / or six independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said substituent R5 being optionally mono-, di- or trisubstituted independently with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, (C1-C4) alkoxycarbonyl, mono-N- or di-N, N -alkyl (C1-C4) carbamoyl, mono-N- or di-N, N-(C1-C4) alkyl amine, (C1-C4) alkylsulfonyl or sulfonamido, said alkyl (0-4) or alkoxy (C1) being -C4) optionally substituted with one or nine fluorine atoms or the pharmaceutically acceptable salts therein. A preferred group of compounds among the group O of compounds, designated as group P, contains those compounds wherein R 4 is (C 1 -C 4) alkyl or (C 3 -C 7) cycloalkyl; and R5 is phenyl, optionally mono or disubstituted or the pharmaceutically acceptable salts thereof. Especially preferred compounds of formula I are the compounds [5-methyl-2-phenyl-2H-1, 2,3-triazole-4-carbinyl] guanidine; [5-methyI-2- (3-methoxy-phenyl) -2H-1, 2,3-triazole-4-carbonyl] guanidine; [2- (3-bromophenii) 5-methyl-2H-1, 2,3-triazole-4-carbinyl] guanidine; and the pharmaceutically acceptable salts thereof. Especially preferred compounds within the group P of compounds are the compounds in which: a. R5 is phenyl; and R 4 is methyl; b. R5 is 3-methoxyl phenyl; and R 4 is methyl; and c. R5 is 3-bromophenyl; and R 4 is methyl or the pharmaceutically acceptable salts thereof. A group of preferred compounds among the group O of compounds, designated as group Q, contains those in which R 4 is (C 1 -C 4) alkyl or (C 3 -C 7) cycloalkyl; and R5 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said substituents R5 being optionally monosubstituted or the pharmaceutically acceptable salts thereof. Preferred special compounds of formula I are the compounds: [2-naphthalen-1-yl) -5-methyl-2H-1, 2,3-triazole-4-carbonyl] guanidine; [2-isoquinolin-5-yl) -5-methyl-2H-1, 2,3-triazole-4-carbonyl] guanidine; [5-methyl-2- (quinolin-5-yl) 2H-1, 2,3-triazole-4-carbonyl] guanidine and the pharmaceutically acceptable salts thereof. Especially preferred compounds within the group Q of compounds are the compounds in which: a. R5 is 1-naphthalenyl; and R 4 is methyl; b. R5 is 5-isoquinolinyl; and R 4 is methyl; and c. R5 is 5-quinolinyl; and R 4 is methyl or the pharmaceutically acceptable salts thereof. Another aspect of this invention relates to the following compounds: 5-methyl-2- (5-quinolin) -2 / - / - 1, 2,3-triazole-4-carboxylic acid, 5-methyl-2- ( 5-isoquinolin) -2 - / - 1, 2,3-triazole-4-carboxylic acid, 2- (1-naphthalenyl) -5-methyl-2 / - / - 1, 2,3-triazole-4 carboxylic acid, 5-cyclopropyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxylate, ethyl 5-methyl-1- (6-quinolin) -1H-pyrazoyl-4-carboxylate, Ethyl 5-Methyl-1-naphthalenyl-1 - / - pyrazole-4-carboxylate, 5-Cyclopropyl-1 - (quinolin-8-yl) -1 H-pyrazole-4-carboxylic acid ethyl ester, 5-Cyclopropyl -1 - (quinolin-5-yl) -1-pyrazol-4-carboxylic acid ethyl ester, methyl 5-ethyl-1- (quinolin-5-yl) -1-pyrazol-4-carboxylate, 1 - (Isoquinolin-5-yl) -3-methyl-1 H-pyrazol-4-carboxylic acid n-butyl ester, 5-methyl-1- (6-quinoline) -1 - pyrrazol-4-carboxylic acid, 5 -methyl-1-naphthalenyl-1-pyrazol-4-carboxylic acid, 5-cyclopropyl-1 - (quinolin-8-yl) -1H-pyrazoyl-4-carboxylic acid, 5-cyclopropyl-1 - (2- trifluoromethelfenil) -1 H-pyrazole-4-carboxylic acid, 5-ethyl-1- (quinolin-5-yl) -1-pyrazol-4-carboxylic acid, 5-cyclopropyl-1 - (quinolin-5-yl) -1 acid H-pyrazole-4-carboxylic acid; or Acidol- (5-quinolin-5-yl) -3-methyl-1H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt of said compounds. A preferred group of compounds, designated as group R, contains those compounds having the formula I as shown above in which Z is R is (C3-C) cycloalkyl, phenyl or phenyl (C1-C4) alkyl, said (C3-C7) cycloalkyl being optionally substituted with one to three fluorine atoms, said substituent R1 being optionally mono- or disubstituted independently with alkoxy (C1 -C4), alkyl (C4) thio, alkyl (C1-C4) sulfinyl or alkyl (C1-C4) sulfonyl and R2 is (C1-C4) alkyl, cycloalkyl (C3-C4), M or M-alkyl (C1 -C4), optionally having all the aforementioned (C1-C4) alkyl radicals of one to nine fluorine atoms; said (C1-C4) alkyl or (C3-C4) cycloalkyl optionally mono- or disubstituted independently with hydroxy, (C1-C4) alkoxy, (C? -C4) thio alkyl, (C-1-C4) alkylsulfinyl, (C 1 -C 4) alkyl sulfonyl, (C 1 -C 4) alkyl, mono-N- or di-N, N-alkyl (Ci-C 4) carbamoyl or mono-N- or di-N, N-alkyl (C 1 -) C4) amine sulfonyl and said (C3-C4) cycloalkyl optionally having from one to seven fluorine atoms; M being a partially saturated, fully saturated or fully unsaturated ring of five to eight links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two partially saturated fused rings, fully saturated or completely unsaturated of three to six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; said M being optionally substituted, on a ring if the moiety is monocyclic, or on one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, where one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, optionally substituted with (C1-C4) alkyl and further R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy, (C1-C4), (C1-C4) alkoxycarbonyl, (C1-C4) alkyl, formyl, (C1-C4) alkanoyl, (C1-C4) alkanoyloxy, alkanoyl (C1-C4) amino, (C1-C4) alkoxycarbonylamino, sulfonamido, alkyl (CiC) sulfonamido, amino, mono-N- or di-N, N-(C1-C4) alkylamino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, cyano, thiol, alkyl (C? -C4) thio, alkyl (C1-C4) s ulfinyl, (C 1 -C 4) alkylsulfonyl, mono-N- or di-N, N-alky (C 1 -C 4) aminosulfonyl, alkenyl (C 2 -C), alkynyl (C 2 -C) or cycloalkenyl (C 5 -C ), said substituents R6, R7 and R8 are (C1-C4) alkoxy, (C1-C4) alkyl, alkanoyl (CrC), alkyl (C? -C4) thio, mono-N- or di-N, N-alkyl (C1-C4) amino or (C3-C7) cycloalkyl optionally independently monosubstituted with hydroxy, (C1-C4) alkoxycarbonyl, (C3-C7) cycloalkyl, (C1-C4) alkanoyl, (C1-C4) alkanoylamino, alkanoyloxy (C-1-C4), (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono-N- or di-N, N-C 1 -C 4 alkylamino, carbamoyl, mono -N- or di-N, N-(C 1 -C 4) alkylcarbamoyl, cyano, thiol, notro, alkyl (C 1 -C 4) thio, alkyl (C 1 -C 4) sulfinyl, alkyl (Cr C 4) sulfonyl or mono- N- or di-N, N-C 1 -C 4 alkyl aminosulfonyl or optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. An especially preferred compound of formula I is the compound [1- (Naphthalen-1-yl) -5-cyclopropyl-1-pyrrazol-4-carbonyl] guanidine or the pharmaceutically acceptable salts thereof. A preferred group of compounds among the group R of compounds, designated as group S, contains those compounds in which R1 is cyclopropyl; and R 2 is 1-naphthalenyl or the pharmaceutically acceptable salts thereof. A group of preferred compounds among the group R of compounds, designated as group T, contains those compounds in which R1 is (C3-C7) cycloalkyl; and R2 is a six-membered monocyclic aromatic ring optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; said ring R2 being optionally monosubstituted on carbon or on nitrogen with a fully saturated or fully unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and, nitrogen, said ring optionally being monosubstituted with alkyl (d-C4); said ring R2 being optionally mono- or disubstituted independently on carbon or nitrogen with hydroxy, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C-1-C4) alkyl, alkanoyl (CrC4), (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkanoy amine, (C 1 -C 4) alkoxy carbonylamino, sulfonamido, (C 1 -C 4) alkyl sulfonamido, amino, mono-A / - or di -? /,? / - alkyl (C1-C4) amino, carbamoyl, mono- / V- od- / V,? / - (C1-C4) alkyl carbamoyl, cyano (C -? - C4) thio alkyl, (C1-C4) alkyl sulfinyl, (C 1 -C 4) alkylsulfonyl or mono -? / - or di -? /,? / - (C 1 -C 4) alkylsulfonyl; said (C1-C4) alkoxy, (C1-C4) alkyl, alkanoyl (C? -C), alkyl (CiQ thio, mono-? / - or di-? /,? / - (C1-C4) alkyl) amino being optionally monosubstituted with hydroxy, (C-1-C4) alkoxycarbonyl, (C1-C4) alkanoyl, (C1-C4) alkanoyl amino, (C1-C4) alkanoyloxy, (C1-C4) alkoxycarbonylamino, sulfonamido, alkyl (C1) -C4) sulfonamido, amino mono-? / - or di-?,? / - aIlkl (d-C4) amino, carbamoyl, mono-? / - or di-? /,? -alkyl (C1-C4) carbamoyl, alkyl (Cr C) thio, (C 1 -C 4) alkylsulfinyl, (C 1 -C 4) alkylsulphonyl or mono -? / - or di -? /,? / - (C 1 -C 4) alkylsulphonyl or optionally substituted with each other nine fluorine atoms or pharmaceutically acceptable salts thereof A preferred group of compounds from the group T of compounds, designated as group U, contains those compounds wherein R 1 is cyclopropyl, and R 2 is phenyl, optionally mono- or disubstituted independently with hydroxy, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) alkyl, alkanoyl (C1-C4) amino, (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, mono-? - or di-?,? / - (C1-C4) alkylamino, carbamoyl, mono-? - or di -? /,? / - (C1-C4) alkylcarbamoyl, (C1-C4) alkylsulphonyl or mono-? / - or di-?,? / - (C1-C4) alkylsulphonyl; said substituents being (C1-C4) alkoxy, (C1-C4) alkyl, mono-? / - or di-? /,? / - (C1-C4) alkyl amino optionally monosubstituted with hydroxyl, alkanoyl (C1-C4) amino , (C 1 -C 4) alkyl sulfonamido, amino, mono- / V- or di-? /,? / - (C 1 -C 4) alkyl amino, mono -? / - or di? /,? / - alkyl (C 1 -) C4) carbamoyl, alkyl (C1-C4) sulfonyl or mono-? / - or di-? /,? / - alky (C1-C4) amino-sulfonyl or optionally substituted with one to five fluorine atoms, or pharmaceutically salts acceptable from them. Especially preferred compounds of formula I are the compounds: [5-cyclopropyl-1- (2-trifluoromethyl-phenyl) -1H-pyrazole-4-carbonyl] guanidine; [5-cyclopropyl-1-phenyl-1 H-pyrazole-4-carbonyl] guanidine; or [5-cyclopropyl-1- (2,6-dichlorophenyl-1H-pyrazol-4-carbonyl] guanidine or the pharmaceutically acceptable salts thereof .. Other especially preferred compounds of formula I are the compounds: [1 - (2 -Chloro-4-methylsulfonylphenyl) -5-cyclopropyl-1 / - / - pyrazole-4-carbonyljuanidine; [1- (2-Chlorophenyl) -5-cyclopropyl-1 - -pyrrazol-4-carbonyl] guanidine; [1- (2-Trifluoromethyl) -4-fluorophen-I) -5-cyclopropyl-1-pyrazol-4-carbonyl] guanidine; [1- (2-Bromophenyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; [1 - (2-Fluorophenyl) -5-cyclopropyl-1 H-pyrazole-4-carbonyl] guanidine; [1 - (2-Chloro-5-methoxy-phenyl) -5-cyclopropyl-1 / - / - pyrazole-4-carbonyl] guanidine; [1- (2-Chloro-4-methylaminosulfonylphenyl) -5-cyclopropyl-1H-pyrazole-4-carbonyljguanidine; [1- (2,5-Dichlorophenyl-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; [1- (2,3-Dichlorophenyl-5-cyclopropyl-1H-pyrazole-4- carbonyl] guanidine; [1 - (2-Chloro-5-aminocarbonylphenyl) -5-cyclopropyl-1 / - / - pyrazole-4-carbonylguanidine; [1- (2-Chloro-5-aminosulfonylphenyl)] -5-cyclopropyl-1 H-pyrazole-4-carbonyljuanidine; [1- (2-Fluoro-6-trifluoromethylphenyl) -5-cyclopropyl-1-pyrazol-4-carbonyljuanidine; [1 - (2-chloro- 5-methylsulfonylphenyl) -5-cyclopropyl-1H-pyrazole-4-carbonyljguanidine; [1- (2-Chloro-5-dimethylaminosulfonyl-phenyl) -5-cyclopropyl-1-pyrazol-4-carbonyljguanidine; [1 - (2-Trifluoromethyl-4-chlorophenyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine, or the pharmaceutically acceptable salts thereof The compounds especially preferred within the group U are the compounds in which: a R2 is 2-chloro-4-methylsulfonyl-phenyl, b.R2 is 2-chlorophenyl, and R2 is 2-trifluoromethyl-4-fluorophenyl, and R2 is 2-bromophenyl; and. R2 is 2-fluorophenyl; F. R2 is 2-chloro-5-methoxyphenyl; g. R2 is 2-chloro-5-methylaminosulfonylphenyl; h. R2 is 2,5-dichlorophenyl; . R2 is 2,3-dichlorophenyl; j. R2 is 2-cyoro-5-aminocarbonylphenyl; k. R2 is 2-chloro-5-aminosulfonylphenyl; I. R2 is 2-fluoro-6-trifluoromethylfenyl; m. R2 is 2-chloro-5-methylsulfonylphenol; n. R2 is 2-chloro-5-dimethylaminosulfonylphenyl; or. R2 is 2-trifluoromethyl-4-chlorophenyl; c the pharmaceutically acceptable salts thereof. A preferred group of compounds from the group R of compounds, designated as group W, contains those compounds wherein R 2 is a non-aromatic heterocyclic ring of five to six links having from one to two heteroatoms independently selected from nitrogen, sulfur and oxygen or R2 is unsubstituted (C1-C4) alkyl, unsubstituted (C3-C7) cycloalkyl or (C1-C4) phenylalkyl, wherein said phenyl (C1-C4) alkyl is optionally mono- or disubstituted independently with hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, mono- ? / - or say -? /,? / - (C1-C4) alkyl amino, carbamoyl, mono- / V- or di-? /,? / - (C1-C4) alkyl carbamoyl, alkyl (C4) sulfonyl or mono-? / - or di-? /,? / - (C1-C4) alkyl aminosulfonyl, said substituents being (C1-C4) alkoxy, (C1-C4) alkyl, mono-? / - or di-? / ,? / - (C1-C4) alkyl amino are optionally monosubstituted two with hydroxy, (C1-C4) alkanoylamino, (C1-C4) alkyl sulfonamido, amino, mono-N- or di-? /,? - (C1-C4) alkylamino, mono-? / - or di- ?,? - alkyl (C4) carbamoyl, (C1-C4) alkylsulphonyl or mono-? / - or di-?,? -alkyl (C1-C4) carbamoyl or optionally substituted with one to five fluorine atoms; or the pharmaceutically acceptable salts thereof. A group of compounds preferred among the group R of compounds, designated as group X, contains those compounds in which R is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or totally unsaturated, considered independently, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said R2 substituent being optionally substituted on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with (C1-C4) alkyl and optionally R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (C-1) -C4), (C1-C4) alkoxycarbonyl, (C1-C4) alkyl, formyl, (C1-C4) alkanoyl, (C-1-C4) alkanoyloxy, (C1-C4) alkanoylamino, (C1-C4) alkoxy ) carbonylamino, sulfonamido, alkyl (C1-C4) sulfonamido, amino, mono -? / - or di -?,? - a! quil (C1-C4) amino, carbamoyl, mono-? / - or di N, N-alkyl (C1-C4) carbamoyl, cyano, thiol, alkyl (C? -C4) thio, alkyl (C -? - C4) sulfinyl, alkyl (C1-C4) sulfonyl, mono-? / - or di-?,? / - (C1-C4) alkyl aminosulfonyl, alkenyl ( C2-C), (C2-C4) alkynyl or (C5-C7) cycloalkenyl, said substituents R6, R7 and R8 are (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C7) alkanoyl, alkyl ( CrC4) thio, mono-? / - or dí?,? / - alkyl (CrC4) amino or (C3-C7) cycloalkyl optionally independently monosubstituted with hydroxy, (C1-C4) alkoxycarbonyl, (C3-C7) cycloalkyl, alkanoyl (CrC), (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono -? / - or di-? /,? / - (C1-C4) alkyl amino, carbamoyl, mono -? / - or di -?,? - (C1-C4) alkyl carbamoyl, cyano, thiol, nitro, alkyl (CrC4) thio, alkyl (C1) -C4) sulfinyl, alkyl (Cr C4) sulfonyl or mono-? / - or di-? /,? / - (C1-C4) alkyl aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. A group of compounds preferred among the group X of compounds, designated as group Y, contains those compounds in which R1 is (C3-C7) cycloalkyl; and R is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said bicyclic ring being R2 optionally monosubstituted on carbon or nitrogen with a fully saturated or fully unsaturated ring of five and six links optionally having up to three heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring being optionally monosubstituted with alkyl (Cr C4) and said ring being bicyclic R2 optionally mono or disubstituted on carbon or the nitrogen with hydroxy, halogen, (C 1 -C 4) alkoxy (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkanoyl, (C 4) alkanoyloxy, alkanoyl ( C1-C4) amino, (C1-C4) alkoxycarbonylamino, sulfonamido, alkyl (C1-C) sulfonamido, am or mono-? - or di-? /,? - (C 1 -C 4) alkyl amino, carbamoyl, mono -? / - or di -? /,? - (C 1 -C 4) alkyl carbamoyl, cyano, alkyl ( C? -C4) thio, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulphonyl or mono-? / - or di-?,? / - (C1-C4) alkylsulfonyl, said alkoxy being (C1- C4), (C1-C4) alkyl, (C1-C7) alkanoyl, alkyl (C? -C) thio, mono-? / - or di-? /,? / - (C1-C4) alkylamino optionally monosubstituted with hydroxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkyl sulfonamido , amino, mono-? - or di-?,? - (C 1 -C 4) alkyl amino, carbamoyl, mono -? / - or di -? /,? / - (C 1 -C 4) alkyl carbamoyl, alkyl (C? -C) thio, (C 1 -C 4) alkyl sulfinyl, (C 1 -C 4) alkylsulphonyl or mono -? / - or di -?,? / - (C 1 -C 4) alkylsulphonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. A group of compounds preferred among the group Y of compounds, designated as group Z, contains those compounds in which R1 is cyclopropyl; and R2 is quinazolinyl, R2 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cincholinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl, benzimidazolyl, indazolyl, indolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiadiazolyl group, said ring bicyclic R2 being optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) alkyl, alkanoyl (CrC4) amine, alkoxy ( C1-C4) carbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, mono-? / - or di-? /,? -alkyl (C1-C4) amino, carbamoyl, mono-? / - or di-? /, ? / - (C 1 -C 4) alkylcarbamoyl, (C 1 -C 4) alkylsulphonyl, or mono- / V- or -N, N- (C 1 -C 4) alkylsulfonyl, said substituents being (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, mono -? / - or di-? ./V- (C1-C4) alkylamino optionally monosubstituted with hydroxy, (C1-C4) alkanoylamino, (C1-C4) alkyl sulfonamido, amino, mono-? / - or di-? /,? / - alkyl ( C1-C4) amino, mono-? / - or di-? /,? / - (C1-C4) alkyl carbamoyl, (C1-C4) alkylsulphonyl or mono-? / - or di-? /,? -alkyl (C1-C4) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. A group of compounds preferred among the group Z of compounds, designated as group AA, contains those compounds in which R2 is a quinolinyl, isoquinolinyl, indazolyl or benzimidazolyl ring, said bicyclic ring R2 being optionally mono- or disubstituted independently on carbon or nitrogen with hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkyl, alkanoyl (dC 4) amino, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkyl sulfonamido, mono-? or di-? /,? / - (C 1 -C 4) alkyl amino, carbamoyl, mono -? / - or di -? /,? - (C 1 -C 4) alkyl carbamoyl, (C 1 -C 4) alkylsulphonyl or mono- ? / - od \ -N, N-C 1 -C 4 alkyl aminosulfonyl, said substituents being (C 1 -C 4) alkoxy or (C 1 -C 4) alkyl are optionally monosubstituted with hydroxy, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkylsulfonamido, amino, mono- or di- ? /,? - (C 1 -C 4) alkyl amino, mono -? / - or di -? /,? / - (C 1 -C 4) alkyl carbamoyl, (C 1 -C 4) alkylsulphonyl or mono -? / - or di -?,? - (C 1 -C 4) aminosulfonyl (optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof). Especially preferred compounds of formula I are the compounds: [5-cyclopropyl-1- (quinolin-8-yl) -1H-pyrazole-4-carbonyl] guanidine; or [5-cyclopropyl-1 - (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine; or the pharmaceutically acceptable salts thereof. The preferred salts of the last-mentioned compound are the mono or dimesylate salts. Other especially preferred compounds of formula I are the compounds [1- (8-Bromoquinolin-5-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; [1- (6-Choroquinoline-5-yl) -5-cyclopropyl-1-pyrazol-4-carbonyl] guanidine; [1 - (ldazol-7-yl) -5-cyclopropyl-1-pyrazol-4-carbonyl] guanidine; [1- (Benzamidazol-5-yl) -5-cyclopropyl-1 - / - pyrazole-4-carbonyl] guanidine; [1 - (1-lsoquinolin) -5-cyclopropyl-1 - pyrrazol-4-carbonyl] guanidine; [5-Cyclopropyl-1- (4-quinolin) -1 - -p -razol-4-carbonyl] guanidine; or the pharmaceutically acceptable salts thereof. Especially preferred compounds within the AA group are the compounds in which a. R2 is 8-bromoquinolin-5-ylo; b. R2 is 6-chloroquinolin-5-yl; c. R is indazol-7-yl; d. R2 is benzimidazol-5-yl; and. R2 is 1-isoquinolyl; F. R2 is 4-quinolinyl; or the pharmaceutically acceptable salts thereof. A preferred group of compounds, designated as group BB, contains those compounds having the formula I as shown above in which Z is R1 is (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or phenyl (C1-C4) alkyl, said (C1-C4) alkyl being optionally substituted with one to nine fluorine atoms, said substituent R1 being optionally mono - or independently disubstituted with (C 1 -C 4) alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl, sulfinyl or C 1 -C 4 alkylsulfonyl and R 2 is a non-aromatic heterocyclic ring of five to six links has one to two heteroatoms independently selected from nitrogen, sulfur and oxygen or R 2 is unsubstituted (C 1 -C 4) alkyl or unsubstituted (C 3 -C 7) cycloalkyl; or R2 is phenyl (C1-C4) alkyl or a bicyclic ring constituted by two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen being said R2 substituents optionally substituted on carbon or nitrogen with up to three substituents selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links having optionally from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted by (C 1 -C 4) alkyl and optionally R 6, R 7 and R 8 are optionally hydroxy, nitro, halogen, alkoxy (CrC 4), (C 1 -C 4) alkoxycarbonyl , (C 1 -C 4) alkyl, formyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkanoyl amino, (C 1 -C 4) alkoxy carbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono -? / - or di -?,? / - alkyl (Cr C 4) amino, carbamoyl, mono -? / - or di- ?,? - (C 1 -C 4) alkylcarbamoyl, cyano, thiol, alkyl (CtC 4) thio, alkyl (C 1 -C 4) sulfinyl, alkyl (C 1 -C 4) sulfonyl, mono -? / - or di -? /,? / -alkyl (C-1-C4) aminosulfonyl, alkenyl (C2-C4), alkynyl (C2-C4) or cycloalkenyl (C5-C7), said alkoxy (C1-C4), (C1-C4) alkyl, alkanoyl being (C -? - C7), alkyl (C? - C4) thio, mono -? / Or di -? /,? - (C1-C4) alkyl amino or cycloalkyl (C3-C7) and substituents R6, R7 and R8 optionally independently monosubstituted with hydroxy, (C1-C4) alkoxycarbonyl, (C3-C7) cycloalkyl, (C1-C4) alkanoyl, (C1-C4) alkanoyl amino, (C-1-C4) alkanoyloxy, (C1-6) alkoxy C4) carbonylamine, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono -? / - or di -? /,? / - (C 1 -C 4) alkyl amino, carbamoyl, mono -? / - or di- ?, ? / - (C 1 -C 4) alkylcarbamoyl, cyano thiol, nitro, alkyl (C 1 -C 4) thio, alkyl (C 1 -C 4) sulfinyl, alkyl ( C-r C4) sulfonyl or mono-? / - or di-?,? / - aiquil (C 1 -C 4) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. A group of compounds preferred among the group BB of compounds, designated as group CC, contains those compounds in which R1 is (C1-C4) alkyl; and R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring being bicyclic R2 optionally monosubstituted on carbon or nitrogen with a five to six link ring, fully saturated or fully unsaturated having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with (C1-C4) alkyl ) and said bicyclic ring R2 being optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoyloxy, (C 4) alkanoylamino, alkoxy (C-) 1-C4) carbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, amino, mono-? / - od? -? /,? - (C1-C4) alkylamino, carbamoyl, mono-? / - or di-? /,? - alkyl (C1-C4) carbamoyl, cyano (C? -C) thio, alkyl (C-1-C4) sulfinyl, alkyl (C1-C4) sulfonyl or mono-? / - or di-? / ,? / - (C 1 -C 4) alkyl aminosulfonyl, said (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, (C 1 -C 7) alkanoyl, (C 1 -C) alkyl, mono-? / - or di -? /,? - (C 1 -C 4) alkylamino optionally monosubstituted with hydroxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoylamino, alkanoyloxy (C 1 -C 4) ), (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono -? / - or dí -? /,? - alkyl (CrC) amino, carbamoyl, mono -? / - od \ -N, N-C 1 -C 4 alkylcarbamoyl, alkyl (CrC) thio, alkyl (C 1 -C 4) sulfinyl, alkyl (C 1 -C 4) sulfonyl or mono -? / - or di -? /,? / - alkyl (C1-C4 ) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. A preferred group of compounds from the CC group of compounds, designated as the DD group, contains those compounds in which R2 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cinolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl, benzimidazolyl ring; ndazolyl, indolyl, benzotriazole, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiadiazolyl, said bicyclic ring R2 being optionally mono- or disubstituted independently with hydroxy, halogen, (C1-C4) alkoxy, (C-1-C4) alkoxycarbonyl , (C1-C4) alkyl, (C1-C4) alkanoylamino, (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, mono-? / - od \ -N, N-alkyl (C1- C4) amino, carbamoyl, mono -? / - or di -?,? - alkyI (C1-C4) carbamoyl, (C1-C4) alkylsulfonyl, or mono-? - or di-? /,? / - alkyl ( C1-C4) aminosulfonyl, said substituents being (C1-C4) alkoxy, (C1-C4) alkyl, mono-? / - or di-? /,? / - a (C 1 -C 4) amino optionally monosubstituted with hydroxy, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkylsulfonamido, amino, mono-ω / - or dí-γ, γ-alkyl ( C1-C4) amine, mono-? / - or di-? /,? / - (C1-C4) alkyl carbamoyl, (C1-C4) alkylsulfonyl or mono- / V- or di-?,? -alkyl ( C1-C4) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. Especially preferred compounds of formula I are the compounds: [1- (ldazol-6-yl) -5-ethyl-1-pyrazol-4-carbonyl] guanidine; [1- (ldazol-5-yl) -5-ethyl-1 - / - pyrazole-4-carbonyl] guanidine; [1 - (Benzimidazol-5-yl) -5-etl-1 - / - pyrazole-4-carbonyl] guanidine; [1- (1-Methylbenzimidazol-6-yl) -5-ethyl-1 H-pyrazole-4-carbonyl] guanidine; [1 - (5-Quinolin-5) -p-propyl-1 H-pyrazole-4-carbonyl] guanidine; [1- (5-Quinolin-5) -sopropyl-1 / - -p-aceol-4-carbonyl] guanidine; [5-Ethyl-1 - (6-quinolin-1-p-pyrazol-4-carbonyl] guanidine; [1 - (2-Methylbenzimidazo-5-yl) -5-etl-1 H-pyrazole-4-carbonyl ] guanidine; [1 - (1, 4-Benzodioxan-6-yl) -5-ethyl-1 H-pyrazole-4-carbonyl] guanidine; [1- (Benzotriazol-5-yl) -5-ethyl-1-pyrazol-4-carbonyl] guanidine; [1- (3-Chloroindazol-5-yl) -5-ethyl-1 - / - pyrazole-4-carbonyl] guanidine; [1 - (5-Quinolin) -5-butyl-1 H-pyrazole-4-carbonyl] guanidine; [5-Propyl-1 - (6-quinolin) -1 - / - pyrazole-4-carbonyl] guanidine; [5-lsopropyl-1 - (6-quinoline) -1-pyrazol-4-carbonyl] guanidine; or the pharmaceutically acceptable salts thereof. Especially preferred compounds within the DD group are compounds in which a. R1 is ethyl; and R 2 is indazol-6-yl; b. R1 is ethyl; and R2 is indazol-5-yl; c. R1 is ethyl; and R2 is benzimidazol-5-yl; 15 d. R1 is ethyl; and R2 is 1-methylbenzimidazol-6-yl; and. R1 is n-propyl; and R2 is 5-quinolinyl; F. R1 is isopropyl; and R 2 is 5-quinolinyl; g. R1 is ethyl; and R2 is 6-quinolinyl; h. R1 is ethyl; and R2 is 2-methylbenzimidazol-5-yl; i. R1 is ethyl; and R2 is 1,4-benzodioxan-6-yl; j. R1 is ethyl; and R2 is benzotriazol-5-yl; k. R1 is ethyl; and R2 is 3-chloroindazol-5-yl; I. R1 is butyl; and R2 is 5-quinolinyl; m. R1 is p-propyl; R2 is 6-quinolinyl; n. R1 is isopropyl; and R2 is 6-quinolinyl; or the pharmaceutically acceptable salts thereof. A preferred group of compounds, designated as group EE, contains those compounds having the formula I as shown above in which Z is R1 is (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or phenyl (C1-C4) alkyl, said (C1-C4) alkyl being optionally substituted with one to nine fluorine atoms, said substituent R1 being optionally mono -, or independently substituted with (C 1 -C 4) alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl or C 1 -C 4 alkylsulfonyl and R 2 is a non-aromatic heterocyclic ring of five to six links; having one to two heteroatoms independently selected from nitrogen, sulfur and oxygen; or R 2 is unsubstituted (C 1 -C 4) alkyl or unsubstituted (C 3 -C 7) cycloalkyl; or R2 is phenyl (C1-C4) alkyl or a bicyclic ring constituted by two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having between one and four heteroatoms independently selected from nitrogen, sulfur and oxygen, said R2 substituents being optionally substituted on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with (C 1 -C 4) alkyl and further R 6, R 7 and R 8 are optionally hydroxy, nitro, halogen, (C 1 -C 4) alkoxy, alkoxy ( C1-C4) carbonyl, (C1-C4) alkyl, formyl, (C1-C4) alkanoyl, (C1-C4) alkanoyloxy, (C 1 -C 4) amino, (C 1 -C 4) alkoxy carbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono -? / - or di -?,? / - (C 1 -C 4) alkyl amine, carbamoyl , mono-? / - od \ -N, N-alkyl (C1-C4) carbamoyl, cyano, thiol, alkyl (C? -C) thio, alkyl (C1-C4) sulfinyl, alkyl (CrC) sulfonyl, mono- ? / - or di -? /,? /; - (C1-C4) alkyl aminosulfonyl, alkenyl (C2-C), alkynyl (C2-C) or cycloalkenyl (C5-C7), said substituents R6, R7 and R8 (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, (C 1 -C 7) alkanoyl, (C 1 -C 4) alkyl, mono -? / - or di -? /,? / - alkyl ( C C4) amine or (C3-C7) cycloalkyl optionally independently monosubstituted with hydroxy, (C-1-C4) alkoxycarbonyl, (C3-C) cycloalkyl, (C1-C4) alkanoyl, (C1-C4) alkanoylamino, alkanoyloxy (C1-C4), (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, amino, mono-? / - or di-? /,? -alkyl (C1-C4) amino, carbamoyl, mono -? / - or dí -? /,? - alkyl (C 1 -C 4) carbamoyl, cyano, thiol, nitro, alkyl (C? -C4) thio, alkyl (C1-C4) sulfinyl, alkyl (Cr C4) sulfonyl or mono-? / - or di-?,? / - (C 1 -C 4) alkylsulphonyl or optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. A group of compounds preferred among the group EE of compounds, designated as group FF, contains those compounds in which R1 is alkyl (d-C4); and R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring being bicyclic R2 optionally monosubstituted on carbon or nitrogen with a fully saturated or fully unsaturated ring of 5 to 6 links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (Ci-C4) and said bicyclic ring R2 also optionally mono- or di-substituted on carbon or nitrogen with hydroxy, halogen, (C1-C4) alkoxy, (C? -C4) alkoxycarbonyl, (C1-C4) alkyl, (C1-C4) alkanoyl, (C-1-C4) alkanoyloxy, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, alkyl (CiC) su lfonamido, amino, mono-N- or di-N, N-C 1 -C 4 alkylamino, carbamoyl, mono-N- or di-N, N-C 1 -C 4 alkylcarbamoyl, cyano, alkyl (C? -C4) thio, alkyl (C1-C) sulfinyl, alkyl (C1-C4) sulfonyl or mono-N- or di-NN-alkyl (C1-C4) aminosulfonyl, said alkoxy (C1-C4), alkyl (C1) -C4), alkanoyl (C? -C7), alkyl (C? -C4) thio, mono-N- or di-N, N-alkyl (C-1-C4) amino optionally monosubstituted with hydroxy, alkoxy (C? -C) carbonyl, alkanoyl (C1-C4), alkanoyl (C1-C4) amino, alkanoyloxy (C-1-C4), alkoxy (C1-C4) carbonylamino, sulfonamido, alkyl (C1-C4) sulfonamido, amino, mono -N- or di-N, N-C1-C4alkylamino, carbamoyl, mono-N- or d '\ - N, N- (C1-C4) alkylcarbamoyl, alkyl (C? -C4) thio, (C 1 -C 4) alkylsulfinyl, (C 1 -C 4) alkylsulphonyl or mono-N- or di-NN-C 1 -C 4 alkylaminosulphonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts of the same.

A group of preferred compounds among the FF group of compounds, designated as the DD group, contains those compounds in which R2 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cinolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl, benzimidazole, indazolyl, indolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiazolyl, said bicyclic ring being R2 optionally mono- or disubstituted independently with hydroxy halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, alkyl (C1-C4), (C1-C4) alkanoylamino, (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, mono-N or di-NN-alkyl (0-4) amino, carbamoyl, mono-N- or di-NN-C 1 -C 4 alkylcarbamoyl, C 1 -C 4 alkylsulfonyl, or mono-N- or di-N, N-C 1 -C 4 alkylaminosulfonyl, said alkoxy substituents being ( CTC4), (C-1-C4) alkyl, mono-N- or di-N, Nalkyl (0 ^ 4 ) amino optionally monosubstituted with hydroxy, (C 1 -C 4) alkanoylamino, alkyl (0 4) sulfonamido, amino, mono-N- or di-NN-alkyl (C 1 -C 4) amino, mono-N- or di -N, N-C 1 -C 4 alkylcarbamoyl, C 1 -C 4 alkylsulfonyl or mono-N- or di-NN-C 1 -C 4 alkylaminosulfonyl or optionally substituted with one to nine fluorine atoms, or pharmaceutically acceptable salts thereof. Especially preferred compounds of formula I are the compounds [1- (ldazol-7-yl) -3-methyl-1 H -pyrazole-4-carbonyl] guanidine; [1 - (2,1, 3-Benzothiadiazol-4-yl) -3-methyl-1 H-pyrazol -carbonyljguanidine; [3- (Methyl- (1-quinolin-5-yl) -1 / -pyrazol-4-carbonyl] guanidine, or the pharmaceutically acceptable salts thereof The especially preferred compounds among the GG group of compounds are the compounds wherein a.R1 is methyl, and R2 is ndazol-7-yl, b.R1 is methyl, and R2 is 1, 2,3-benzothiadiazol-4-yl, c.R1 is methyl, and R2 is quinolin-5-yl, or the pharmaceutically acceptable salts thereof A preferred group of compounds, designated as the HH group, contains those compounds having the formula I, as shown above in which Z is R4 is (C1-C4) alkyl, (C3-C) cycloalkyl, phenyl or phenyl (C1-C4) alkyl, said (C1-C4) alkyl being optionally substituted with one to nine fluorine atoms, said substituent R4 being optionally mono - or independently disubstituted with (C 1 -C 4) alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl, sulfinyl or C 1 -C 4 alkylsulfonyl and R 5 is a non-aromatic heterocyclic ring of five to six links, having from one to two heteroatoms independently selected from nitrogen, sulfur and oxygen or R5 is unsubstituted (C1-C4) alkyl or (C3-C7) cycloalkyl; or R5 is phenyl (C1-C4) alkyl or a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said substituents R5 being optionally substituted on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with (C 1 -C 4) alkyl and further R 6, R 7 and R 8 are optionally hydroxy, nitro, halogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkyl, formyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoyloxy, alkoxy anion (C 1 -C 4) amine, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkyl sulfonamido, amino, mono-N- or di-N, N-(C 1 -C 4) alkylamino, carbamoyl, mono -N- or di-N, N-alkyl (CrC) carbamoyl, cyano, thiol, alkyl (C1-C4) thio, alkyl (CrC4) sulfinyl, alkyl (C1-C4) sulfonyl, mono-N- or di-N, N-alkyl (C-C4) aminosulfonyl, alkenyl (C2-C), alkynyl (C2-C) or cycloalkeno (C5-C7), said substituents R6, R7 and R8 are alkoxy (C1-C4), (C1-C4) alkyl, (C1-C7) alkanoyl, (C? -C4) alkyl, mono-N or di-N, N-(C1-C4) alkyl amino or cycloalkyl (C3) -C7) optionally independently monosubstituted with hydroxy, (C1-C4) alkoxycarbonyl, (C3-C7) cycloalkyl, (C1-C4) alkanoyl, (C1-C4) alkanoyl amino, (C1-C4) alkanoyloxy, (C1-6) alkoxy C4) carbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono-N-di-N, N-C 1 -C 4 alkylamino, carbamoyl, mono-N- or di-N, N-alkyl ( C1-C4) carbamoyl, cyano, thiol, nitro, alkyl (CC ^ thio, alkyl (C? -C) sulfynyl, alkyl (Ci-C4) sulfonyl or mono-N- or di-N, N-alkyl (C1-) C4) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof A preferred group of compounds from the group HH of compounds, designated as group II, It has those compounds in which R4 alkyl (C C4); and R5 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, independently having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring being Bicyclic R5 optionally monosubstituted on carbon with a fully saturated or fully saturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with (C1-C4) alkyl and said bicyclic ring R5 being optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, (C1-C4) alkoxy, (C4) alkoxycarbonyl, (C1-C4) alkyl, (C1-C4) alkanoyl, alkanoyloxy (C1) -C4), (C1-C4) alkanoylamino, (C1-C4) alkoxycarbonylamino, sulfonamido, a alkyl (C1-C4) sulfonamido, amino, mono-N- or di-N, N-alkyl (C1-C4) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, cyano, alkyl (C? -C4) thio, (C-1-C4) alkylsulfinyl, alkyl (Cr C) sulfonyl or mono-N- or di-N, N-alkyl (C-1-C4) aminosulfonyl, said (C1-C4) alkoxy, (C1-C4) alkyl, alkanoyl (C? -C7), alkyl (C? -C) thio, mono-N- or di-N, N-alkyl (C1-C4) amino optionally monosubstituted with hydroxyl, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoyl amino, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, alkyl (0 ^ 4) sulfonamido, amino, mono-N- or di-N, N-alkyl (CiC) amino, carbamoyl, mono-N- or di-N, N-alkyl (C-1-C4) carbamoyl, (C1-C) alkylthio, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulphonyl or mono-N- or di-N, N-(C1-C4) alkylsulphonyl or optionally substituted with one to nine atoms of fluorine, or the pharmaceutically acceptable salts thereof.

A group of compounds preferred among group II of compounds, designated as group JJ, contains those compounds in which R5 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cinolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl, benzimidazolyl, indazolyl ring. , indolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiazololyl, said bicyclic ring R5 being optionally mono- or di-substituted independently with hydroxy, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, alkyl ( C1-C4), (C1-C4) alkanoylamino, (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkyl sulfonamido, mono-N- or di-N, N-C1-C4alkylamino, carbamoyl, mono-N- or di-N, N-alkyl (C-1-C4) carbamoyl, alkyll (C1-C4) sulfonyl, or mono-N- or di-N, N-alkyl (C1-C4) aminosulfonyl , said substituents being (C1-C4) alkoxy, (C1-C4) alkyl, mono-N- or di-N, N-alkyl (C1-C4) amino optionally monosubstituted with hydroxy, alkanoyl (CrC4) amino, alkyl (C1-C4) sulfonamido, amino, mono-N- or di-N, N-alkyl (C1-C4) amino, mono-N or di-N, N-C 1 -C 4 alkylcarbamoyl, C 1 -C 4 alkylsulfonyl or mono-N- or di-N, N-C 1 -C 4 alkylsulphonyl or optionally substituted with one to nine fluorine atoms , or the pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated as group KK, contains those compounds having the formula I as shown above in which Z is R is (C 1 -C 4) alkyl, (C 3 -C 7) cycloalkyl, M or M (C 1 -C 4) alkyl, optionally any of said above (C 1 -C 4) alkyl moieties of one to nine fluorine atoms; said (C1-C4) alkyl or (C3-C4) cycloalkyl optionally mono- or di-substituted independently with hydroxy, (C1-C4) alkoxy, alkyl (CrC ^ thio, C1-C4 alkyl) sulfinyl, (C1-C4) alkyl sulfonyl, (C 1 -C 4) alkyl, mono-N- or di-N, N-alkyl (C 1 -C 4) carbamoyl or mono-N-od-N, N-C 1 -C 4 alkyl aminosulfonyl and having said cycloalkyl (C3-C4) optionally from one to seven fluorine atoms, M being a partially saturated, fully saturated or fully unsaturated ring of five to eight links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two partially saturated, fully saturated or fully unsaturated fused rings of three to six links, independently considered, optionally having from one to four independently selected heteroatoms, between nitrogen, sulfur and oxygen; said optionally substituted M being on a ring if the moiety is monocyclic, on one or both rings if the remainder is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, where one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with (C1-C4) alkyl and further R6, R7 and R8 are optionally hydroxy, nitro, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) alkyl, formyl, (C1-C4) alkanoyl, (C1-C4) alkanoyloxy, alkanoyl ( C1-C4) amine, (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, amino, mono-N- or di-N, N-(C1-C4) alkylamino, carbamoyl, mono-N - or di-N, N-alkyl (C1-C4) carbamoyl, cyano, thiol, alkyl (C? -C4) thio, alkyl (C1-C4) sulf inyl, (C 1 -C 4) alkylsulphonyl, mono-N- or N, N-C 1 -C 4 alkylaminosulfonyl, alkenyl (C 2 -C 4), alkynyl (C 2 -C) or cycloalkenyl (C 5 -C 7), said substituents R6, R7 and R8 being (C1-C4) alkoxy, (C1-C4) alkyl, alkanoyl (C? -C7), alkyl (C -? - C4) t, mono-N- or di-N , N-alkyl (C1-C4) amino or cycloalkyl (C3-C7) optionally independently monosubstituted with hydroxy, (C 1 -C 4) alkoxycarbonyl, (C 3 -C 7) cycloalkyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, alkyl ( C1-C4) sulfonamido, amino, mono-N- or di-N, N-alkyl (C1-C4) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, cyano, thiol, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl or mono-N- or di-N, N-C 1 -C 4 alkylaminosulfonyl or optionally substituted with one to nine fluorine atoms; and R3 is (C1-C4) alkyl, (C3-C7) cycloalkyl, phenyl or phenyl (C1-C4) alkyl, said (C1-C4) alkyl being optionally substituted with one to nine fluorine atoms, said substituent R3 being optionally mono- or di-substituted independently with (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, alkyl (dC) sulfinyl or (C 1 -C 4) alkylsulfonyl or (C 1 -C 4) alkyl or a pharmaceutically acceptable salt thereof . A preferred group of compounds among the group KK of compounds, designated as group LL, contains those compounds in which R3 is (C1-C4) alkyl; R2 is phenyl, said phenyl being optionally monosubstituted on carbon with a fully saturated or fully unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (C1 -C4), said ring R2 also being optionally mono- or disubstituted independently on carbon with hydroxy, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) alkyl, alkanoyl (C-1) C4), (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono-N- or di-N, N-alkyl (C 1 -C 4) amino, carbamoyl, mono-N- or di-N, N-C 1 -C 4 alkylcarbamoyl, cyano, alkyl (dC) thio, alkyl (C 1 -C 4) sulfinyl, alkyl (C? -C4) sulfonyl or mono-N- or di-N, N-alkyl (C1-C4) aminosilfonilo, said alkoxy (C1-C4), alkyl (C1-C4), alkanoyl (C1-C7), alkyl (C) ? -C4) t io, mono-N- or di-N, N-C 1 -C 4 alkylamino optionally monosubstituted with hydroxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoy amino, alkanoyloxy ( C1-C4), (C1-C4) alkoxycarbonylamino, sulfonamido, (C1-C4) alkylsulfonamido, amino, mono-N- or di-N, N-alkyl (C4) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, alkyl (Cr C4) thio, alkyl (C? -C4) sulfinyl, alkyl (C1-C4) sulfonyl or mono-N- or di-N, N-alkyl (C1-C4) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. A group of preferred compounds among the KK group of compounds, designated as the MM group, contains those compounds wherein R3 is (C1-C4) alkyl; R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated bonds independently considered, said bicyclic ring R2 being optionally monosubstituted on carbon with a fully saturated or fully saturated ring of five to six said links optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen said ring being optionally monosubstituted with (C1.-C4) alkyl, said bicyclic ring R2 being optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkoxy carbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono-N- or di-N, N-C 1 -C 4 alkylamino, carbamoyl, mono-N- or di- N, N-alkyl (C1-C4) carbamoyl, cyano (C 1 -C) thio, (C 1 -C 4) alkylsulfinyl, (C 1 -C 4) alkylsulphonyl or mono-N- or di-N, N-C 1 -C 4 alkylaminosulfonyl. said (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, (C 1 -C 7) alkanoyl, alkyl (C 1 -C 4) thio, mono-N- or di-N, N-C 1 -C 4 alkyl being optionally monosubstituted with hydroxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, alkyl (C1) -C4) sulfonamido, amino, mono-N- or di-N, N-alkyl (C1-C4) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, alkyl (C1) -C) thio, alkyl (C-1-C4) sulfinyl, alkyl (C-1-C4) sulfonyl or mono-N- or di-N, N-alkyl (C4) aminosulfonyl or optionally substituted with one to nine atoms of fluorine, or the pharmaceutically acceptable salts thereof. A group of preferred compounds among the group KK of compounds, designated group NN, contains those compounds in which R3 is alkyl (C4); R is a monocyclic aromatic ring of five to six links having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said bicyclic ring R2 being optionally monosubstituted on carbon with a fully saturated or fully unsaturated ring of five to six links, optionally having from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with (C 1 -C 4) alkyl, said ring R 2 being also optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, alkoxy ( C1-C4), (C1-C4) alkoxycarbonyl, (C-1-C4) alkyl, (C1-C4) alkanoyl, (C1-C4) alkanoyloxy, (C-1-C4) alkanoy amine, (C1-6) alkoxy C4) carbonylamino, sulfonamido, alkyl (C 1 -C 4) sulfonamido, amino, mono-N- or di-N, N-alkyl (C 1 -C 4) amino, carbamoyl, mono-N- or di-N, N-alkyl ( C1-C4) carbamoyl, cyano, alkyl (C? -C4) thio, a (C 1 -C 4) alkylsulfinyl, (C 1 -C 4) alkylsulphonyl or mono-N- or N, N-alkyl (CrC) aminosulfonyl, said alkoxy (C 1 -C 4), (C 1 -C 4) alkyl, alkanoyl being (C1-C7), alkyl (C? -C4) thio, mono-N- or di-N, N-alkyl (C-1-C4) amino optionally monosubstituted with hydroxy, (C1-C4) alkoxycarbonyl, alkanoyl ( C1-C4), (C1-C4) alkanoylamino, (C1-C4) alkanoyloxy, (C1-C4) alkoxycarbonylamino, sulfonamido, (C-1-C4) alkylsulfonamido, amino, mono-N- or di-N , N-alkyl (CiC) amino, carbamoyl, mono-N- or di-N, N-C 1 -C 4 alkylcarbamoyl, alkyl (C 1 -C) thio, alkyl (CrC 4) sulfinyl, alkyl (C-1) C4) sulfonyl or mono-N- or di-N, N-alkyl (CrC4) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts thereof. A preferred group of compounds from the KK group of compounds, designated as OO group, contains those compounds in which R3 is (C1-C4) alkyl; R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated bonds independently considered, having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen, said bicyclic ring R3 being optionally monosubstituted carbon with a fully saturated or fully unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with (C1-C4) alkyl and said bicyclic ring being R2 optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoyloxy ), (C 1 -C 4) alkanoyl amino, (C 1 -C 4) alkoxy carbonylamino, sulfonamido, (C 4) alkyl sulfonamido, a mino, mono-N- or di-N, N-(C 1 -C 4) alkyl amino, carbamoyl, mono-N- or di-N, N-alkyl (C 1 -C 4) carbamoyl, cyano (C -? - C4) alkyl ) thio, alkyl (C 1 -C 4) sulfinyl, alkyl (C 1 -C 4) sulfonyl, or mono-N- or di-N, N-alkyl (C 1 -C 4) aminosulfonyl, said alkoxy (C 1 -C 4) being , (C1-C4) alkyl, (C-1-C7) alkanoyl, (C? -C) thio alkyl, mono-N- or di-N, N-(C1-C4) alkylamino are optionally monosubstituted with hydroxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkanoyl, (C 1 -C 4) alkanoyl amino, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkoxycarbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono-N- or di-N, N-alkyl (CiC) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4), carbamoyl, alkyl (Ci-C4) thio, alkyl (0 ^ 4) sulfinyl, (C 1 -C 4) alkylsulphonyl or mono-N- or di-N, N-C 1 -C 4 alkylaminosulphonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salts of the same. Another aspect of this invention relates to the esters 5-cyclopropyl-1- (2-trifluoromethylene) -1H-pyrazole-4-carboxylate, 5-methyl-1- (6-quinoline) -1H-pyrazole- 4-carboxylate, 5-methyl-1-naphthalenyl-1 H-pyrazole-4-carboxylate, 5-cyclopropyl-1 - (quinolin-8-yl) -1 H -pyrazole-4-carboxylate, 5-cyclopropyl -1 - (quinolin-5-yl) -1-pyrazol-4-carboxylate, 5-ethyl-1 - (quinolin-5-yl) -1 H-pyrazole-4-carboxylate or A7-butyl-1- ( isoquinolin-5-yl) -3-methyl-1-p-pyrazol-4-carboxylate, wherein said esters are benzyl, alkyl (C? -C6) or cycloalkyl (C4-C8), said cycloalkyl being (C4- C8) optionally substituted with (C1-C4) alkyl or a salt of said esters.

Another aspect of this invention relates to the following compounds: 5-Methyl-2- (5-quinolin) -2H-1, 2,3-triazole-4-carboxylic acid, 5-methyl-2- ( 5-isoquinolin) -2 / - -1,2,3-triazole-4-carboxylic acid, 2- (2-naphthalenyl) -5-methyl-2 / - / - 1, 2,3-triazole-4 acid -carboxylic acid, 5-methyl-1- (6-quinoline) -1 / - / - pyrazol-4-carboxylic acid, 5-methyl-1-naphthalenyl-1 / - / - pyrazole-4-carboxylic acid, 5- Cyclopropyl-1 - (quinolin-8-yl) -1 H-pyrazole-4-carboxylic acid, 5-cyclopropyl-1- (2-trifluoromethyl-phenyl) -1H-pyrazole-4-carboxylic acid, 5-eti-1-acid (quinolin 5-yl) -1 H-pyrazoyl-4-carboxylic acid, 5-cyclopropyl-1 - (quinolin-5-yl) -1 / - / - pyrazole-4-carboxylic acid, 1- (isoquinolin-5-yl ) -3methyl-1H-pyrazole-4-carboxylic acid, or the acid chlorides or a salt of said compounds or said chlorides. Another aspect of this invention is a method of treating a mammal (e.g., man) that has a disease or disorder in which NHE-1 is involved by administering a pharmaceutically acceptable amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug compound. Another aspect of this invention relates to a method for reducing tissue damage (for example, by substantially preventing tissue damage, inducing tissue protection) as a consequence of ischemia, which comprises administration to a mammal ( for example, a woman or a man) in need of such treatment, of a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Among the preferred ischemic tissues, considered individually or as a group are heart tissue, brain, liver, kidney, lung, intestine, skeletal muscle, spleen, pancreas, nervous, spinal cord, retinal tissue, vascular system or intestinal tissue . A particularly preferred ischemic tissue is cardiac tissue. It is especially preferred to administer the compounds to prevent perioperative myocardial ischemic damage. Preferably, the compounds of this invention are administered prophylactically. Ischemic damage can occur during the transplantation of an organ. Preferably, the compounds of this invention are administered before, during or shortly after cardiac surgery or non-cardiac surgery. In one aspect of this invention a compound of formula I is administered locally.

A preferred dosage is between about 0.001 and 100 mg / kg / day of a compound of formula I or a prodrug thereof. An especially preferred dosage is between about 0.01 and 50 mg / kg / day of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for reducing damage to myocardial tissue (e.g., substantially preventing tissue damage, inducing tissue protection) during surgery (e.g., in graft surgery). of a coronary artery bypass (CABG), vascular surgery, percutaneous transluminal coronary angioplasty (PTCA) or any percutaneous transluminal coronary intervention (PTCI), organ transplantation or non-cardiac surgery) comprising the administration of a mammal (e.g. a woman or a man) in need of such treatment, of a pharmaceutically acceptable amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the reduction of damage in myocardial tissue (for example, substantially avoiding damage to the tissue, inducing tissue protection) in patients presenting with progressive heart disease (acute coronary syndromes, for example , myocardial infarction or unstable angina) or episodes of cerebral ischemia (for example, stroke) comprising administering to a mammal (e.g., a female or a male) a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a chronic method for the reduction of damage in myocardial tissue (for example, by substantially preventing tissue damage, inducing tissue protection) in a patient with previously diagnosed coronary heart disease (e.g. myocardial infarction or unstable angina) or patients at high risk of suffering a myocardial infarction (age >; 65 and two or more risk factors for coronary heart disease) comprising administering to a mammal (e.g., a female or male) a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically salt acceptable of said compound or said prodrug. Another aspect of this invention pertains to a method of preventing ischemic injury comprising chronic oral administration to a mammal in need of such treatment of a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt thereof. said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of vascular diseases comprising administration to a mammal (e.g., a woman or a man) of a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of atherosclerosis comprising the administration to a mammal (e.g., a female or a male) of a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of hypertension comprising administration to a mammal (for example, a woman or a man) of a therapeutically effective amount of a compound formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of arrhythmia comprising the administration to a mammal (e.g., a female or a male) of a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of angina which comprises administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of cardiac hypertrophy comprising the administration to a mammal (e.g., a woman or a man) of a therapeutically effective amount of a compound of formula I, a prodrug of the invention. same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of kidney diseases comprising administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of diabetic complications comprising administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of restenosis comprising administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of cell proliferation diseases comprising administration to a mammal (e.g., a woman or a man), a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of cancer diseases comprising administering to a mammal (e.g., a woman or a man), a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of fibrotic diseases comprising administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of glomerular nephrosclerosis which comprises administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of hypertrophies or hyperplasias of organs comprising administration to a mammal (e.g., a woman or a man), of a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of pulmonary fibrosis comprising administration to a mammal (e.g., a woman or a man), of a therapeutically effective amount of a compound of formula I, a prodrug of the invention. same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of ischemic brain disorders comprising administration to a mammal (e.g., a woman or a man), a therapeutically effective amount of a compound of formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of myocardial shock that comprises administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of myocardial dysfunction comprising administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of cerebrovascular diseases comprising administering to a mammal (e.g., a female or a male), a therapeutically effective amount of a compound of formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or of said prodrug. This invention also relates to pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I, a prodrug of said compound or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier. This invention relates to pharmaceutical compositions for the reduction of tissue damage resulting in ischemia, which contain a therapeutically effective amount of compound of formula I, a prodrug of said compound or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle. Still another aspect of this invention are combinations of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and other compounds as described below. Still another aspect of this invention relates to pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof and a cardiovascular agent and to the use of said compositions for the reduction of tissue damage as a consequence of the ischemia in mammals (for example, humans, a woman, or a man). In the above pharmaceutical compositions and methods the preferred compounds of formula I include the preferred groups of compounds described above designated as group A to group OO. Another aspect of this invention is a method for a reduction of tissue damage (eg, by substantially avoiding damage to tissue, inducing tissue protection) as a consequence of or that could be a consequence of ischemia, comprises administration to a mammal (e.g., a woman or a man) of a. a first compound, said first compound being a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; and b. a second, compound, said second compound being a cardiovascular agent where the amounts of the first and second compounds produce a therapeutic effect. Another aspect of this invention is a case comprising a. a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient or carrier or diluent in a first unit dosage form; b. a therapeutically effective amount of a cardiovascular agent and a pharmaceutically acceptable excipient, carrier or diluent in a second unit dosage form; c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. In the above combination compositions, combination methods and kits, the cardiovascular agents are preferably, for example, α-blockers (eg, acebutolol, atenolol, bopindolol, labetolol, mepindolol, nadolol, oxprenol, pindolol, propanolol, sotalol), blockers. of the calcium channel (eg, amlodipine, nifedipine, nisoldipine, nitrendipine, verapamil), agents that cause the opening of the potassium channel, adenosine, adenosine agonists, ACE inhibitors (eg, captopril, enalapril), nitrates (e.g., isosorbide dinitrate, isosorbide 5-mononitrate, glyceryl trinitrate), diuretics (e.g., hydrochlorothiazide, indapamide, pyretanin, xipamide), glycosides (eg, digoxin, metildigoxin), thrombolytics (e.g., tPA ), platelet inhibitors (eg, reopro), aspirin, dipyridamole, potassium chloride, clonidine, prazosin or A3 adenosine receptor agonists. In the above combination compositions, combination methods and kits, preferred compounds of formula I include the preferred groups of the compounds described above designated as group A to group OO. This invention also relates to a composition of a pharmaceutical combination comprising: a therapeutically effective amount of a composition containing: a first compound, said first compound being a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; a second compound, said second compound being an inhibitor of glycogen phosphorylase; and / or optionally a pharmaceutical excipient, vehicle or diluent.

Another aspect of this invention is a method for reducing damage in a tissue (for example, by substantially preventing tissue damage, inducing tissue protection) as a consequence of or that could be a consequence of ischemia, comprises administration to a tissue. a mammal (for example, a woman or a man) of a. a first compound, said first compound being a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; and b. a second compound, said second compound being an inhibitor of glycogen phosphorylase wherein the amounts of the first and second compounds produce a therapeutic effect. Another aspect of this invention is a case comprising a. a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a therapeutically effective amount of a glycogen phosphorylase inhibitor and a pharmaceutically acceptable excipient, carrier or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. In the above combination compositions, combination methods and kits, preferred compounds of formula I include the preferred groups of the compounds described above designated as group A to group OO. In the above combination compositions, combination methods and kits the preferred glycogen phosphorylase inhibitors are [(1S) - ((R) -hydroxy-d-methylcarbamoyl-methyl] -2-phenyl-ethyl] - 5-Chloro-1 H-indole-2-carboxylic acid amide,. { (1S) - [(R) -hydroxy- (methoxy-methyl-carbamoyl-methyl] -2-phenyl-ethyl} -amide of 5,6-dichloro-1 H -indole-2-carboxylic acid, (1 S) - [(R) -hydroxy] - (methoxy-methyl-carbamoyl-methyl] -2-phenyl-ethyl} -amide of 5-chloro-1 H-indol-2 acid -carboxylic, ((1S) - { (R) -hydroxy - [(2-hydroxy-ethyl) -methyl-carbamoyl-methyl] -2-phenyl-ethyl}. 5-chloro-1 H-indol-2-carboxylic acid, { (1S) - [(R) -h'drox¡- (methyl-pyridin-2-yl-carbamoyl) -methyl] -2-phenyl- ethyl.} - 5-chloro-1 H-indole-2-carboxylic acid or ((1S) - { (R) -hydroxy- [methyl- (2-pyridin-2-yl-et L) -carbamoyl] -methyl] -2-phenyl-ethyl) -amide of 5-chloro-1 H-indole-2-carboxylic acid, hydrochloride of [(1S) -benzyl- (2R) -hydroxy] 5-Chloro-1 H-indole-2-carboxylic acid (3-methyl-piperazin-1-yl) -3-oxo-propyl] -amide, [(1 S) -benzyl- (2R) -hydroxy] -3- (3-hydroxy-azetidin-1-yl) -3-oxo-propyl-amide of 5-chloro-1 H-indole-2-carboxylic acid, ((1S) -benzyl- (2R) -hydroxy-3-isoxazole! d¡n-2-yl-3-oxo-propyl) am 5-chloro-1 H-indole-2-carboxylic acid, ((1S) -benzyl- (2R) -hydroxy-3- [1,2] oxazinan-2-yl) -3-oxo-propyl) amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) -benzyl- (2R) -hydroxy-3 - ((3S) -hydroxy-pyrrolidin-1-yl) -3-oxo- 5-Chloro-1 H-indole-2-carboxylic acid propyljamide, [(1 S) -benzyl-3 - ((3S, 4S) -dihydroxy-pyrrol-d-n-1-yl) - (2R) - 5-Chloro-1 H-indole-2-carboxylic acid hydroxy-3-oxo-propyl], [(1 S) -benzyl-3 - ((3R, 4S) -dihydroxy-pyrrolidin-1 - il) - (2R) -hydroxy-3-oxo-propyl] -amide of 5-chloro-1 H-indol-2-carboxylic acid or ((1 S) -benzyl- (2R) -hydroxy-3-morpholine 5-Chloro-1 H-indole-2-carboxylic acid-4-yl-3-oxo-propyl), [(1 S) -benzyl-2- (3-hydroxyiminopyrrolidin-1 - 5-Chloro-1H-indole-2-carboxylic acid-2-oxo-ethyl], [2- (cis-3,4-dihydroxy-pyrrolidin-1-yl) -2-oxo] -ethyl] -amido of 5-chloro-1 H-indole-2-carboxylic acid, [2 - ((3S, 4S) -dihydroxyrrolidin-1-yl) -2-oxo-ethyl] amide 5-chloro-1 H-indole-2-carboxylic acid, [(1 S) -benzyl-2- (3,4-dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] -amide of 5-chloro-1 H-indole-2-carboxylic acid, [2- 5-Chloro-1 H-indole-2-carboxylic acid (1, 1-dioxo-thiazolidin-3-yl) -2-oxo-ethyl] -amide, (2-oxo-2-thiazolidin-3-yl- ethyl) -amido of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) - 5-chloro-1 H-indole-2- (4-fluoro-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-etl] -amide carboxylic acid, [(1 S) -benzyl-2 - ((3RS) -hydroxy-piperidin-1I) -2-oxo-ethyl] amide, of 5-chloro-1 H-indole-2-carboxylic acid, [2- oxo-2 - ((1 RS) -oxo-1-thiazolidin-3-yl) -ethyl] amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) - (2-fluoro) 5-Chloro-1 H-indole-2-carboxylic acid (2-benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-etl] -amide, [(1S) -benzyl-2 5-Chloro-1 H-indole-2-carboxylic acid ((3S, 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxo-etl], [(1 S) -benzyl-2 5-Chloro-1 H-indole-2-carboxylic acid (3-hydroxy-azetidin-1-yl) -2-oxo-etl] -amide, [(1 S) -benzyl-2- 5-Chloro-1 H-indole-2-carboxylic acid (3-hydroxyimino-azetidin-1-yl) -2-oxo-ethyl] -amide or [(1 S) -benzyl-2- (4-hydroxyimino) 5-chloro-1 H-indole-2-carboxylic acid-piperidn-1-yl) -2-oxo-ethyl] -amide.

This invention also relates to a composition of a pharmaceutical combination comprising: a therapeutically effective amount of a composition containing: a first compound, said first compound being a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; a second compound, said second compound being an aldose reductase inhibitor, and / or optionally a pharmaceutical excipient, vehicle or diluent. Another aspect of this invention is a method for reducing damage to a tissue (for example, by substantially preventing tissue damage, inducing tissue protection) as a consequence of or that could be a consequence of ischemia, comprises administration to a tissue. a mammal (for example, a woman or a man) of a. a first compound, said first compound being a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; and b. a second compound, said second compound being an inhibitor of aldose reductase wherein the amounts of the first and second compounds produce a therapeutic effect. Another aspect of this invention is a case comprising a. a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a therapeutically effective amount of an aldose reductase inhibitor and a pharmaceutically acceptable excipient, carrier or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. In the above combination compositions, combination methods and kits, preferred compounds of formula I include the preferred groups of the compounds described above designated as group A to group OO. In the above combination compositions, combination methods and kits, a preferred inhibitor of aldose reductase is zopolrestat: 3,4-dihydro-4-oxo-3 - [[5-trifluoromethyl) -2-benzothiazole I] metl] -1-phthalic acid. In the methods of treatment as they have been applied to the combinations described above, the following are the administration routes, modes, etc. preferred.

Among the preferred ischemic tissues, considered individually or as a group, are cardiac tissue, brain, liver, kidney, lung, intestine, skeletal muscle, spleen, pancreas, nervous, spinal cord, retinal tissue, vascular system or tissue intestinal. A particularly preferred ischemic tissue is cardiac tissue. It is especially preferred to administer the compounds to prevent perioperative myocardial ischemic injury. Preferably, the compounds of this invention are administered prophylactically. Ischemic damage can occur during the transplantation of an organ. Preferably, the compounds of this invention are administered before, during or shortly after cardiac surgery or non-cardiac surgery. In one aspect of this invention the compounds are administered locally. In one aspect of this method, damage to myocardial tissue is reduced during surgery. In another aspect of this method, damage to myocardial tissue is reduced in patients with progressive heart disease or cerebral ischemic episodes.

In yet another aspect of this method, damage to myocardial tissue is reduced by chronic administration of the combination to a patient diagnosed with coronary heart disease. The term "reduction" is intended to include partial prevention or prevention that, although greater than that which would result if no compound or placebo were taken, is less than 100% in addition to substantially total prevention. The term "damage as a result of ischaemia" as used herein refers to disorders directly associated with a reduction of blood flow in the tissue, for example due to a clot or obstruction of blood vessels supplying blood to said tissue and that produces, among others, a decrease in oxygen transport to said tissue, an alteration of tissue function and tissue dysfunction and / or necrosis. In other cases, although the blood flow or perfusion in the organ may be quantitatively adequate, the oxygen carrying capacity of the blood or the perfusion medium to the organ may be reduced, for example, in a hypoxic environment, so that it diminishes the supply of oxygen to the tissue and produces an alteration of the function of the tissue, a dysfunction of the tissue and / or the subsequent necrosis of the tissue. The term "to treat", "treat" or "treatment" as used herein includes a preventive (eg, prophylactic) and palliative treatment.

By "pharmaceutically acceptable" it is meant that the carrier, diluent, excipients and / or salt must be compatible with other ingredients of the formulation and not be deleterious to the recipient. The term "prodrug" refers to compounds that are drug precursors and that once administered release the drug in vivo through some chemical or physiological processes (e.g., a prodrug that brought to physiological pH becomes the desired drug by the enzymatic action). Examples of aromatic rings of five to six links with optionally one or two heteroatoms independently selected from oxygen, nitrogen and sulfur are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, midazolyl, pyrazolyl, isoxazolyl, izothiazolyl, pyridyl, pyridiazanyl, pyrimidinyl. and pyrazinyl. Examples of five to eight partially saturated, fully saturated or fully unsaturated linkages optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other examples of five-membered rings are furium, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, -pyrazzolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1,4-oxadiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,4-thiadiazolyl, 3H-1, 2,3-dioxazolyl, 1, 2, 4-dioxazolyl, 1,2-dioxazolyl, 1,4-dioxazolyl, 5H-1, 2,5-oxathiazolyl and 1,3-oxathiolyl. Other examples of six-membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxoinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3,5-triazinyl, 1, 2,4-triazinyl, 1, 2,3-triazinyl, 1, 3,5-tritylan, 4H-1,2-oxazinyl, 2H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1, 2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1, 2,5-oxathiazinyl, 1, 2,6-oxathiazinyl and 1,4,2-oxadiazinyl. Other examples of seven-membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl. Other examples of rings of eight elements are cyclooctyl, cyclooctenyl and cyclooctadienyl. Examples of bicyclic rings consisting of two fused rings with five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, cyclopenta (b) pyridinyl, pyran (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c) thienyl, 1 H-indazolyl, indoxazinyl, benzoxazole, anthranilyl , benzimidazolyl, benzatiazolilo, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido (3,4-b ) -pyridinyl, pyrid (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1 H-2 , 3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1, 2-benzoxazinyl and 4H-1,4-ben zoxazinyl. Alkylene is understood to mean a saturated hydrocarbon (straight or branched chain), in which a hydrogen atom has been removed from each of the terminal carbons. Examples of such groups (assuming that the designated length includes a particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene. By halogen is meant chlorine, bromine, iodine or fluoro. By "alkyl" is meant a saturated straight-chain hydrocarbon or a branched saturated hydrocarbon. Examples of such alkyl groups (assuming that the designated length includes a particular example) are methylethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl. By "alkoxy" is meant a saturated straight-chain alkyl or a branched saturated alkyl attached by an oxy. Examples of such alkoxy groups (assuming that the indicated length includes a particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy. and octoxi.

As used herein, the term mono-N or di-N, N-alkyl (d-Cx) ... refers to the alkyl moiety (C? -Cx) considered independently when it is di-N, N '-alkyl (C? -Cx) ... (x refers to integers). It is understood that if a carbocyclic or heterocyclic moiety can be bound or otherwise bound to the indicated substrate by different ring atoms without indicating a specific binding point, then all possible points are considered, either by a carbon atom or, example, a trivalent nitrogen atom. For example, the term "pyridyl" denotes 2-, 3-, or 4-pyridyl, the term "thienyl" means 2-, or 3-thienyl etc. The term "pharmaceutically acceptable salt" refers to the non-toxic anionic salts containing anions, such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene sulfonate. When there is more than one basic moiety, the term includes multiple salts (eg, di-salt). The expression also refers to the non-toxic cationic salts, such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine, (N.N'-dibenzylethylenediamine), choline, ethanolamine, diatol amine, ethylenediamine, meglamine (N-methyl-glucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

As used herein, the terms "reaction inert solvent" and "inert solvent" refer to a solvent or mixture of solvents that does not interact with the starting materials, reagents, intermediates or products in a manner that affects adversely to the performance of the desired product. The chemist skilled in the art will realize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configuous isomers. All of these isomers and mixtures thereof are included in this invention. Hydrates of the compounds of this invention are also included. DMF means N, N-dimethylamido. DMSO means dimethyl sulfoxide. THF means tetrahydrofuran. The present invention also includes the radioactively labeled compounds, which are identical to those cited in formula I, except for the fact that one or more atoms are substituted with an atom having an atomic mass or mass number different from the atomic mass or the mass number that usually exists in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine or chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P , 35S, idp and respectively. The compounds of the present invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, those into which radioactive isotopes, such as 3H and 14H, are incorporated, are useful in drug distribution and / or substrate tissue distribution assays. The tritiated isotopes, that is, with 3 H and carbon 14, that is 14 C, are especially preferred for their ease of preparation and detectability. Also, substitution with heavier isotopes, such as deuterium, ie, 2H, may represent certain therapeutic advantages as a consequence of their greater metabolic stability, for example, an increase in half-life in vivo or lower requirements of the dosage, and Consequently, they may be preferred in certain circumstances. The compounds of formula I of this invention labeled with isotopes and prodrugs thereof, can generally be prepared by carrying out the procedures described in the schemes and / or in the following schemes, substituting an isotopically non-labeled reagent for an isotope-labeled reagent. easily available. Other features and advantages will become apparent from the specification and the claims describing the invention.

DETAILED DESCRIPTION OF THE INVENTION In general, the compounds of the invention can be prepared by methods including methods known in the chemical art, particularly in light of the description contained herein. Certain methods for the preparation of the compounds of this invention are provided as other characteristics of the invention and are illustrated by the following reaction schemes. Other procedures are described in the experimental part. In summary and in general, a compound of formula Z-C (0) OH is coupled with guanidine in the presence of an appropriate coupling agent.

SCHEME I R5NHNHY VI SCHEME II X XI XII XIII SCHEME lll CICOC02R XV XVI XVII XVIII SCHEME IV CICOC02R XX XXI XXII XXIII SCHEME V O O R 'OR XXIX XXX SCHEME VI SCHEME Vil XLl XLll XLIII SCHEME Vllll Lili LV LIV LVI According to scheme I the compound of formula IA, in the that R4 is as described above, is dissolved or suspended in an aqueous solution of alkali metal hydroxide (e.g., 1 N sodium hydroxide) together with sodium nitrite and the mixture is added to an aqueous acidic solution (e.g. 10% v / v sulfuric acid) at a pH of about 0 at a temperature between about 0 ° C and about 5 ° C between about 30 minutes and about 1 hour. The resulting mixture is filtered to give the oxime of formula II. Alternatively, the compound of formula IA is dissolved in acetic acid / propionic acid 1: 1 and solid sodium nitrite is added at about 0 ° C. The reaction mixture is stirred at about 0 ° C for about 2 hours, then poured into ice water and the oxime of formula II is obtained by filtration. The compound of formula II reacts with a compound of formula III, wherein R5 is as described above in a protic solvent, such as ethanol at a temperature of between about 50 ° C and about 110 ° C between about 10 minutes and about 1 hour giving the hydrazone of formula IV. The hydrazone of formula IV is cyclized and hydrolyzed to give the triazole of formula V in an alcoholic solvent, such as 2-ethoxyethanol under basic conditions (eg, potassium hydroxide) at a temperature of between about 100 ° C and about 175 ° C. between about 1/2 hour and about 2 hours followed by acidification to give the triazole acid of formula V. The acid of formula V is coupled with guanidine in the presence of an appropriate coupling agent. An appropriate coupling agent is one that transforms a carboxylic acid into a reactive species which forms an amide linkage with an amine during the reaction.

The coupling agent can be a reagent which effects this condensation in a process without isolation of intermediates when mixed with the carboxylic acid and the guanidine. Examples of coupling reagents are 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydroxybenzotriazole hydrochloride (EDC / HBT), dicyclohexylcarbodiimide / hydroxybenzotriazole (HBT), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and diethylphosphoryl cyanide. The coupling is carried out in an inert solvent, preferably an aprotic solvent at a temperature between about -20 ° C and about 50 ° C between about 1 and about 48 hours, in the presence of an excess of guanidine as the base. Examples of solvents include acetonitrile, dichloromethane, dimethylformamide and chloroform or mixtures thereof. The coupling agent can also be an agent which converts the carboxylic acid into an activated intermediate which is isolated and / or formed in a first step and which is allowed to react with guanidine in a second step. Examples of said coupling agents and activated intermediates are thionon chloride or oxalyl chloride to form the acid chloride, cyanuric fluoride to form an acid fluoride or an alkyl chloroformate, such as isobutyl chloroformate or isopropenyl or propanophosphonic anhydride (propanephosphonic anhydride, PPA) (with a tertiary amine base) to give a mixed anhydride of the carboxylic acid or carbonyldiimidazole giving an acylimidazole If the coupling agent is oxalyl chloride, it is advantageous to use a small amount of dimethylformamide as a co-solvent with another solvent (such as dichloromethane) to catalyze the formation of the acid chloride. This derivative of the activated acid can be coupled by mixing it with excess guanidine in an appropriate solvent together with an appropriate base. Suitable combinations of solvent / base are, for example, dichloromethane, dimethylformamide or acetonitrile or mixtures thereof in the presence of an excess of guanidine as a base. Other suitable solvent / base combinations include water or an alcohol (C-1-C5) or a mixture thereof together with a cosolvent, such as dichloromethane, tetrahydrofuran or dioxane and a base, such as sodium, potassium or lithium hydroxide. in sufficient quantity to consume the acid released in the reaction. The use of these coupling agents and appropriate selection of solvents and temperatures is known to those skilled in the art or can be readily determined from the literature. These conditions and examples of other conditions useful for the coupling of carboxylic acids are described in Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., G. Theme Verlag, 1974, Stuttgart; M. Bodansky, Principies of Peptide Synthesis, Springer Verlag, Berlin 1984; and The Peptides, Analysis, Synthesis and Biology (ed. E. Gross and J. Meienhofer), vols 1-5 (Academic Press, NY 1979-1983). According to the scheme, the primary amine of formula X in which R5 is as described above reacts with an α-diazo-^ -ceto-ester of formula XI in which R4 is as described above and R is a lower alkyl, in the presence of titanium tetrachloride, analogously to the method described in Eguchi S. ef al. Synthesis 1993, 793 giving the triazole carboxylic acid ester of formula XII. The ester of formula XII is directly converted to acylguanidine XIII by reaction with guanidine in an alcohol solvent at a temperature between about 60 and about 110 ° C, preferably at reflux in methanol, for a period of between 8 and 20 hours. According to scheme III, the compound of formula XV wherein R4 and R5 are as described above is treated with Lawesson's reagent (i.e., 2,4-bis (4-methoxypheni) -1, 3-dithia. -2,4-diphosphetane-2,4-disulfide) in an aprotic solvent, such as dimethoxyethane at a temperature between about 20 ° C and about 120 ° C between about one and eight hours. The resulting thioamide is treated with an alkylating agent, such as methyl iodide in an inert polar solvent, such as acetone, conveniently at room temperature between about eight hours and about forty-eight hours. The resulting compound reacts with anhydrous hydrazine in an alcoholic solvent at a temperature between about 0 ° C and about 25 ° C between about one and eight hours to give the compound of formula XVI (analogously to that described in Doyle and Kurzer, Synthesis 1974, 583). The compound of formula XVI is treated with a monoalkyloxalyl chloride in an aprotic solvent at a temperature between about 25 ° C and about 50 ° C between about one and eight hours to give the carboxylic ester compound of formula XVII, wherein R is lower alkyl. The ester of formula XVII is directly coupled with guanidine in an alcohol solvent at a temperature between about 60 ° C and about 110 ° C, preferably methanol at reflux for a period of between eight and twenty hours to obtain the triazole carbonyl guanidines of formula XVIII. According to scheme IV, the compound of formula XX in which R5 is as described above is treated with methyl iodide in an inert solvent, conveniently at room temperature between about four and twenty-four hours. The resulting compound is reacted with anhydrous R4-hydrazine (wherein R4 is as described above) in an alcohol solvent at a temperature between about 0 ° C and about 25 ° C between about one and eight hours to give the amidrazone compound of formula XXI (analogous to that described in Doyle and Kurzer, Synthesis 1974, 583). The compound of formula XXI is treated with a monoalkyl oxalyl chloride in an aprotic solvent at a temperature between about 25 ° C and about 50 ° C between about one and eight hours to give the carboxylic ester compound of formula XXII, wherein R is lower alkyl. The ester of formula XXII is directly coupled with guanidine in an alcohol solvent at a temperature between about 60 ° C and about 110 ° C, preferably methanol at reflux, for a period of eight to twenty hours to obtain the triazole carbonylguanidines of formula XXIII . According to scheme V, the compound of formula XXV, wherein R1 is as described above, is combined with excess of (CH30) 2C (R3) N (CH3) 2 (N, N-dimethyl amide dimethyl acetal ) wherein R3 is as described above, optionally in the presence of an acid catalyst, such as p-toluenesulfonic acid at a temperature of between about 90 ° C and about 110 ° C between about one and about two hours to prepare the composed of formula XXVI above. The compound of formula XXVI is cyclized with a compound of formula XXVII, wherein R2 is as described above, in an inert solvent, such as ethanol at a temperature between about 20 ° C and about 30 ° C between about 5 minutes and about one hour, followed by heating to a temperature of between about 70 ° C and about 110 ° C between about two hours and about four hours to obtain the pyrazole of formula XXVIII. Alternatively according to scheme V, the compound of formula XXV, wherein R1 is as described above, is combined with a triethyl orthoester (ie, R3C (OEt) 3, wherein R3 is as described above) and acetic anhydride at a temperature between about 120 ° C and about 150 ° C between about two and about five hours to prepare the compound of formula XXXI. The compound of formula XXXI is cyclized with a compound of formula XXVII, wherein R2 is as described above, obtaining the pyrazole of formula XXVIII. The pyrazole of formula XXVIII is hydrolysed with a base, such as sodium hydroxide or lithium hydroxide in a solvent, such as water and / or methanol and / or THF conveniently at room temperature or at an elevated temperature (e.g., reflux) between about one hour and five hours to prepare the acid of formula XXIX. The acid of formula XXIX is coupled with guanidine in the presence of an appropriate coupling agent as described for the above coupling of the acid of formula V and guanidine. In one embodiment, the acid of formula XXIX is activated with thionon chloride at a temperature between about 60 ° C and about 90 ° C between about fifteen minutes and about two hours. The resulting activated acid chloride is combined with guanidine hydrochloride and an organic base (e.g., sodium hydroxide) in anhydrous tetrahydrofuran and optionally methanol and / or water. The solution is heated, conveniently to reflux, between about one hour and about eight hours to prepare the compound of formula XXX. Alternatively according to scheme V the compound of formula XXVIII can be converted directly to the compound of formula XXX by various methods. For example, the compound of formula XXVIII can be heated in the presence of excess guanidine, in a polar protic solvent, for example, methanol or iopropanol at a suitable temperature conveniently at reflux between about one and about seventy-two hours. This transformation can also be carried out by repeatedly removing the solvent, for example, removing ethanol or toluene about four times, from a mixture of the compound of formula XXVIII and excess guanidine at a pressure of between about one and about 100 mm Hg and at a temperature between about 25 ° C and about 95 ° C. This reaction can also be performed in the absence of solvent by heating the mixture of the compound of formula XXVIII and excess guanidine at a temperature of between about 100 ° C and about 180 ° C, optionally at about a pressure of between about 1 and about 100 mm of Hg between approximately five minutes and approximately eight hours. According to scheme VI, the compound of formula XXXV, wherein R3 is as described above, reacts with a compound of formula XXXVI, wherein R1 and R2 are as described above, in an aprotic solvent a a temperature between about 0 ° C and about 25 ° C between about two hours and about twenty-four hours in the presence of an appropriate amine base, such as triethylamine, forming the compound of formula XXXVII.

The resulting compound of formula XXXVII is hydrolyzed and coupled with guanidine using one of the methods described in the above schemes, such as the method using carbonyldiimidazole, forming the compound of formula XXXVIII. According to scheme VII, hydrazine of formula XL, wherein R 2 is as described above, reacts with the appropriate compound of formula XLl to give the pyrazole ester of formula XLll, wherein R is a lower alkyl of according to the method of Bajnati, A. and Hubert-Habart, M. Bull. Soc. Chim. France 1988, 540. The resulting pyrazole ester is converted to the acyl guanidine of formula XLll using the hydrolysis and coupling methods described above. According to scheme VIII, the compound of formula L, wherein R 2 and R 1 are as described above is transformed into the lithium salt of formula Ll where R is lower alkyl according to the method described in J. Het . Chem. 1989, 26, 1389. The lithium salt of formula Ll is combined with the hydrazine of formula Lll, wherein R 3 is as described above, in an inert solvent, such as ethanol, in the presence of a mineral acid , at a temperature between about 20 ° C and about 30 ° C between about five minutes and about one hour, followed by heating to a temperature between about 70 ° C and about 110 ° C between two hours and about four hours forming the pyrazoles of formula Lili and LIV. The pyrazoles of formula Lili and LIV are converted into the guanidine acyl of formula LV and LVI respectively using the hydrolysis and coupling methods described above. Some of the preparation methods useful for the preparation of the compounds described herein may require the protection of remote functionalities (eg, primary amine, secondary amine, carboxyl in the precursors of formula I). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection will be readily determined by those skilled in the art. The use of such protection / deprotection methods are also within the technical scope. For a general description of the protective groups and their use, see T.W. Greene, Protective Groups in Orqanic Synthesis, John Wiley & Sons, New York, 1991. The starting materials and reagents for the compounds described above are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, the aromatic hydrazines used in this invention can be prepared from the corresponding aromatic amines by diazotization followed by conveniently reducing using stannous chloride using procedures known to those skilled in the art. For example, many of the compounds used herein are related to, or are derived from, the compounds found in nature, for which there is a great scientific interest and a commercial need and accordingly, many of these compounds are commercially available or are cited in the literature or readily prepared from other commonly available substances by methods described in the literature. Some of the compounds of this invention have at least one asymmetric carbon atom and, therefore, are enantiomers or diastereomers. The diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods known per se, for example, by chromatography and / or fractional crystallization. The enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (for example, hydrolyzing), the individual diastereomers into the corresponding pure enantiomers. All these isomers, including the diastereoisomers, enantiomers and mixtures thereof are considered part of this invention. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Those skilled in the art will recognize that compounds of formula I can exist in various tautomeric forms. All these tautomeric forms are considered as part of this invention. For example, all tautomeric forms of the carbonylguanidine moiety of the compounds of formula I are included in this invention. Thus, for example, all the enol-keto forms of the compounds of formula I are included in this invention. Some of the compounds of this invention are acidic in nature and form a salt with a pharmaceutically acceptable cation. All compounds of this invention are basic in nature and form a salt with a pharmaceutically acceptable anion. All these salts, including the double salts, are within the scope of this invention and can be prepared by conventional methods. For example, they can be prepared by simply contacting the acidic and basic entities in an aqueous, non-aqueous or partially aqueous medium, as the case may be. The salts are collected by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or in the case of aqueous solutions, by lyophilization, if appropriate. In addition, when the compounds of this invention form metabolites, hydrates and solvates are also within the scope of the invention. Other cardiovascular agents known to those skilled in the art are for example the β-blockers (eg, acebutolol, atenolol, bopindolol, labetolol, mepindolol, nadolol, oxprenol, pindolol, propranolol, sotalol), calcium channel blockers (e.g. , amlodipine, nifedipine, nisoldipine, nitrendipine, verapamil), agents that cause the opening of the potassium channel, adenosine, adenosine agonists, ACE inhibitors (for example, captopril, enalapril), nitrates (for example, nitrate dinitrate). sosorbide, 5-mono-isosorbide, glyceryl glyceryl glyceryl), diuretics (eg, hydrochlorothiazide, indapamide, pyretanin, xipamide), glycosides (eg, digoxin, metildigoxin), thrombolytics (eg, tPA), platelet inhibitors (eg, reopro), aspirin, dipyridamole, potassium chloride, clonidine, prazosin, aldose reductase inhibitors (eg, zopolrestat) or adeno-A3 receptor agonists can be used together with the compounds of the invention. In the treatment of combination therapy, both compounds of the invention and other pharmacological therapies are administered to mammals (eg, in humans, man or woman) by conventional methods. Any inhibitor of aldose reductase can be used as the second active component (active agent) of this invention for combination therapies. The term "aldose reductase inhibitor" refers to compounds that inhibit glucose bioconversion in sorbitol catalyzed by the enzyme aldose reductase. An inhibition of this type is readily determined by those skilled in the art in accordance with standard assays (J. Malone, Diabetes, 29: 861-864, 1980. "Red Cell Sorbitol, an Indicator of Diabetic Control"). A variety of aldose reductase inhibitors are described and cited below, however, other aldose reductase inhibitors will be well known to those skilled in the art.

The disclosures of the US patents cited below are incorporated herein by reference. Likewise, the common USAN chemical names or other designation are given in parentheses, as the case may be, together with the reference to the corresponding patent that describes the compound. The activity of an aldose reductase inhibitor in a tissue can be determined by determining the amount of aldose reductase inhibitor that is required to decrease tissue sorbitol (i.e., by inhibiting the production of sorbitol as a result of blocking aldose reductase ) or to reduce fructose in the tissue (by inhibiting the production of sorbitol as a result of aldose reductase blockage and the consequent production of fructose). Without wishing to accept any particular theory or mechanism, it is believed that an inhibitor of aldose reductase, by inhibiting aldose reductase, prevents or reduces ischemic damage as will be described hereinafter. Accordingly, examples of aldose reductase inhibitors useful in the compositions and methods of the invention include: 1. 3- (4-Bromo-2-fluorobenzyl) -3,4-dihydro-4-oxo-1- acid phthalazine acetic (ponalrestat, US 4,251,528); 2. N [[(5-trifluoromethyl) -6-methoxy-1-naphthalenyl] thio-xomethyl} -N-methylglycine (tolrestat, US 4,600,724); 3. 5 - [(Z, E) - ^ - Methylcinamylidene] -4-oxo-2-thioxo-3-thiazolin-dinacetic acid (epalrestat, US 4,464,382, US 4,791,126, US 4,831,045). 4. 3- (4-Bromo-2-fluorobenzyl) -7-chloro-3,4-dihydro-2,4-dioxo-1 (2H) -quinazoline acetic acid (zenarestat, US 4,734,419 and 4,883,800). 5. 2R, 4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (US 4,883,410); 6. 2R, 4R-6,7-dichloro-6-fIuoro-4-hydroxy-2-methylchroman-4-acetic acid (US 4,883,410); 7. 3,4-Dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazin-4-acetic acid (US 4,771,050); 8. 3,4-Dihydro-3-oxo-4 - [[4,5,7-trifluoro-2-benzothiazolyl) methyl] -2H-1,4-benzothiazine-2-acetic acid (SPR-210, US 5,252) .572); 9. N- [3,5-dimethyl-4 - [(n -tromethyl) sulfonyl] -l-phenyl] -2-methyl-benzeneacetamide (ZD5522, US 5,270,342 and US 5,430,060); 10. (S) -6-fluorospiro [chroman-4,4'-imidazolin] -2,5'-dione (sorbinyl, US 4,130,714); 11. d-2-methyl-6-fluoro-spiro (chroman-4 ', 4'-imidazole) -2', 5'-dione (US 4,540,704); 12. 2-fluoro-spiro (9H-fIuoren-9,4'-diazolin) 2'5'-dione (US 4,438,272); 13. 2,7-difluoro-spiro (9H-fluoren-9,4'imidazoln) 2'5'-dione (US 4,436,745, US 4,438,272); 14. 2,7-difluoro-5-methoxy-spiro (9H-fluoren-9,4'midazolin) 2'5'-dione (US 4,436,745, 4,438,272); . 7-fluoro-spiro (5H-indenol [1,2-b] pyridin-5,3'-pyrrolidine) 2,5'-dione (US 4,436,745, US 4,438,272); 16. d-cis-6'-chloro-2 ', 3'-dibro-2'-methyl-espyro- (imidazoln-4,4'-4'-H-pyran (2,3 -b) pyridine) -2,5-dione (US 4,980,357); 17. Spiro [midazolin-4,5 '(6H) -quinolin] 2,5-dione-3'-chloro-7', 8'-dihydro-7'-methyl- (5'-cys) ) (US 5,066,659); 18. (2S, 4S) -6-fIuoro-2'5'-dioxospiro (chroman-4,4'-ylidazole) -2-carboxamide (US 5,447,946); and 19. 2 - [(4-bromo-2-fluorophenyl) methyl] -6-fluorospyrro- [isoquinolin-4- (1 H), 3'-pyrrolid] -1, 2 ', 3.5 '(2H) -tetron (ARI-509, US 5,037,831). Other inhibitors of aldose reductase include those compounds having the formula IB CH2COR1 or a pharmaceutically acceptable salt thereof, wherein Z is O or S; R is hydroxy or a group capable of being separated in vivo to give a compound of formula IB, wherein R1 is OH; and X and Y are identical or different and are selected from hydrogen, trifluoromethyl, fluoro and chloro.

A preferred subgroup within the above group of aldose reductase inhibitors include several compounds numbered 1, 2, 3, 4, 5, 6, 9, 10 and 17 and the following compounds of formula IB: 20. 3,4-dihydro acid -3- (5-Fluorobenzothiazol-2-methylmethyl) -4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = F; Y = H]; 21. 3- (5,7-Difluorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = Y = F]; 22. 3- (5-Chlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophtalazin-1-I-acetic acid [R1 = hydroxy]; X = CI; Y = H]; 23. 3- (5,7-Dichlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = Y = CI]; 24. 3,4-Dihydro-4-oxo-3- (5-trifluoromethyl-benzoxazol-2-ylmethyl) -phthalazin-1-acetic acid [R 1 = hydroxy]; X = CF3; Y = H]; 25. 3,4-Dihydro-3- (5-fluorobenzoxazol-2-ylmethyl) -4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy]; X = F; Y = H]; 26. 3- (5,7-Difluorobenzoxazol-2-ylmethyl) -3,4-d, 4-d-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = Y = F]; 27.- 3- (5-Chlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy]; X = CI; Y = H]; 28.- 3- (5,7-dichlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = Y = CI]; and 29.- zopolrestat; 3,4-Dhydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-phthalazine acetic acid [R1 = hydroxy; X = trifluoromethyl; Y = H].

In compounds 20-23 and 29 Z is S. In compounds 24-28, Z is O. Of the above subgroup, compounds 20-29 are most preferred, with 29 being especially preferred. An especially preferred inhibitor of aldose reuctase is 3,4-dihydro-4-oxo-3 - [[5- trifluoromethyl) -2-benzothiazolyl] methyl] -1-phthalazine acetic acid. The aldose reductase inhibitor compounds of this invention are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis, especially in view of the corresponding patent specifications. An amount of aldose reductase inhibitor of this invention that is effective for the activities of this invention can be used. Typically, an effective dosage for the aldose reductase inhibitors of this invention is in the range of between about 0.1 mg / kg / day and 100 mg / kg / day in single or divided doses, preferably between 0.1 mg / kg / day and 20 mg / kg / day in single or divided doses. Any inhibitor of glycogen phosphorylase can be used as the second compound of this invention. The term glycogen phosphorylase inhibitor refers to any substance or agent or to any combination of substances and / or agents that reduces, delays or eliminates the enzymatic action of glycogen phosphorylase. The currently known enzymatic action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a macromolecule of glycogen and inorganic phosphate in glucose-1-phosphate and a glycogen macromolecule that is a glycosyl residue shorter than the original macromolecule of glycogen (detection of advancement of glycogenolysis). Such actions can easily be determined by those skilled in the art in accordance with standard tests (for example, as described hereinafter). A variety of these compounds are included in the following international patent applications: PCT publication application WO 96/39384 and WO 96/39385. However, other inhibitors of glycogen phosphorylase will be known to those skilled in the art. Preferred glycogen phosphorylase inhibitors include compounds having the formula IC and pharmaceutically acceptable salts and prodrugs thereof where the dotted line (-) is an optional bond; A is -C (H) =, C (alkyl or -C (halo) = where the dotted line (-) is a bond, or A is methylen or -CH (aiquiIo (dd)) - where the dotted line (-) is not a bond: R2, R10 or Rn are each independently H, halogen, 4-, 6- or 7-nitro, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, fluoromethyl , difluoromethyl or trifluoromethyl, R2 is H, R3 is H or (C1-C5) alkyl, R4 is H, methyl, ethyl, n-propyl, hydroxy (C1-C3) alkyl, alkoxy (d-C3) alkyl (C1-C3) ), phenylalkyl (C1-C4), phenylhydroxy (C1-C4) alkyl, phenylalkoxy (d-C4) (C1-C4) alkyl, thien-2- or 3-yl (d-C4) alkyl or fur-2- or 3-yl alkyl (dC), wherein said R4 rings are mono-, di- or trisustitides independently on carbon with H, halogen, alkyl (C-1-C4), alkoxy (d-C4), trifluoromethyl, hydroxy, amino or cyano; or R4 is pyrid-2, -3- or -4-yl (d-C4) alkyl, thiazole-2-, -4- or -5-yl (C1-C4) alkyl, imidazole -1-, -2- , -4- or -5-yl (C1.-C4) alkyl, pyrrol-2- or -3-yl (C1-C4) alkyl, oxazol-2-, -4- -5-yl-alkyl (C1 -C4), pyrazole-3-, -4- or -5-yl alkyl (C1-C4), isoxazole-3-, -4- or -5-yl (C1-C4) alkyl, siathiazole-3, -4- or -5-N alkyl (C1-C4), pyridazin-3- or -4-y (C1-C4) alkyl, pyrimidin-2-, -4-, -5- or -6-y (C1-C4) alkyl, pyrazin-2- or -3-yl (d-C4) alkyl or 1, 3,5-triazin-2-y (C1-C4) alkyl, wherein said preceding R4 heterocycles are optionally mono- or di-substituted independently with halogen, trifluoromethyl, alkyl (C1) -C4), alkoxy (dd), amino or hydroxy and said mono- or di-substituents being attached to a carbon; R5 is H, hydroxy, fluoro, alkyl (d-C5), alkoxy (C1-C5), alkanoyl (C? -C6), amino alkoxy (d-C4), mono-N- or di-N, N-alkyl (C1- C4) amino (C1-C4) alkoxy, carboxy (C1-C4) alkoxy, alkoxy (d-C5) -carbonyl (C1-C4) alkoxy, benzyloxycarbonyl (C-1-C4) alkoxy or carbonyloxy, wherein said carbonyloxy carbon is bonded with thiazolyl, imidazolyl, 1 H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1, 3,5-triazinyl and said preceding R5 rings being optionally monosubstituted with halogen, alkyl (dC), (C 1 -C 4) alkoxy, hydroxy, amino or trifluoromethyl, said monosubstituents being attached carbon; R7 is H, fluoro or (C1-C5) alkyl; or R5 and R7 can be joined and form an oxo; R6 is carboxy, alkoxy (dCS) carbonyl, C (0) NR8Rg or C (0) R2, where Rs is H, (C1-C3) alkyl, hydroxy or (C1-C3) alkoxy; and Rg is H, alkyl (d-Cs), hydroxy, alkoxy (d-Cs), perfluorinated methylenealkyl (Ci-Cß), phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl , pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl or 1, 3,5-triazinyl, said preceding R9 rings being linked by carbon-nitrogen; or Rg is mono-, di or trisubstituted (C-1-C5) alkyl, wherein said substituents are independently H, hydroxy, amino, mono-N- or di-N, N-(C1-C5) alkylamino; or Rg is mono- or di-substituted alkyl (C Cs), wherein said substituents are independently phenyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolidin, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl or 1, 3,5-triazinyl, where the non-aromatic nitrogen-containing R9 rings are optionally monosubstituted on nitrogen with (d-C6) alkyl, benzyl, benzoyl or alkoxy (d-Cß) carbonyl and wherein the Rg rings are optionally monosubstituted on carbon with halogen, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy, amino or mono-N- and di-N, N-alkyl (C1-C5) amino , with the proviso that quaternized nitrogen is not included and that there are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen bonds; R 2 is piperazin-1-yl, 4-alkyl (C 1 -C 4) piperazin-yl, 4-formylpiperazin-1-yl, morpholino, thomorpholino, 1-oxo-thiomorpholino, 1,1-dioxo-thiomorpholino, thiazolidin- 3-yl, 1-oxo-thiazolidin-3-yl, 1, 1-dioxo-thiazolin-3-yl, 2-alkoxy (C6-6) carbonylpyrroline-1-yl, oxazolodin-3-yl or 2 (R ) -hydroxymethylpyrroline-1-ylo; or R12 is oxazetidin-2-yl 3- and / or 4- mono or disubstituted, oxazolidin-3-yl 2-, 4- and / or 5- mono or disubstituted, thiazolini- 3-yl 2-, 4- and / or 5- mono or disubstituted, 1-oxothiazolidin-3-yl 2-, 4- and / or 5- mono- or disubstituted, 1, 1- dioxothiazolidin-3-yl 2-4 and / or 5- mono- or disubstituted, pyrrolidin -1-yl 3- and / or 4-mono or disubstituted, piperidin-1-yl 3-, 4- and / or 5-mono-, di- or trisubstituted, piperazin-1-yl 3- 4- and / or 5 mono-, di- or trisubstituted, 3-substituted azetidin-1-yl, 1,2-oxazinan-2-yl 4- and / or 5 mono-, or disustitide, pyrazidin-1-yl 3- and / or 4 mono-, or disubstituted, isoxazolidin-2-yl 4- and / or mono-, or disubstituted, isothiazolidinzin-2-yl 4- and / or mono- and / or disubstituted, said substituents of R 2 being independently H , halogen, (C1-C5) alkyl, hydroxy, amine, mono-N- or di-N, N-(C1-C5) alkylamino, formyl, oxo, hydroxyimino, (C1-C5) alkoxy, carboxy, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, (C1-C4) alkoxy imino, (C1-C4) alkoxy methoxy, alkoxy ( d-C6) carbonyl, carboxy (C1-C5) alkyl or hydroxy (C1-C5) alkyl; with the proviso that if R is H, methyl, ethyl or n-propyl R5 is OH; with the proviso that if R5 and R7 are H, then R4 is not H, methyl, ethyl, n-propyl, hydroxy alkyl (d-C3) or alkoxy (d-C3) alkyl (d-C3) and R6 is C (0) NR8R9, C (0) R12 or alkoxy (d-C4) carbonyl. Preferred glycogen phosphorylase inhibitors include compounds having the formula ID Formula ID and pharmaceutically acceptable salts and prodrugs thereof where the dotted line (-) is an optional bond; A is -C (H) =, C (alky (d-C4) =), -C (halo) = or -N =, where the dotted line (-) is a bond, or A is methylene or -CH (alkyl (d-C4)) - where the dotted line (-) is not a bond; R-i, Rio or Rn are each independently H, halogen, cyano, 4-6 or 7-nitrate, alkyl (d-d), alkoxy (d-d), fluoromethyl, difluoromethyl or trifluoromethyl; R2 is H; R3 is H or alkyl (d-C5); R4 is H, methyl, ethyl, n-propyl, hydroxyalkyl (C Cs), alkoxy (d-C3) alkyl (d-C3), phenylalkyl (Crd), phenylhydroxy alkyl (dd), phenylalkoxy (dd) alkyl (dd) , tien-2- or -3-yl alkyl (dd) or fur-2- or 3-yl alkyl (d-C4), where said R4 rings are mono-, di- or trisubstituted independently on carbon with H, halogen, alkyl (dd), (C 1 -C 4) alkoxy, trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1 H-imidazol-2-yl; R4 is pyrid-2, -3- or -4-alkyl (CrC4), thiazole-2-, -4- or -5-y (C1-C4) alkyl, imidazole-2-, -4- or - 5-N (C1-C4) alkyl, pyrrole-2- or -3-y (C1-C4) alkyl, oxazoI-2-, -4- or 5-yl-alkyl (dd), pyrazole-3-, - 4- or -5-yl alkyl (dd), isoxazol-3-, -4- or -5-yl alkyl (dd), isothiazol-3, -4- or -5-alkyl (CrC4), pyridazin- 3- or -4-yl alkyl (dd), pyrimidine-2-, -4-, -5- or -6-yl alkyl (dd), pyrazin-2- or -3-yl alkyl (dd), 1, 3,5-triazin-2-yl (C 1 -C 4) alkyl or nol-2-alkyl (dd), wherein said preceding R 4 heterocycles are optionally mono- or disubstituted independently with halogen, trifluoromethyl, alkyl (dd), alkoxy ( Crd), amino, hydroxy or cyano and said substituents being attached to a carbon; or R 4 is R 5 -carbonyloxymethyl, wherein said R 15 is phenyl, thiazolyl, imidazolyl, 1 H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridylanyl, pyrimidinyl, pyrazinyl or 1, 3,5- triazinyl and wherein said above R15 rings are optionally mono- or di-substituted independently with halogen, amino, hydroxy, alkyl (dd), alkoxy (dd) or trifluoromethyl and said mono- or di-substituents being attached to a carbon; R5 is H; Re is carboxy, (d-Cß) alkoxycarbonyl, benzyloxycarbonyl, C (0) NR8R9 or C (0) R12, where R8 is H, alkyl (d-Cß), cycloalkyl (C3-C6), cycloalkyl (C3-C6) ) (C1-C5) alkyl, hydroxy or alkoxy (CrC8); and Rg is H, cycloalkyl (C-C8), cycloalkyl (C3-C8) alkyl (C1-C5), cycloalkenyl (C4-C), cycloalkyl (C3-C7) alkoxy (C1-C5), cycloalkyloxy (C3-C7) ), hydroxyl, methylenealkyl (C? -C8) perfluorinated, phenyl or a heterocycle, said heterocycle being pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolidin, pyrazolindinyl, isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl , morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3,5-triazinyl, benzothiazolyl, benzoxazolyl, benzimidazole, thiochromanyl or tetrah id robenzothiazole, said heterocyclic rings being linked by carbon-nitrogen; or Rg is alkyl (CrCd) or alkoxy (d-C8) wherein said alkyl (CrCe) or alkoxy (CrC8) is optionally monosubstituted with cycloalken (dC) -1-yl, phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolidinyl, pyrrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3,5-triazinyl or indolyl and wherein said alkyl (CrC6) or alkoxy (CrC8) are additionally optionally independently mono- or disubstituted with halogen, hydroxy, alkoxy (CrCs), amino, mono-N- or di-N, N-alkyl (CrC5) amino, cyano, carboxy or alkoxy (dd) carbonyl; and wherein the Rg rings are optionally mono- or disubstituted independently on carbon with halogen, alkyl (dd), alkoxy (dd), hydroxy, hydroxy alkyl (dd), aminoalkyl (dd), mono-N- or di-N, N -alkyl (dd) aminoalkyl (dd), alkoxy (dd) alkyl (dd), amino, mono-N- or di-N, N-alkyl (dd) amino, cyano, carboxy, alkoxy (C 1 -C 5) carbonyl , carbamoyl, formyl or trifluoromethyl and said Rg rings can optionally and additionally be mono- or disubstituted independently with (d-C5) alkyl or halogen; with the proviso that a quaternized nitrogen is not included on any Rg heterocycle; R 2 is morpholino, thiomorpholino, 1-oxo-thiomorpholino, 1,1-dioxo-thiomorpholino, thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-. Ilo, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl,! soxazolidin-2-yl, isothiazolin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4-dihydroisoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 3, 4-dihydro-2H-quinol-1-yl, 2,3-dihydro-benzo [1,4] oxazin-4-yl, 2,3-dihydro-benzo [1,4] -thiazin-4- ilo, 3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo [c] [1,2] -oxazin-1-yl, 1,4-dihydro-benzo [d] [ 1,2] oxazin-3-ylo, 3,4-dihydro-benzo [e] [1, 2] -oxazin-2-yl, 3H-benzo [d] isoxazol-2-yl, 3H-benzo [c] isoxazol-1-yl or azepane-1-yl, wherein said R12 rings are optionally mono-, di- or trisubstituted independently with halogen, alkyl (CrC5), alkoxy (d-C5), hydroxy, amino, mono-N- or di-N, N-alkyl (C1-C5) amino, formyl, carboxy, carbamoyl , mono-N- or di-N, N-C 1 -C 5 alkylcarbamoyl, C 1 -C 6 alkoxy C 1 -C 3 alkoxy, C 1 -C 5 alkoxycarbonyl, benzyloxycarbonyl, C 1 -C 5 alkoxy alkyl carbonyl (CrCs), alkoxy (dd) carbonylamino, carboxy (C1-C5) alkyl, carbamoyl (d-C5) alkyl, mono-N- or di-N, N-(C1-C5) alkyl carbamoyl (C1- C5), hydroxy (C1-C5) alkyl, (C1-C4) alkoxy alkyl (dd), amino alkyl (CrC4), mono-N- or di-N, N-alkyl (dd) amino alkyl (dd), oxo , hydroxyamino or alkoxy (CrC6) iimino and when no more than two substituents are selected from oxo, hydroxyimino or alkoxy (d-Cß) imino and oxo, hydroxyimino or alkoxy (d-Cß) are on a non-aromatic carbon; and when said R-? 2 rings are optionally additionally mono- or disubstituted independently with alkyl (CrC5) or halogen; with the proviso that when RQ is (C1-C5) alkoxycarbonyl or benzyloxycarbonium, then R1 is 5-halogen, 5-alkyl (dd) or 5-cyano and R4 is (phenyl) (hydroxy) alkyl (dd), ( phenyl) (alkoxy (dd)) alkyl (dd), hydroxymethyl or Ar-alkyl (CrC2), where Ar is thien-2- or -3-yl, fur-2- or -3-yl or phenyl, wherein said Ar is optionally mono- or disubstituted independently with halogen, with the proviso that when R 4 is benzyl and R 5 is methyl, R 2 is not 4-hydroxy-piperidin-1-ylo or when R 4 is benzyl and R 5 is methyl, Rβ is not C (0) N (CH 3) 2; with the proviso that when R-i and R-n are H, R is not midazoI-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl; with the proviso that when R8 and R9 are both n-pentyl, R1 is 5-chloro, 5-bromo, 5-cyano, 5-(C1-C5) alkyl, 5-alkoxy (CrC5) or trifluoromethyl; with the proviso that when R 12 is 3,4-dihydroisoquinol-2-ylo, said 3,4-dihydroisoquinol-2-yl is not substituted with carboxy alkyl (d-d); with the proviso that when R8 is H and Rg is alkyl (d-Cß), Rg is not substituted with carboxy or alkoxy (d-d) carbonyl on carbon, which is attached to the nitrogen atom N of the NHRg; and with the proviso that when R6 is carboxy and R-i, R-m, Rn and R5 are all H, then R4 is not benzyl, H, (phenyl) (hydroxy) methyl, methyl, ethyl or n-propyl.

In general, an effective dosage for the pharmacological combination compositions of this invention, for example, for the ischemic damage reduction activities of the combinations containing the glycogen phosphorylase inhibitor compounds of this invention, is in the range of 0.005 to 50 mg / kg / day, preferably between 0.01 and 25 mg / kg / day and more preferably between 0.1 and 15 mg / kg / day. The compounds of the present invention inhibit the sodium / proton exchange (Na + / H +) transport system, and therefore are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the acceleration of the trans / sodium / proton exchange system ( Na + / H +), for example, in cardiovascular diseases [for example, arteriosclerosis, hypertension, arrhythmia (for example, ischemic arrhythmia, arrhythmia due to myocardial infarction, myocardial shockmyocardial dysfunction, arrhythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (eg, congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after a PTCA, PTCI, shock (for example, hemorrhagic shock, endotoxin shock, etc.), kidney diseases (for example, diabetes mellitus, diabetic nephropathy, acute ischemic renal failure, etc.), organic disorders associated with ischemia or ischemic reperfusion [(eg, disorders associated with ischemic reperfusion of the heart muscle, acute renal failure or disorders induced by surgical treatment, such as surgery for the implantation of a coronary artery bypass (CABG), vascular surgery, transplantation of organs, non-cardiac surgery or percutaneous transluminal coronary angioplasty (PTCA), cerebrovascular diseases res (for example, ischemic stroke, hemorrhagic stroke, etc.), cerebral ischemic disorders (for example, disorders associated with cerebral infarction, disorders caused after a cerebral stroke as sequelae or cerebral edema. The compounds of this invention can also be used as an agent for myocardial protection during surgery for the implantation of a coronary artery bypass (CABG), vascular surgery, percutaneous transluminal coronary angioplasty (PTCA), PTCI, organ transplantation or non-cardiac surgery. Preferably, the compounds of this invention can be used as agents for myocardial protection before, during or after surgery for the implantation of a coronary artery bypass (CABG), vascular surgery, percutaneous transluminal coronary angioplasty (PTCA), transplantation of organs or non-cardiac surgery. Preferably, the compounds of this invention can be used as agents for myocardial protection in patients presenting with cardiac heart disease (acute coronary syndromes, eg, myocardial infarction or unstable angina) or cerebral ischemic episodes (eg, stroke). Preferably, the compounds of this invention can be used as agents for chronic myocardial protection in patients with diagnosed coronary heart disease (eg, previous myocardial infarction or unstable angina) or patients at high risk of myocardial infarction (age greater than 65 years and with two or more risk factors for coronary heart disease). In addition to this, the compounds of this invention are characterized by their strong inhibitory effect on cell proliferation, for example, the proliferation of fibroblast cells and the proliferation of smooth muscle cells of blood vessels. For this reason, the compounds of this invention are valuable therapeutic agents for use in diseases in which cell proliferation represents a primary or secondary cause and, therefore, can be used as anti-atherosclerotic agents and as agents against late complications of the diabetes, cancerous diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosclerosis, hypertrophies or hyperplasias of organs, in particular hyperplasia or hypertrophy of the prostate, pulmonary fibroses, diabetic complications or recurrent stenosis after a PTCA, or diseases produced by an endothelial cell injury. The utility of the compounds of the present invention as medical agents in the treatment of diseases, such as those detailed herein in mammals (eg, humans) eg myocardial protection during surgery or myocardial protection in patients presenting with heart disease Progression or cerebral ischemic episodes or chronic cardiotoprotection in patients with coronary heart disease diagnosed, or at risk of coronary heart disease, cardiac dysfunction or myocardial shock, is demonstrated by the activity of the compounds of this invention in conventional preclinical cardioprotection assays [see the in vivo assay in Klein, H. et al., Circulation 92: 912-917 (1995); the isolated heart assay in Scholz, W. et al., Cardiovascular Research 29: 260-268 (1995); the antiarrhythmic assay in Yasukate M. et al., Am. J. Physiol., 36: H2430-H2440 (1994), the NMR assay in Kolke et al., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)] and the additional in vitro and in vivo assays described below. Such assays also provide a means by which the activities of the compounds of this invention can be compared to the activities of other known compounds. The results of these comparisons are useful for the determination of dosage levels in mammals, including man, for the treatment of said diseases.

Measurement of the inhibitory activity of human NHE-1 The methodologies for the activity and the inhibitory potency of human NHE-1 are based on those published by Watson et al., Am. J. Physiol. 24: G229-G238, 1991), where the recovery of the intracellular pH mediated by the NHE is measured after intracellular acidification. Thus, fibroblasts stably expressing human NHE-1 (Counillon, L. et al., Mol Pharmacol., 44: 1041-1045 (1993) are placed on a 96-well covered collagen plate (50,000 / well ) and allowed to grow to confluence in a growth medium (DMEM high glucose, fetal bovine serum 10%, 50 u / ml penicillin and streptomycin) Confluent plates are incubated for 30 minutes at 37 ° C with the fluorescent sample pH-sensitive BCEFC (5 μM, Molecular Probes, Eugene, OR) Cells loaded with BCECF are incubated for 30 minutes at 37 ° C in an acid loading medium (70 mM choline chloride, 50 mM NHCl 4, 5 mM KCl , 1 mM MgCl 2, 1.8 mM CaCl 2, 5 mM glucose, 10 mM HEPES, pH 7.5) and then placed in a Fluorescent Image Plate Reader (Molecular Devices, CA) The fluorescence of the BCECF is controlled using wavelengths of excitation and emission of 485 nM and 525 mM, respectively, intracellular acidification is initiated by rapid replacement of the acid loading medium with recovery medium (120 mM NaCl, 5 mM KCl, 1 mM MgCl 2, 1.8 mM CaCl 2, 5 mM glucose, 10 mM HEPES, pH 7.5) ± test compound and intracellular pH recovery mediated by the NHE is controlled as the subsequent increase in fluorescence of the BCECF depending on time. The potency of human NHE-1 inhibitors is calculated as the concentration that reduces the recovery of intracellular pH by 50% (Cl50). Under these conditions, the reference NHE inhibitors amyloride and HOE-642 had values of Cl50 for human NHE-1 of respectively 50 μm and 0.5 μM. There is a history that brief periods of myocardial ischemia after reperfusion of the coronary artery protects the heart from subsequent severe myocardial ischemia (Murry et al., Circulation 74: 1124-1136, 1986). The therapeutic effects of the compounds of this invention in preventing damage to cardiac tissue as a consequence of ischemic access can be demonstrated in vitro in a manner similar to that presented in Liu et al. (Cardiovasc. Res., 28: 1057-1061, 1994), as specifically described herein. Cardioprotection, as indicated by a reduction in the infarcted myocardium, can be induced pharmacologically using adenosine receptor agonists in isolated, retrogradely perfused rabbit hearts, as in the in vitro model of ischemic preconditioning of the myocardium (Liu et al. Cardiovasc. Res., 28: 1057-1061, 1994). The in vitro assay described below demonstrates that a test compound (i.e., a compound as claimed herein) can also pharmacologically induce cardiotoprotection, i.e., reduce the size of myocardial infarction, when administered to an isolated heart. of rabbit. The effects of the test compound are compared with ischemic preconditioning and the A1 / A3 adenosine agonist, APNEA (N6- [2- (4-aminophenyl) ethyl] adenosine), which has been shown to pharmacologically induce cardioprotection in the rabbit isolated heart (Líu e al. Cardiovasc. Res., 28: 1057-1061, 1994), rabbit. The exact methodology is described later. The protocol used for these experiments is very similar to that described by Líu eí al. Cardiovasc. Res., 28: 1057-1061, 1994. Male New Zealand White rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30 mg / kg i.v.). After having reached deep anesthesia (determined by the absence of the ocular flicker reflex) the animal is incubated and ventilated with 02 using a positive pressure ventilator. A left thoracotomy is performed, the heart is exposed, and a loop (2-0 silk) is placed loosely around a prominent branch of the left coronary artery, approximately 2/3 of the distance to the apex of the heart. . The heart is removed from the chest and quickly (<; 30 seconds) is mounted on a Langerdorff device. The heart is retrogradely perfused in a non-recirculating manner with a modified Krebs solution (118.5 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 1.2 mM KH2P04, 24.8 mM NaHCO3, 2.5 mM CaCl2 and 10 mM glucose) at a constant pressure of 80 mm of Hg and at a temperature of 37 ° C. The pH of the perfusate is maintained at 7.4-7.5 by bubbling with 02 95% / C02 5%. The temperature of the heart is strictly controlled using heated deposits for the physiological solution and a jacket with water around the perfusion tube and the isolated heart. The heart rate and left ventricular pressure are determined by a latex balloon that is inserted into the left ventricle and connected by a stainless steel tube to a pressure transducer. The intraventricular balloon is inflated to provide a systolic pressure of between 80 and 100 mm Hg and a diastolic pressure < 10 mm Hg. Total coronary flow is also monitored continuously using a built-in normalized flow probe for the weight of the heart. s The heart is left to equilibrate for 30 minutes, at which time the heart must show a left ventricular pressure within the parameters indicated above. If the heart rate falls below 180 Ipm at any time before the 30-minute period of regional ischemia, the heart is marked with a rate of 20 bpm for the rest of the experiment. Ischemic preconditioning is induced by total cessation of cardiac perfusion (global ischemia) for 5 minutes, followed by reperfusion for 10 minutes. Regional ischemia is caused by narrowing the loop placed around the branch of the coronary artery. After the 30-minute regional ischemia, the loop is loosened and the heart is re-infused for another 120 minutes. The pharmacological cardioprotection is induced by infusion of the test compound at determined concentrations, beginning 30 minutes before the 30-minute regional ischemia and continuing until the end of the 12-minute reperfusion period. The hearts that receive the test compounds do not undergo the period of ischemic preconditioning. The reference compound, APNEA (500 nM) is perfused through the hearts (which do not receive the test compound) for a period of 5 minutes ending 10 minutes before the regional ischemia period of 30 minutes. At the end of the 120-minute reperfusion period, the coronary artery loop is squeezed and perfused through the heart by a 0.5% suspension of zinc sulfate and fluorescent cadmium particles (1-10 μM) Duke Scientific Corp. (Palo High CA); This stains all the myocardium, with the exception of the risk area of developing a heart attack (risk area). The heart is removed from the Langerdorff apparatus, dried, wrapped in aluminum foil and stored at -20 ° C overnight. The next day, the heart was cut in 2 mm cross sections from the apex to the top of the ventricles. The slices are stained with 1% triphenyltetrazolium chloride (TTC) in saline with phosphate buffer for 20 minutes at 37 ° C. Since TTC reacts with living tissue (containing NAD-dependent dehydrogenases), this staining differentiates between living tissue (stained red) and dead tissue (infarcted non-stained tissue). The infarcted area (unstained) and the risk area (without fluorescent particles) are calculated for each slice of left ventricle using a precalibrated image analyzer. To normalize the ischemic lesion in terms of the differences between the hearts, the data are expressed as the percentage of infarcted area versus the risk area (% IA / AAR). All data are expressed as mean ± SE and are statistically compared using a nonparametric Mann-Whitney test with a Bonferroni correction for multiple comparisons. The significance is considered as p < 0.05. The results of the above in vitro test demonstrate that the compounds of this invention induce significant cardioprotection relative to the control group. The therapeutic effects of the compounds of this invention with respect to the prevention of cardiac tissue damage as a consequence of ischemic access can also be demonstrated in vivo in a manner similar to that presented in Liu et. to the. (Circulation, Vol 84: 350-356, 1991) as specifically described herein. The in vivo assay demonstrates the cardioprotection of the test compound compared to the control group receiving the saline vehicle. Cardioprotection, as indicated by a reduction in an infarcted myocardium, can be induced pharmacologically using adenosine receptor agonists administered intravenously in intact anesthetized rabbits studied as in the in situ model of myocardial ischemic preconditioning (Liu et al., Circulation 84: 350-356, 1991). The in vivo test shows whether the compounds can pharmacologically induce cardiotoprotection, that is, the reduction in the size of myocardial infarction, when they are administered parenterally to intact anesthetized rabbits. The affections of the compounds of this invention can be compared to ischemic preconditioning using the adenosine A1 agonist, N6-1- (phenyl-2-isopropyl) (PIA) which has been shown to pharmacologically induce cardioprotection in intact anesthetized rabbits. studied in situ (Liu et al., Circulation 84: 350-356, 1991).

Surgery Male New Zealand White rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30 mg / kg i.v.). A tracheotomy is performed by means of a cervical incision in the ventral midline, with ventilation of the rabbits with 100% oxygen using a positive pressure ventilator. Catheters are placed in the left jugular vein for administration of the drug and in the left carotid artery to measure blood pressure. The hearts are then exposed by a left thoracotomy and a loop (silk 00) placed around a prominent branch of the left coronary artery. Ischemia is induced by tightening the loop and fixing it in place. The release of the loop allows reperfusion of the affected area. Myocardial ischemia is evidenced by a regional cyanosis; reperfusion is evidenced by reactive hyperemia.

Protocol Once the blood pressure and heart rate are stable for at least 30 minutes, the test begins. Ischemic preconditioning is induced by occluding the coronary artery for 5 minutes followed by a reperfusion of 10 minutes. The pharmacological preconditioning is induced by infusing the test compound, for, for example, 5 minutes and leaving it 10 minutes before another intervention or by infusion of the adenosine agonist, PIA (0.25 mg / kg). After ischemic preconditioning, pharmacological preconditioning or non-conditioning (nonconditioning, vehicle control) the artery is occluded for 30 minutes and then perfused again for two hours to induce myocardial infarction. The test compound and the PIA are dissolved in solution or other suitable vehicle and administered in a dose of between 1 and 5 mg / kg, respectively.

Staining (Liu et al Circulation 84: 350-356, 1991): At the end of the 2-hour reperfusion period, the hearts are quickly removed, placed in a Langerdorff apparatus and washed for 1 minute with a saline flush. Normal temperature warmed to body temperature (38 ° C). The silk suture used as a loop is then tightly squeezed to reocclus the artery and a 0.5% suspension of zinc sulfate and fluorescent cadmium (1-10 μM) particles is infused Duke Scientífic Corp. (Palo Alto, CA) with the perfused to stain all the myocardium, with the exception of the risk area (non-stained ventricle). The hearts are then frozen rapidly and stored at -20 ° C overnight. The next day, the hearts are cut into 2 mm cross sections and stained with 1% triphenyl tetrazolium chloride (TTC). As TTC reacts with living tissue, this staining differentiates between living tissue (dyed red) and dead tissue (non-stained infarcted tissue). The infarcted area (unstained) and the risk area (without fluorescent particles) are calculated for each slice of left ventricle using a precalibrated image analyzer. To normalize the ischemic lesion in terms of the differences in the risk area between the hearts, the data are expressed as the percentage of infarcted area versus the risk area (% IA / AAR). All data are expressed as mean ± SEM and compared statistically using a single ANOVA factor or a nonparametric Mann-Whitney test. The significance is considered as p < 0.05. The compounds of this invention can be tested for their usefulness in reducing or preventing ischemic injury in non-cardiac tissues, for example, the brain or the liver, using methods disclosed in the scientific literature. The compounds of this invention in such assays can be administered via the preferred route and vehicle of administration or before the ischemic episode, during the ischemic episode, after the ischemic episode (reperfusion period) or during any of the experimental steps mentioned below. ). The benefit of the invention for reducing ischemic brain damage can be demonstrated, for example, in mammals using the method of Park et al. (Ann Neurol, 1988; 24: 543-551). According to the procedure of Park et al., Adult male Sprague Dawley rats are initially anesthetized with halothane 2% and then by mechanical ventilation with a mixture of nitrous oxide-oxygen (70%: 30%) containing halothane 0.5-1 %. Then a tracheotomy is performed. The ventilator stroke volume is adjusted to maintain the arterial carbon dioxide tension at approximately 35 mm Hg and adequate arterial oxygenation (PaO2> 90 mm Hg). The body temperature can be controlled by a rectal thermometer and the animals can be maintained normothermic, if necessary, by external heating. The animals are then subjected to a subtemporal craniectomy to expose the main trunk of the left middle cerebral artery (MCA) under a surgical microscope and the exposed artery is occluded with microbipolar coagulation to generate extensive ischemic lesions in the cerebral cortex and basal ganglia. After three hours of occlusion of the MCA, the rats are subjected to deep anesthesia with halothane 2% and a thoracotomy is performed to infuse the heparinized saline solution into the left ventricle. The effluent is collected by an incision of the right atrium. The washing with saline is followed by 200 ml of a solution of formaldehyde 40%, glacial acetic acid and a solution of absolute methanol (FAM, 1: 1: 8, v / v / v), then the animals are decapitated and the The head is preserved in a fixing solution for 24 hours. The brain is then separated, dissected, embedded in paraffin wax and sectioned (approximately 100 0.2 mm sections per brain). The sections are then stained with hematoxylin-eosin or with a combination of cresyl violet and Luxol blue and examined with an optical microscope to identify and quantify the ischemic damage using a precalibrated image analyzer. The volumes and ischemic areas are expressed in absolute units (mm3 and mm2) and as a percentage of the total region examined. The effect of the compositions and methods of this invention to reduce the ischemic brain damage induced by the occlusion of the MCA is seen based on a reduction of the area or volume of relative or absolute ischemic damage in the brain sections from rats in the group of treatment compared to cerebral sections from rats of a control group treated with placebo. Other methods that could optionally be used to demonstrate the benefit of the invention for reducing ischemic brain damage include those described by Nakayama et al. in Neurology 1988. 38: 1667-1673; Memezawa, et al. in Stroke 1992. 23: 552-559; Folbergrova, et al. in Proc. Nati Acad. Scí. 1995. 92: 5057-5059 and Gotti, et al. in Brain Res. 1990, 522: 290-307. The benefit of the compounds, compositions and methods of this invention for reducing ischemic liver damage can be demonstrated, for example, in mammals using the method of Yokoyama, et al. (Am. J. Physiol., 1990; 258: G564-G570). According to the procedure of Yokoyama, et al., Male fasting Sprague Dawley rats are anesthetized with pentobarbital (40 mg / kg i.p.), then the animals are tracheotomized and mechanically ventilated with the room air. The liver is removed and placed in a chamber maintained at constant temperature (37 ° C) then perfused through the portal vein at a constant pressure of 15 cm H20 with a modified hemoglobin buffer from Krebs-Henseleit (in mM : NaCl 118, KCl 4.7, NaHCO3 27, CaCl2 2.5, MgSO4 1.2, KH2P04 1.2, EDTA 0.05 and glucose 11 mM, plus 300 U of heparin). The pH of the perfusate is maintained at 7.4 by gassing the buffer with 02 95% - C02 5%. Each liver is perfused at a flow rate of 20 ml / min in the form of a single pass during a washed period and equilibrium of 30 minutes (pre-ischemic period), followed by a period of 2 hours of global ischemia and then a period of 2 hours. of reperfusion in conditions identical to the pre-ischemic period. Aliquots (20 ml) of the perfusate are collected during the pre-ischemic period, immediately after the occlusive ischemic period and every 30 minutes of the 2-hour reperfusion period. Perfusate samples are tested for the existence of hepatocellular enzymes, for example, aspartate amino-transferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), which are taken to reflect quantitatively the degree of damage to the ischemic liver tissue during the procedure. The activities of the AST, ALT and LDH in the perfusate can be determined by various methods, for example, by the reflectometry method using a Kodak Ektachem 500 automatic analyzer disclosed by Nakano et al. (Hepatology 1995, 22: 539-545). The effect of the compounds, compositions and methods of this invention for the reduction of ischemic liver injury induced by occlusion is seen based on a reduction in the release of the hepatocellular enzymes immediately after the occlusive period and / or during post-ischemic reperfusion in the perfused livers from the rats in the treatment group compared to the perfused livers from rats of a control group treated with palcebo. Other methods and parameters that could be used as an alternative to demonstrate the benefit of the compositions and methods of this invention for the reduction of ischemic liver injury include those described by Nakano, et al. (Hepatology 1995; 22: 539-545).

Assays with the aldose reductase inhibitor By injection of 55 mg / kg of streptozocin i.v. In citrate buffer with pH 4.5, diabetic male Sprague-Dawley rats are obtained. They are fed ad libitum under controlled conditions of accommodation, temperature and light. After five weeks of diabetes, the rats are anesthetized with an overdose of pentobarbital and the tissues are rapidly removed and analyzed for sorbitol and fructose. Sorbitol levels are analyzed according to the method of Donald M Eades et al., "Rapid Analyzes of Sorbitol, Galacticol, Mannitol and Myoinositol Mixtures From Biological Sourses," Journal of Chromatography, 490. 1-8. (1989). Fructose is enzymatically measured in rat tissues using a modification of the Ameyama method (Methods in Enzimoloqy, 89: 20-29, 1982), in which the ferriyanide is replaced by resazurin, a dye that is reduced to give highly fluorescent resorufin . The amount of fluorescent resorufin is stoichiometric with the amount of fructose oxidized by the fructose dehydrogenase. The assay contains neutralized nerve extract with 0.1 ml of 6% perchloric acid in a final volume of 1.5 ml. After incubation for 60 minutes at room temperature in a closed cuvette, the fluorescence of the sample is determined for excitation = 560 nm, emission = 580 nm with 5 mm slots each in a Perkin-Elmer model 650 fluorescence spectrophotometer. -40. Fructose concentrations are calculated by comparison with a series of known fructose standards.

Tests with the glycogen phosphorylase inhibitor The three different isoenzymes of purified glycogen phosphorylase (GP), where glycogen phosphorylase is in the activated state "a" (referred to as glycogen phosphorylase a or its abbreviation Gpa) and referred to herein as human hepatic glycogen phosphorylase a (HLGPa), human muscle glycogen phosphorylase a (HMGPa) and human brain glycogen phosphorylase a (HBGPa), can be obtained by the following procedures.

Expression and fermentation The HLGP and HMGP cDNAs are expressed from plasmid pKK233-2 (Pharmacia Biotech, Inc., Piscataway, New Jersey) in the XL-1 Blue layer of E. Coli (Stratagene Cloning Systems, LaJolla, CA ). The layer is inoculated in LB medium (constituted by 10 g of tryptone, 5 g of yeast extract, 5 g of NaCl and 1 ml of 1 N NaOH per liter) plus 100 mg / l of ampicillin, 100 mg / l of pyridoxine and 600 mg / L of MnCl2 and grown at 37 ° C to a cell density of DOsso = 1.0. At this point, the cells are induced with 1 mM 1-methyl-propyl-1-1-thio-β-D-galactositol (IPTG). Three hours after induction, the cells are harvested by centrifugation and the cell pellets are frozen to -70 ° C until they are needed for purification. The HBGP cDNA can be expressed by various methodologies, for example, by the method described by Crerar, et al. (J. Biol. Chem. 270: 13748-13756). The method described by Crerar et al. (J. Biol. Chem. 270: 13748-13756) for the expression of HBGP is as follows: the HBPG cDNA can be expressed from plasmid pTACTAC in strain 25A6 of E. coli. The strain inoculates in LB medium (constituted by 10 g of tryptone, 5 g of yeast extract, 5 g of NaCl and 1 ml of 1 N NaOH per liter) plus 50 mg / l of ampicillin and allowed to grow overnight , then resuspended in fresh LB medium plus 50 mg / l of ampicillin and inoculated again in a 40X volume of an LB / amp medium containing 1-thiopropyl-1-thio- > 9-D-galactosid (IPTG) 250 μM, 0.5 mM pyridoxine and 3 mM MgCl2 and allowed to grow at 22 ° C for 48-50 hours. The cells can then be harvested by centrifugation and the cell pellets frozen at -70 ° C until needed for purification. The HLGP cDNA is expressed from plasmid pBlueBac III (Invitrogen Corp., San Diego, CA), which is co-transfected with BaculoGold linear viral DNA (Pharmingen, San Diego, CA) into Sf9 cells. The recombinant virus is plaque purified below. For the production of the protein, Sf9 cells grown in a serum-free medium are infected with a multiplicity of infection (moi) of 0.5 and with a cell density of 2 × 10 6 cells / ml. After growth for 72 hours at 27 ° C, the cells are centrifuged and the cell pellets are frozen at -70 ° C until needed for purification.

Purification of glycogen phosphorylase expressed in E. coli E. coli cells in the sediments described above are resuspended in 25 mM / - glycerophosphate (pH 7.0) with 0.2 mM DTT, 1 mM MgCl2, plus the following protease inhibitors : 0.7 μg / ml Pepstatin A 0.5 μg / ml Leupeptin 0.2 mM Phenylmethylsulfonyl fluoride (PMSF) and 0.5 mM EDTA, are lysed by pretreatment with 200 μg / ml lysozyme and 3 μg / ml DNase followed by sonication in batches of 250 ml for 5 x 1.5 minutes on ice using a Branson Model 450 ultrasonic cellular disintegrator (Branson Sonic Power Co., Danbury CT). The cell lysates of E. coli are then rinsed by centrifugation at 35,000 x g for one hour followed by filtration through 0.45 micron filters. The GP in the soluble fraction of the lysates (estimated to be less than 1% of the total protein) is purified by controlling the enzymatic activity (as described in the section on Testing the activity of GPa, below) after a series of chromatographic steps detailed below.

Affinity metal immobilized chromatography (IMAC) This step is based on the method of Luong et al (Luong et al, Journal of Chromatography (1992) 584, 77-84). 500 ml of the filtered soluble fraction of the cell lysates (prepared from approximately 160-250 g of original cell pellet) are loaded onto a 130 ml column of IMAC with chelating sepharose (Pharmacia LKB Biotechnology, Piscataway, New Jersey), the which has been loaded with 50 mM CuCI2 and 25 mM ß-glycerophosphate, 250 mM NaCl and 1 mM midazole in equilibration buffer at pH 7. The column is washed with equilibration buffer until the A28o returns to the baseline. The sample is then eluted from the column with the same buffer containing 100 mM midazole to remove the bound GP and other bound proteins. Fractions containing GP activity are pooled (approximately 600 ml) and ethylenediaminetetraacetic acid (EDTA), DL-dithiothreitol (DTT), phenylmethyl-sulfonyl fluoride (PMSF), leupeptin and pepstatin A are added to obtain concentrations of 0.3 mM , 0.2 mM, 0.2 mM, 0.5 μg / ml and 0.7 μg / ml respectively. The GP pool is desalted on a Sephadex G-25 column (Sigma Chemical Co., St. Louis, Missouri) equilibrated with 25 mM Tris-HCl (pH 7.3), 3 mM DDT buffer (buffer A) to remove the imidazole and Preserves on ice until the second chromatographic step.

Chromatography in 5'-AMP-Sepharose The desalted pooled GP sample (approximately 600 ml) is then mixed with 70 ml of 5'-AMP Sepharose (Pharmacia LKB Biotechnology, Piscataway, New Jersey), which is equilibrated with Buffer A (see above). This mixture is stirred gently for one hour at 22 ° C and then packaged in a column and washed with buffer A until the A 280 returns to the baseline. The GP and other proteins are eluted from the column with 25 mM Tris-HCl, 0.2 mM DTT and 10 mM adenosine-5'-monophosphate (AMP) at pH 7.3 (buffer B). Fractions containing GP are pooled after identification by determination of enzymatic activity (described below) and visualization of the Mr of the GP protein band of approximately 97 Kdal by polyacrylamide gel electrophoresis with sodium dodecyl sulfate ( SDS-PAGE) followed by silver staining (2D-type Stain II "Daíichi Case", Daüchi Puré Chemicals Co., LTD., Tokyo, Japan) and meet below. The pooled GP is expressed in 25 mM yß-glycerophosphate, 0.2 mM DTT, 0.3 mM EDTA, 200 mM NaCl, pH 7.0 buffer (Buffer C) and kept on ice until used. Before using the GP enzyme, the enzyme is converted from the inactive form as expressed in the XL-1 Blue strain of E. coli (called GPb) (Stragene Cloning Syst La Jolla, California) to the active one (called GPa) by means of the procedure described in section (A) Activation of the posterior GP.

Purification of glycogen phosphorylase expressed in cells Sf9 The Sf9 cells in the sediments described above are resuspended in 25 mM /? - glycerophosphate (pH 7.0) with 0.2 mM DTT, 1 mM MgCl2, plus the following protease inhibitors: 0.7 μg / ml Pepstatin A 0.5 μg / ml 0.2 mM Leupeptin 0.2 mM Phenylmethylsulfonyl fluoride (PMSF) and 0.5 mM EDTA, are lysed by pretreatment with 3 μg / ml DNase followed by sonication in batches for 3 x 1 minutes on ice using a Branson Model 450 Ultrasonic Cell Splitter (Branson Sonic Power Co., Danbury CT). The Sf9 cell lysates are then rinsed by centrifugation at 35,000 x g for one hour followed by filtration through 0.45 micron filters. The GP in the soluble fraction of the lysates (estimated to be less than 1.5% of the total protein) is purified by controlling the enzymatic activity (as described in the section on Activity Assay of the GPa, below) after a series of chromatographic steps detailed below.

Affinity Chromatography with Immobilized Metal (IMAC) Affinity chromatography with immobilized metal is performed as described in the previous section. The combined and desalted GP is then preserved on ice until further processing.

Activation of the GP Prior to chromatography, the fraction of the inactive enzyme as expressed in the Sf9 cells (called GPb) is converted to the active form (called GPa) by the procedure described in section (A) Activation of the GP later.

Anion exchange chromatography After activation of the GPb purified by IMAC in GPa by reaction with the immobilized phosphorylase kinase, the pooled fractions of GPa are dialyzed against 25 mM Tris-HCl, pH 7.5 containing 0.5 mM DTT, 0.2 mM EDTA , 1.0 mM phenylethylsulfonyl fluoride (PMSF), 1.0 μg / ml leupeptin A and 1.0 μg / ml pepstatin A. The sample is then loaded onto a MonoQ anion exchange chromatography column (Pharmacia Biotech, Inc., Piscataway, New Jersey). The column is washed with a equilibration buffer until the A 2β returns to the baseline. The sample is eluted from the column with a linear gradient of 0-0.25 M NaCl to remove the bound GP and other bound proteins. Fractions containing GP elute in a range of NaCl between 0.1 and 0.2 M, as detected by eluent control for a peak of the protein with an absorbance at A28o- The GP protein is identified below by visualizing the Mr of the band of GP protein of approximately 97 Kdal by polyacrylamide gel electrophoresis with sodium dodecyl sulfate (SDS-PAGE) followed by silver staining (2D-silver Stain II "Daiichi Case", Daiichi Puré Chemicals Co., LTD., Tokyo, Japan ) and meet below. The pooled GP is dialyzed into 25 mM N, N-bis [2-hydroxyethyl] -2-aminoethanesulfonic acid, 1.0 mM DTT, 0.5 mM EDTA, 5 mM NaCl, buffer pH 6.8 (Buffer C) and kept on ice until its use.

Determination of the enzymatic activity of GP A) Activation of the GP: Conversion of GPb into Gpa. Prior to the determination of the enzymatic activity of the GP, the enzyme is converted from the inactive form as expressed in the XL-1 Blue strain of E. coli. (called GPb) (Stragene Cloning Systems, La Jolla, California) the active form (called GPa) by phosphorylation of GP using phosphorylase kinase as follows. The inactive enzyme fraction as expressed in Sf9 cells (called GPb) is also converted to the active form (called GPa) by the following procedure.

Reaction of GP with activated phosphorylase kinase The phosphorylase kinase (Sigma Chemical Company, St. Louis, MO) is immobilized on an Affi 10 gel (BioRad Corp., Melville, NY) following the manufacturer's instructions. Briefly, the enzyme phosphorylase kinase (10 mg) is incubated with washed Affi gel beads (1 ml) in 2.5 ml of 100 mM HEPES and 80 mM CaCl2 at pH 7.4 for 4 hours at 4 ° C. The Affi gel beads are then washed once with the same buffer before blocking with 50 mM HEPES and 1 M glycine methyl ester at pH 8.0 for one hour at room temperature. The blocking buffer is removed and replaced with 50 mM HEPES (pH 7.4), 1 mM /? - mercaptoethanol and 0.2% NaN3 for preservation. Prior to its use to convert GPb to GPa, the phosphorylase kinase beads immobilized on the Affi gel are equilibrated by washing in the buffer used to perform the kinase reaction, consisting of 25 mM β-glycerophosphate, 0.3 mM DTT and 0.3 EDTA mM at pH 7.8 (kinase assay buffer). The partially purified inactive GPb obtained from the chromatography on 5'-AMP-Sepharose above (from E. coli) or the mixture of GPa and GPb obtained from the previous IMAC (from the Sf9 cells) was Dilute 1: 10 with the kinase assay buffer and then mix with the aforementioned phosphorylase kinase enzyme immobilized on the Affi gel beads. NATP is added up to 5 mM and MgCl2 up to 6 mM. The resulting mixture is mixed gently at 25 ° C for 30 to 60 minutes. The sample is removed from the beads and the percentage of activation of the GPb is estimated by conversion in the GPa determining the activity of the GP enzyme in the presence and absence of AMP 3, 3 mM. The percentage of activity of the total GP enzyme due to the activity of the GPa enzyme (independent of AMP) is calculated as follows: HLGP activity - AMP% total HLGPa = HLGP activity + AMP Alternatively, the conversion of the GPb in GPa it can be controlled by isoelectric focusing, based on the displacement of the electrophoretic mobility that can be seen after the conversion of the GPb into GPa. The GP samples are analyzed by isoelectric focusing (IEF) using the Pharmacia PfastGel System (Pharmacia Biotech, Inc., Piscataway, New Jersey) using pre-mixed gels (interval p1 4-6.5) and the method recommended by the manufacturer. The resolved GPa and GPb bands are then visualized on the silver stained gels (2D-silver Stain ll "Daüchi Case", Daíichi Puré Chemicals Co., LTD., Tokyo, Japan). The identification of GPa and GPb is done by comparison with the GPa and GPb standards obtained from E. coli that run in parallel on the same gels as the experimental samples.

B) GPa activity assay The disease / disorder treatment / prevention activities described herein of the glycogen phosphorylase inhibitor compounds of this invention can be determined indirectly by assessing the effect of the compounds of this invention on the activity of the activated form of glycogen phosphorylase (GPa) by one of two methods; the activity of glycogen phosphorylase is measured in a progressive direction by controlling the production of glucose-1-phosphate from glycogen or following the reverse reaction, measuring the synthesis of glycogen from glucose-1-phosphate by releasing inorganic phosphate. All reactions can be performed in triplicate in 96-well microtiter plates and by measuring the change in absorbance due to the formation of the reaction product at the wavelength specified later in an MCC / 340 MKII Elisa reader (Lab Systems, Finland ), connected to a Titertech microplate stacker (ICN Biomedical Co, Huntsville, Alabama). To measure the activity of the GPa enzyme in the progressive direction, the production of glucose-1-phosphate from glycogen is controlled by the general multienzyme coupled method of Pesce et al. [Pesce, M.A., Bodourian, S.H., Harris, R.C. and Nicholson, J.F. (1977) Clinical Chemistry 23, 1711-1717] modified as follows: between 1 and 100 μg of GPa, 10 units of phosphoglucomutase and 15 units of glucose-6-phosphate dehydrogenase (Boehringer Mannheim Biochemicals, Indianapolis, IN) is diluted to 1 ml of Buffer A (described below). Buffer A has a pH of 7.2 and contains 50 mM HEPES, 100 mM KCl, ethylene glycoltetraacetic acid (EGTA), 2.5 mM MgCl2, 3.5 mM KH2P04 and 0.5 mM dithiothreitol. 20 μl of this stock solution is added to 80 μl of buffer A containing 0.47 mg / ml glycogen, glucose 9.4 mM, 0.63 mM of the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP +). The compounds to be tested are added as 5 μl of solution in dimethyl sulfoxide (DMSO) at 14% before the addition of the enzymes. The basal percentage of GPa enzyme activity in / absence of inhibitors is determined by adding 5 μl of 14% DMSO and a percentage of total inhibition of GPa enzyme activity is obtained by adding 20 μl of 50 mM of the substance of positive control trial, caffeine. The reaction is followed at room temperature by measuring the conversion of oxidized NADP + to the reduced NADPH at 340 nm. To measure the activity of the GPa enzyme in the reverse direction, the conversion of glucose-1-phosphate to glycogen plus inorganic phosphate is measured by the general method described by Engers et al. [Engers, H.D., Shechosky, S. and Madsen, N.B. (1970) Can. J. Biochem. 48, 746-754] modified as follows: from 1 to 100 μg of GPa is diluted to 1 ml in buffer B (described hereinafter). Buffer B has a pH of 7.2 and contains 50 mM HEPES, 100 mM KCl, 2.5 mM EGTA, 2.5 mM MgCl 2 and 0.5 mM dithiotreitol. 20 μl of this stock solution is added to 80 μl of buffer B with 1.25 mg / ml glycogen, glucose 9.4 mM, 0.63 mM glucose-1-phosphate. The compounds to be tested are added as 5 μl of solution in 14% DMSO before the addition of the enzyme. The basal percentage of the activity of the GPa enzyme in the absence of added inhibitors is determined by adding 5 μl of 14% DMSO and a percentage of total inhibition of GPa enzyme activity is obtained by adding 20 μl of 50 mM of caffeine. This mixture is incubated at room temperature for 1 hour and the inorganic phosphate released from glucose-1-phosphate is measured by the general method of Lanzetta et al. [Lanzetta, P.A., Alvarez, L.J., Reinach, P.S. and Candía, O.A. (1979) Anal. Bíochem. 100, 95-97] modified as follows: 150 μl of 10 mg / ml of ammonium molybdate, 0.38 mg / ml of malachite green in 1N HCl is added to 100 μl of the enzyme mixture. After an incubation of 20 minutes at room temperature, the absorbance is measured at 620 nm. The above tests carried out with a range of concentrations of the test compound allow the determination of an IC 50 value, (concentration of the test compound required for a 50% inhibition) for the inhibition in vitro of the activity of the GPa enzyme. by the test compound. The administration of the compounds of this invention can be by any method that provides a compound of this invention preferably to the desired tissue (e.g., liver and / or cardiac tissue). These models include the oral, parenteral, intraduodenal, etc. Generally, the compounds of the present invention are administered in single doses (eg, once a day) or in multiple doses or by constant infusion. The compounds of this invention are useful, for example, for the reduction or minimization of damage exerted directly on any tissue that may be susceptible to injury by schaemia / reperfusion (eg, cardiac, cerebral, pulmonary, renal, hepatic, instestinal, of skeletal muscle, retinal) as the result of an ischemic episode (for example, myocardial infarction). Accordingly, the active compound is usually used prophylactically to prevent, i.e. (prophylactically or prematurely) to attenuate or arrest tissue damage (e.g., myocardial tissue) in patients at risk of ischemia (e.g., myocardial ischemia). Generally the compounds of this invention are administered orally or parenterally (for example, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, when the patient suffers from gastrointestinal disorders or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. The amount and range of administration of the compounds will therefore depend on the subject to be treated, the severity of the affliction, the manner of administration and the physician's opinion. Thus, due to the variability that exists between the patients, the dosages given below are a guide, with the doctor being able to titrate the doses of the drug to achieve the treatment that the doctor considers appropriate for the patient. Considering the degree of the desired treatment, the doctor must take into consideration several factors, such as the age of the patient, the existence of a previous disease as well as the existence of other diseases (for example, cardiovascular disease). Thus, for example, in a mode of administration the compounds of this invention can be administered just prior to surgery (eg, in the twenty-four hours before surgery, eg, cardiac surgery) during or subsequent to surgery (eg. example, within twenty-four hours after surgery) when there is a risk of myocardial ischemia. The compounds of this invention can also be administered on a chronic daily basis. An amount of the compounds of this invention is used so that it is effective for ischemic protection. A preferred dosage is approximately between 0.001 and 100 mg / kg / day of the compound of this invention. An especially preferred dosage is between about 0.01 and 50 mg / kg / day of the compound of this invention. The compounds of the present invention are generally administered in the form of a pharmaceutical composition containing at least one of the compounds of this invention together with a pharmaceutically acceptable carrier or diluent. Thus, the compounds of this invention can be administered individually or in combination in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, a pharmaceutical composition may be in the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate are used together with various disintegrants, such as starch, preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are very useful for the manufacture of tablets. Solid compositions of similar type filled in soft and hard gelatin capsules are also used; in this regard, the preferred materials also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When what is desired are aqueous suspensions and / or elixirs for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various combinations of them. For parenteral administration, for example, solutions in sesame oil or arachis oil or in aqueous propylene glycol can be used, as well as the sterile aqueous solutions of the corresponding water-soluble salts. Said aqueous solutions may be appropriately buffered where necessary, and the liquid diluent must first be made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous media used can all be obtained easily by standard techniques well known to those skilled in the art. For transdermal (e.g., topical) administration, dilute, aqueous or partially aqueous solutions are prepared (usually at a concentration of about 0.1% to 5%), and on the other hand, similar to the above solutions for parenteral use. The methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known or will be apparent in light of this description for those skilled in the art. See Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975) for examples of methods of preparation of pharmaceutical compositions. The pharmaceutical compositions according to the invention may contain between 0.0001% and 95% of the compound (s) of this invention.

In any case, the composition of the formulation to be administered will contain an amount of a compound (s) of this invention in an amount effective to treat the disease / disorder of the subject to be treated. The two different compounds of this combination of this invention can be coadministered simultaneously or sequentially in any order, or as a single pharmaceutical composition containing a compound of formula I and an aldose reductase inhibitor as described above or an inhibitor of the glycogen phosphorylase as described above or a cardiovascular agent. Since the present invention has an aspect related to the treatment of the diseases / disorders described herein with a combination of active ingredients, which can be administered separately, the invention also relates to the combination of the individual pharmaceutical compositions in the form of the case The kit contains two individual pharmaceutical compositions: a compound of formula I, a prodrug thereof or a salt of said compound or of said prodrug and a second compound, as described above. The kit contains the means for containing the individual compositions, such as a container, a divided bottle or a divided aluminum foil pack. Typically, the kit contains instructions for the administration of the individual components. The case form is particularly advantageous when it is preferred to administer the individual compounds in different dosage forms (e.g., oral and parenteral), with different dosage ranges or when the prescribing physician desires a titration of the individual components of the combination. . An example of a case of this type is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules and the like). The blister packs generally consist of a sheet of relatively rigid material preferably covered with a cover of a transparent plastic material. During the packaging process, cavities are drilled in the plastic cover. The cavities have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the cavities and the sheet of relatively rigid material is sealed with the plastic cover on the side of the cover opposite the direction in which the cavities were formed. In this way, the tablets or capsules are sealed in the cavities between the plastic cover and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying a pressure on the cavities, so that an opening is produced in the sheet at the cavity location. The tablet or the capsule can then be withdrawn through said opening. It might be desirable to include a reminder in the case, for example, in the form of numbers near the tablets or capsules, so that the numbers correspond to the days of the regimen in which the tablets or capsules thus specified should be ingested. Another example of a reminder of this type is a calendar printed on the cardboard, for example as follows, "First week, Monday, Tuesday ... etc ... Second week, Monday, Tuesday ..." etc. Other variations of reminders will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to take on a given day. Also a daily dose of a compound of formula I may consist of a tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules and vice versa. The reminder should reflect this aspect. In another specific embodiment of the invention, a dispenser designed to dispense the daily doses, one each time in the order of its intended use, is provided. Preferably, the dispenser is equipped with a reminder to facilitate compliance with the regimen. An example of a reminder of this type is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of a reminder of this type is a battery-operated memory chip, coupled to a liquid crystal display, or an audible reminder signal, which, for example, reads the date of the last daily dose taken and / or remembers when the next dose should be taken. The compounds of this invention will be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention. In the following formulations, "active ingredient" denotes a compound or compounds of this invention.

Formulation 1: Gelatin capsules Hard gelatine capsules were prepared using the following: Ingredient Quantity (mg / capsule) Active ingredient 0.25-100 Starch, NF 0-650 Fluid starch powder 0-50 Silicone fluid 350 centiestokes 0-15 A tablet formulation is prepared using the following ingredients: Formulation 2: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Microcrystalline cellulose 200-650 Silicon dioxide, non-volatile 10-650 5-15 acid stearate The components are combined and compressed to form the tablets. As an alternative, tablets containing 0.25-100 mg of active ingredients are prepared as follows: Formulation 3: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch 45 Microcrystalline cellulose 35 Polyvinyl pyrrolidone (as 10% of 4 solution in water) Carboxymethylcellulose sodium 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredient, starch and cellulose are passed through a No. 45 U.S mesh screen and thoroughly mixed. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are passed through a No. 14 US mesh screen.The granules thus produced are dried at 50 ° -60 ° C and passed through a mesh screen. No. 18 US Sodium carboxymethyl starch, magnesium stearate and talcum, previously passed through a No. 60 US sieve, are added to the granules which, after mixing, are compressed into a tablet machine for give the tablets. Suspensions containing 0.25-100 mg of active ingredient per 5 ml of dose are prepared as follows: Formulation 4: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.25-100 mg Carboxi sodium methylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Flavoring agent c.v. Colorant c.v. Purified water 5 ml The active ingredient is passed through a No. 45 mesh U.S. and it is mixed with the sodium carboxymethyl cellulose and the syrup to form a paste without lumps. The benzoic acid solution, the flavor and the dye are diluted with some water and added with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoro-methane) 74.00 The active ingredient is mixed with the ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C, and transferred to a filling device. The required quantity is introduced into a stainless steel container and diluted with the remaining propellant. The valve units are then fixed to the container. Suppositories are prepared as follows: Formulation 6: Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 Saturated fatty acid glycerides 2,000 The active ingredient is passed through a No. mesh screen 60 U.S. and suspended in the glycerides of saturated fatty acids previously melted with the minimum necessary heat. The mixture is then poured into a suppository mold with a nominal capacity of 2 g and allowed to cool. An intravenous formulation is prepared as follows: Formulation 7: Intravenous solution Ingredient Quantity Active ingredient 25 mg-10.000 mg Isotonic saline solution 1.000 ml The solution of the above ingredients is administered intravenously to a patient.

The above active ingredient can also be a combination of agents.

General experimental procedures The NMR spectra were recorded on a spectrometer Varian XL-300 (Varian Co., Palo Alto, California) a Bruker AM-300 AM-300 spectrometer (Bruker Co., Billerica, Massachusetts) or a Varian 400 unit at approximately 23 ° C to 300 or 400 MHz for the proton . Chemical shifts are expressed in parts per million downstream of trimethylsilane. The shapes of the peaks are called as follows: s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; sa = wide singlet. The so-called interchangeable resonances did not appear in a separate NMR experiment where the sample was shaken with several drops of D20 in the same solvent. The chemical ionization mass spectra at atmospheric pressure (APCIMS) were obtained in a Fisons Platform II Spectrometer. The chemical ionization mass spectra (CIMS) were obtained on a Hewlett-Packard 5989 instrument (Hewlett-Packard Co., Palo Alto, California) (ammonia ionization, PBMS). Where the intensity of the ions containing chloride or bromide is described, the expected intensity ratio (approximately 3: 1 for ions containing 35CI / 37CI and 1: 1 for ions containing 79Br / 81Br) was observed and M is based on 35CI and 79Br. In some cases only the representative 1H NMR and APCIMS peaks are given.

Column chromatography was performed either with Baker Silica Gel (40 μm) (JT, Baker, Phillipsburg, NJ) or Silica Gel 60 (EM Sciences, Gibbstown, NJ) on glass columns or on Flash 40 ™ or Flash 12 ™ columns. (Biotage) (Charlottesville, VA) under reduced nitrogen pressure. Radial chromatography was carried out using a Chromatron, (Harrison Research) (Palo Alto, CA). Unless otherwise specified, the reagents were used as obtained from commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran, and dichloromethane used as the reaction solvents were anhydrous grade, supplied by Aldrich Chemical Company (Milwaukee, Wisconsin). The microanalyses were carried out by the Schwarzkopf Microanalytical Laboratory, Woodside, NY. The terms "concentrate" and "coevaporate" refer to the removal of the solvent with a water pump or a rotary evaporator with a temperature bath of less than 50 ° C. The reactions carried out at "0-20 ° C" or "0-25 ° C" were carried out with an initial cooling of the vessel in an isolated ice bath that was allowed to warm to room temperature for several hours. The abbreviation "min" and "h" mean "minutes" and "hours", respectively. Reference to the hydrochloride salt in the examples named below includes mono or di salts as appropriate in the particular example.

EXAMPLE 1 ethyl 5-methyl-1-phenyl-1-yl-1,2,3-triazole-4-carboxylate Titanium tetrachloride (0.28 ml, 2.56 mmol) is added to a solution of ethyl diazoacetate (0.35 ml, 2.56 mmole) and aniline (0.47 ml, 5.12 mmole) in 5 ml of dichloroethane. After heating to reflux for 16 hours, the solution was quenched with an aqueous solution of 2 N KOH, and 10 ml of hexanes and diethyl ether were added. The separated organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography on silica gel eluting with 0-15% ethyl acetate in hexanes to give 168 mg of the title compound. 1 H NMR (CD 3 OD) d 1.4 (t, 3 H), 2.6 (s, 3 H), 4.4 (q, 2 H), 7.5-7.6 (m, 2 H), 7.6-7.7 (m, 3 H).

EXAMPLE 2 Methyl 4-methyl-5-phenyl-4 -1,2,4-triazole-3-carboxylate N-methyl benzamide (5 g, 37 mmol) was converted into the thioamide by treatment with Lawesson's reagent (10 g, 25 mmol) in dimethoxyethane (100 ml) at 60 ° C for 4 hours. After carrying out an aqueous extraction with methylene chloride, drying over sodium sulfate, and filtering, the organic phases were concentrated in vacuo, giving 2.68 g of the thioamide as a yellow solid. This material (2.86 g, 17.75 mmol) was treated directly with methyl iodide (3.87 ml, 62 mmol) in acetone (100 ml). After stirring at room temperature overnight, the mixture was concentrated in vacuo to give 248 g of N, S-dimethylisothiobenzamide iodohydrate as a yellow solid. This material (2.48 g, 8.46 mmol) was dissolved in 50 ml of methanol and added slowly to the solution cooled in an ice bath as an anhydrous hydrazine (0.518 ml, 16.51 mmol, dissolved in 10 ml of methanol). While cooling in an ice bath, the mixture was stirred for 2.5 h and ether (approximately 20 ml) was added forming a precipitate. The resulting suspension was stirred for an additional 3 hours before collecting the solid by filtration and rinsing with ether, giving 2.15 g of N-methyl benzamidrazone hydroiodide as a white solid. 1H RM? (CD3OD) d 2.95 (s, 3H), 7.6 (m, 4H), 7.7 (m, 1 H). The above α-methyl benzamidrazone iodide (1 g, 3.61 mmol) was dissolved in 5 ml of pyridine and treated with methyl oxalyl chloride (0.89 ml, 9.6 mmol). After the exothermic addition, the reaction mixture was stirred at room temperature overnight before being concentrated in vacuo. The resulting residue was combined with 10 ml of water and extracted with ethyl acetate (3 x 75 ml). The combined organic phases were washed with water (2 x 25 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid which was purified by chromatography on silica gel eluting with 5% methanol in methylene chloride giving 200 mg of the title compound. 1 H NMR (CD 3 OD) d 3.9 (s, 3 H), 4.0 (s, 3 H), 7.6 (m, 3 H), 7.7 (m, 2 H). The compounds of Examples 3A-3T were prepared using procedures analogous to those described in Klinsberg, E. Synthesis 1972, 475.

EXAMPLE 3A 5-Methyl-2- (4-methoxyphenyl) -2H-1, 2,3-triazole-4-carboxylic acid Acetoacetanilide (25.0 g, 0.14 mol) and sodium nitrite (12.65 g, 0.18 mol) were dissolved in an aqueous solution of sodium hydroxide (140 ml, 1 N) and the resulting solution was added dropwise during 20 min to an aqueous solution. of sulfuric acid (120 ml of H2S? 4 conc. in 950 ml of water) cooled in an ice bath. The reaction mixture was stirred at 0 ° C for 30 min, then the precipitate was filtered and washed with water to give 2-hydroxyiminoacetanilide (22.64 g, 78% yield) as a pale yellow solid. Sodium methoxide (0.89 g, 0.017 mmol) was added to a solution of methoxyphenylhydrazine hydrochloride (2.89 g, 0.016 mol) in 10 ml of ethanol and after 5 min the mixture was filtered and the filtrate was added to a hot solution of 2 ml. -hydroxy-aminoacetoacetanilide (3.25 g, 0.0158 mol) in 5 ml of ethanol. The resulting solution was briefly heated to reflux, then allowed to cool to room temperature, with which a precipitate formed. The precipitate was filtered and washed with hexane / ethyl acetate 2: 1 to give 2-hydroxyimino-3- (4-methoxyphenyl) -hydrazonobutanoic acid anhydride as a yellow solid (3.16 g, 61% yield). 2-Hydroxyimino-3- (4-methoxyphenyl) -hydrazonobutanoic acid anuide (3.16 g, 0.01 mol) was added over a period of 2 min. to a refluxing solution of potassium hydroxide (3.2 g, 0.05 mol) in 12 ml of 2-ethoxyethanol. The reaction mixture was refluxed for 15 minutes, then cooled to room temperature. The precipitate that formed was filtered and washed with diethyl ether. The solid was dissolved in 15 ml of water and the resulting solution was acidified with dilute aqueous hydrochloric acid. The aqueous solution was extracted with 3 x 20 ml of ethyl acetate and the combined ethyl acetate extracts were washed with 40 ml of water and 40 ml of brine, dried (anhydrous sodium sulfate) and concentrated in vacuo to give the compound of the title (0.84 g) as a reddish solid. By means of a similar treatment of the solids formed in the filtrate from washing with ether, an additional 0.805 g of the product was obtained (yields 1.65 g total, 73% yield). 1 H NMR (CD 3 OD) d 2.58 (s, 3H); 3.83 (s, 3H); 6.9-7.0 (m, 2H); 7.74 (d, 1 H); 7.99 (d, 1 H). The title compounds of Examples 3B-3T were prepared using analogous procedures to those used in Example 3A.

EXAMPLE 3B 5-Methyl-2- (4-sulfamoyl-phenyl) -2H-1,2,3-triazole-4-carboxylic acid 21% yield 1 H NMR (CD 3 OD) d 2.59 (s, 3 H), 8.05 (d, 2 H), 8.25 (d, 2 H).

EXAMPLE 3C 5-Methyl-2- (2-methoxy-phenyl) -2H-1, 2,3-triazole-4-carboxylic acid 98% yield 1 H NMR (CDCl 3) d 2.33 (s, 3 H), 3.87 (s, 3 H), 6.97-7.14 (m, 2 H), .3-7.55 (m, 2 H).

EXAMPLE 3D 5-Methyl-2- (4-methylsulfonylphenyl) -2f -1,2,3-triazole-4-carboxylic acid 50% yield 1 H NMR (CDCl 3) d 2.6 (s, 3 H), 3.06 (s, 3 H), 8.01 (d, 2 H); 8.29 (d, H).

EXAMPLE 3E 5-Methyl-2- (3-methoxyphenyl) -2H-1, 2,3-triazole-4-carboxylic acid 46% yield 1 H NMR (CDCl 3) d 2.34 (s, 3 H), 3.82 (s, 3 H), 6.92 (m, 1 H), 7.36 (t, 1 H), 7.61-7.68 (m, 2H).

EXAMPLE 3F 5-Methyl-2- (5-quinolinyl) -2-yl-1,2,3-trilazole-4-carboxylic acid 67% yield 1 H NMR (DMSO-de) d 2.56 (s, 3 H), 7.67 (m, 1 H), 7.89-7.99 (m, 2 H), 8.2 (d, 1 H), 8.55 (d, 1 H), (9.01) , s, 1 H).

EXAMPLE 3G 5-Methyl-2- (5-isoquinolinyl) -2H-1, 2,3-triazole-4-carboxylic acid 31% yield 1 H NMR (DMSO-de) d 2.57 (s, 3 H), 7.85 (t, 1 H), 8.09 (d, 1 H), 8.17 (d, 1 H), 8.34 (d, 1 H), 8.63 (d , 1 H), 9.48 (s, 1 H).

EXAMPLE 3H 5-Methyl-2- (p-tolyl) -2fM, 2,3-triazole-4-carboxylic acid 44% yield 1 H NMR (400 MHz, CDCl 3) d 2.35 (s, 3 H), 2.50 (s, 3 H), 7.36 (d, J = 8.2 H), 7.87 (d, J = 8.2 H), 13.42 (s, 1 H) . APCIMS 216 [M-1] " EXAMPLE 31 2- (4-Chlorophenyl) -5-methyl-2H-1, 2,3-triazole-4-carboxylic acid 22% yield 1 H NMR (400 MHz, CDCl 3) d 2.5 (s, 3 H), 7.41 (d, J = 8.2 H), 8.00 (d, J = 8.2 H), 13.53 (s, 1 H). APCIMS 236 [M-1] " EXAMPLE 3J 2- (3,4-Dichlorophenyl) -5-methyl-2H-1, 2,3-triazole-4-carboxylic acid 14% yield 1 H NMR (400 MHz, CDCl 3) d 2.48 (s, 3 H), 7.43 (d, J = 8.1 H), 7.86 (d, J = 2.4, 8.8, 1 H), 8.15 (d, J = 2.4, 1 H ). APCIMS 271 [M-1] - EXAMPLE 3K 2,5-Diphenyl-2 // - 1, 2,3-triazole-4-carboxylic acid 29% yield 1 H NMR (400 MHz, DMSO) d 7.48 (m, 4 H) 7.60 (m, 2 H), 7.88 (m, H), 8.10 (m, 2 H), 13.61 (s, 1 H). APCIMS 264 [M-1T EXAMPLE 3L 2- (3,5-Dichlorophenol) -5-methyl-2f / -1,2,3-triazole-4-carboxylic acid 40% yield 1 H NMR (400 MHz, DMSO) d 2.47 (s, 3 H), 7.67 (d, J = 1.6, 1 H), .92 (d, J = 1.6, 2 H). APCIMS 270 [M-1] " EXAMPLE 3M 5-Methyl-2- (tt.-tolyl) -2H-1, 2,3-triazole-4-carboxylic acid 66% yield 1 H NMR (400 MHz, DMSO) d 2.37 (s, 3 H), 2.47 (s, 3 H), 7.23 (m, H), 7.41 (m, 1 H), 7.77 (m, 2 H), 13.40 (s, 1 H). APCIMS 216 [M-1] - EXAMPLE 3N 2- (3-Chlorophenyl) -5-methyl-2-tf-1, 2,3-triazole-4-carboxylic acid 62% yield 1 H NMR (400 MHz, DMSO) d 2.50 (s, 3H), 7.51 (m, 1 H), 7.59 (m, H), 7.96 (m, 2H). APCIMS 236 [M-1] ' EXAMPLE 3O S-phenyl-S-fn-propiD ^ H-1, 2,3-triazole-4-carboxylic acid % yield 1 H NMR (400 MHz, CD30D) d 1.00 (t, J = 7.3 H), 1.78 (m, 2 H), .13 (m, 2 H), 7.42 (m, 1 H), 7.52 (m, 2 H), 8.07 (m, 2H). APCIMS 230 [M-1] - EXAMPLE 3P 2-Phenyl-5-ethyl-2H-1, 2,3-triazole-4-carboxylic acid 63% yield 1 H NMR (400 MHz, CD30D) d 1.33 (t, J = 7.6, 3 H), 3.15 (m, 2 H), .41 (m, 1 H), 7.52 (m, 2 H), 8.08 (m, 2 H). APCIMS [M-1] - EXAMPLE 3Q 5-Methylene-2- (3-trifluoromethylphenyl) -2H-1,2,3-triazole-4-carboxylic acid 37% yield 1 H NMR (400 MHz, CD 3 OD) d 2.57 (s, 3 H), 7.71 (m, 2 H), 8.32 (m, 2H). APCIMS 270 [M-1] - EXAMPLE 3R 2- (1-Naphthalenyl) -5-methyl-2AY-1, 2,3-triazole-4-carboxylic acid 54% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.57 (s, 3 H), 7.64 (m, 3 H), 7.82 (d, J = 7.2, 1 H) and 7.94 (dd, J = 2, 5.6, 1 H) 8.12 (m, 2H). APCIMS 252 [M-1] " EXAMPLE 3S 5-Methylene-2- (8-quinolinyl) -2A--1,2,3-triazole-4-carboxylic acid 24% yield 1 H NMR (400 MHz, CD 3 OD) d 2.63 (s, 3 H), 7.64 (dd, J = 4.4, 8.1 H), 7.76 (t, J = 7.8, 1 H), 8.00 (dd, J = 1.4, 7.4, 1 H), 8.18 (dd, J = 1.2, 8.4, 1 H), 8.50 (dd, J = 1.6, 8.4, 1 H), 8.88 (dd, J = 1.6, 4.1 H).

APCIMS 253 [M-11] " EXAMPLE 3T 2- (3-Bromophenyl) -5-methyl-2, 2,3-triazole-4-carboxylic acid 44% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.47 (s, 3 H), 7.51 (t, J = 8.1 H), 7.64 (dd, J = 8.2, 1.1 H), 7.98 (dt, J = 8.0, 1.1 H ), 8.10 (d, J = 1, 1 H), 13.54 (sa, 1 H). APCIMS 236 [M-] " EXAMPLE 4 5- (N, N-Dimethylcarbamoyl) -2-phenyl-2H-1,2,3-triazole-4-carboxylic acid A solution of 5-methyl-2-phenyl-2 / - / - 1, 2,3-triazole-4-carboxylic acid (10.2 g, 50 mmol) and NaOH (17.6 g, 440 mmol) in water was treated. (375 ml) at 23 ° C with KMnO 4 (30.8 g, 195 mmol). The resulting solution was refluxed for 17 h, cooled to 23 ° C and treated with ethanol (50 ml). The resulting mixture was filtered to remove MnO2. The filtrate was acidified with HCl (conc.) To pH 1. The resulting white solid was collected by filtration. The filtrate was concentrated to half the volume and more solid was collected by filtration. The two combined batches of solid were dried under vacuum to give 11.1 g (95%) of 2-phenyl-2H-1, 2,3-triazole-4,5-d-carboxylic acid. A suspension of 2-phenyl-2-phenylcarbamic acid was treated. 2-1, 2,3-triazole-4,5-dicarboxylic acid (2.00 g, 8.58 mmol) in methanol (50 ml) at 23 ° C with H2SO4 (conc., 0.477 ml, 8.58 mmol). The mixture was refluxed for 15 h, cooled to 23 ° C and partitioned between NaHCO3 (sat aq) and AcOEt. The aqueous layer was extracted with another portion of AcOEt. The combined organic extracts were washed with brine, dried over MgSO and concentrated in vacuo to give 1.61 g (72%) of dimethyl 2-phenyl-2H-1, 2,3-triazole-4,5-dicarboxylate. 1 H NMR (400 MHz, CDCl 3) d 4.01 (s, 6H), 7.49 (m, 3H), 8.13 (m, 2H). APCIMS 262 [M + 1] + A solution of dimethyl 2-phenyl-2-1,2,3-triazole-4,5-dicarboxylate (0.522 g, 2.00 mmol) in methanol (40 ml) at pH 23 was treated. ° C with a KOH solution (0.236 g, 4.20 mmoles) in methanol (5 ml). The resulting solution was stirred at 23 ° C for 17 hours and partitioned between NaHCO 3 (sat aq.) And ether. The aqueous layer was washed with ether and carefully acidified to pH 1 with HCl (conc.). The resulting mixture was extracted with AcOEt. The organic extract was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by radial chromatography (plate 2 mm, CH2-CI2-methanol-acetic acid 90: 10: 1) to give 0.42 g (85%) of 5-methoxycarbonyl-2-phenyl-2H-1, 2, 3-triazole-4-carboxylic acid. A solution of 5-methoxycarbonyl-2-phenyl-2 was treated - 1, 2,3-triazol-4-carboxíIíco (0.203 g, 0.82 mmol) in dry DMF (3ml) at 23 ° C with carbonyldiimidazole (0.146 g, 0.90 mmol). The resulting mixture was stirred for 1.5 h at 23 ° C, cooled to 0 ° C and treated with dimethylamine (2.0 M in THF, 2.05 mL, 4.10 mmol). The resulting mixture was allowed to warm to 23 ° C for 16 h and concentrated in vacuo. The residue was partitioned between water and AcOEt. The aqueous layer was extracted with an additional portion of AcOEt. The combined organic extracts were washed with HCl (1M), brine, NaHCOs (aq sat.) And brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by filtration through a plug of silica gel (EtOAc-hexanes 50:50) giving 0.201 g (89%) of 5- (N, N-dimethyl-carbamoyl) -2-phenyl-2 - - 1, 2,3-triazole-4-carboxylic acid methyl. A solution of methyl 5- (N, N-dimethylcarbamoyl) -2-phenyl-2 / -1, 2,3-triazole-4-carboxylate (0.195 g, 0.71 mmol) in THF ( 3.6 ml) at 23 ° C with LiOH (1 M ac, 3.6 ml, 3.6 mmol). The resulting suspension was stirred for 15 min at 23 ° C and partitioned between ether and water. The aqueous layer was acidified to pH 1 with HCl (conc). The resulting white solid was collected by filtration, washed with water, and dried with air to yield 0.164 g (89%) of 5- (NN-dimethylcarbamoyl) -2-pheny-2 / -1, 2,3- triazole-4-carboxylic acid. 1H RM? (400 MHz, CDCI3) d 3.26 (sa, 3H), 3.65 (sa, 3H), 7.50 (sa, 3H), 8.13 (sa, 2H). APCIMS 261 [M +] + EXAMPLE 5 (5-Methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl) guanidine hydrochloride Guanidine hydrochloride (2.42 g, 25.32 mmol) was dissolved in 20 ml of anhydrous methanol and then treated with sodium methoxide (1.50 g, 27.83 mmol), added in one portion at room temperature. The reaction mixture was stirred under nitrogen for 1 hour, then filtered under nitrogen atmosphere. The solids were washed with anhydrous methanol (3 x ml) and the filtrate was concentrated under reduced pressure. Anhydrous benzene (60 ml) was added to the residue, the mixture reconcentrated in vacuo and the residue dried under high vacuum. Anhydrous dimethylformamide (10 ml), anhydrous tetrahydrofuran (20 ml) and methyl 4-methyl-2-phenyl-2H-1, 2,3-triazole-5-carboxylate (1.00 g, 4.60 mmol) were added to the solid residue and The resulting mixture was heated at 70 ° C under nitrogen for 7 hours, then stirred at room temperature overnight. The reddish colored solution was then diluted with water (90 ml) to give the free base corresponding to the title compound as a tan solid (0.53 g, 47% yield). APCIMS 242.9 [MH] "1 H NMR (DMSO-de) d 2.54 (s, 3H), 7.37 (t, 1 H), 7.53 (m, 2H), 7.92 (m, 2H) .The title compound was prepared by suspending the free base (100 mg, 0.41 mmol) in 10 ml of diethyl ether and bubbling excess hydrogen chloride gas into the mixture The mixture was stirred under nitrogen overnight then filtered to give the title compound as a white solid (85.2 mg, 74% yield) 1 H NMR (DMSO-de) d 2.55 (s, 3 H), 7.48 (t, 1 H), 7.6 (m, 2 H), 8.12 (m, 2 H), 8.56 (s, 2H), 8.73 (s, 2H), 11.62 (s, 1 H).

EXAMPLE 6A r5-Methyl-2- (2-methoxyphenyl) -2 hydrochloride? -1,2,3-triazole-4-carboninguanidine Guanidine hydrochloride (5.29 g, 55.3 mmol) was dissolved in 30 ml of anhydrous methanol and then treated with sodium methoxide (3.04 g, 56.2 mmol), added in one portion at room temperature. The reaction mixture was stirred under nitrogen for 1 hour, then filtered under nitrogen atmosphere. The solids were washed with anhydrous methanol (3 x 15 ml) and the filtrate was concentrated under reduced pressure. Anhydrous benzene (60 ml) was added to the residue, the mixture reconcentrated in vacuo and the resulting guanidine free base was dried under high vacuum. The residue was resuspended in a mixture of 10 ml of anhydrous THF and 10 ml of anhydrous DMF and the resulting mixture was used in the next step. A solution of 5-methyl-2- (2-methoxyphenyl) -2-1, 2,3-triazole-4-carboxylic acid (2.15 g, 9.2 mmol) was stirred at room temperature under nitrogen for 2 h. ) and carbonyldiimidazole (1.64 g, 10 mmol) in 30 ml of DMF. The resulting mixture was added to the mixture of guanidine in THF and DMF previously prepared and the reaction mixture was stirred overnight under nitrogen at room temperature. The reaction mixture was then poured into 200 ml of cold water and the aqueous mixture was extracted with 10 x 70 ml of ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to an orange solid (1.83 g). The crude product was triturated with diethyl ether to give 0.59 g of the free base corresponding to the title compound. The title compound was prepared by dissolving the free base in 40 ml of methanol and bubbling excess hydrogen chloride gas into the solution. After stirring for several hours the resulting precipitate was filtered and washed with diethyl ether to give the title compound as a tan solid (0.5 g, 17% yield). 1 H NMR (DMSO-de) d 2.54 (s, 3 H), 3.8 (s, 3 H), 7.14 (t, 1 H), 7.32 (d, 1 H), 7.52-7.7 (m, 3 H), 8.45 (s) , 2H), 8.66 (s, 2H), 11.37 (s, 1 H). The title compounds of Examples 6B-6V were prepared according to procedures analogous to those described in Example 6A.

EXAMPLE 6B r5-Methyl-2- (4-methoxyphenyl) -2H-1,2,3-triazole-4-carbonylguanidine hydrochloride 50% yield 1 H NMR (DMSO-de) d 2.55 (s, 3 H), 3.83 (s, 3 H), 7.15 (d, 2 H), 8.06 (d, 2 H), 8.56 (s, 2 H), 8.73 (s, 2 H), 11.58 (s, 1H).

EXAMPLE 6C r5-Methyl-2- (4-sulfamoylphenyl) -2H-1,2,3-triazole-4-carbonylguanidine hydrochloride 50% yield 1 H NMR (DMSO-de) d 2.58 (s, 3 H), 7.55 (s, 3 H), 8.04 (d, 2 H), 8.35 (d, 2 H), 8.62 (s, 2 H), 8.79 (s, 2 H), 11.84 (s, 1H).

EXAMPLE 6D r5-Methyl-2- (4-methylsulfonylphenyl) -2H-1, 2,3-triazole-4-carbonylguanidine hydrochloride % yield 1 H NMR (DMSO-de) d 2.58 (s, 3 H), 3.3 (s, 3 H), 8.15 (d, 2 H), 8.47 (d, 2 H), 8.81 (s, 2 H), 8.99 (s, 2 H), 12.12 (s, 1 H).

EXAMPLE 6E r5-Methyl-2- (3-methoxyphenyl) -2H-1,2,3-triazole-4-carbonillquanidine hydrochloride % yield 1 H NMR (DMSO-d 6) d 2.47 (s, 3 H), 3.86 (s, 3 H), 7.05 (dd, 1 H), 7.5 (t, 1 H), 7.67 (m, 2 H), 8.47 (s, 2 H) , 8.74 (sa, 2H).

EXAMPLE 6F r5-Methyl-2- (5-quinolinyl) -2 and-1,2,3-triazole-4-carbonylguanidine hydrochloride 67% yield 1 H NMR (DMSO-de) d 2.62 (s, 3 H), 7.79 (m, 1 H), 8.02 (m, 1 H), 8.17 (d, 1 H), 8.32 (d, 1 H), 8.69 (sa, 4H), 8.92 (d, 1 H), 9.12 (s, 1 H), 11.7 (s, 1 H).

EXAMPLE 6G r5-Methyl-2- (5-isoquinolinyl) -2 -1, 2,3-triazole-4-carbonylguanidine hydrochloride 52% yield 1 H NMR (DMSO-de) d 2.63 (s, 3 H), 8.01 (t, 1 H), 8.46 (d, 1 H), 8.52 (d, 1 H), 8.7 (m, 6H), 9.74 (s, 1 H), 11.7 (s, 1 H).

EXAMPLE 6H r2- (p-tolyl) -5-methyl-2 / -1,2,3-triazole-4-carbonnguanidine 97% yield 1 H NMR (400 MHz, DMSO) d 2.30 (s, 3 H), 2.50 (s, 3 H), 7.30 (d, J = 8, 2 H), 7.79 (d, J = 8, 2 H).

APCIMS 259 [M + 1] " EXAMPLE 61 r2- (4-chlorophenyl) -5-methyl-2H-1,2,3-triazole-4-carbon-p-guanidine 98% yield 1 H NMR (400 MHz, DMSO) d 2.51 (s, 3 H), 7.56 (d, J = 8, 2 H), (d, J =, 2 H). APCIMS 279 [M + 1] + EXAMPLE 6J r2- (3,4-Dichlorophenyl) -5-methyl-2 -1,2,3-triazole-4-carboninguanidine 100% performance 1 H NMR (400 MHz, DMSO) d 2.55 (s, 3 H), 7.81 (d, J = 8, 1 H), (dd, J = 2.8, 8.8, 1 H), 8.11 (d, J = 2.4, 1 H). APCIMS 311 [M-1] ' EXAMPLE 6K (2,5-diphenyl-2 / -1,2,3-triazole-4-carbonyl) quanidine 88% yield 1 H NMR (400 MHz, DMSO) d 7.41 (m, 4 H), 7.52 (m, 2 H), 7.90 (m, 2H), 8.04 (m, 2H). APCIMS 307 [m + 1] + EXAMPLE 6L f2- (3,5-Dichlorophenyl) -5-methyl-2H-1,2,3-triazole-4-carbon-p-guanidine 90% yield 1 H NMR (400 MHz, DMSO) d 2.54 (s, 3 H), 7.63 (s, 1 H), 7.89 (s, 2H). APCIMS 313 [M + 1] + EXAMPLE 6M r2 - (/ 77-tolyl) -5-methyl-2H-1, 2,3-triazole-4-carbonyl-1-quinidine 92% yield 1 H NMR (400 MHz, DMSO) d 2.35 (s, 3 H), 2.51 (s, 3 H), 7.16 (m, 1 H), 7.37 (m, 1 H), 7.83 (m, 2 H). APCIMS 259 [M + 1] + EXAMPLE 6N r2- (3-Chlorophenyl) -5-methyl-2H-1,2,3-triazole-4-carbonyl-guanidine 92% yield 1 H NMR (400 MHz, DMSO) d 2.54 (s, 3 H), 7.46 (m, 1 H), 7.56 (m, H), 7.91 (m, 2 H). APCIMS 279 [M + 1] + EXAMPLE 60 r2-Phenyl-5 - (/ 7-propyl) -2tf-1, 2,3-triazoM-carboni Hguanidine hydrochloride 83% yield 1 H NMR (400 MHz, CD 3 OD) d 1.02 (t, J = 7, 3 H), 1.81 (m, 2 H), .15 (m, 2 H), 7.48 (m, 1 H), 7.50 (m, 2 H), 8.15 (m, 2H). APCIMS 273 [M + 1] + EXAMPLE 6P (2-Phenyl-5-ethyl-2A-1, 2,3-triazole-4-carbomT) guanidine hydrochloride 79% yield 1 H NMR (400 MHz, CD 3 OD) d 1.36 (t, J = 8.4, 3 H), 7.15 (m, 2 H), .48 (m, 1 H), 7.55 (m, 2 H), 8.16 (m, 2 H). APCIMS 259 [M + 1] + EXAMPLE 6Q (2-Phenyl-2 H-1,2,3-triazole-4-carbonyl) guanidine 82% yield 1 H NMR (400 MHz, DMSO) d 7.30 (m, 1 H), 7.57 (m, 2 H), 8.01 (m, 2 H), 8.19 (s, 1 H). APCIMS 231 [M + 1] + EXAMPLE 6R [2- (3-Trifluoromethylphenyl) -5-methyl-2 / - / - 1, 2,3-triazole-4-carboni-D-guanidine hydrochloride 94% yield 1 H NMR (400 MHz, CD 3 OD) d 2.66 (s, 3 H), 7.81 (d, J = 4.8, 2 H), 8.41 (m, 2 H). APCIMS 313 [M + 1] + EXAMPLE 6S r2- (1-Naphthalenyl) -5-methylene-2 / y-1,2,3-triazole-4-carboni-Hydrochloride D Guanidine 93% yield 1 H NMR (400 MHz, CD 3 OD) d 2.61 (s, 3 H), 7.61 (m, 3 H), 7.82 (d, J = 6, 1 H), 7.97 (m, 1 H), 8.02 (m, 1 H), 8 10 (d, J = 8, 1H). APCIMS 295 [M + 1] + EXAMPLE 6T r2- (8-guinolinyl) -5-methyl-2 / 7-1,2,3-triazole-4-carboni-guanidine hydrochloride 6% yield 1 H NMR (400 MHz, CD 3 OD) d 2.64 (s, 3 H), 7.61 (m, 1 H), 7.73 (t, J = 7.8, 1 H), 7.96 (dd, J = 1.4, 7.4, 1 H), 8.13 (dd, J = 1.4, 4.2, 1 H), 8.45 (dd, J = 1.8, 8.6, 1 H), 8.86 (dd, J = 1.6, 4.4, 11 H). APCIMS 296 [M + 1] + EXAMPLE 6U r2- (3-Bromophenyl) -5-methy1-2ft hydrochloride, 2,3-triazole-4-carbonylguanidine 89% yield 1 H NMR (400 MHz, CD 3 OD) d 2.63 (s, 3 H), 7.50 (t, J = 8.2, 1 H), 7.64 (dd, J = 2.0, 1, 1 H), 8.12 (m, 1 H), 8.34 (t, J = 2, 1H). APCIMS 323 [M + 1] + EXAMPLE 6V r5-? /. N-dimethylcarbamoyl) -2-phenyl-2H-1, 2,3-triazole-4-carbonylguanidine hydrochloride 80% yield 1 H NMR (400 MHz, DC 3 OD) d 3.08 (s, 3 H), 3.19 (s, 3 H), 7.59 (m, 3H), 8.18 (m, 2H). APCIMS 302 [M + 1] + EXAMPLE 7 (2-Phenyl-5-hydroxymethyl-2A7-1, 2,3-triazole-4-carbonyl) quanidine hydrochloride A solution of guanidine hydrochloride (1.15 g, 12.0 mmol) in methanol (5 ml) was treated at 23 ° C and under a nitrogen atmosphere in one portion with sodium methoxide (0.65 g, 12 mmol): The resulting suspension was stirred for 1 h and it was filtered. The filtrate was concentrated in vacuo. The residue was dissolved in ethanol (10 ml) and added to the lactone of 2-phenyl-5-hydroxymethyl-2 / - / - 1, 2,3-triazole-4-carboxylic acid (0.41 g, 2.0 mmol. ) (Pollet, P .; Gelin, S. Synthesis 1979, 977) at 23 ° C. The resulting solution was stirred for 15 min and concentrated in vacuo. The residue was triturated with water and filtered. The solid was dried with air offering 0.43 g (81% yield) of the free base corresponding to the title compound. This material in 5 ml of methanol was treated with hydrogen chloride (4 M in dioxane, 2 ml, excess) for 1 h at 23 ° C and concentrated in vacuo affording the title compound (0.48 g, 79% yield). 1 H NMR (400 MHz, DMSO-de) d 8.74 (sa, 2H), 8.59 (sa, 2H), 8.16 (d, J = 7.6, 2H), 7.62 (t, J = 8.0, 2H), 7.52 (t , J = 7.4, 1H), 4.83 (s, 2H). APCIMS 261 [M + 1] + EXAMPLE 8A (5-methyl-1-1-phenyl-1 HA, 2,3-triazole-4-carbonyl) quanidine hydrochloride The 5-methyl-1-phenyl-1-1,2,3-triazole-4-carboxylic acid ethyl ester (333 mg, 1.44 mmol) was reacted with guanidine (7.9 mmol), obtained as in example 5 , in 10 ml of refluxing methanol. After 16 hours, the mixture was concentrated in vacuo, the residue was taken to ice water and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography on silica gel eluting with 10% methanol in methylene chloride affording 63 mg of the desired acylguanidine. Transformation to the hydrochloride salt in the manner described in Example 7 gave the title compound. 1 H NMR (DMSO-de) d 2.54 (s, 3 H), 7.6 - 7.7 (m, 5 H), 8.5 (br s, 2 H), 8.7 (br s, 2 H), 11.6 (br s, 1 H). APCIMS 245 [M + 1] + The title compound of Example 8B was prepared using a procedure analogous to that used for Example 8A.

EXAMPLE 8B (4-Methyl-5-phenyl-4A7-1, 2,4-triazole-3-carbonyl) guanidine hydrochloride 1 H NMR (DMSO-de) d 3.9 (s, 3 H), 7.6 (m, 3 H), 7.8 (m, 2 H), 8.5 (sa, 2H), 8.9 (sa, 2H), 11.8 (sa, 1 H). APCIMS 245 [M + 1] + The title compounds of examples 9A-9N were prepared using procedures analogous to those described in Bajnati, A., Kokel, B., Hubert-Habart, M. Bull. Soc. Chim. Fr. 1987, 318.

EXAMPLE 9A ethyl 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxylate 3% yield 1 H NMR (CDCl 3) d 1.36 (t, 3 H), 2.54 (s, 3 H), 3.84 (s, 3 H), 4.3 (q, H), 6.96 (d, 2 H), 7.56 (d, 2 H), 8.23 ( s, 1H).

EXAMPLE 9B 5-methyl-1- (4-methoxyphenyl) -1 / ethyl f-pyrazole-4-carboxylate 6% yield 1 H NMR (CDCl 3) d 1.33 (t, 3 H), 2.48 (s, 3 H), 3.81 (s, 3 H), 4.27 (q, H), 6.94 (q, 2 H), 7.26 (q, 2 H), 7.96 ( s, 1 H).

EXAMPLE 9C 5-methyl-1- (4-sulfamoylphenyl) -1H-pyrazole-4-carboxylic acid ethyl ester 77% yield 1 H NMR (DMSO-de) d 1.28 (t, 3H), 2.56 (s, 3H), 4.25 (q, 2H), 7.52, 2H), 7.78 (d, 2H), 7.96 (d, 2H), 8.05 ( s, 1 H).

EXAMPLE 9D 5-metiM - (4-trifluoromethoxypheniD-1 H-razol -4-carboxy ethyl ester 32% yield 1 H NMR (CDCIs) d 1.37 (t, 3 H), 2.58 (s, 3 H), 4.32 (q, 2 H), 7.34 (q, 2H), 7.46 (q, 2H), 8.03 (s, 1 H).

EXAMPLE 9E ethyl 5-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxylate 63% yield 1 H NMR (CDCIs) d 1.34 (t, 3 H), 2.34 (s, 3 H), 3.77 (s, 3 H), 4.3 (q, 2 H), 7.02 (m, 2 H), 7.28 (q, 1 H), 7.41 (m, 1 H), 8.01 (s, 1 H).

EXAMPLE 9F ethyl 5-methyl-1- (4-methylsulfonylphenyl) -1 / -pyrazol-4-carboxylate 46% yield 1 H NMR (CDCl 3) d 1.35 (t, 3 H), 6.63 (s, 3 H), 3.08 (s, 3 H), 4.3 (q, 2 H), 7.65 (d, 2 H), 8.05 (d, 2 H), 8.08 ( s, 1 H).

EXAMPLE 9G ethyl 5-methyl-1- (2-pyridyl) -1H-pyrazole-4-carboxylate 50% yield 1 H NMR (DMSO-de) d 1.28 (t, 3 H), 2.78 (s, 3 H), 4.24 (q, 2 H), 7. 43-7.47 (m, 1 H), 7.78 (m, 12H), 8.02 (m, 2H), 8.53 (m, 1 H).

EXAMPLE 9H ethyl 5-methyl-1- (5-quinolinyl) -1H-pyrazole-4-carboxylate 6% yield 1 H NMR (DMSO-de) d 1.27 (t, 3 H), 2.27 (s, 3 H), 4.25 (q, 2 H), 7.55 (m, 1 H), 7.60 (m, 1 H), 7.74 (d, 1 H), 7.89 (t, 1 H), 8.1 (s, 1 H), 8.2 (d, 1 H), 8.97 (m, 1H).

EXAMPLE 91 Ethyl 5-methyl-1- (4-pyridyl) -1H-pyrazole-4-carboxylate 22% yield 1 H NMR (DMSO-de) d 1.27 (t, 3 H), 2.64 (s, 3 H), 4.23 (q, 2 H), 7.64 (d, 2H), 8.09 (s, 1 H), 8.73 (d, 2H).

EXAMPLE 9J ethyl 5-methyl-1- (3-methoxylphenyl) -1 and -pyrrazole-4-carboxylate 77% yield 1 H NMR (DMSO-de) d 1.26 (t, 3 H), 2.49 (s, 3 H), 3.78 (s, 3 H), 4.22 (q, 2H), 7.03-7.08 (m, 3H), 7.42 (t, 1 H), 7.97 (s, 1 H).

EXAMPLE 9K ethyl 5-methyl-1- (1-phthalazinyl) -1f-pyrazole-4-carboxylate 43% yield 1 H NMR (DMSO-de) d 1.28 (t, 3 H), 2.51 (s, 3 H), 4.25 (q, 2 H), 7.89 (d, 1 H), 8.09 (q, 1 H), 8.1 (q, 1 H) ), 8.19 (s, 1 H), 8.32 (d, 1 H), 9.84 (s, 1 H).

EXAMPLE 9L ethyl 5-methyl-1- (4-quinolinyl) -1f-pyrazol-4-carboxylate and ethyl 3-methyl-1- (4-quinolinyl) -1-pyrazole-4-carboxylate 68% yield 1 H NMR (DMSO-d 6) or 1.19, 1.25 (2t, 3H), 2.33 (s, 3H), 4.06, 4.25 (2q, 2H), 7.41, 7.70 (2d, 1 H), 7.61, 7.82 (2t, 1 H), 8.15 (m, 2H), 9.06 (d, 1 H).

EXAMPLE 9M ethyl 5-methyl-1- (6-quinolinyl) -1H-pyrazole-4-carboxylate 40% yield 1 H NMR (DMSO-de) d 1.26 (t, 3 H), 2.57 (s, 3 H), 4.22 (q, 2 H), 7.61 (m, 1 H), 7.89 (d, 1 H), 8.04 (s, 1 H), 8.16 (d, 1H), 8.19 (s, 1H), 8.43 (d, 1H), 8.96 (d, 1H).

EXAMPLE 9N 1 - ethyl (2-bromophenyl) -5-cyclopropyl-1H-pyrazole-4-carboxylate 78% yield 1 H NMR (400 MHz, CDCl 3) d 0.80 (br s, 4 H), 1.36 (t, J = 7.2, 3 H), 1.87 (m, 1 H), 4.30 (q, J = 7.2, 2 H), 7.41 (m, 3 H) ), 7.71 (dd, J = 1.4, 8, 1H), 8.03 (s, 1 H). APCIMS 335 [M + 1] +, 337 [M + 3] + The title compounds of Examples 10A-10K were prepared using procedures analogous to those described in Menozzí, G .; Mosti, L .; Schenone, P. J. Heterocycl. Chem., 1987, 24, 1669.

EXAMPLE 10A-ethyl cyclopropyl-1- (2,6-dichlorophenyl) -1 / - / - pyrazole-4-carboxylate 82% yield APCIMS 325 [M + 1] + 1 H NMR (CDCl 3) d 1.77-1.84 (m, 1 H), 8.07 (s, 1 H).

EXAMPLE 10B ethyl 5-methyl-1- (naphthalen-1-yl) -1H-pyrazole-4-carboxylate 93% yield APCIMS 281 [M + 1] + 1 H NMR (CDCl 3) d 2.31 (s, 3 H), 8.14 (s, 1 H).

EXAMPLE 10C ethyl 5-methyl-1- (quinolin-8-yl) -1A-pyrazole-4-carboxylate 66% yield APCIMS 282 [M + 1] + 1 H NMR (CDCl 3) d 2.33 (s, 3 H), 8.13 (s, 1 H).

EXAMPLE 10D 5-cyclopropyl-1 - (quinolin-8-yl) -1 / -pyrazole-4-carboxylate ethyl 89% yield APCIMS 308 [M + 1] + 1 H NMR (CDCl 3) d 1.81-1.88 (m, 1 H), 8.10 (s, 1 H).

EXAMPLE 10E 5-cyclopropyl-1 - (quinolin-5-yl) -1 H-pyrazole-4-carboxylate ethyl 88% yield APCIMS 308 [M + 1] + 1 H NMR (CDCl 3) d 8.95 (dd, J = 1.8, 4.2, 1 H), 8.24 (d, J = 8.8, 1H), .10 (s, 1H), 7.79 (t , J = 7.8, 1 H), 7.72 (dt, J = 8.4, 0.8, 1 H), 7.58 (d, J = 7.2, 1 H), .41 (m, 1H), 4.31 (q, J = 7.2 , 2H), 1.76 (m, 1H), 1.37 (t, J = 7.2, 3H), 0.67 (m, H).

EXAMPLE 10f 5-cyclopropyl-1 - (q? Inolin-8-yl) -1 H-pyrazole-4-carboxylate ethyl 82% yield APCIMS 380 [M + 1] + 1 H NMR (CDCl 3) d 1.80-1.87 (m, 1 H), 8.09 (s, 1 H).

EXAMPLE 10G ethyl 5-ethyl-1- (quinolin-5-yl) -1H-pyrazole-4-carboxylate % yield APCIMS 280 [M + 1] + 1 H NMR (CDCl 3) d 0.94-0.97 (t, 3H), 8.10 (s, 1H).

EXAMPLE 10H ethyl 5-cyclopropyl-1- (isoquinolin-8-yl) -1 H-pyrazole-4-carboxylate 24% yield APCIMS 308 [M + 1f 1 H NMR (CDCl 3) d 3.25-3.31 (m, 1 H), 9.57 (s, 1 H).

EXAMPLE 10J -c? Clopropyl-1 - (2-trifluoromethylphenyl) -1 // - pyrazole-4-carboxylate ethyl 88% yield APCIMS 325 [M + 1] + 1 H NMR (CDCl 3) d 1.70-1.77 (m, 1 H), 8.00 (s, 1 H).

EXAMPLE 10K ethyl 5-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxylate 89% yield APCIMS 257 [M + 1] + 1 H NMR (CDCl 3) d 1.87-2.00 (m, 1H), 8.00 (s, 1 H).

EXAMPLE 11 Ethyl 2-methyl-5-phenyl-2H-pyrazole-3-carboxylate (Example 11 A) and ethyl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate (Example 11B) The lithium salt of ethyl 2,4-dioxo-4-phenylbutyrate (Murray, WV, Wachter, MPJ Heterocycl, Chem, 1989, 26, 1389) (1.0 g, 4.4 mmol) in 4 ml of ethanol was combined. absolute with methyl hydrazine (0.2 g, 4.4 mmol), and hydrochloric acid (1.2 mL of a 4 N solution in dioxane, 4.8 mmol). After heating the mixture at reflux for 2 h, the solution was concentrated in vacuo and the residue was purified by chromatography on silica gel using 5-20% ethyl acetate in hexanes as eluent to provide eluent 11A (0.32). g, 315) and later the example 11 B eluted (0.38 g, 38%).

EXAMPLE 11 To ethyl 2-methyl-5-phenyl-2-pyrazole-3-carboxylate 1 H NMR (CD 3 OD) d 1.4 (t, 3 H), 4.15 (s, 3 H), 4.3 (q, 2 H), 7.2 (s, 1 H), 7.3 (t, 1 H), 7.4 (t, 2 H), 7.8 (d, 2H). APCIMS 231 [M + 1] + EXAMPLE 11B ethyl 1-methyl-5-phenyl-1-t-pyrazole-3-carboxylate 1 H NMR (CD 3 OD) d 1.4 (t, 3 H), 3.9 (s, 3 H), 4.3 (q, 2 H), 6.8 (s, 1 H), 7.4-7.5 (m, 5 H). APCIMS 231 [M + 1] + The title compounds of Example 12A-12B were prepared using procedures analogous to those described in Bajnati. TO.; Hubert-Habart M. Bull. Soc. Chim. Fr, 1988, 540.

EXAMPLE 12A 3-methyl-1- (quinolin-5-yl) -1H-pyrazole-4-carboxylate n-butyl ester A mixture of 5-acetyluracyl (0.231 g, 1.5 mmol), 5-quinolinylhydrazine dihydrochloride (0.418 g, 1.8 mmol) and HCl (conc., 0.75 mL, 9 mmol) in n-butanol (15 mL) was heated to reflux for 20 h, cooled to 23 ° C and concentrated in vacuo. The residue was dissolved in n-butanol (10 ml). The resulting solution was treated with H2SO4 (conc., 0.96 mL, 18 mmol), heated to reflux for 20 h, cooled to 23 ° C and concentrated in vacuo. The residue was partitioned between AcOEt and NaOH (1 M). The aqueous layer was extracted three times with AcOEt. The combined organic extracts were dried over Na2S? 4 and concentrated in vacuo. The brown solid residue was purified by flash chromatography (Flash 40S, hexanes-acetone 8: 2) affording 0.279 g (60%) of the desired product as a white solid. 1 H NMR (400 MHz, CDCl 3) d 0.96 (t, J = 7, 3H), 1.45 (sextuplet, J = 7.2, 2H), 1.72 (quintuplet, J = 6.8, 2H), 2.60 (s, 3H), 4.28 (quadruplet, J = 6.6, 2H), 7.24 (s, 1 H), 7.47 (ddd, J = 0.8, 4.4, 8.8, 1 H), 7.58 (d, J = 7.2, 1 H), 7.76 (t, J = 8, 1 H), 8.21 (m, 1 H), 8.30 (d, J = 8, 1 H), 8.98 (dd, J = 1.4, 3, 1 H). APCIMS 310 [M + 1] + The title compound of Example 12B was prepared using an analogous procedure as used for Example 12A.

EXAMPLE 12B 1- (isoquinolin-5-yl) -3-methyl-1H-pyrazole-4-caboxylate n-butyl ester 43% yield 1 H NMR (400 MHz, CDCl 3) d 0.94 (t, J = 7.4, 3H), 1.44 (sextuplet, J = 7.6, 2H), 1.70 (quintuplet, J = 6.8, 2H), 2.58 (s, 3H), 4.26 (t, J = 6.6, 2H), 7.66 (t, J = 7.7, 1 H), 7.75 (m, 2H), 8.05 (d, J = 8, 1 H), 8.21 (s, 1 H), 8.57 (d, J = 6, 1 H), 9.33 (s, 1H). APCIMS 310 [M + 1] + EXAMPLE 13A 5-Methyl-1- (2-methoxyphenyl) -1 H -pyrazole-4-carboxylic acid To a solution of ethyl 5-methyl-1- (2-methoxy-phenyl) -1 - / - pyrrazol-4-carboxylate in 15 ml of methanol and 17 ml of water was added 20 ml of 1 N sodium hydroxide and the The resulting mixture was refluxed overnight under nitrogen. The methanol was removed in vacuo and the aqueous phase was acidified with a dilute aqueous hydrochloric acid solution and extracted with 2 x 70 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 70 ml of water and 70 ml of brine, dried over sodium sulfate and concentrated in vacuo to a white solid (2.14 g, 85% yield). 1 H NMR (CDCl 3) d 2.37 (s, 3 H), 3.79 (s, 3 H), 7.04 (q, 2 H), 7.3 (d, 1 H), 7.44 (m, 1 H), 8.09 (s, 1 H). The title compounds of Examples 13B-13Z were prepared using procedures analogous to those used for Example 13A.

EXAMPLE 13B 3-Methyl-1- (4-methoxyphenyl) -1 H -pyrazole-4-carboxylic acid 57% yield 1 H NMR (DMSO-de) d 2.39 (s, 3 H), 3.77 (s, 3 H), 7.01 (d, 2 H), H), 8.72 (s, 1 H).

EXAMPLE 13C 5-Methyl-1- (4-methoxyphenyl) -1 H -pyrazole-4-carboxylic acid 91% yield 1 H NMR (DMSO-de) d 2.43 (s, 3 H), 3.81 (s, 3 H), 7.08 (d, 2 H), H), 7.9 (s, 1 H), 12.4 (s, 1 H).

EXAMPLE 13D 5-Methyl-1- (4-sulfamoylphenyl) -1 H -pyrazole-4-carboxylic acid 51% yield 1 H NMR (DMSO-de) d 2.46 (s, 3 H), 7.48 (s, 2 H), 7.72 (d, 2 H), H), 7.98 (s, 1 H).

EXAMPLE 13E * * 5-Methyl-1- (4-trifluoromethoxyphenyl) -1 A -pyrazole-4-carboxylic acid 91% yield 1 H NMR (DMSO-de) d 2.45 (s, 3H), 7.53 (s, 1 H), 7.65 (m, 2H), s, 1 H), 12.5 (s, 1 H).

EXAMPLE 13F 5-Methyl-1- (4-methylsulfonyl-1-AY-pyrazoM-carboxylic acid 82% yield 1 H NMR (DMSO-de) d 2.55 (s, 3 H), 3.26 (s, 3 H), 7.81 (d, 2 H), s, 1 H), 8.02 (d, 2 H), 12.5 (s, 1 H).

EXAMPLE 13G 5-Methyl-1- (2-pyridyl) -1-t-pyrazole-4-carboxylic acid 91% yield 1 H NMR (DMSO-de) d 2.78 (s, 3 H), 7.45 (q, 1 H), 7.77 (d, 1 H), .05 (m, 2H), 8.53 (d, 1 H), 12.55 (s, 1 H).

EXAMPLE 13H ij É 5-Methyl-1- (5-quinolinyl) -1tf-pyrazole-4-carboxylic acid 75% yield 1 H NMR (DMSO-de) d 2.27 (s, 3 H), 7.56 (m, 1 H), 7.62 (m, 1 H), ), 7.91 (t, 1H), 8.07 (s, 1H), 8.21 (d, 1 H), 8.99 (m, 1H).

EXAMPLE 131 5-Methyl-1- (4-pyridyl) -1H-pyrazole-4-carboxylic acid 3% yield 1 H NMR (DMSO-de) d 2.62 (s, 3 H), 7.61 (q, 2 H), 7.95 (s, 1 H),).

EXAMPLE 13J 5-Methyl-1- (3-methoxyphenyl) -1 H -pyrazole-4-carboxylic acid 98% yield 1 H NMR (DMSO-de) d 2.46 (s, 3 H), 3.76 (s, 3 H), 7.04 (m, 3 H), H), 7.91 (s, 1 H), 12.4 (s, 1 H).

EXAMPLE 13K 5-Methyl-1- (1-phthalazinyl) -1H-pyrazole-4-carboxylic acid 84% yield 1 H NMR (DMSO-de) d 2.57 (s, 3 H), 7.88 (d, 1 H), 8.07-8.18 (m, H), 8.34 (d, 1 H), 9.86 (s, 1 H).

EXAMPLE 13L 5-Methyl-1- (4-quinolinyl) -1H-pyrazole-4-carboxylic acid 66% yield 1 H NMR (DMSO-d 6) d 2.31 (s, 3 H), 7.42 (d, 1 H), 7.62 (dd, 1 H), .7 (d, 1 H), 7.83 (t, 1 H), 8.10 ( dys, 2H), 9.06 (d, 1 H), 12.5 (sa, 1 H).

EXAMPLE 13M 5-Methyl-1- (6-guinolinyl) -1H-pyrazole-4-carboxylic acid 84% yield 1 H NMR (DMSO-de) d 2.63 (s, 3 H), 7.66 (m, 1 H), 7.98 (d, 1 H), .07 (s, 1 H), 8.22 (m, 2 H), 8.48 (d , 1 H), 9.02 (d, 1 H).

EXAMPLE 13N 4-Methyl-1-phenyl-1 H-pyrazole-3-carboxylic acid 1 H NMR (CDCIs) d 2.4 (s, 3 H), 7.4 (t, 1 H), 7.5 (t, 2 H), 7.7 (d, 2 H),. 8 (s, 1 H). APCIMS 203 [M + 1] + EXAMPLE 13O 3-Methyl-1-phenyl-1 H-pyrazole-4-carboxylic acid 1 H NMR (CD 3 OD) d 2.5 (s, 3 H), 7.4 (t, 1 H), 7.5 (t, 2 H), 7.8 (d, H), 8.6 (s, 1 H). APCIMS 203 [M + 1] + EXAMPLE 13P 5-Cyclopropyl-1-phenyl-1 H -pyrazole-4-carboxylic acid 94% yield APCIMS 227 [M-l] "1 H NMR (DMSO-de) d 1.99-2.06 (m, 1 H), 7.88 (s, 1 H).

EXAMPLE 13Q «% -z 5-Cyclopropyl-1- (2,6-dichlorophenyl) -1 f-pyrazoM-carboxylic acid 99% yield APCIMS 295 [M-1T 1 H NMR (DMSO-de) d 1.73-1.80 (m, 1 H), 7.98 (s, 1 H).

EXAMPLE 13R 1- (2-Bromophenyl) -5-cyclopropyl-1 H-pyrazole-4-carboxylic acid 93% yield. 1 H NMR (400 MHz, DMSO-d 6) d 0.66 (br s, 4 H), 1.82 (m, 1 H), 7.50 (m, 3 H), 7.80 (dd, J = 1.2, 7.6, 1 H), 7.89 (s, 1 H), 12.33 (s, 1H). APCIMS 307 [M + 1] +, 309 [M + 3] + 15 EXAMPLE 13S 5-Methyl-1 - (naphthalen-1-yl) -1 H-pyrazole-4-carboxylic acid • 79% yield 20 APCIMS 251 [M-1] - 1 H NMR (DMSO-d 6) d 2.22 (s, 3 H), 7.09-7.11 (d, 1 H).

EXAMPLE 13T 5-Methyl-1 - (quinolin-8-yl) -1 H-pi-razol-4-carboxylic acid 65% yield APCIMS 252 [M-1T 1 H NMR (DMSO-de) d 2.13 (s, 3 H), 8.84-8.85 (d, 1 H).

EXAMPLE 13U 5-Methyl-1 - (isoquinolin-5-yl) -1 Y-pyrazole-4-carboxylic acid 45% yield APCIMS 252 [M-1] - 1 H NMR (DMSO-d 6) d 2.24 (s, 3 H), 8.05 (s, 1 H).

EXAMPLE 13V 5-Cyclopropyl-1 - (quinolin-8-yl) -1 H-pi-4-carboxylic acid 66% yield APCIMS 278 [M-1] "1 H NMR (DMSO-de) d 1.69-1.76 (m, 1 H), 7.97 (s, 1 H).

EXAMPLE 13W 5-Cyclopropyl-1 - (quinolin-5-yl) -1H-pyrazole-4-carboxylic acid 56% yield APCIMS 278 [M-1] '1 H NMR (DMSO-de) d 8.94 (dd, J = 1.6, 4.0, 1 H), 8.15 (dd, J = 0.8, 8.4, 1 H), 7.87 (s, 1 H ), 7.85-7.83 (m, 1 H), 7.71 (dd, J = 1.2, 7.2, 1 H), 7.59-7.51 (m, 2H), 1.79 (m, 1 H), 0.69 (m, 2H), 0.51-0.47 (m, 2H).

EXAMPLE 13X 5-Cyclopropyl-1- (2-trifluoromethylphenyl) -1 H -pyrrazole-4-carboxylic acid 72% yield APCIMS 295 [M-1] "1 H NMR (DMSO-de) d 1.71-1.78 (m, 1 H), 7.89 (s, 1 H).

EXAMPLE 13 AND 5-Ethyl-1- (guinolin-5-yl) -1H-pyrazole-4-carboxylic acid 98% yield APCIMS 266 [M-1] "1 H NMR (DMSO-d 6) d 0.75-0.79 (t, 3H), 8.94-8.94 (d, 1 H).

EXAMPLE 14A 2-Methyl-5-phenyl-2f-pyrazole-3-carboxylic acid The ethyl ester of 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid (0.32 g, 1.39 mmol) was dissolved in 4.5 ml of tetrahydrofuran, 1.5 ml of methanol and 1.5 ml of water, and treated with hydrate. of lithium hydroxide (0.12 g, 2.78 mmol). After stirring at room temperature overnight, the mixture was acidified (pH = 1) with hydrochloric acid and extracted with ethyl acetate (3 x 10 ml) and the combined organic phases were washed with 10 ml brine. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo affording a quantitative yield of the title compound. 1 H NMR (CD 3 OD) d 4.2 (s, 3 H), 7.2 (s, 1 H), 7.3 (t, 1 H), 7.4 (t, 2 H), 7.8 (d, 2 H). APCIMS 203 [M + 1] + The title compounds of Examples 14B-14D were prepared using a procedure analogous to that used for Example 14A.

EXAMPLE 14B 1-methyl-5-phenyl-1-t-pyrazole-3-carboxylic acid 1 H NMR (CD 3 OD) d 3.9 (s, 3 H), 6.8 (s, 1 H), 7.4-7.5 (m, 5 H). APCIMS 203 [M + 1] + EXAMPLE 14C 3-Methyl- (guinolin-5-yl) -1H-pyrazole-4-carboxylic acid 86% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.45 (s, 3 H), 7.60 (ddd, J = 1.2, 4.0, 8.8, 1 H), 7.73 (d, J = 7.6, 1 H), 7.84 (t, J = 8, 1 H), 8.12 (d, J = 8.4, 1 H), 8.26 (d, J = 8.8, 1H), 8.59 (s, 1 H), 8.97 (dd, J = 1.2, 2.8, 1 H), 8.98 (dd, J = 1.4, 3, 1 H). APCIMS 252 [M-1] ' EXAMPLE 14D 1 - (Isoquinolin-5-yl) -3-methyl-1 W-pyrazole-4-carboxylic acid 97% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.46 (s, 3 H), 7.60 (m, 2 H), 7.92 (d, J = 7.2, 1H), 8.25 (d, J = 8, 1 H), 8.56 (d, J = 6, 1 H), 8.64 (s, 1 H), 9.44 (s, 1 H), 12.50 (sa, 1 H). APCIMS 252 [M-1] "The title compounds of Examples 15A-15II were prepared using procedures analogous to that used for Example 6A.

EXAMPLE 15A R3-Methyl-1- (4-methoxyphenyl) -1 H-pyrazole-4-carbonylguanidine hydrochloride 34% yield 1 H NMR (DMSO-de) d 2.42 (s, 3H), 3.76 (s, 3H), 7.08 (d, 2H), 7.63 (d, 2H), 8.32 (sa, 2H), 8.43 (sa, 2H), 9.45 (s, 1 H).

EXAMPLE 15B r5-Methyl-1- (4-methoxyphenyl) -1 H-pyrazole-4-carbonylguanidine hydrochloride 24% yield 1 H NMR (DMSO-de) d 2.49 (s, 3 H), 3.82 (s, 3 H), 7.08 (d, 2 H), 7. 44 (d, 2H), 8.35 (sa, 2H), 8.63 (sa, 2H), 8.64 (s, 1 H).

EXAMPLE 15C r5-Methyl-1- (4-sulfamoylphenyl) -1-pyrazole-4-carbonylguanidine hydrochloride 19% yield 1 H NMR (DMSO-de) d 2.46 (s, 3H), 7.51 (s, 2H), 7.77 (d, 2H), 7.95 (d, 2H), 8.31 (sa, 2H), 8.47 (sa, 2H), 8.58 (s, 1 H).

EXAMPLE 15D r5-Methyl-1- (4-trifluoromethoxy-phenyl) -1H-pyrazole-4-carbonylguanidine hydrochloride % yield 1 H NMR (DMSO-de) d 2.49 (s, 3 H), 7.58 (d, 2 H), 7.7 (d, 2 H), 8.36 (sa, 1 H), 8.61 (sa, 2H), 8.69 (s, 1 H), 11.75 (s, 1 H).

EXAMPLE 15E [5-Methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carbonylguanidine hydrochloride 27% yield. 1 H NMR (DMSO-de) d 2.27 (s, 3 H), 3.76 (s, 3 H), 7.1 (t, 1 H), 7.27 (d, 1 H), 7.34 (d, 1 H), 7.54 (t, 1 H), 8.34 (sa, 2H), 8.62 (sa, 3H).

EXAMPLE 15F 5-Methyl-1- (4-methylsulfonyl) -1-pyrazole-4-carbonillquanidine hydrochloride 51% yield 1 H NMR (DMSO-de) d 2.61 (s, 3 H), 3.29 (s, 3 H), 7.85 (d, 2 H), 8. 09 (d + s, 3H), 8.4-8.7 (day, 4H), 11.9 (s, 1 H).

EXAMPLE 15G [5-Methyl-1- (2-pyridyl) -1 H-pyrazole-4-carbonylguanidine hydrochloride 60% yield 1 H NMR (DMSO-de) d2.8 (s, 3H), 7.51 (s, 1H), 7.38 (d, 1H), 8.07 (t, 1H), 7.5-8.2 (sa, 2H), 8.44 (s, 1H), 8.56 (s, 1H), 8.71 (s, 1H), 8.8 (s, 1H), 11.9 (s, 1H).

EXAMPLE 15H r5-Methyl-1 - (5-q? Inolinyl) -1 H-pyrazole-4-carbonillquanidine hydrochloride 53% yield 1 H NMR (DMSO-de) d 2.31 (s, 3 H), 7.59 (m, 1 H), 7.68 (d, 1 H), 7. 79 (d, 1H), 7.93 (t, 1H), 8.27 (d, 1H), 8.55 (sa, 2H), 8.81 (sa, 2H), 8.98 (s, 1H), 9.00 (d, 1H).

EXAMPLE 151 r5-Methyl-1- (4-pyridyl) -1 H-pyrazole-4-carbonylguanidine hydrochloride 9% yield 1 H NMR (DMSO-de) d 2.68 (s, 3H), 7.87 (d, 2H), 8.41 (sa, 2H), 8. 67 (sa, 2H), 8.86 (s and d, 3H).

EXAMPLE 15J R5-Methyl-1- (3-methoxyphenyl) -1 f / -pyrazol-4-carbon-p-phanidine hydrochloride 57% yield 1 H NMR (DMSO-de) d 2.5 (s, 3 H), 3.77 (s, 3 H), 7.07 (m, 3 H), 7.43 (m, 1 H), 8.36 (ss, 2 H), 8.66 (ss, 2 H) , 8.69 (s, 1 H).

EXAMPLE 15K r5-Methyl-1- (1-phthalazinyl) -1-pyrazol-4-carbonylguanidine hydrochloride 18% yield 1 H NMR (DMSO-de) d 2.57 (s, 3 H), 7.87 (d, 1 H), 8.09 (q, 1 H), 8.16 (q, 1 H), 8.36 (d, 1 H), 8.49 (s) , 1 H), 8.76 (ss, 2H), 9.90 (s, 1 H).

EXAMPLE 15L F5-methyl-1- (4-q? Inolinyl) -1 H-pyrazole-4-carbonylguanidine hydrochloride 45% yield H NMR (DMSO-de) d 2.39 (s, 3H), 7.5 (d, 1H), 7.70 (t, 1 H), 7.86 (d, 1 H), 7.92 (t, 1 H), 8.23 (d, 1 H), 8.5 (sa, 2 H), 8.77 (sa, 2 H), 9.01 (s, 1 H), 9.18 (s, 1 H) ), 12.2 (s, 1 H).

EXAMPLE 15M r5-methyl-1- (6-guinolinyl) -1 H-pyrazole-4-carbonylguanidine hydrochloride 92% yield 1 H NMR (DMSO-de) d 2.69 (s, 3 H), 7.87 (m, 1 H), 8.11 (d, 1 H), 8.33 (d, 1 H), 8.42 (s, 1 H), 8.46 (s) , 2H), 8.73 (sa, 2H), 8.79 (d, 1 H), 8.88 (s, 1H), 9.16 (d, 1 H), 12.1 (s, 1 H).

EXAMPLE 15N (5-Methyl-1-phenyl-1H-pyrazole-4-carbonylguanidine hydrochloride 62% yield H NMR (DMSO-de) d 2.49 (s, 3H), 7.52 (m, 5H), 8.34 (s, 2H), 8.36 (s, 1 H), 8.67 (s, 2H), 11.79 (s, 1 H) ).

EXAMPLE 15O Ri- (2-bromophenyl) -5-cyclopropyl-1H-pyrazole-4-carbonylguanidine hydrochloride 66% yield 1 H NMR (400 MHz, DMSO-d 6) d 0.59 (br s, 2 H), 0.74 (d, J = 7.6, 2 H), 1.92 (m, 1 H), 7.55 (m, 3 H), 7.85 (d, J = 7.6, 1 H), 8.41 (sa, 2H), 8.66 (s, 1 H), 8.70 (sa, 2H), 11.83 (s, 1 H). APCIMS 348 [M + 1] \ 350 [M + 3] + EXAMPLE 15P (4-Methyl-1-phenyl-1H-pyrazole-3-carbonyl) guanidine hydrochloride 1 H NMR (CD 3 OD) d 2.3 (s, 3 H), 7.3 (t, 1 H), 7.4 (t, 2 H), 7.8 (d, 2 H), 8.0 (s, 1 H). APCIMS 244 [M + 1] + EXAMPLE 15Q (5-Methyl-1-phenyl-1-1H-pyrazole-3-carbonyl) quanidine hydrochloride 1 H NMR (CD 3 OD) d 2.4 (s, 3 H), 7.4 (t, 1 H), 7.5 (t, 2 H), 7.8 (d, 2 H), 8.2 (s, 1 H). APCIMS 244 [M + 1] + EXAMPLE 15R Pl - (4-bromophenyl) -4-methyl-1 H -pyrazole-3-carboninguanidine hydrochloride 1 H NMR (CD 3 OD) d 2.4 (s, 3 H), 7.7 (d, 2 H), 7.8 (d, 2 H), 8.2 (s, 1 H). APCIMS 322 [M + 1] +, 324 [M + l EXAMPLE 15S H - (4-Bromophenyl) -5-methyl-1 H-pyrrazol-3-carbonnquanidine hydrochloride 1 H NMR (CD 3 OD) d 2.3 (s, 3 H), 6.7 (s, 1 H), 7.4 (d, 2 H), 7.7 (d, 2H). APCIMS 322 [M + 1, 324 [M + 3] + EXAMPLE 15T (1-Phenyl-1H-pyrazole-3-carbonyl) guanidine hydrochloride 1 H NMR (CD 3 OD) d 6.9 (d, 1 H, J = 3 Hz), 7.3 (t, 1 H), 7.5 (t, 2 H), 7.8 (d, 2 H), 8.2 (d, 1 H, J = 3 Hz). APCIMS 230 [M + 1] + EXAMPLE 15U (3-Methyl-1-phenyl-1-pyrazol-4-carbonyl-guanidine hydrochloride 1 H NMR (DMSO-de) d 2.4 (s, 3H), 7.4 (t, 1 H), 7.6 (t, 2H), 7.8 (d, 2H), 8.4 (sa, 2H), 8.5 (sa, 2H) , 9.6 (s, 1 H), 12.0 (s, 1 H). APCIMS 244 [M + 1] + EXAMPLE 15V (2-Methyl-5-phenyl-2H-p¡razole-3-carbonyl) guanidine hydrochloride 1 H NMR (DMSO-de) d 4.1 (s, 3H), 7.3 (s, 1 H), 7.4 (t, 1 H), 7.4 (t, 2H), 7.7 (d, 2H), 8.5 (sa, 2H) ), 8.6 (sa, 2H), 11.4 (sa, 1 H). APCIMS 244 [M + 1] + EXAMPLE 15W (1-Methyl-5-phenyl-1H-pyrazole-3-carbonyl) guanidine hydrochloride 1 H NMR (DMSO-de) d 4.0 (s, 3H), 7.1 (s, 1 H), 7.5-7.6 (m, 5H), 8.5 (sa, 2H), 8.6 (sa, 2H), 12.1 (sa, 1 HOUR). APCIMS 244 [M + 1 EXAMPLE 15X r2-Methyl-5- (naphthalen-1-yl) -2H-pyrazole-3-carboninguanidine hydrochloride 1 H NMR (DMSO-de) or 4.2 (s, 3 H), 7.6 (m, 3 H), 7.67 (d, 1 H), 7.9 (s, 1 H), 8.0 (m, 2 H), 8.5 (m, 3 H) ), 8.6 (sa, 2H). APCIMS 292 [M-1] - EXAMPLE 15Y Hydrochloride of r5- (tert-butyl) -2-methyl-2 / - / - p -razol-3-carbonyl1g-anidine 1 H NMR (DMSO-de) d 1.2 (s, 9H), 9.0 (s, 3H), 7.4 (s, 1 H), 8.4 (sa, 2H), 8.6 (sa, 2H), 11.8 (sa, 1 H) ). APCIMS 224 [M + 1] + EXAMPLE 15Z (1,5-Diphenyl-1H-pyrazole-3-carbonyl) guanidine hydrochloride 1 H NMR (DMSO-de) d 7.2 (m, 2 H), 7.3 (m, 4 H), 7.4 (m, 2 H), 7.5 (m, 3 H), 8.5 (br s, 4 H). APCIMS 306 (M + 1] + EXAMPLE 15AA (1,4-Dimethyl-5-phenyl-1 / - -pyrazol-3-carbonyl) guanidine hydrochloride 1 H NMR (DMSO-de) d 2.1 (s, 3H), 3.8 (s, 3H), 7.4-7.6 (m, 5H), 8.5 (sa, 2H), 8.6 (sa, 2H), 11.1 (sa, 1 H). APCIMS 258 [M + 1] + EXAMPLE 15BB Í3 Hydrochloride -methi 1-1 - (naphthalen-1 -yl) -1 H-pyrazole-4-carbonylguanidine 1 H NMR (DMSO-de) d 2.5 (s, 3 H), 7.6 (m, 4 H), 7.75 (d, 1 H, J = 8 Hz), 8.1 (m, 2 H), 8.3 (sa, 2 H), 8.4 (sa, 2H), 9.15 (s, 1 H), 11.8 (s, 1 H). . APCIMS 294 [M + 1] + EXAMPLE 15CC (2-Methyl-5-phenyl-2H-pyrazole-3-carbonyl) quanidine hydrochloride 1 H NMR (DMSO-de) d 4.1 (s, 3H), 7.3 (s, 1 H), 7.4 (t, 1 H), 7.4 (t, 2H), 7.7 (d, 2H), 8.5 (sa, 2H) ), 8.6 (sa, 2H), 11.4 (sa, 1 H). APCIMS 244 [M + 1] + EXAMPLE 15DD (1-methyl-5-phenyl-1 / - / - pyrazole-3-carboni-guanidine hydrochloride 1 H NMR (DMSO-de) d 4.0 (s, 3H), 7.1 (s, 1 H), 7.5-7.6 (m, 5H), 8.5 (sa, 2H), 8.6 (sa, 2H), 12.1 (sa, 1 HOUR). APCIMS 244 [M + 1] + EXAMPLE 15EE r5- (Tert-butiD-2-methyl-2H-pyrrazol-3-carbonylguanidine hydrochloride 1 H NMR (DMSO-de) d 1.2 (s, 9H), 4.0 (s, 3H), 7.4 (s, 1 H), 8.4 (sa, 2H), 8.6 (sa, 2H), 11.8 (sa, 1 H) ). APCIMS 244 [M + 1] + EXAMPLE 15FF (1,5-Diphenyl-1-pyrazol-3-carbonyl) guanidine hydrochloride 1 H NMR (DMSO-de) d 7.2 (m, 2 H), 7.3 (m, 4 H), 7.4 (m, 2 H), 7.5 (m, 3 H), 8.5 (br s, 4 H). APCIMS 306 [M + 1] + EXAMPLE 15GG (1,4-Dimethyl-5-phenyl-1 H -pyrazole-3-carbonyl) guanidine hydrochloride 1 H NMR (DMSO-de) d 2.1 (s, 3H), 3.8 (s, 3H), 7.4-7.6 (m, 5H), 8.5 (sa, 2H), 8.6 (sa, 2H), 8.6 (sa, 2H) ), 11.1 (sa, 1 H). APCIMS 258 [M + 1] + EXAMPLE 15HH r3-Methyl-1 - (quinolin-5-yl) -1 / - / - pyrazole-4-carbonylguanidine hydrochloride 23% yield 1 H NMR (400 MHz, CD 3 OD) d 2.62 (s, 3 H), 8.07 (m, 2 H), 8.22 (t, J = 7.8, 1 H), 8.36 (d, J = 7.6, 1 H), 9.12 (s, 1 H), 9.20 (d, J = 8.8, 1 H), 9.27 (d, J = 5.2, 1 H). APCIMS 296 [M + 1] + EXAMPLE 1511 Ri- (isoguinolin-5-yl) -3-methyl-1H-pyrazole-4-carbonylguanidine hydrochloride 93% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.49 (s, 3 H), 7.03 (s, 1 H), 8.02 (m, 1 H), 8.18 (m, 2 H), 8.58 (m, 6 H), 9.50 (s) , 1 H), 9.28 (s, 1 H), 12.38 (s, 1 H). APCIMS 295 [M + 1 EXAMPLE 16A r5-Cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonylguanidine hydrochloride A mixture of 5-cyclopropyl-1- (quinolin-5-yl) -1-pyrazol-4-carboxylic acid (4.08 g, 14.6 mmol) and 25 ml of SOCI2 was heated at reflux for 1 hour. The excess of SOCI2 was removed in vacuo via codestillation with toluene. The solid residue was added in portions over 45 minutes to a vigorously stirred solution at 40 ° C of guanidine hydrochloride (5.02 g, 52.6 mmol) in 59 ml of 2N NAOH and 29 ml of THF. The resulting mixture was refluxed for 1 hour and then cooled to 23 ° C. The organic solvent and 40 ml of water were removed in vacuo. The tan solid that precipitated was filtered and washed with 2 x 5 ml portions of cold H20. This solid was air dried for 1 hour and then dried for 24 h under high vacuum at 40 ° C offering 3.5 g of the free base of the title compound. This solid was dissolved in 25 ml of hot methanol and treated with 1.85 ml of conc. This pale yellow solution was stirred for 15 min at room temperature and concentrated in vacuo to a light amber gum. The residual H20 was removed in vacuo via co-distillation with 3 x 25 ml portions of anhydrous ethanol. The resulting light yellow solid was recrystallized from hot ethanol offering 3.58 g of the title compound (62% yield). APCIMS 319 [M-1] - 1 H NMR (DMSO-de) d9.16 (m, 1 H), 8.86 (s, 1 H), 8.85 (br s, 2 H), 8.50 (br s, 2 H), 8.37 (d , J = 8.4, 1 H), 8.08-7.97 (m, 3H), 7.78 (dd, J = 4.4, 8.4, 1 H), 1.99-1.93 (m, 1 H), 0.64-0.62 (m, 2H) , 0.42 (m, 2H). The title compounds of Examples 16B-16AA were prepared using procedures analogous to that used in Example 16A.

EXAMPLE 16B ri- (3,4-dichlorophenyl) -5-methyl-1W-pyrazole-4-carbonylguanidine hydrochloride 23% yield APCIMS 301 [M-1] - 1 H NMR (DMSO-de) d 2.59 (s, 3 H), 7.93 (s, 1 H).

EXAMPLE 16C (1-Benzyl-5-methyl-1W-pyrazole-4-carbonyl) quanidine hydrochloride 24% yield APCIMS 256 [M-1 H NMR (DMSO-d6) d 2.48 (5, 3H), 8.84 (s, 1 H).

EXAMPLE 16D r5-methyl-1 - (jo-toliD-1 H-pyrazole-4-carboninguanidine hydrochloride 29% yield APCIMS 256 [M-1T 1 H NMR (DMSO-de) d 2.49 (S, 3 H), 8.64 (s, 1 H).

EXAMPLE 16E (5-isopropyl-1-phenyl-1 H-pyrrazol-4-carbonyl) guanidine hydrochloride 42% yield APCIMS 270 [M-1T 1 H NMR (DMSO-de) d 1.22 (d, 6H), 8.63 (s, 1 H).

EXAMPLE 16F (1,5-Diphenyl-1H-pyrazole-4-carbonyl) guanidine hydrochloride 17% yield APCIMS 304 [M-1] - 1 H NMR (DMSO-de) d 7.17-7.35 (m, 10H), 8.81 (s, 1 H).

EXAMPLE 16G (5-Ethyl-1-phenyl-1 / - / - pyrazole-4-carbonyl) guanidine hydrochloride 7% yield APCIMS 256 [M-1] "1 H NMR (DMSO-de) d 1.01-1.06 (t, 3H), 8.64 (s, 1 H).

EXAMPLE 16H H -phenyl-5 - (/ 7-propyl) -1H-pyrazole-4-carbonylguanidine hydrochloride 4% yield APCIMS 270 [M-1] "1 H NMR (DMSO-de) d 0.68-0.71 (t, 3H), 7.08 (s, 1 H).

EXAMPLE 161 n- (3,5-Dichlorophenyl) -5-methyl-1H-pyrazole-4-carbonylguanidine hydrochloride 6% yield APCIMS 311 [M-1] ~ H NMR (DMSO-de) d 2.57 (s, 3H), 8.7 (s, 1 H).

EXAMPLE 16J M - (2-chlorophenyl-5-methyl-1 H -pyrazole-4-carbonylguanidine hydrochloride 22% yield APCIMS 276 [M-1] "1 H NMR (DMSO-de) d 2.30 (s, 3H), 8.68 (s, 1 H).

EXAMPLE 16K r5-Methyl-1- (3-trifluoromethylphenyl) -1H-pyrazole-4-carbonylquinidine hydrochloride 53% yield APCIMS 310 [M-1] -1 H NMR (DMSO-de) d 2.45 (s, 1 H), 8.76 (s, 1 H).

EXAMPLE 16L P1 - (3-Chlorophenyl) -5-methyl-1 H-pyrazole-4-carbonylguanidine hydrochloride 6% yield APCIMS 276 [M-1T 1 H NMR (DMSO-de) d 2.54 (s, H), 8.67 (s, 1 H) EXAMPLE 16M r5-methyl-1 - (naphthalen-1-yl) -1 H-pyrazole-4-carbonillquanidine hydrochloride 58% yield APCIMS 292 [M-1] "1 H NMR (DMSO-de) d 2.26 (s, 3 H), 8.65 (5, 1 H) EXAMPLE 16N [1- (4-Chlorophenyl) -5-methyl-1 H-pyrazole-4-carbonylguanidine hydrochloride 60% APCIMS yield 276 [M-1] "1 H NMR (DMSO-de) d 2.52 (s, 3H), 8.71 (s, 1 H).

EXAMPLE 160 r5-Methyl-1- (2-trifluoromethylphenyl) -1tf-pyrazole-4-carbonylguanidine hydrochloride 82% yield APCIMS 310 [M-1 H NMR (DMSO-d6) d 2.28 (s, 3 H), 8.65 (s, 1 H).

EXAMPLE 16P (3,5-Dimethyl-1-phenyl i 1-1 f / -pyrazole-4-carbonyl) guanidine hydrochloride 1% yield APCIMS 256 [M-1T 1 H NMR (DMSO-de) d 2.38 (s, 3 H), 2.42 (s, 3 H).

EXAMPLE 16Q (1-Cyclohexyl-5-methyl-1 H-pyrazole-4-carboninguanidine hydrochloride 59% yield APCIMS 248 [M-1T 1 H NMR (DMSO-de) d 2.50 (s, 3 H), 8.41 (s, 1 H).

EXAMPLE 16R r5-methyl-1 - (quinolin-8-yl) -1 H-pyrazole-4-carboninquanidine hydrochloride 60% yield APCIMS 293 [M-1] "1 H NMR (DMSO-de) d 2.22 (s, 3 H), 8.75 (s, 1 H).

EXAMPLE 16S ri- (2,6-dichlorophenyl) -5-methyl-1H-pyrazole-4-10 carbonylguanidine hydrochloride • 33% yield APCIMS 311 [M-1] - 1 H NMR (DMSO-de) d 2.27 (s, 3 H), 8.76 (s, 1 H). EXAMPLE 16T r5-Cyclopropyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carbonylquinidine hydrochloride 70% yield. APCIMS 336 [M-1] "1 H NMR (DMSO-de) d 1.83-1.90 (m, 1 H), 8.57 (s, 1 H).

EXAMPLE 16U Ri - (isoquinolin-5-yl) -5-methyl-1H-pyrazole-4-carbonylguanidine hydrochloride 51% yield APCIMS 293 [M-1] - 1 H NMR (DMSO-de) d 2.33 (s, 3 H), 8.98 (s, 1 H). EXAMPLE 16V p1- (2,3-Dichlorophenyl) -5-methyl-1-pyrazol-4-carbonylguanidine hydrochloride 39% yield APCIMS 311 [M-1] - 1 H NMR (DMSO-de) d 2.32 (s, 3 H), 8.78 (s, 1 H).

EXAMPLE 16W [5-Cyclopropyl-1-phen i 1-1 / - / - pyrazole-4-carbonylg-anidine hydrochloride] 22% yield APCIMS 268 [M-1] "1 H NMR (DMSO-de) d 2.11-2.17 (m, 1 H), 8.56 (s, 1 H).

EXAMPLE 16X H - (3-Chlorophenyl-5-methyl-1H-pyrazole-4-carbonylguanidine hydrochloride A mixture of 5-methyl-1- (3-chlorophenyl) -prazole-4-carboxylic acid (234 mg, 1.0 mmol) and 5 ml of SOCI2 was heated at reflux for 45 min. The excess SOCI2 was removed in vacuo via codestylation with toluene. The residue was dissolved in 2 ml of anhydrous THF and added dropwise over 30 minutes to a vigorously stirred solution at 40 ° C of guanidine hydrochloride (344 mg, 3.6 mmol) in 3.25 ml of 2 N NaOH and 1.9 ml of THF The resulting mixture was heated to reflux for 4 hours and then cooled. The organic solvent was removed in vacuo. The residue was diluted with 10 ml of 1 N NaOH and extracted with 5 x 5 ml of AcOEt. The combined organic layers were dried (Na2SO4) filtered and concentrated in vacuo to a white solid. This material was dissolved in 1 ml of MeOH and 18.4 μl 12 N of HCl was added with stirring. The solvents were removed in vacuo with toluene azeotropes and the resulting solid was stirred in 1 ml of ether / acetone (1: 1) and filtered to remove residual H20. Drying under high vacuum at 40 ° C gave the desired product (20 mg, 6%). APCIMS 276 [M-1T, 1 H NMR (DMSO-de) d 2.54 (5, 3H), 8.68 (s, 1 H).

EXAMPLE 16Y r5-Cyclopropyl-1- (2,6-dichlorophenyl) -1f / -pyrazole-4-carbonillquanidine hydrochloride 61% yield APCIMS 337 [M-1 H NMR (DMSO-de) d 1.82-1.89 (m, 1 H), 8.65 (s, 1 H).

EXAMPLE 16Z r5-Cyclopropyl-1- (quinolin-8-yl) -1H-pyrazolecarbonylguanidine hydrochloride APCIMS 319 [M-ir 1 H NMR (DMSO-de) d 1.77-1.84 (m, 1 H), 8.87 (s, 1 H). Performance of 3.5% HCl salt EXAMPLE 16AA r5-ethyl-1- (guinolin-5-yl) -1H-pyrazole-4-carboninguanidine hydrochloride 14% yield APCIMS 307 [M-1] "1 H NMR (DMSO-de) d 0.86-0.89 (t, 3H), 8.93 (s, 1 H) The title compound of Example 17 was prepared using an analogous procedure to that described by Klinsberg , E. Synthesis 1972, 475, and Example 3A.

EXAMPLE 17 2- (Naphthalen-2-yl) -5-methyl-2-tf-1, 2,3-triazole-4-carboxylic acid 52% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.52 (5, 3 H), 7.55 (m, 2 H), 7.96 (d, J = 8, 1 H), 8.12 (m, 3 H), 8.53 (5, 1 H ). APCIMS 252 [M-1T The title compound of Example 18 was prepared using a procedure analogous to that used for Example 16A.

EXAMPLE 18 r5- (naphthalen-2i l) -5-methyl-2 Y-1, 2,3-triazole-carboniHuangidine hydrochloride 94% yield 1 H NMR (400MHz, DMSO-d 6) d 2.54 (s, 3H), 7.11 (m, 1 H), 7.56 (m, 3H), 8.10 (m, 4H), 8.29 (m, 2H), 8.63 (m, 2H). APCIMS 295 [M + 1] + The title compounds of Examples 19A-19000 were prepared using procedures analogous to that described by Menozzi, G., Mosti, L., Schenone, P.J. Heterocycl. Chem., 1987, 24, 1669.

EXAMPLE 19 5-Cyclopropyl-1 - (2,3-dimethoxyphenyl) -1 / - / - pyrazole-4-carboxylate ethyl 89% yield APCIMS 317 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.66-0.88 (m, 4 H), 1.36 (t, J = 7.2, 3 H), 1.93 (m, 1 H), 3.60 (s, 3 H) , 3.92 (s, 3H), 4.30 (q, J = 7.2, 2H), 6.93 (d, J = 8, 1 H), 7.02 (d, J = 8.4, 1H), 7.13 (t, J = 8, 1H), 8.01 (s, 1H).

EXAMPLE 19B ethyl 5-cyclopropyl-1 - (naphthalen-1 -yl) -1-pyrazole-4-carboxylate 72% yield APCIMS 307 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.6-0.8 (m, 4 H), 1.39 (t, J = 7.2, 3 H), 1.80 (m, 1 H), 4.33 (q, J = 7.2, 2H), 7.30 (d, J = 7.6, 1 H), 7.52 (m, 4H), 7.92 (d, J = 8, 1 H), 7.98 (d, J = 7.6, 1 H), 8.12 (s, 1 H).

EXAMPLE 19C 5-Cyclopropyl-1- (naphthale? N-2-yl) -1H-pyrazole-4-carboxylate ethyl 96% yield APCIMS 307 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.64 (m, 2H), 0.91 (m, 2H), 1.39 (m, 3H), 2.07 (m, 1 H), 4.33 (m, 2H), 7.25 (m, 1 H), 7.56 (m, 2H), 7.66 (m, 1 H), 8.06 (m, 4H).

EXAMPLE 19D ethyl 5-cyclopropyl-1- (o-biphenyl) -1-pyrazole-4-carboxylate 57% yield APCIMS 333 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.46 (m, 4 H), 0.99 (m, 1 H), 1.28 (m, 3 H), 4.19 (m, 2 H), 7.03 (m, 2H), 7.22 (m, 3H), 7.41-7.53 (m, 4H), 7.97 (s, 1H).

EXAMPLE 19E ethyl 5-cyclopropyl-1- (2-nitrophenyl) -1H-pyrazole-4-carboxylate 51% yield APCIMS 302 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.68 (m, 2 H), 0.86 (m, 2 H), 1.36 (m, 3 H), 1.82 (m, 1 H), 4.32 (m, 2H), 7.55-7.76 (m, 3H), 8.03 (m, 3H). EXAMPLE 19F ethyl 5-cyclopropyl-1- (2-ethylphenyl) -1H-pyrrazol-4-carboxylate 53% yield APCIMS 285 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.75 (m, 2 H), 0.85 (m, 2 H), 1.07 (m, 3 H), 1.35 (m, 3 H), 1.78 (m, 1 H), 2.36 (q, J = 7.4, 2H), 4.27 (m, 2H), 7.23 (m, 2H), 7.29-7.42 (m-2H), 7.98 (s, 1 H).

EXAMPLE 19G ethyl 5-cyclopropyl-1 - (2-methylphenyl -) - 1 tf-pyrazole-4-carboxylate 73% yield APCIMS 291 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.75-0.81 (m, 4H), 1.34 (dt, J = 7, .8, 3H), 1.83 (m, 1 H ), 2.05 (5, 3H), 4.28 (dq, J = 7.2, 0.4, 2H), 7.30-7.38 (m, H), 7.99 (s, 1 H).

EXAMPLE 19H ethyl 5-cyclopropyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxylate 75% yield APCIMS 291 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.6-0.9 (br s, 4 H), 1.34 (d, J = 7.2, .6, 3 H), 1.85 (m, 1 H), 4.28 ( q, J = 7.2, 2H), 7.37-7.44 (m, 3H), 7.52 (m, 1 H), .03 (s, 1 H).

EXAMPLE 191 Ethyl 5-cyclopropyl-1- (2-trifluoromethylphenyl) - 1-pyrazol-4-carboxylate 69% yield APCIMS 341 [M + 1 1 H NMR (400 MHz, CDCl 3) d 0.62 (d, J = 8.8, 2H), 0.78-0.85 (m, 2H), 1.35 (t, J = 7.2, 3H), 1.85 (m, 1 H), 4.20 (dq, J = 14.4, 7.2, 2H), 7.35-7.6 (m, 4H), 8.03 (s, 1 H).

EXAMPLE 19J 5-Cyclopropyl-1 - (2-fluorophenyl -) - 1 7-pyrrazol-4-carboxylic acid ethyl ester 81% yield APCIMS 275 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.63 (m, 2H), 0.83 (m, 2H), 1.36 (t, J = 7.2, 3H), 1.92 (m, 1 H), 4.20 (q, J = 7.2, 2H), 7.21-7.29 (m, 2H), 7.43-7.48 (m, 2H), 8.04 (5, 1 H) ).

EXAMPLE 19K ethyl 5-cyclopropyl-1- (indazol-7-yl) -1H-pyrazole-4-carboxylate 59% yield APCIMS 297 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.56-0.60 (m, 2H), 1.00-1.23 (m, 2H), 1.37 (m, 3H), 2.07 (m, 1 H), 4.33 (dq, J = 6.8, 1.6, 2H), 7.22 (m, 1 H), 7.60 (d, J = 6.8, 1H), 7.75 (d, J = 7.6, 1 H), 8.12 (s, 1 H) ), 10.97 (sa, 1 H).

EXAMPLE 19L methyl 5-ethyl-1- (benzothiazol-2-yl) -1-y-pyrazol-4-carboxylate 69% yield APCIMS 288 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 1.34 (t, J = 6.8, 3 H), 3.69 (q, J = 6.8, 2H), 3.85 (5, 3H), 7.36 (t, J = 7.6, 1 H), 7.46 (t, J = 7.2, 1 H), 7.38 (d, J = 8.0, 1 H), 7.91 (d, J = 8.0, 1 H), 8.01 (s, 1 H).

EXAMPLE 19M -Cyclopropyl-1- (2,4-dichloro-6-trifluoromethylphenyl) -1A-pyrazole-4-carboxylic acid ethyl ester 43% yield APCIMS 393 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.78-0.85 (m, 2H), 0.85-0.91 (m, H), 1.37 (t, J = 7.2, 3H), 1.70 (m, 1 H), 4.30 (q, J = 6.8, 2H), 7.3-7.7 (m, 2H) .08 (s, 1 H).

EXAMPLE 19N-Cyclopropyl-1- (2-chloro-4-. {Methylsulfonyl.}. Phenyl) -1H-pyrazole-4-carboxylate ethyl 70% yield APCIMS 369 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.68 (d, J = 4.8 2 H), 0.82 (d, J = 7.6, H), 1.37 (t, J = 7.2, 3 H), 1.84 (m, 1 H), 4.30 (q, J = 7.2, 2H), 7.61 (d, J = 8.4, H), 7.96 (m, 1 H), 8.04 (s, 1 H), 8.12 (s, 1 H).

EXAMPLE 190-Cyclopropyl-1- (2-chloro-4- (methylsulfonylmethylenesulfonyl.) Phenyl) -1 / -p-ethol-4-carboxylic acid ethyl ester 61% yield APCIMS 447 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.65 (s, 2 H), 0.84 (d, J = 7.2, 2 H), .35 (t, J = 7.6, 3 H), 1.84 (m , 1 H), 3.29 (s, 3H), 4.30 (q, J = 6.8, 2H), 4.62 (s, H), 7.64 (d, J = 7.6, 1H), 8.01 (dd, J = 8.4, 2.0 , 1 H), 8.06 (s, 1H), 8.16 (s, 1H).

EXAMPLE 19P-Cyclopropyl-1 - (2,5-dichlorophenyl) -1 / -pyrazol-4-carboxylate ethyl 72% yield APCIMS 325 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.73 (s, 2 H), 0.84 (d, J = 6.8, 2 H), .34 (t, J = 7.2, 3 H), 1.85 (m , 1 H), 4.32 (q, J = 7.2, 2H), 7.39-7.47 (m, 3H), 8.02, 1 H).

EXAMPLE 19Q 5-Cyclopropyl-1- (2,4-dichlorophenyl) -1 A-pyrazole-4-carboxylic acid ethyl ester 72% yield APCIMS 325 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.73 (s, 2 H), 0.84 (d, J = 6.8, 2 H), .34 (t, J = 7.2, 3 H), 1.85 (m , 1H), 4.32 (q, J = 7.2, 2H), 7.39-7.47 (m, 3H), 8.02, 1 H).

EXAMPLE 19R 5-Cyclopropyl-1 - (2,3-dichlorophenyl) -1 H- or 4-carboxylic acid ethyl ester 74% yield APCIMS 325 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.67 (s, 2 H), 0.78 (s, 2 H), 1.34 (t, J = .2, 3 H), 1.83 (m, 1 H), 4.32 (m, 2H), 7.30-7.35 (m, 2H), 7.59 (m, 1H), 8.02 (s, H).

EXAMPLE 19S 5-Chloropropyl-1- (2-chloro-5-methyl) -l-phenyl-phenyl) -1-trifluoro-4-carboxylic acid ethyl ester 38% yield APCIMS 369 [M + 1f 1 H NMR (400 MHz, CDCl 3) d 0.70 (s, 2 H), 0.82 (d, J = 7.2, 2 H), 1.35 (t, J = 7.2, 3 H), 1.83 (m, 1 H ), 3.08 (5, 3H), 4.33 (q, J = 7.2, 2H), 7.75 (d, J = 6.4, 2.4, 1 H), 7.98-8.04 (m, 2H), 8.05 (s, 1 H) .

EXAMPLE 19T methyl 5-ethyl-1- (benzimidazol-5-yl) -1f / -pyrazol-4-carboxylate 56% yield APCIMS 271 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.98-1.16 (m, 3H), 2.81-3.07 (m, 2H), 3.76 (s, 3H), 7.23 (d, J = 8.4, 1 H), 7.68 (sa, 2H), 7.96 (s, 1 H), 8.38 (sa, 1 H), 12.75 (sa, 1 H).

EXAMPLE 19U ethyl 5-cyclopropyl-1 - (benzimidazol-5-yl) -1 tf-pyrazole-4-carboxylate 75% yield APCIMS 297 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.61 (dd, J = 5.4, 1.4, 2H), 0.85-0.87 (m, 2H), 1.37 (m, 3H), 1.98 (m, 1 H), 4.31 (q, J = 7.2, 2H), 7.44 (m, 1 H), 7.76 (d, J = 8.8, 1 H), 7.85 (s, 1 H), 8.01 (s, 1 H) , 8.37 (sa, 1 H), 11.82 (sa, 1 H).

EXAMPLE 19V methyl 5-ethyl-1- (3-chloroindazol-5-yl) -1 H-pyrrazole-4-carboxylate 63% yield, APCIMS 305 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 1.16 (t, J = 7.6, 3H), 2.96 (q, J = 7.6, 2H), 3.88 (s, 3H), 7.43-7.46 (m, 1 H), 7.53 (d, J = 8.8, 1 H), 7.74 (s, 1 H), 8.06 (s, 1H).

EXAMPLE 19W methyl 5-ethyl-1- (3-methylbenzimidazol-5-yl) -1 H-pyrazole-4-carboxylate 65% yield APCIMS 284 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 1.11 (t, J = 7.6, 3H), 2.62 (s, 3H), 2.93 (q, J = 7.6, 2H), 7.18 (dd, J = 8.4, 2.0, 1 H), 7.54-7.56 (m, 2H), 8.01 (s, 1 H).

EXAMPLE 19X 5-Cyclopropyl-1- (2-chloro-5-hydroxysulfonylphenyl) -1-pyrazole-4-carboxylate ethyl 82% yield APCIMS 369 [M-1T 1 H NMR (CDCl 3) d 0.89-1.11 (m, 4 H), 1.39 (t, J = 7.2, 3 H), 1.83 (q, J = 7.0, 1 H), 4.35 (q, J = 7.0, 2H), 6.92 (sa, 1 H), 7.58 (d, J = 8.4, 1 H), 7.91-7.95 (m, 2H) 8.44 (s, 1 H).

EXAMPLE 19 AND 5-Cyclo-opropyl-1- (2-chloro-4-hydroxysulfonylphenyl) -1H-pyrazole-4-carboxylate ethyl 96% yield APCIMS 369 [M-1-] "1 H NMR (CDCl 3) d 0.85-0.91 (m, 4H), 1.37 (dt, J = 7.0, 5.2, 3H), 1.75-1.87 (m, 1H), 4.33 (q, J = 7.0, 2H), 7.42 (s, J = 8.0, 1 H), 7.80 (d, J = 8.0, 1H), 8.02 (s, 1H), 8.16 (s, 1 H).

EXAMPLE 19Z 5-lsopropyl-1- (5-quinolinyl-1-pyrazol-4-carboxylate ethyl) 88% yield APCIMS 310 [M + 1f 1 H NMR (400 MHz, CDCl 3) d 8.95 (dd, J = 4, 1.6, 1H), 8.26 (d, J = 8, 1H), 8.12 (s, 1H), 7.79 (t, J = 8, 1 H), 7.53 (m, 2H), 7.39 (dd, J = 9.4, 1H), 4.32 (q, J = 7, 2H), 3.01 (m, 1H), 1.38 (t, J = 7, 3H), 1.21 (m, 6H).

EXAMPLE 19AA 5- / 7-propyl-1- (5-quinolinyl) -1H-pyrazole-4-carboxylic acid ethyl ester 97% yield. APCIMS 310 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 8.95 (d, J = 4.1 H), 8.25 (d, ILLEGIBLE), J = 8, 1H), 7.56 (m, 2H), 7.38 (dd, J = 8.4, 1H), 4.32 (q, J = 7, 2H), 2.71 (sa, 2H), 1.36 (m, 5H), 0.70 (t, J = 7, 3H).

EXAMPLE 19BB 5-CyclopropiM - (2,1, 3-benzothiazol-4-yl) -1 7-pyrazole-4-carboxylic acid ethyl ester 67% yield APCIMS 315 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 8.11 (m, 2 H), 7.70 (m, 2 H), 4.31 (q, J = 7, 2 H), 1.97 (m, 1 H), 1.36 (t, J = 7, 3H), 0.53-0.85 (m, 4H).

EXAMPLE 19CC 5-Cyclopropyl-1- (2-aminosulfonylphenol) -1-ethyl pyrazole-4-carboxylate 72% yield APCIMS 336 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 8.17 (d, J = 7.1 H), 8.04 (s, 1 H), 7.69 (t, J = 7.1 H), 7.63 (t, J = 7, 1H), 7.42 (d, J = 7, 1H), 5.81 (s, 2H), 4.29 (q, J = 7, 2H), 1.80 (m, 1 H), 1.34 (t , J = 7. 3H), 0.4-1.0 (sa, 4H).

EXAMPLE 19DD ethyl 5-cyclopropyl-1- (2-methylthiophenyl) -1 H-pyrazole-4-carboxylate 76% yield APCIMS 303 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 8.02 (s, 1 H), 7.43 (m, 1 H), 7.30 (d, J = 8, 1H), 7.23 (m, 2H), 4.27 (q, J = 7, 2H), 2.36 (s, 3H), 1.86 (m, 1H), 1.34 (t, J = 7, 3H), 0.75 (m, 4H).

EXAMPLE 19EE methyl 5-methoxymethiM - (5-quinolinyl) -1 tf-pyrazole-4-carboxylate 90% yield APCIMS 298 [M + 1] + 1 H NMR (300 MHz, CDCl 3) d 8.99 (d, J = 4.1 H), 8.30 (d, J = 9, H), 8.20 (s, 1 H), 7.83 ( t, J = 8, 1 H), 7.71 (m, 2H), 7.43 (dd, J = 9.5 1 H), 4.56, 2H), 3.93 (s, 3H), 3.21 (s, 3H).

EXAMPLE 19FF ethyl 5-cyclopropyl-1 - (isoquinolin-5-yl) -1 H-pyrazole-4-carboxylate 69% yield APCIMS 308 [M + 1] + 1 H NMR (CDCl 3) d 1.68-1.75 (m, 1H), 8.07 (s, 1H).

EXAMPLE 19GG 5-benzyloxymethyl-1 - (quinolin-5-yl) -1 H-pyrazole-4-carboxylate ethyl 93. 5% yield APCIMS 388 [M + 1] + 1 H NMR (CDCl 3) d 1.32-1.36 (s, 3H), 8.15 (s, 1 H).

EXAMPLE 19HH-methyl-1- (benzotriazol-5-yl) -1H-pyrazole-4-carboxylic acid methyl ester 95% yield APCIMS 272 [M + 1] + 1 H NMR (CDCl) d 1.12-1.16 (t, 3H), 8.07 (s, 1 H).

EXAMPLE 1911 methyl 5-ethiM- (indazol-6-yl) -1A-pyrazol-4-carboxylate 87% yield APCIMS 270 [M + 1] + 1 H NMR (CDCb) d 1.06-1.10 (t, 3H), 8.07 (s, 1H).

EXAMPLE 19JJ methyl-1- (benzothiazol-6-yl) -1H-pyrazole-4-carboxylate methyl 74% yield APCIMS 288 [M + 1] + 1 H NMR (CDCb) d 1.11-1.15 (t, 3H), 8.20 (s, 1 H).

EXAMPLE 19LL ethyl 5-cyclobutyl-1- (quinolin-5-yl) -1f-pyrazole-4-carboxylate 93% yield APCIMS 322 [M + 1f 1 H NMR (CDCb) d 3.44-3.53 (m, 1H). 8.08 (s, 1H).

EXAMPLE 19MM ethyl-cyclopropyl-1- (6-chloroquinolin-5-yl) -1-pyrazol-4-carboxylate 23% yield APCIMS 342 [M + 1] + 1 H NMR (CDCb) d 1.70-1.80 (m, 1 H), 8.04 (s, 1 H).

EXAMPLE 19NN methyl 5-ethyl-1- (índazol-5-yl) -1H-pyrazole-4-carboxylate 71. 5% yield APCIMS 271 [M + 1] + 1 H NMR (CDCb) d 1.06-1.10 (t, 3H), 8.02 (s, 1 H).

EXAMPLE 19OO-methyl-1- (1,4-benzodioxan-6-yl) -1 H-pyrazole-4-carboxylic acid methyl ester 85% yield- APCIMS 289 [M + 1] + 1 H NMR (CDCb) d 1.12-1.16 (t, 3H), 7.96 (s, 1H).

EXAMPLE 19PP ethyl 5-isobutyl-1 - (quinolin-5-yl) -1 H-pyrazole-4-carboxylate 98% yield APCIMS 324 [M + 1] + 1 H NMR (CDCb) d 2.68-2.70 (m, 1H), 8.14 (s, 1H).

EXAMPLE 19QQ methyl-1 - (1,3-benzodioxol-5-yl) -1 H-pyrazole-4-carboxylic acid methyl ester 76. 6% yield APCIMS 275 [M + 1] + 1 H NMR (CDCb) d 1.10-1.14 (t, 3H), 7.94 (s, 1H).

EXAMPLE 19RR ethyl 5-cyclopropyl-1- (8-bromoquinolin-5-yl) -1 H-pyrazole-4-carboxylate 49% yield APCIMS 388 [M + 2] + 1 H NMR (CDCb) d 1.64-1.72 (m, 1 H), 8.04 (s, 1 H).

EXAMPLE 19S 5-Cyclopropyl-1- (6-trifluoromethylquinolin-7-yl) -1-ethyl pyrazole-4-carboxylate 65% yield APCIMS 376 [M + 1] + 1 H NMR (CDCb) d 1.81-1.88 (m, 1 H), 8.12 (s, 1 H).

EXAMPLE 19TT ethyl 5-methyl-1- (6-quinolinyl) -1 / 7-pyrazole-4-carboxylate 40% yield 1 H NMR (DMSO-de) d 1.26 (t, 3H), 2.57 (s, 3H), 4.22 (q, 2H), 7.6 (dd, 1H), 7.89 (dd, 1 H), 8.04 (s, 1 H), 8.12-8.19 (m, 2H), 8.43 (d, 1 H), 8.95 (dd, 1 H).

EXAMPLE 19UU Ethyl 5-cyclopropyl-1- (6-quinolinyl) -1 - / - pyrazole-4-carboxylate 73. 2% yield 1 H NMR (DMSO-d 6) d 0.43 (dd, 2 H), 0.83 (m, 2 H), 1.29 (t, 3 H), 2.18 (m, 1 H), 4.24 (q, 2 H), 7.61 (dd, 1 H ), 7.98-8.04 (dd + s, 2H), 8.12 (d, 1 H), 8.26 (s, 1 H), 8.46 (d, 1 H), 8.96 (t, 1 H), EXAMPLE 19W ethyl 5-methyl-1- (6-methoxy-5-quinolinyl) -1 H-pyrazole-4-carboxylate % yield 1 H NMR (DMSO-de) d 1.27 (t, 3 H), 2.16 (s, 3 H), 3.9 (s, 3 H), 4.23 (q, 2 H), 7.34 (dd, 1 H), 7.46 (m, 1 H) ), 7.87 (d, 1 H), 8.07 (s, 1 H), 8.24 (d, 1 H), 8.8 (dd, 1 H).

EXAMPLE 19WW 5-cyclopropyl-1- (6-methyl-5-quinolinyl) -1 H-pyrazole-4-carboxylic acid ethyl ester 55. 2% yield 1 H NMR (DMSO-de) d 0.48-0.78 (m, 4H), 1.27 (t, 3H), 1.66 (m, 1 H), 2.13 (s, 3H), 4.21 (q, 2H), 7.35 (dd, 1 H), 7.5 (m, 1H), 7.8 (d, 1H), 8.11 (m, 2H), 8.89 (t, 1 H).

EXAMPLE 19XX Ethyl 5-ethyl-1- (2-methyl-6-quinolinyl) -1 / - / - pyrazole-4-carboxylate 36. 1% yield 1 H NMR (DMSO-de) d 1.05 (t, 3 H), 1.3 (t, 3 H), 2.64 (s, 3 H), 2.9 (q, 2H), 4.2 (2q, 2H), 7.45 (d, 1H), 7.56 (d, 1H), 7.82 (m, 3H), 8.6 (d, 1H).

EXAMPLE 19Y and ethyl 5-ethyl-1- (6-methyl-5-quinolinyl) -1 / - / - pyrazole-4-carboxylate 70. 8% yield 1 H NMR (DMSOe) d 0.83 (t, 3 H), 1.33 (t, 3 H), 2.15 (s, 3 H), 2.50 (2q, 2 H), 4.31 (q, 2 H), 7.33 (d, 1 H), 7.53 ( q, 1H), 7.87 (d, 1H), 8.19 (d + s, 2H), 8.95 (d, 1 H).

EXAMPLE 19ZZ ethyl 5-ethyl-1- (6-quinolinyl) -1 H-pyrrazol-4-carboxylate 99. 1% yield 1 H NMR (DMSOe) d 1.04 (t, 3H), 1.26 (t, 3H), 2.94 (q, 2H), 4.23 (q, 2H), 7.61 (q, 1 H), 7.82 (dd, 1 H), 8.03 (s, 1 H), 8.15 (d, 2H), 8.47 (d, 1 H), 8.97 (d, 1) H).

EXAMPLE 19AAA 1- (2-quinoxalinyl) -5-ethyl-1-pyrazole-4-carboxylic acid methyl ester 77% yield 1 H NMR (400 MHz, DMSO-d 6) d 9.41 (s, 1 H), 8.17 (s, 1 H), 8.13 (dd, J = 1.2, 8, 1 H), 8.01 (dd, J = 1, 8, 1 H), 7.87 (m, 2H), 3.78 (s, 3H), 3.40 (q, J = 7, 2H), 1.30 (t, J = 7, 3H). APCIMS 283 [M + 1] + EXAMPLE 19BBB 1- (2-benzimidazyl) -5-ethyl-1H-pyrazole-4-carboxylic acid methyl ester 61% yield 1 H NMR (400 MHz, DMSO-d 6) d 13.14 (s, 1 H), 8.19 (s, 1 H), 7.63 (d, J = 8, 1 H), 7.45 (d, J = 8 , 1 H), 7.2 (m, 2H), 3.77 (s, 1 H), 3.52 (q, J = 7, 2H), 1.22 (t, J = 7, 3H). APCIMS 271 [M + 1f EXAMPLE 19CCC 1- (2-trifluoromethyl-4-chlorophenyl) -5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester 54% yield 1 H NMR (400 MHz, DMSO-d 6) d 8.07 (d, J = 2.4, 1 H), 7.96 (d, J =, 1 H), 7.93 (d, J = 2, 1 H), 7.76 (d, J = 8, 1H), 4.19 (q, J = 7, 2H), 1.76 (m, 1s), .24 (t, J = 7, 3H), 0.73 (d, J = 8, 2H), 0.62 (d, J = 4, 2H). APCIMS 359 [M + 1] + EXAMPLE 19DDD - Ethyl (2-fluoro-6-trifluoromethylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carboxylate 70% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.08 (s, 1 H), 7.97-7.87 (m, 3 H), .24 (q, J = 7, 2 H), 1.74 (m, 1 H), 1.30 (t , J = 7, 3H), 0.86-0.68 (m, 4H). APCIMS 343 [M + 1] + EXAMPLE 19EEE - ethyl (2-trifluoromethyl-4-fluorophenol) -5-cyclopropyl-1 H-pyrazole-4-carboxylate 72% yield 1 H NMR (400 MHz, DMSO-de) d 7.97 (s, 1 H), 7.93 (dd, J = 8, 3, H), 7.84-7.73 (m, 2H), 4.21 (q, J = 7, 2H ), 1.77 (m, 1 H), 1.26 (t, J = 7, 3H), .75-0.65 (m, 4H). APCIMS 343 [M + 1] + EXAMPLE 19FFF 1- (2-quinolinyl) -5-ethyl-1H-pyrazole-4-carboxylic acid methyl ester 82% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.63 (d, J = 9, 1 H), 8.15 (s, 1 H), .11-8.00 (m, 3 H), 7.86 (m, 1 H), 7.69 (t, J = 9, 1 H), 3.82 (s, 3H), 3.50 (q, J = 7, H), 1.33 (t, J = 7, 3H). APCIMS 282 [M + 1] + EXAMPLE_19GGG 1- (2-chloro-5-hydroxycarbonylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carboxylate ethyl 89% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.11 (dd, J = 2.1, 8, 1 H), 8.06 (d, J = 1.8, 1 H), 8.040 (s, 1 H), 7.88 (d, J = 8, 1 H), 4.25 (q, J = 7, 2H), 1.87 (m, 1H), 1.30 (t, J = 7, 3H), 0.800-0.74 (m, 2H), 0.70-0.64 (m , 2H). APCIMS 335 [M + 1] + EXAMPLE 19HHH 1 - (4-benzimidazoliQ-5-cyclopropyl-1 H-pyrazole-4-carboxylate ethyl) 60% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.28 (s, 1 H), 8.01 (sa, 1H), 7.72 (s, 1 H), 7.38-7.33 (m, 2H), 4.26 (q, J = 7 , 2H), 2.02 (m, 1 H), 1.31 (t, J = 7, 3H), 0.56-0.48 (m, 4H). APCIMS 297 [M + 1] + EXAMPLE 19111 1- (2-Chloro-5-vodophenyl) -5-cyclopropyl-1 H-pyrazole-4-carboxylate ethyl 79% yield H NMR (300 MHz, DMSO-d6) d 8.06 (s, 1H), 7.93 (d, J = 1.5, 1H), 7.76 (dd, J = 1.5, 8, 1H), 7.15 (d, J = 8, 1H), 4.33 (q, J = 7.2, 2H), 1.88 (m, 1H), 1.39 (t, J = 7.5, 3H), 0.91-0.76 (m, 4H). APCIMS 417 [M + 1] + EXAMPLE 19JJJ ethyl 1-phenyl-4-cyclopropyl-1-pyrrazole-3-carboxylate 76% yield APCIMS 269 [M-1] "1 H NMR (300 MHz, DMSO-d 6) d 8.92 (s, 1 H), 7.87-7.84 (m, 2 H), 7.49 (t, J = 8, 2 H), 7.33 (t, J = 7.5, 1 H), 4.28 (q, J = 7, 2H), 2.54 (m, 1 H), 1.32 (t, J = 7, 3H), 1.00-0.91 (m, 4H).

EXAMPLE 19KKK 1 - ethyl (2-chloro-5-methoxyphenyl) -5-cyclopropyl-1-t-pyrazole-4-carboxylate 70% yield APCIMS 321 [M + 1] + 1 H NMR (300 MHz, CDCl 3) d 8.07 (s, 1 H), 7.44 (d, J = 9, 1 H), 7.01 (m, 1 H), 6.69 (d, J = 3, 1 H), 4.34 (q, J = 7, 2H), 1.94 (m, 1 H), 1.40 (t, J = 7, 3H), 0.82 (sa, 4H).

EXAMPLE 19LLL 1- (1-Isoquinolyl) -5-cyclopropyl-1-pyrazole-4-carboxylate ethyl % yield APCIMS 308 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 8.51 (d, J = 6, 1 H), 8.13 (d, J = 8, 1 H), 8.08 (d, 6, 1 H), 8.07 (s, 1 H), 7.85 (t, J = 9, 1 H), 7.67 (t, J = 8, 1 H), 7.44 (d , J = 8, 1 H), 4.23 (q, J = 7, 2H), 1.96 (m, 1 H), 1.27 (t, J = 7, 3H), 0.62-0.56 (m, 2H), 0.47- 0.41 (m, 2H).

EXAMPLE 19MMM methyl 5-butyl-1- (5-quinolinyl) -1H-pyrazole-4-carboxylate 93% yield APCIMS 310 [M + 1] + 1 H NMR (300 MHz, CDCl 3) d 9.01 (m, 1 H), 8.31 (d, J = 8, 1 H), 8.16 (s, 1 H), 7.85 (t, J = 8, 1H), 7.61 (m, 2H), 7.44 (dd, J = 9, 4, 1H), 3.91 (s, 3H), 2.79 (sa, 2H), 1.37 (quintuplete, J = 8, 2H), 1.15 (quintuplet, 2H), 0.69 (t, J = 7, 3H).

EXAMPLE 19NNN 5-isopropyl-1- (6-quinolinyl) -1-pyrazole-4-carboxylic acid ethyl ester 81. 1% yield 1 H NMR (DMSO-de) d 1.27 (d + t, 9 H), 3.17 (m, 1 H), 4.23 (q, 2 H), 7.63 (q, 1 H), 7.75 (dd, 1 H), 8.01 (s, 1H), 8.11 (d, 1H), 8.15 (d, 1H), 8.48 (dd, 1H), 8.98 (q, 1H).

EXAMPLE 19OOO ethyl 5-propy1- (6-quinolinyl) -1H-pyrazole-4-carboxylate 91. 5% yield H NMR (DMSO-de) d 0.69 (t, 3H), 1.26 (t, 3H), 1.42 (q, 2H), 2.93 (t, 2H), 4.22 (q, 2H), 7.61 (q, 1 H), 7.82 (dd, 1 H), 8.04 (s, 1 H), 8.16 (d + s, 2H), 8.47 (d, 1 H), 8.98 (q, 1 H).

The title compounds of Examples 20A-20G were prepared using procedures analogous to that described by Bajnatí, A .; Hubert-Habart, M. Bull. Soc. Chim. Fr. 1988, 540, and example 12A.

EXAMPLE 20A 1- (2,3-dimethoxyphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid n-butyl ester 33% yield 1 H NMR (400 MHz, CDCl 3) d 0.93 (m, 3 H), 1.43 (m, 2 H), 1.68 (t, 6.8, 2 H), 2.58 (s, 3 H), 3.68 (s, 3 H), 3.89 (s, 3H), 4.23 (m, 2H), 6.87 (m, 1 H), 7.11 (m, 1H), 7.23 (s, 1H), 7.28 (m, 1 H), 8.45 (s, 1H) . APCIMS 319 [M + 1] + EXAMPLE 20B 1- (naphthalen-2-yl) -3-methyl-1 / - / - pyrazole-4-carboxylic acid n-butyl ester 24% yield 1 H NMR (400 MHz, CDCl 3) d 0.96 (m, 3 H), 1.46 (m, 2 H), 1.72 (m, H), 2.57 (s, 3 H), 4.26 (m, 2 H), 7.49 ( m, 2H), 7.78-7.94 (m, 4H), 8.10 (s, 1H), 8.44 (s, 1 H). APCIMS 309 [M + 1] + EXAMPLE 20B 1- (O-Biphenyl) -3-methyl-1H-pyrazole-4-carboxylic acid n-butyl ester 75% yield 1 H NMR (400 MHz, CDCl 3) d 0.88 (t, J = 7.6, 3 H), 1.33 (m, 2 H), 1.56 (m, 2 H), 2.47 (s, 3 H), 4.10 (m, 2 H) ), 7.10 (m, 2H), 7.26 (m, 3H), 7.42 (m, H), 7.57 (m, 1 H). APCIMS 335 [M + 1] + EXAMPLE 20D 1-phenyl-3-tyl-1 t'-pyrazole-4-carboxylic acid n-butyl ester 36% yield 1 H NMR (400 MHz, CDCb) d 0.95 (t, J = 7.8, 3H), 1.29 (t, J = 7.6, 3H), 1.43 (m, 2H), 1.68 (m, 2H), 2.95 (q, J = 7.6, 2H), 4.24 (t, J = 6.4, 2H), 7.27 (m, 1 H), 7.42 (m , 2H), 7.65 (m, 2H), 8.31 (s, 1 H). APCIMS 273 [M + 1f EXAMPLE 20E 1 - (2,1, 3-benzothiadiazol-4-yl) -3-methyl-1-f7-pyrazole-4-carboxylic acid n-butyl ester % yield 1 H NMR (400 MHz, CDCb) d 0.97 (t, J = 7.2, 3H), 1.46 (m, 2H), 1.74 (m, 2H), 2.58 (s, 3H), 4.28 (t, J) = 6.8, 2H), 7.68 (t, J = 8.6 1 H), 7.92 (d, J = 8.8, 1H), 8.21 (d, J = 7.2, 1 H), 9.53 (s, 1 H). APCIMS 217 [M + 1] + EXAMPLE 20F 1-fndazol-7-yl) -3-methyl-1H-pyrazole-4-carboxylic acid n-butyl ester % yield 1 H NMR (400 MHz, CDCb) d 0.90 (t, J = 7.4, 3 H), 1.40 (m, 2 H), 1.64 (m, 2 H), 2.83 (s, 3 H), 4.19 (t, J = 6.4, 2H), 7.17 (t, J = 7.6, 1H), 7.72 (d, J = 7.6, 1 H), 8.18 (s, 1 H), 9.03 (s, 1 H), 13.13 (sa, 1 H). APCIMS 299 [M + 1] + EXAMPLE 20G 1-benzyl-3-methyl-1A-pyrazol-4-carboxylic acid n-butyl ester 68% yield 1 H NMR (400 MHz, CDCb) d 0.93 (t, J = 7.2, 3H), 1.40 (m, 2H), 1.66 (m, 2H), 2.45 (s, 3H), 4.19 (t, J) = 6.6, 2H), 5.2 (s, 2H), 7.20-7.24 (m, 2H), 7.32-7.36 (m, 3H), 7.77 (s, 1H). APCIMS 273 [M + 1] + EXAMPLE 21 Ethyl 5-cyclopropyl-1- (2-pyrrol-1-ylphenyl -) - 1 H-pyrazole-4-carboxylate Stirred under H 2 atmosphere (50 psig) for 3 h, a mixture of ethyl 5-cyclopropyl-1- (2-nitrophenyl-) - 1 H-pyrazole-4-carboxylate (2.5 g, 8.3 mmol) and Pd / C (10%, 0.550 g, 20% w / w) in ethyl acetate (60 ml). The resulting mixture was filtered through Celite® and concentrated in vacuo affording 2.52 g of a reddish oil. A portion of the residue (458.5 mg, 1.69 mmol) and 2,5-dimethoxytetrahydrofuran (0.328 ml, 2.53 mmol) in glacial acetic acid (6 ml) was heated at 110 ° C under N2 atmosphere for 1 h. The reaction mixture was cooled to 23 ° C and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed twice with NaHCO 3 (sol aq sat) and brine, dried over MgSO 4, and filtered. The filtrate was passed through a short column of silica gel. The eluate was concentrated in vacuo yielding 0.4695 g (91%) of the title compound as a dark oil. APCIMS 322 [M + 1] + 1 H NMR (400 MHz, CDCb) d 0.35-0.80 (m, 4H), 1.01 (m, 1 H), 1.36 (t, J = 9.4, 3H), 4.30 (q, J) = 8.8, 2H), 7.42-7.61 (m, 4H), 8.08 (s, 1 H).

EXAMPLE 22A 5-Cyclopropyl-1- (2-chloro-5-. {Dimethylaminosulfonyl > phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester A mixture of ethyl 5-cyclopropyl-1- (2-chloro-5- ({-hydroxysulfonyl}. Phenyl) -1H-pyrazole-4-carboxylate (1.48 g) was heated at 95 ° C for 30 min., 4.0 mmol) and PCI5 (1.76 g, 8.6 mmol) in POCI3 (6 ml) under nitrogen atmosphere, cooled to 23 ° C and poured slowly onto ice. The resulting mixture was extracted with AcOEt. The organic layer was washed three times with cold water, brine, dried over MgSO 4, filtered and concentrated in vacuo affording 1.48 g (95% yield) of 5-cyclopropyl-1- (2-chloro-5-. {Chlorosulfonyl.} phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester as a yellow oil. A solution of ethyl 5-cyclopropyl-1- (2-chloro-5-. {-chlorosulfonylphenyl}. -1H-pyrazole-4-carboxylate (0.315 g, 0.812 mmol) in CHCl2 (3 ml) was treated with 23 ° C with dimethylamine (2 M in THF, 3 mL, 6 mmol) The resulting mixture was stirred for 15 min and concentrated in vacuo The residue was purified by flash chromatography 40S ™ (65:35 hexanes-AcOEt) affording 0.276 g (86% yield) of the desired product as a colorless oil APCIMS 397 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 0.68 (d, J = 5.6, 2H), 0.81 (d, J = 8.4, 2H), 1.35 (t, J = 7.2, 3H), 1.83 (m, 1 H), 2.74, (s, 6H), 4.30 (q, J = 7.2, 2H), 7.70-7.25 (m, 1 H), 7.80-7.83 (m, 2H), 8.04 (s, 1 H).

The title compounds of Examples 22B-2E were prepared using procedures analogous to that used for Example 22A.

EXAMPLE 22B 5-cyclopropyl-1- (2-chloro-5-aminosulfonyl > phenyl) -1-pyrazole-4-carboxylate ethyl 58% APCIMS yield 368 [M-1] "1 H NMR (400 MHz, CDCb) d 0.73 (s, 2H), 0.84 (d, J = 5.6, 2H), 1.37 (t, J = 7.2, 3H), 1.85 (m, 1 H), 4.31 (q, J = 7.2, 2H), 7.69 (d, J = 7.2, 1H), 7.96 (m, 2H), 8.06 (s, 1H).

EXAMPLE 22C 5-Cyclopropyl-1- (2-chloro-5- (methylaminosulfonyl.) Phenyl) -1 / - / - pyrazole-4-ethyl carboxylate 97% yield APCIMS 368 [M + 1f 1 H NMR (400 MHz, CDCl 3) d 0.72 (s, 2 H), 0.86 (d, J = 8, 2 H), 1.37 (t, J = 7.2, 3 H), 1.85 (m, 1 H ), 2.70 (s, 3H), 4.32 (q, J = 7.2, 2H), 7.71 (d, J = 9.2, 1H), 7.90-7.93 (m, 2H), 8.06 (s, 1H).

EXAMPLE 22D 5-Cyclopropyl-1- (2-chloro-4-fmethylaminosulfonyl > phenyl) -1-L-pyrazole-4-ethyl carboxylate 100% performance APCIMS 397 [M + 1] + 1 H NMR (400 MHz, CDCb) d 0.67 (br s, 2 H), 0.82 (d, J = 6.4, 2 H), 1.35 (t, J = 7.2, 3 H), 1.85 (m, 1 H), 2.76 (s, 6H), 4.32 (q, J = 7.2, 2H), 7.57 (d, J = 8.4, 1 H), 7.78 (dd, J = 8.4, 2.0, 1 H), 7.94 ( s, 1 H), 8.05 (s, 1 H).

EXAMPLE 22E 5-Cyclopropyl-1- (2-chloro-4-Cmethylaminosulfonyl) phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester 93% yield APCIMS 384 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.58-0.61 (m, 2H), 0.73-0.78 (m, 2H), 1.35 (t, J = 6.8, 3H), 1.85 ( m, 1 H), 2.47 (s, 6H), 4.21 (q, J = 7.2, 2H), 7.77 (dd, J = 9.6, 4.8, 1H), 7.88 (s, 1H), 8.03 (d, J = 3.5, 1 H). The title compounds of Examples 23A-23B were prepared using analogous procedures to that described by Kíkugawa, Y. Synthesis, 1981, 124.

EXAMPLE 23A methyl 1 - (1-methylbenzimidaz-2-yl) -5-ethyl-1-t-pyrazole-4-carboxylate 61% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.23 (s, 1 H), 7.78-7.69 (m, 2 H), 7. 45-7.32 (m, 2H), 8.83 (s, 3H), 3.72 (s, 3H), 3.04 (q, J = 7, 2H), 1.14 (t, J = 7, 3H). APCIMS 285 [M + 1] + EXAMPLE 23B methyl 5-ethyl-1- (1-methylbenzimidazol-6-yl) -1 A7-pyrazole-4-carboxylate % yield APCIMS 284 [M + 1] + 1 H NMR (300 MHz, CDCl 3) d 1.03 (t, J = 7.35, 3H), 2.87 (q, J = 7. 352H), 3.80 (s, 3H), 3.88 (s, 3H), 7.26-7.30 (m, 1 H), 7.78-7.81 (m, 2H), 8.02 (s, 1H), 8.36 (s, 1H).

EXAMPLE 24 Ethyl 5-cyclopropyl-1- (2-methylsulfonylphenyl) -1 H-pyrazole-4-carboxylate A solution of ethyl 5-cyclopropyl-1- (2-methyl-thiophenyl) -1-pyrazole-4-carboxylate (0.456 g, 1.51 mmol) in methanol (6 ml) was treated at 0 ° C with an aqueous solution of sodium (1.40 g, 2.27 mmol) in water (6 ml). The resulting suspension was stirred at 23 ° C for 18 h. The mixture was treated with additional sodium peroxide (0.46 g, 0.76 mmol), stirred for 14 h and partitioned between CH2Cl2 and water. The organic layer was washed with water, dried over MgSO4 and concentrated in vacuo affording 0.504 g (100%) of the title compound. APCIMS 335 [M + 1] + 1 H NMR (400 MHz, CDCl 3) d 8.23 (dd, J = 8.2, 1 H), 8.03 (s, 1 H), 7.77 (t, J = 8, 1 H), 7.71 (t, J = 8, 1 H), 4.43 (d, J = 7, 1 H), 4.30 (q, J = 7, 2H), 3.27 (s, 3H), 1.81 (m, 1 H), 1.36 (t, J = 7, 3H), 0.4-1.0 (sa, 4H).

EXAMPLE 25 ethyl 5-cyclopropyl-1- (2-methylaminosulfonylphenyl) -1 / -pyrazol-4-carboxylate and (example 25A) 5-cyclopropyl-1- (2-dιmethylaminosulfonylphenyl) -1H-pyrazole-4-carboxylate of ethyl (Example 25B) A solution of ethyl 5-cyclopropyl-1- (2-aminosulfonylphenyl) -1 / - -p-acetic acid-4-carboxylate (0.503 g, 1.50 mmol) in dry DMSO (5 ml) at 23 ° C was treated. with NaH (60% in mineral oil, 0.090 g, 2.25 mmol) and stirred for 1.5 h. The resulting mixture was treated with dimethyl sulfate (0.213 ml, 2.25 mmol), stirred for 20 h and partitioned between AcOEt and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography 40M ™ (hexanes-AcOEt 60:40 to 50:50) to afford 0.141 g (27%) of Example 25A and 0.231 g (42%) of Example 25B.

EXAMPLE 25A 5-cyclopropyl-1- (2-methylaminosulfonylphenyl) -1 H-pyrazole-4-carboxylate ethyl APCIMS 350 [M + 1] + 1 H NMR (400 MHz, CDCb) d 8.13 (dd, J = 8, 1.4, 1 H), 8.04 (s, 1 H), 7.71 (t, J = 8, 1.6, 1 H), 7.65 (t, J = 8, 1.6, 1 H), 7.44 (dd, 8, 1.2, 1 H), 5.93 (q, J = 5, 1 H), 4.31 (q, J = 7, 2H ), 2.65 (d, J = 5, 3H), 1.82 (m, 1 H), 1.36 (t, J = 7, 3H), 0.4-1.1 (m, 4H).

EXAMPLE 25B 5-cyclopropyl-1- (2-dimethylaminosulfonylphenyl) -1 H-pyrazole-4-carboxylic acid ethyl ester APCIMS 364 [M + 1] + 1 H NMR (400 MHz, CDC b) d 8.07 (dd, J = 7, 2, 1 H), 8.00 (s, 1 H), 7.68 (m, 2 H), 7.35 (dd, J = 7, 2, 1 H), 4.29 (q, J = 7, 2H), 2.67 (s, 6H), 1.88 (m, 1H), 1.36 (t, J = 7, 3H), 0.64-0.93 ( m, 4H).

EXAMPLE 26A 1- (2-chloro-5-methylaminocarbonylphenyl) -5-cyclopropyl-1 y-pyrazole-4-carboxylic acid ethyl ester A solution of ethyl 1- (2-chloro-5-hydroxycarbonyl-phenyl) -5-cyclopropyl-1-pyrrazo-4-carboxylate (1.32 g, 3.73 mmol) in thionyl chloride (7.5 ml) was heated to reflux for 2 h under nitrogen atmosphere. The resulting solution was concentrated in vacuo. A solution of the residue in anhydrous CH 2 Cl 2 (10 mL) under nitrogen atmosphere was treated with methylamine (2 M solution in THF, 9.33 mL, 18.7 mmol) followed by a catalytic amount of 4-dimethylamine pyridine. The resulting mixture was stirred for 6 h and partitioned between ethyl acetate and HCl (1 M ac). The organic layer was washed with brine, NaHCO 3 (sol aq sat), and brine, dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified by 40M ™ flash chromatography (75:25 ethyl / hexanes) affording 1.00 g (77% yield) of the title compound. 1 H NMR (300 MHz, CDC b) d 8-08 (s, 1 H), 7.88 (dd, J = 2, 8, 1 H), 7.81 (d, J = 2, 1 H), 7.63 (d, J = 9, 1 H), 6.40 (sa, 1 H), 4.33 (q, J = 7, 2H), 3.02 (d, J = 4, 3H), 1.89 (m, 1H), 1.40 (t, J = 7, 3H), 0.92-0.75 (m, 4H). APCIMS 348 [M + 1] + The title compounds of Examples 26B-26C were prepared using procedures analogous to that used for Example 26A.

EXAMPLE 26B 1- (2-chloro-5-dimethylaminocarbonylphenyl) -5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester 45% yield 1 H NMR (300 MHz, CDCb) d 8.07 (s, 1 H), 7.59 (d, J = 6, 1 H), 7.52 (dd, J = 2, 6, 1 H), 7.48 (d , J = 2, 1 H), 4.33 (q, J = 7, 2H), 3.12 (sa, 3H), 3.05 (sa, 3H), 1.88 (m, 1 H), 1.39 (t, J = 7, 3H), 0.94-0.80 (m, 4H). APCIMS 362 [M + 1] + EXAMPLE 26C 1 - (2-chloro-5-aminocarbonylphenyl) -5-cyclopropyl-1-7-pyrazole-4-carboxylic acid ethyl ester 27% yield 1 H NMR (300 MHz, CDCb) d 8.17 (s, 1 H), 8.10-8.07 (m, 2 H), 8.05 (s, 1 H), 7.85 (d, J = 9, 1 H), 7.67 (s, 1 H), 4.25 (q, J = 7, 2H), 1.88 (m, 1 H), 1.30 (t, J = 7, 3H), 0.81-0.74 (m, 2H), 0.70-0.63 ( m, 2H). APCIMS 334 [M + 1] + The title compound of Example 27 was prepared using a procedure analogous to that used for Example 13A.

EXAMPLE 27 5-Ethyl-1- (benzothiazol-6-yl) -1-t-pyrazole-4-carboxylic acid 78% APCIMS yield 272 [M-1T 1 H NMR (DMSO-de) d 0.96-1.02 (t, 3H), 7.81 (s, 1 H) The title compounds of examples 28A-28RRR were prepared using an analogous procedure to that used for example 14A.

EXAMPLE 28A 5-Cyclopropyl-1- (2,3-dimethoxyphenyl) -1H-pyrazole-4-carboxylic acid 83% yield 1 H NMR (400 MHz, CDCb) d 0.68 (d, J = 8.4, 4H), 1.83 (m, 1 H), 3. 54 (s, 3H), 3.85 (s, 3H), 6.94 (d, J = 7.6, 1 H), 7.19 (m, 2H), 7.87 (s, 1 H), 12.26 (s, 1 H). APCIMS 287 [M-11] - EXAMPLE 28B 3-Methyl-1- (2,3-dimethoxyphenyl) -1 - / - pyrazole-4-carboxylic acid 81% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.38 (s, 3 H), 3.64 (s, 3 H), 3.84 (s, 3 H), 7.14 (m, 3 H), 8.41 (s, 1 H) , 12.41 (s, 1 H). APCIMS 261 [M-1] - EXAMPLE 28C 5-Cyclopropyl-1- (naphthalen-1 -yl) -1H-pyrazole-4-carboxylic acid 87% yield 1 H NMR (400 MHz, DMSO-d 6) d 0.56 (d, J = 7.2, 4 H), 1.82 (m, 1 H), 7.12 (d, J = 7.6, 1 H), 7.58 (m, 4H), 8.10 (m, 3H), 12.38 (s, 1 H). APCIMS 279 [M + 1] + EXAMPLE 28D 5-Cyclopropyl-1- (naphthalen-2-yl) -1H-pyrazole-4-carboxylic acid 91% yield 1 H NMR (400 MHz, DMSO-d 6) d 0.48 (m, 2 H), 0.80 (m, 2 H), 2.15 (m, 1 H), 7.58 (m, 2 H), 7.71 (m, 1 H) , 8.01 (m, 4H), 8.16 (s, 1 H), 12.35 (s, 1H). APCIMS 277 [M-1] 'EXAMPLE 28E 3-Methyl-1 - (naphthalen-2-yl) -1 H- acid? razol -4-carboxyl ico 91% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.50 (s, 3 H), 7.57 (m, 2 H), 8.06 (m, 4 H), 8.43 (s, 1 H), 9.04 (s, 1 H) ). APCIMS 251 [M-1] ' EXAMPLE 28F 3-Methyl-1- (2-biphenyl) -1 / Y-pyrazole-4-carboxylic acid 87% yield 1 H NMR (400 MHz, DMSO-d 6) d 2.28 (s, 3 H), 7.05 (m, 2 H), 7.27 (m, 3 H), 7.45-7.54 (m, 4 H), 7.72 (s, 1 H). APCIMS 277 [M-1] " EXAMPLE 28G 5-Cyclopropyl-1- (o-biphenyl) -1H-pyrazole-4-carboxylic acid 75% yield 1 H NMR (400 MHz, DMSO-d 6) d 0.44 (m, 4 H), 1.04 (m, 1 H), 6.98 (m, 2 H), 7.25 (m, 3 H), 7.44-7.62 (m, 4H), 7.85 (s, 1 H), 12.14 (s, 1 H). APCIMS 303 [M-1] "EXAMPLE 28H 3-Methyl-1-phenyl-1 H -pyrazole-4-carboxylic acid 88% yield 1 H NMR (400 MHz, DMSO-d6) d 1.18 (t, J = 6.3, 3H), 2.82 (q, J = 7.2, 2H), 7.28 (t, J = 7.2, 1 H), 7.44 (m, 2H), 7.84 (m, 2H), 8.84 (s, 1 H), 12.43 (s, 1H). APCIMS 215 [M-1] - EXAMPLE 28! 5-Cyclopropyl-1 - (2-nitrophenyl) -1-f pyrazole-4-carboxylic acid 89% yield 1 H NMR (400 MHz, DMSO-d 6) d 0.58 (m, 2 H), 0.77 (m, 2 H), 1.94 (m, 1 H), 7.79 (m, 1 H), 7.91 (m, 2 H) ), 8.13 (d, J = 7.6, 1 H), 12.48 (s, 1 H). APCIMS 273 [M-1] ' EXAMPLE 28J 5-Cyclopropyl-1- (2-pyrrol-1-phenyl) -1 H -pyrazole-4-carboxylic acid 95% yield 1 H NMR (400 MHz, DMSO-d 6) d 0.41-0.62 (m, 4H), 1.04 (m, 1 H), 6.13 (m, 2H), 6.52 (m, 2H), 7.50-7.71 ( m, 4H), 7.89 (s, 1 H).

APCIMS 292 [M-1] ~ EXAMPLE 28K 5-Cyclopropyl-1- (2-ethylphenyl) -1-pyrazole-4-carboxylic acid 73% yield 1 H NMR (400 MHz, CDCl 3) d 0.78 (dd, J = 8.4, 1.6, 2H), 0.88 (m, H), 1.09 (dt, J = 7.6, 1.2, 3H), 1.84 (m, 1 H), 2.37 (q, J = 7.6, 2H), 7.24 (m, H), 7.40 (m, 2H), 8.0 7 (s, 1 H). APCIMS 255 [M-1] - EXAMPLE 28L 5-Cyclopropyl-1- (2-methylphenyl) -1 H-pi-4-carboxylic acid 1 H NMR (400 MHz, CDC b) d 0.8-0.89 (m, 4 H), 1.87 (m, 1 H), 2.09, 3 H), 7.2-7.5 (m, 4 H), 8.10 (s, 1 H). APCIMS 241 [M-1] " EXAMPLE 28M 5-Cyclopropyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxylic acid 55% APCIMS yield 261 [M + 1] + 1 H NMR (400 MHz, CDCb) d 0.84 (sa, 4H), 1.95 (m, 1H), 7.41-7.52 (m, 3H), 7.58 (dd, J = 9.4, 2.2, 1 H), 8.15 (s, 1 H).

EXAMPLE 28N 5-Cyclopropyl-1- (2-trifluoromethoxyphenyl) -1 fY-pyrazole-4-carboxylic acid 100% APCIMS yield 311 [M-1] '1 H NMR (400 MHz, DMSO-d 6) d 0.56 (d, J = 5.6, 2H), 0.71 (dd, J = 8.4, 4.4, 2H), 1.78 (m , 1 H), 7.5-7.7 (m, 4H), 7.93 (s, 1 H), 12.38 (s, 1H).

EXAMPLE 280 5-Cyclopropyl-1- (2-fluorophenyl) -1H-pyrazole-4-carboxylic acid 84% APCIMS yield 245 [M-1j ~ 1 H NMR (400 MHz, DMSO-d 6) d 0.56 (m, 2 H), 0.72 (m, 2 H), 1.85 (m, 1 H), 7.35 (m, 1 H) , 7.45 (m, 1 H), 7.58 (m, 2H), 7.92 (s, 1 H).

EXAMPLE 28P 3-Methyl-1- (2,1, 3-benzothiadiazol-4-yl) -1 H-pyrolyl-4-carboxylic acid 79% APCIMS yield 259 [M-1] "1 H NMR (400 MHz, DMSO-d 6) d 2.47 (s, 3 H), 7.82 (m, 1 H), 8.05 (dd, J = 8.4, 2.8, 1 H), 8.15 (dd, J = 7.6, 2.8, 1H), 9.41 (s, 1 H), 12.63 (s, 1H).

EXAMPLE 28Q 5-Cyclopropyl-1 - (indazol-7-yl) -1-pyrazole-4-carboxylic acid 78% APCIMS yield 267 [M-1] "1 H NMR (400 MHz, DMSO-d 6) d 0.47-0.51 (m, 2 H), 0.61-0.66 (m, 2 H), 1.96 (m, 1 H), 7.20 (t, J = 7.6, 1 H), 7.45 (d, J = 7.6, H), 7.87 (d, J = 8.0, 1 H), 7.99 (s, 1 H), 8.19 (s, 1 H).

EXAMPLE 28R 3-Methyl-1 - (indazol-7-yl) -1H-pyrazole-4-carboxylic acid 79% yield APCIMS 241 [M-1] "1 H NMR (400 MHz, DMSO-d 6) d 2.51 (s, 3 H), 7.17 (t, J = 8.0, 1 H), 7.73 (d, J = 8.0, 1 H), 7.81 (d, J = 7.6, 1 H), 8.22 (S, 1 H), 9.03 (sa, 1 H).

EXAMPLE 28S 5-Ethyl-1- (benzothiazol-2-yl) 1 H -pyrazole-4-carboxylic acid 84% yield APCIMS 272 [M-1] "1 H NMR (400 MHz, DMSO-d 6) d 1.25 (t, J = 6.8, 3 H), 3.61 (q, J = 6.8, 2 H), 7.41-7.53 (m, 2 H), 7.92 (d, J = 8.4, 1 H), 8.08 (s, 1 H).

EXAMPLE 28T 5-Cyclopropyl-1- (2-chloro-4- (methylsulfonyl) phenyl) -1A / -pyrazole-4-carboxylic acid 98% yield APCIMS 339 [M-1] "1 H NMR (400 MHz, DMSO-d 6) d 0.68-0.70 (m, 2 H), 0.76-0.79 (m, 2 H), 1.87 (m, 1 H), 3.34 (s, 3 H ), 7.95-8.10 (m, 3H), 8.29 (s, 1H).

EXAMPLE 28U 5-Cyclopropyl-1- (2-chloro-4- (methylsulfonylmethylenesulfonyl) phenyl) -1H-pyrazole-4-carboxylic acid 78% yield APCIMS 417 [M-1] - 1 H NMR (400 MHz, DMSO-d 6) d 6.63 (m, 2 H), 0.73-0.79 (m, 2 H), 1.88 (m, 1 H), 3.27 (s, 3 H), 7.99-8.16 (m, 3H), 8.30 (s, 1 H).

EXAMPLE 28V 5-Cyclopropyl-1- (2-chloro-5- (dimethylaminosulfonyl) phenyl) -1 Y-pyrazole-4-carboxylic acid 82% yield APCIMS 368 [M-1] '1 H NMR (400 MHz, DMSO-d 6) d 0.61 (d, J = 2.0, 2 H), 0.72 (d, J = 7.6, 2 H), 1.86 (m, 1 H), 2.63 (s, 6H), 7.92-8.01 (m, 3H), 12.44 (s, 1 H).

EXAMPLE 28W 5-Cyclopropyl-1 - (2-chloro-5-faminosulfonyl > phenyl) -1-p-pyrazol-4-carboxylic acid 82% yield APCIMS 368 [M-1] "H NMR (400 MHz, DMSO-d6) d 0.65 (s, 2H), 0.75 (d, J = 8.0, H), 1.84 (m, 1 H), 7.61 (s) , 1 H), 7.92-7.98 (m, 2H), 12.47 (s, 1 H).

EXAMPLE 28X 5-Cyclopropyl-1 - (2-chloro-5-p-methylaminosulfonyl.) Phenol) -1 H -pyrazole-4-carboxylic acid 75% yield APCIMS 354 [M-1] '1 H NMR (400 MHz, DMSO-d 6) d 0.62 (s, 2 H), 0.73 (d, J = 8.0, H), 1.86 (m, 1 H), 2.43 (d, J = 2.8, 3H), 7.67 (d, J = 4.8 1 H), 7.92-7.98 (m, 3H), 2.47 (s, 1 H).

EXAMPLE 28 AND 5-Cyclopropyl-1- (2,5-dichlorophenyl) -1,5-pyrazole-4-carboxylic acid 97% yield APCIMS 295 [M-1T 1 H NMR (400 MHz, DMSO-d 6) d 0.62-0.64 (m, 2H), 0.70-0.74 (m, H), 1.82 (m, 1H), 7.65 (dd, J = 8.8, 2.4, 1H), 7.72 (d, J = 8.4, 1H), 7.85 (d, J = .4 1H), 7.93 (s, 1H).

EXAMPLE 28Z 5-Cyclopropyl-1- (2,4-dichlorophenyl) -1 H -pyrazole-4-carboxylic acid 94% yield APCIMS 295 [M-1] "1 H NMR (400 MHz, DMSO-d 6) d 0.64-0.65 (m, 2H), 0.71-0.74 (m, H, 1.83 (m, 1H), 7.60-7.68 (m, 3H ), 7.92 (s, 1H), 12.41 (s, 1 H).

EXAMPLE 28AA-5-C-Clopropyl-1- (2,3-dichlorophenyl) -1-p-aceol-4-carboxylic acid 91% yield APCIMS 295 [M-1p 1 H NMR (400 MHz, DMSO-d 6) d 0.65 (s, 2 H), 0.73 (s, 2 H), 1.83 (m, 1 H), 7.53 (t, J = 8.0, 1 H). , 7.63 (dd, J = 8.0, 1.6, 1 H), 7.86 (dd, J = 8.0, 1.2, 1H), 7.96 (s, 1 H), 12.41 (s, 1 H).

EXAMPLE 28BB 5-Cyclopropyl-1- (2-chloro-5-methylsulfonylphenyl) -1A-pyrazole-4-carboxylic acid 77% yield APCIMS 339 [M-1] - 1 H NMR (400 MHz, DMSO-d 6) d 0.61-0.63 (m, 2H), 0.71 (d, J = 6.8, 2H), 1.83 (m, 1 H), 3.29 (s) , 3H), 7.97-8.09 (m, 3H), 8.18 (s, 1 H), 12.44 (s, 1 H).

EXAMPLE 28CC 5-Ethyl-1- (benzimidazol-5-yl) -1 f / -pyrazole-4-carboxylic acid 82% yield APCIMS 255 [M-1] - 1 H NMR (400 MHz, DMSO-d 6), d 0.97 (t, J = 7.2, 3 H), 2.84 (q, J = .2, 2 H), 7.21 (d, J = 8.4 , 1 H), 7.65-7.69 (m, 2H), 7.88 (s, 1 H), 8.33 (s, 1 H).

EXAMPLE 28DD 5-Cyclopropyl-1- (2-chloro-4- (dimethylaminosulfonylphenyl) -1,5-pyrazole-4-carboxylic acid 92% yield APCIMS 368 [M-1] - 1 H NMR (400 MHz, DMSO-d 6) d 0.60-0.63 (m, 2H), 0.80-0.82 (m, H), 1.80 (m, 1 H), 2.68 (s, 6H ), 7.70 (s, 1 H), 7.78-7.97 (m, 2H), 7.97 (s, 1 H).

EXAMPLE 28EE 5-Cyclopropyl-1- (2-chloro-4- (methylaminosulfonyl) phenyl) -1H-pyrazole-4-carboxylic acid 84% yield APCIMS 354 [M-1] "H NMR (400 MHz, DMSO-d6) d 0.63 (d, J = 4.8, 2H), 0.73 (d, J = 8.4, 2H), 1.84 (m, 1H), 247 ( s, 3H), 7.76 (t, J = 4.6, 1H), 7.88 (s, 1H), 8.00 (d, J = 15.2, 1 H), 12.42 (s, 1 H).

EXAMPLE 28FF 5-Cyclopropyl-1 - (benzimidazol-5-yl) -1H-pyrazole-4-carboxylic acid 59% yield APCIMS 267 [M-1] "H NMR (400 MHz, DMSO-d6), d 0.50-0.54 (m, 2H), 0.71-0.76 (m, 2H), 2.05 (m, 1H), 7.33 (dd, J = 9.4, 1.8, 1H), 7.66 (d, J = 8.4, 1H), 7.73 (s, 1H), 7.89 (s, 1H), 8.32 (s, 1H), 12.25 (s, 1H), 12.69 (s) , 1 HOUR).

EXAMPLE 28GG 3-Methyl-1-benzyl-1 AY-pyrazole-4-carboxylic acid 96% yield APCIMS 215 [M-1] - 1 H NMR (400 MHz, DMSO-d 6) d 2.29 (s, 3 H), 5.26 (s, 2 H), 7.25-7.38 (m, 5 H), 8.27 (s, 1 H), 12.18 (sa, 1 H).

EXAMPLE 28HH 5-Ethyl-1- (3-chloroindazol-5-yl) -1H-pyrazole-4-carboxylic acid 85% yield APCIMS 289 [M-1] "1 H NMR (400 MHz, DMSO-d 6) d 0.97 (t, J = 7.2, 3H), 2.83 (q, J = 7.2, 2H), 7.48 (dd, J = 8.8, 1.6 , 1 H), 7.69-7.75 (m, 2H), 7.92 (s, 1 H), 12.41 (s, 1 H), 13.60 (s, 1 H).

EXAMPLE 28II 5-Ethyl-1- (1-methyl-benzimidazol-6-yl) -1 H -pyrrazole-4-carboxylic acid 76% yield APCIMS 269 [M-1] '1 H NMR (400 MHz, DMSO-de) d 0.97 (t, J = 7.6, 3H), 2.86 (q, J = .2 2 H), 3.90 (s, 3H), 7.38 ( dd, J = 8.6, 2.2, 1 H), 7.81-7.93 (m, 3H), 8.75 (s, H).

EXAMPLE 28JJ 5-Ethyl-1 - (2-methyl-benzimidazol-5-yl) -1 / - / - p -razol-4-carboxylic acid 72% yield APCIMS 269 [Ml] '1 H NMR (400 MHz, DMSO-d 6) d 0.97 (t, J = 7.4, 3H), 2.49 (s, 3H), .81 (q, J = 7.4, 2H), 7.38 (d, J = 8.8, 1 H), 7.50-7.55 (m, 2H), 7.88 (s, 1 H), 2.36 (s, 1 H), 12.61 (sa, 1 H).

EXAMPLE 28KK 5-Isopropyl-1- (quinolin-5-yl) -1A / -pyrazole-4-carboxylic acid 90% yield 1 H NMR (400 MHz, DMSO-d 6) d 12.51 (s, 1 H), 8.99 (t, J = 1.6, 1 H), 8.24 (d, J = 8, 1 H), 8.06 (s, 1 H), 7.91 (t , J = 8, 1H), 7.76 (d, J = 7, 1H), 7.58 (dd, J = 8, 4, 1H), 7.47 (d, J = 8, 1H), 2.93 (quintuplet, J = 7 , 1H), 1.15 (m, 6H). APCIMS 282 [M + 1] " EXAMPLE 28LL 1 - (Quinolin-5-yl) -5-n-propyl-1 H -pyrazole-4-carboxylic acid 91% yield 1 H NMR (400 MHz, CDC b) d 9.03 (d, J = 4, 1 H), 8.35 (d, J = 8, 1 H), 8.25 (s, 1 H), 7.86 (t, J = 8, 1 H), 7.66 (d, J = 8, 1H), 7.61 (d, J = 7, 1H), 7.47 (dd, J = 8, 4, 1H), 2.81 (sa, 2H), 1.45 (sextuplete, J = 8, 2H), 0.75 (t, J = 8, 3H). APCIMS 282 [M + 1] + EXAMPLE 28MM 5-Cyclopropyl-1- (2-dimethylaminosulfonylphenyl) -1-7-pyrazole-4-carboxylic acid 88% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.01 (m, 1 H), 7.91 (s, 1 H), 7.84 (m, 2 H), 7.60 (m, 1 H), 2.64 (s, 6 H), 1.81 ( m, 1 H), 0.59-0.77 (m, 4H). APCIMS 336 [M + 1] + EXAMPLE 28NN 5-Cyclopropyl-1- (2-methylsulfonylphenyl) -1H-pyrazole-4-carboxylic acid 79% yield 1 H NMR (300 MHz, DMSO-de) d 8.15 (m, 1 H), 7.83-7.99 (m, 3 H), 7.75 (m, 1 H), 3.34 (s, 3 H), 1.86 (m, 1 H) , 0.5-0.9 (m, 4H). APCIMS 307 [M + 1] + EXAMPLE 28OO 5-Cyclopropyl-1- (2-methylaminosulfonylphenyl) -1H-pyrazole-4-carboxylic acid 70% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.02 (m, 1 H), 7.94 (s, 1 H), 7.73-7.86 (m, 2 H), 7.69 (m, 1 H), 6.88 (q, J = 5 , 1 H), 2.50 (s, 3H), 1.89 (m, 1 H), 0.5-0.9 (m, 4H). APCIMS 322 [M + 1] + EXAMPLE 28PP 5-Cyclopropyl-1- (2,1, 3-benzothiadiazol-4-yl) -1 AY-pyrazole-4-carboxylic acid 91% yield 1 H NMR (400 MHz, CDCl 3) d 8.21 (s, 1 H), 8.14 (dd, J = 7, 3, 1 H), 7.73 (m, 2 H), 2.01 (m, 1 H), 0.68 (m, 2 H) ), 0.61 (m, 2H). APCIMS 287 [M + 1] + EXAMPLE 28QQ 5-Methyl-1- (2,4-difluorophenyl) -1-t-pyrazole-4-carboxylic acid 86% yield 1 H NMR (400 MHz, CDC b) d 8.10 (s, 1 H), 7.43 (m, 1 H), 7.03 (m, 2 H), 2.45 (s, 3 H).

APCIMS 239 [M + 1] 4 EXAMPLE 28RR 5-Cyclopropyl-1- (2-aminosulfonylphenyl) -1 / 7-pyrazole-4-carboxylic acid 93% yield 1 H NMR (400 MHz, DMSO-d 6) d 12.34 (s, 1 H), 8.03 (m, 1 H), 7.93 (s, 1 H), 7.73 (m, 2 H), 7.63 (m, 1 H), 7.18 (s, 2H), 1.85 (m, 1 H), 0.3-0.9 (m, 4H). APCIMS 308 [M + 1] + EXAMPLE 28SS 5-Cyclopropyl-1- (2-methylthiophenyl) -1H-pyrazole-4-carboxylic acid 97% yield 1 H NMR (400 MHz, DMSO-d 6) d 12.27 (s, 1 H), 7.87 (s, 1 H), 7.51 (t, J = 8, 1 H), 7.41 (d, J = 8, 1 H) , 7.34 (d, J = 8, 1 H), 7.27 (t, J = 7, 1H), 2.36 (s, 3H), 1.83 (m, 1 H), 0.65 (m, 4H). APCIMS 275 [M + 1] + EXAMPLE 28TT 5-Methyl-1- (6-quinolinyl) -1-pyrazole-4-carboxylic acid 84. 4% yield 1 H NMR (DMSO-de) d 2.62 (s, 3 H), 7.66 (dd, 1 H), 7.95 (dd, H), 8.06 (s, 1 H), 8.18-8.24 (m, 2 H), 8.51 (d, 1 H) ), 9.01 (t, 1H).

EXAMPLE 28UU 5-Cyclopropyl-1- (6-quinolinyl) -1H-pyrazole-4-carboxylic acid 75. 5% yield 1 H NMR (DMSO-de) d 0.49 (m, 2 H), 0.86 (m, 2 H), 2.2 (m, H), 7.64 (dd, 1 H), 8.01 (m, 1 H), 8.03 (s, 1 H), 8.16 (dd, 1H), 8.28 (d, H), 8.49 (d, 1H), 9.0 (dd, 1H).

EXAMPLE 28W 5-Cyclopropyl-1- (4-quinolinyl) -1H-pyrazole-4-carboxylic acid 78. 2% yield 1 H NMR (DMSO-de) d 0.56 (m, 2H), 0.64 (m, 2H), 1.91 (m, H), 7.49 (dd, 1H), 7.68 (m, 1H), 7.8 (d, 1H), 7.88 (m, 1H), 8.13 (s, 1H), .19 (d, 1H), 9.11 (d, 1H).

EXAMPLE_28WW 5-Methyl - (6-methoxy-5-quinolinyl) -1H-pyrazole-4-carboxylic acid 80. 1% yield 1 H NMR (DMSO-de) d 2.2 (s, 3H), 3.96 (s, 3H), 7.38 (dd, 1H), 7.52 (m, 1H), 7.92 (d, 1H), 8.08 (s, 1H), 8.3 (d, 1H), 8.86 (dd, 1H).

EXAMPLE 28XX 5-Cyclopropyl-1- (6-methoxy-5-quinolyl) -1 AY-pyrazole-4-carboxylic acid 41. 6% yield 1 H NMR (DMSO-de) d 0.45 (m, 2H), 0.65 (m, 2H), 1.72 (m, 1H), 3.91 (s, 3H), 7.33 (d, 1H), 7.47 (m, 1H), 7.85 (d, 1H), 7.99 (s, 1H), 8.23 (d, 1H), 8.8 (dd, 1H), 12.3 (s, 1H).

EXAMPLE 28YY 5-Cyclopropyl-1- (6-methyl-5-quinolinyl) -1-t-pyrazole-4-carboxylic acid 82. 5% yield 1 H NMR (DMSO-de) d 0.52-0.77 (m, 4H), 1.7 (m, 1H), 2.19 (s, 3H), 7.4 (dd, 1H), 7.57 (m, 1H), 7.85 (d, 1H) ), 8.15 (m, 2H), 8.93 (t, 1H).

EXAMPLE 28ZZ 5-Ethyl-1- (2-methyl-6-quinolinyl) -1H-pyrazole-4-carboxylic acid % yield 1 H NMR (DMSO-de) d 1.06 (t, 3 H), 2.71 (s, 3 H), 2.95 (q, H), 7.55 (d, 1 H), 7.82 (d, 1 H), 8.02-8.13 (m , 3H), 8.38 (d, 1 H).

EXAMPLE 28AAA 5-EtH-1 - (6-Methyl-5-quinolinyl-1 H-pyrazole-4-carboxylic acid 81. 5% yield 1 H NMR (DMSO-de) d 0.83 (t, 3H), 2.5-2.6 (2q, 2H), 2.15, 3H), 7.33 (q, 1 H), 7.54 (q, 1 H), 7.86 (dd, 1 H), 8.14 (s, 1 H), 8.19 (d, H), 8.94 (d, 1 H).

EXAMPLE 28BBB 5-Ethyl-1- (6-quinolinyl) -1H-pyrazole-4-carboxylic acid 71. 9% yield 1 H NMR (DMSO-d 6) d 1.04 (t, 3 H), 2.96 (q, 2 H), 7.63 (q, H), 7.85 (dd, 1 H), 8.01 (s, 1 H), 8.17 (s + d , 2H), 8.49 (d, 1 H), 8.99 (q, H).

EJ £ MPL0.28CCC 1 - (2-quinoxalinyl) -5-ethyl-1 7-pyrazole-4-carboxylic acid 82% yield 1 H NMR (400 MHz, DMSO-d 6) d 9.42 (s, 1 H), 8.14-8.11 (m, 2 H), 8.00 (d, J = 8, 1 H), 7.91-7.83 (m, 2 H), 3.44 (q, J = 7, 2H), 1.29 (t, J = 7, 3H): APCIMS 267 [M-1T EXAMPLE 28DDD 1 - (2-Becimidacil) -5-ethyl-1 H-pyrazole-4-carboxylic acid 66% yield 1 H NMR (400 MHz, DMSO-d 6) d 13.1 (s, 1 H), 12.74 (s, 1 H), 8.12 (s, 1 H), 7.63 (d, J = 6, 1 H) , 7.44 (d, J = 6, 1 H), 7.20 (sa, 2H), 3.52 (q, J = 7, 2H), 1.21 (t, J = 7, 3H). APCIMS 257 [M + 1f EXAMPLE 28EEE m 1 - (2-Fluoromethyl-4-chlorophenyl) -5-cyclopropyl-1 H -pyrazole-4-carboxylic acid 92% yield 1 H NMR (400 MHz, DMSO-d 6) d 12.43 (br s, 1 H), 8.07 (s, 1 H), 7.96-7.93 (m, 2 H), 7.76 (d, J = 8, 1 H), 1.76 (m, 1 H), 0.68-0.74 (m, 4H). APCIMS 331 [M + 1] + EXAMPLE 28FFF 1 - (2-Fluoro-6-trifiuoromethylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carboxylic acid 55% yield 1 H NMR (400 MHz, DMSO-d 6) d 12.50 (s, 1 H), 7.98 (s, 1 H), 7.92-7.82 (m, 3 H), 1.68 (m, 1 H), 0.79-0.67 (m, 4 H) . APCIMS 315 [M + 1] + EXAMPLE 28GGG 1 - (2-Trifluoromethyl-4-fluorophenyl) -5-cyclopropyl-1-t-pyrazol-4-carboxylic acid 86% yield 1 H NMR (300 MHz, DMSO-d 6) d 7.97-7.93 (m, 2 H), 7.91- 7.74 (m, 2 H), 1.79 (m, 1 H), 0.75 (d, J = 9, 4 H) ). APCIMS 315 [M + 1] + EXAMPLE 28HHH 1 - (1-Methylbenzimidaz-2-yl -) - 5-ethyl-1 / V-pyrazole-4-carboxylic acid 39% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.17 (s, 1 H), 7.77-7.70 (m, 2 H), 7.47-7.32 (m, 2 H), 3.72 (s, 3 H), 3.04 (q, J = 7, 2H), 1.13 (t, J = 7, 3H). APCIMS 269 [M-1] " EXAMPLE 28111 1- (2-quinolinyl) -5-ethyl-1-pyrazole-4-carboxylic acid 93% yield H NMR (300 MHz, DMSO-de) d 12.62 (s, 1 H), 8.57 (d, J = 7, 1H), 8.05 (s, 1 H), 8.02-7.94 (m, 3H), 7.81 (t, J = 5, 1 H), 7.64 (t, J = 5, 1 H), 3.47 (q, J = 5, 2H), 1.30-1.27 (m, 3H). APCIMS 268 [M + 1] + EXAMPLE 28JJJ 1 - (2-Chloro-5-methylaminocarbonylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carboxylic acid 87% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.67 (m, 1 H), 8.06 (d, J = 2, 1 H), 8.04 (s, 1 H), 8.00 (s, 1 H), 7.85 d, J = 9, 1 H), 2.79 (d, J = 5, 3H), 1.88 (m, 1 H), 0.75-0.66 (m, 4H). APCIMS 320 [M + 1] + EXAMPLE 28 KKK 1 - (4-Benzimidazolyl) -5-cyclopropyl-1 W-pyrazole-4-carboxylic acid 83% yield 1 H NMR (400 MHz, DMSO-d 6) d 8.24-8.20 (m, 1H), 7.98-7.89 (m, 1 H), 7.77-7.64 (m, 1 H), 7.33-7.21 (m, 2H), 1.96 (m, 1 H), 0.64-0.47 (m, 4H).

EXAMPLE 28LLL 1 - (2-Chloro-5-vodophenyl) -5-cyclopropyl-1-pyrazole-4-carboxylic acid 86% yield 1 H NMR (300 MHz, DMSOde) d 8.15 (s, 1 H), 7.96-7.89 (m, 2 H), 7.42 (d, J = 1.2, 8, 1 H), 1.85 (m, 1 H), 0.77- 0.67 (m, 4H). APCIMS 389 [M + 1f EXAMPLE 28MMM 1 - (2-Chloro-5-aminocarbonylphenyl) -5-cyclopropyl-1-pyrazol-4-carboxylic acid 31% yield 1 H NMR (300 MHz, DMSO-d 6) d 8.17 (s, 1 H), 8.09-8.07 (m, 2 H), 8.00 (s, 1 H), 7.84 (d, J = 9, 1 H ), 7.66 (s, 1 H), 1.85 (m, 1 H), 0.76 (d, J = 8, 2H), 0.68 (d, J = 5, 2H). APCIMS 306 [M + 1] + EXAMPLE 28NNN 1 - (2-Chloro-5-dimethylaminocarbonylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carboxylic acid 45% yield 1 H NMR (300 MHz, DMSO-d 6) d 7.98 (s, 1 H), 7.79 (d, J = 9, 1 H), 7.72 (d, J = 2, 1 H), 7.63 (dd) , J = 2, 8, 1 H), 2.99 (s, 3H), 2.93 (s, 3H), 1.89 (m, 1 H), 0.77-0.73 (m, 2H), 0.67-0.65 (m, 2H) . APCIMS 334 [M + 1] + EXAMPLE 28OOO 1-Phenyl-4-cyclopropyl-1-t-pyrazole-3-carboxylic acid 100% APCIMS yield 229 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 8.85 (s, 1 H), 7.85-7.82 (m, 2 H), 7.51-7.45 (m, 2 H), 7.32 (t, J = 7, 1 H), 2.57 (m, 1 H), 0.99-0.90 (m, 4H).

EXAMPLE 28PPP 1 - (1-Isoquinolyl-5-cyclopropyl-1 H -pyrazole-4-carboxylic acid 75% yield 1 H NMR (400 MHz, DMSO-d 6) d 12.45 (s, 1 H), 8.49 (d, J = 6, 1 H), 8.11 (d, J = 8, 1 H), 8.38 (d , J = 6, 1 H), 8.01 (s, 1 H), 7.84 (t, J = 8, 1 H), 7.66 (t, J = 8, 1 H), 7.42 (d, J = 9, 1 H), 1.98 (m, 1 H), 0.57 (d, J = 6, 2H), 0.428 (D, J = 3.6, 2H).

EXAMPLE 28QQQ ft I • 5-Isopropyl-1- (6-q? Inolinyl) -1-f pyrazole-4-carboxylic acid 89. 8% yield 1 H NMR (DMSO-d 6) d 1.29 (d, 6 H), 3.2 (m, 1 H), 7.64 (q, 1 H), 7.77 (dd, 1 H), 7.99 (s, 1 H), 8.12 (s, 1 H), 8.16 (dd, 1 H), 8.5 (d, 1 H), 8.99 (d, 1H), 12.4 (sa, 1 H).

EXAMPLE 28RRR 5-Propyl-1- (6-quinolinyl) -1H-pyrazole-4-carboxylic acid 86. 4% yield 1 H NMR (DMSO-de) d 0.68 (t, 3 H), 1.42 (q, 2 H), 2.97 (t, 2 H), 7.62 (q, 1 H), 7.84 (t, 1 H), 8.01 (s, 1 H), 8.16 (d, 2H), 8.48 (d, 1 H), 8.98 (d, 1 H), 12.45 (ss, 1 H). The title compounds of Examples 29A-29D were prepared using analogous procedures as used in Example 8A.

EXAMPLE 29A R5-Cyclopropyl-1- (2,4-dichloro-6-rtrifluoromethylphenyl) -1H-pyrazole-4-carbonin guanidine hydrochloride 14% yield APCIMS 406 [M +] + 1 H NMR (400 MHz, DMSO-d 6) d 0.83-0.86 (m, 4 H), 1.79 (m, 1 H), 8.21 (s, 1 H), 8.44 (br, 3 H), 8.71. (sa, 2H), 11.76 (s, 1 H). EXAMPLE 29B r5-methoxymethyl-1- (5-quinolyl) -1 / - / - pyrazole-4-carbonylguanidine dihydrochloride 13% yield APCIMS 325 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 9.12 (br s, 1 H), 9.03 (m, 1 H), 8.81 (br s, 2 H), 8.55 (br s, 2 H), 8.36 ( m, 1 H), 7.06-8.06 (m, 4H), 4.61 (s, 2H), 3.01 (s, 3H).

EXAMPLE 29C ri- (5-methoxy-2-chlorophenyl) -5-cyclopropyl-1-t-pyrazol-4-carbonylguanidine hydrochloride 17% yield APCIMS 334 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 8.72 (br s, 2 H), 8.67 (s, 1 H), 8.43 (br s, 2 H), 7.63 (d, J = 9, 1 H ), 7.29 (d, J = 3, 1 H), 7.21 (dd, J = 3, 9, 1 H), 3.82 (s, 3H), 1.99 (m, 1 H), 0.79 (d, J = 9) , 2H), 0.63 (d, J = 4, 2H).

EXAMPLE 29D H - (5-quinolinyl) -5-butyl-1-pyrazol-4-carboninquanidine dihydrochloride 38% yield APCIMS 337 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.53 (ts, J = 7.0, 3H), 1.01 (t, J = 6.8, 2H), 1.26 (s, 2H), 2.75 ( s, 2H), 7.72-7.79 (m, 2H), 7.92 (d, J = 7.2, 1H), 8.03 (t, J = 7.8, 1 H), 8.36 (d, J = 8.4, 1 H) , 8.48 (sa, 2H), 8.81 (sa, 2H), 9.00 (s, 1 H), 9.12 (s, 1 H), 12.169 (s, 1 H).

EXAMPLE 30A Ri- (guinolin-5-yl) -5-cyclopropyl-1AY-pyrazole-4-carboninguanidine hydrochloride monohydrate A solution of guanidine hydrochloride (3.11 g, 32.6 mmol) in hot anhydrous ethanol (8 ml) under a nitrogen atmosphere was treated in one portion with sodium method (1.76 g, 32.6 mmol). The resulting suspension was concentrated in vacuo. The residue was treated with anhydrous toluene (10 ml) and concentrated to dryness in vacuo (twice). Each time the vacuum was released taking nitrogen atmosphere. The residue was treated in one portion with ethyl 1- (quinolinyl-5-yl) -5-cyclopropyl-1-pyrazol-4-carboxylate (1.00 g, 3.26 mmol) in anhydrous ethanol (8 ml). The resulting mixture was concentrated in vacuo (rotary evaporator, water bath at 80 ° C). The residue was treated with anhydrous toluene (10 ml), and the resulting mixture was concentrated in vacuo (three times). The resulting solid was triturated with water (85 ml) and filtered. The solid was air-dried providing 0.880 g (76% yield) of [1- (quinolin-5-yl) -5-cyclopropyl-1-pyrazol-4-carbonyljguanidine dihydrate. APCIMS 321 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.51-0.53 (m, 4H), 1.88-1.95 (m, 1H), 7.52-7.60 (m, 2H), 7.73 (d, J = 8, 1H), 7.86 (t, J = 9, 1H), 7.94 (s, 1H), 8.16 (d, J = 9, 1 H), 8.95 (t, J = 1.8, 1 H).

A suspension of [1- (quinolin-5-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine dihydrate (1.28 g, 3.59 mmol) in tetrahydrofuran (38.4 ml) with vigorous stirring was treated with acid concentrated hydrochloric acid (0.30 ml, 3.6 mmol). The mixture became homogeneous in one minute and then a solid began to precipitate. The resulting mixture was stirred vigorously for 1 h and filtered. The solid was dried with air to provide 1.11 g (82% yield) of the title compound. APCIMS 321 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.42 (m, 2 H), 0.59-0.61 (m, 2 H), 1.88-1.95 (m, 1 H), 7.57 (dd, J = 9, 4, 1 H), 7.67 (d, J = 4, 1 H), 7.82 (d, J = 7, 1 H), 7.90 (t, J = 8, 1 H), 8.22 (d, J = 8, 1 H), 8.38 (sa, 2H), 8.69 (sa, 2H), 8.72 (s, 1 H), 8.98 (dd, J = 4, 1.4, 1 H). The title compounds of Examples 30B-30M were prepared using procedures analogous to those used for Example 30A.

EXAMPLE 30B H - (Isoquinolin-5-yl) -5-cyclopropyl-1 H -pyrazole-4-carbonillquanidine hydrochloride 14% APCIMS yield 321 [M + 1] + 1 H NMR (CDCb) d 1.9-2.0 (s, 1 H), 8.80 (s, 1 H) EXAMPLE 30C ri- (quinolin-5-yl) -5-benzyloxymethyl-1H-pyrazole-4-carbonylquinidine hydrochloride 41% APCIMS yield 401 [M + 1] + 1 H NMR (CDCb) d 4.16 (s, 2H), 8.87 (s, 1 H) EXAMPLE 30D Ri- (benzotriazol-5-iD-5-ethyl-1AY-pyrrazol-4-carbonylguanidine hydrochloride monohydrate) 49% yield APCIMS 299 [M + 1] + 1 H NMR (CDCb) d 0.99-1.03 (t, 3H), 8.61 (s, 1 H) EXAMPLE 30E Ri- (indazol-6-yl) hydrochloride monohydrate - 5-ethyl-1f / -pyrazol-4-carbonylguanidine 27% APCIMS yield 298 [M + 1] + 1 H NMR (CDCb) d 1.01-1.05 (t, 3H), 8.64 (s, 1 H) EXAMPLE 30F ri- (guinolin-5-yl) -5-cyclobutyl-1/7-pyrazole-4-carbonylguanidine hydrochloride 24% APCIMS yield 335 [M + 1] + 1 H NMR (CDCb) d 3.61-3.70 (m, 1 H), 8.75 (s, 1 H) EXAMPLE 30G H - (6-chloroguinolin-5-yl) dihydrochloride -5-cyclopropyl-1 H-pyrazole-4-carbonylguanidine 8% yield APCIMS 354 [M + 1] + 1 H NMR (CDCb) d 1.78-1.83 (m, 1 H), 8.79 (s, 1 H) ss EXAMPLE 30H f 1 - (Indazol-5-yl) hydrochloride - 5-ethyl-1 / tf-pyrazole-4-carbonyl .guanidine 39. 3% yield APCIMS 298 [M + 1j + 1H NMR (CDCb) d 0.99-1.05 (t, 3H), 8.70 (s, 1 H) EXAMPLE 301 Ri- (1,4-benzodioxan-6-yl) -5-ethyl-1AY-pyrazole-4-carbonyl] guanidine hydrochloride monohydrate 27% yield APCIMS 316 [M + 1] + 1 H NMR (CDCb) d 1.01-1.08 (t, 3H), 8.64 (s, 1 H) EXAMPLE 30J [1 - (Quinolin-5-yl) -5-isobutyl-1 H -pyrazole-4-carboninguanidine hydrochloride] 13. 7% yield APCIMS 337 [M + 1] 1+ 1 H NMR (CDCb) d 1.53-1.60 (m, 1 H), 8.97 (s, 1 H) EXAMPLE 30K Ri- (1,3-benzodioxol hydrochloride monohydrate -5-yl) -5-ethyl-1H-pyrazole-4-carbonylguanidine 9. 4% APCIMS yield 302 [M + 1] + 1 H NMR (CDCb) d 0.99-1.02 (t, 3H), 8.63 (s, 1 H) EXAMPLE 30L Ri- (8-bromoquinolin-5-yl) -5-cyclopropyl-1H-pyrazole-4-carbonylguanidine hydrochloride monohydrate 23% yield APCIMS 401 [M + 2] + 1 H NMR (CDCb) d 1.88-1.95 (m, 1 H), 8.71 (s, 1 H) EXAMPLE 30M ri- (6-trifluoromethylquinolin-8-yl) -5-cyclopropyl-1H-pyrazole-4-carbonipquanidine hydrochloride monohydrate 18% yield APCIMS 389 [M + 1] + 1 H NMR (CDCb) d 1.80-1.87 (m, 1 H), 8.80 (s, 1 H) The title compounds of Examples 31A-310 were prepared using analogous procedures to that described for Example 6A.

EXAMPLE 31A P-metiM - (2-biphenyl) -1 / - pyrazole-4-carboni Hguanidine hydrochloride 61% APCIMS yield 320 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 2.29 (s, 3 H), 7.05 (m, 2 H), 7.26 (m, 3 H), 7.54 (m, 4 H) , 7.64 (s, 1 H), 8.35 (sa, 2H), 8.51 (sa, 2H), 8.85 (s, 1 H), 9.06 (s, 1 H).

EXAMPLE 31 B r5-Cyclopropyl-1- (2,1,3-benzothiadiazol-4-yl) -1H-4-carbonylguanidine hydrochloride 66% yield APCIMS 328 [M + 1f 1 H NMR (400 MHz, DMSO-de) d 0.42 (m, 2H), 0.58 (m, 2H), 1.99 (m, 1H), 7.81 (m, 2H), 8.30 (d, J = 8.4, 1H), 8.40 (ss, 2H), 8.69 (s, 1H), 8.70 (ss, 2H), 11.83 (s, 1H).

EXAMPLE 31 C r5-Methyl-1- (2,4-difluorophenip-1A - / - pyrazole-4-carbonylguanidine hydrochloride 77% APCIMS yield 280 [M + 1f 1 H NMR (400 MHz, DMSO-d 6) d 2.37 (s, 3 H), 7.33 (m, 1 H), 7.63-7.74 (m, 2 H), 8.48 (br s, 2 H) , 8.74 (sa, 2H), 8.83 (s, 1H), 12.09 (s, 1H).

EXAMPLE 31 D r5-Cyclopropyl-1- (2-aminosulfonylphenyl) -1 H-pyrazole-4-carbonylquinidine hydrochloride % yield APCIMS 349 [M + 1] + 1H NMR (400 MHz, DMSO-d6) d 0.49 to 0.81 (m, 4H), 1.97 (m, 1H), 7.29 (bs, 2H), 7.66 (d , J = 7.2, 1 H), 7.77 (m, 2H), 8.07 (d, J = 8, 1 H), 8.43 (sa, 2H), 8.68 (s, 1 H), 8.71 (sa, 2H), 11.81 (s, 1 H).

EXAMPLE 31 E r5-Cyclopropyl-1- (2-methylthiophenyl) -1H-pyrazole-4-carbonylguanidine hydrochloride % APCIMS yield 316 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.60 (m, 2H), 0.74 (m, 2H), 1.96 (m, 1H), 7.31-7.98 (m, 4H), 8.40 (sa, 2H), 8.62 (s, 1H), 8.68 (sa, 2H).

EXAMPLE 31 F f 1 - (2-pyrrol-1-phenyl) -5-cyclopropyl-1 H-pyrazole-4-carbonylguanidine hydrochloride 12% yield APCIMS 335 [M + 1] + 1H NMR (400 MHz, DMSO-d6) d 0.32 to 0.53 (m, 4H), 1.04 (m, 1H), 6.09 (s, 2H), 6.49 (s , 2H), 7.49-7.69 (m, 4H), 9.05 (ss, 5H), 10.80 (s, 1 H).

EXAMPLE 31G [5-Methyl-1- (6-quinolinyl) -1 H-pyrazole-4-carbonylguanidine hydrochloride 92. 4% yield 1 H NMR (DMSO-de) d 2.64 (s, 3 H), 7.86 (m, 1 H), 8.11 (d, 1 H), 8.33 (d, 1 H), 8.41 (sa + s, 3 H), 8.74 (sa, 2H), 8.79 (d, 1 H), 8.88 (s, 1H), 9.16 (d, 1 H).

EXAMPLE 31 H f5-cyclopropyl-1- (6-quinolinyl) -1H-pyrazole-4-carbonylguanidine hydrochloride 98. 8% yield H NMR (DMSO-de) d 0.36 (m, 2H), 0.84 (m, 2H), 2.3 (m, 1 H), 7.63 (s, 1 H), 7.95 (q, 1 H), 8.28 (dd, 1 H), 8.43 (d, 1 H), 8.56 (sa, 2H), 8.79 (sa, 2H), 8.97 (d, 1 H), 9.08 (s, 1 H), 9.21 (d, 1 HOUR).

EXAMPLE 311 r5-Cyclopropyl-1- (4-guinolinyl) -1 Y-pyrazole-4-carboninquanidine hydrochloride 72. 4% yield 1 H-NMR (DMSO-de) d 0.41 (m, 2 H), 0.65 (m, 2 H), 1.99 (m, 1 H), 7.52 (d, 1 H), 7.69 (m, 1 H), 7.89 (m, 2H), 8.21 (d, 1 H), 8.46 (sa, 2H), 8.76 (sa, 2H), 8.85 (d, 1H), 9.13 (t, 1H), 12.1 (s, 1H).

EXAMPLE 31 J r5-Methyl-1- (6-methoxy-5-guinolinyl) -1 A7-pyrazole-4-carbonylguanidine hydrochloride 55. 9% yield 1H NMR (DMSO-de) d 2.24 (s, 3H), 3.96 (s, 3H), 7.57-7.67 (m, 2H), 8.0 (dd, 1 H), 8.37 (d, 1 H) , 8.43 (sa, 2H), 8.73 (sa, 2H), 8.88 (s, 1H), 8.94 (d, 1 H), 12.0 (s, 1 H).

EXAMPLE 31 K r5-Cyclopropyl-1- (6-methoxy-5-quinolinyl) -1-t-pyrazol-4-carbonyl-quinidine hydrochloride 24. 1% yield 1 H NMR (DMSO-de) d 0.34 (m, 1 H), 0.52 (m, 1 H), 0.62 (m, 2 H), 1.79 (m, 1 H), 3.94 (s, 3 H), 7.51 (d , 1H), 7.6 (m, 1H), 7.95 (d, 1 H), 8.32 (d, 1H), 8.37 (sa, 2H), 8.68 (sa, 2H), 8.71 (s, 1H), 8.89 (d , 1 HOUR).

EXAMPLE 31 L r5-Cyclopropyl-1- (6-methyl-5-quinolinyl) -1 H-pyrazole-4-carbonyguanidine hydrochloride 70. 7% yield 1? L NMR (DMSO-de) d 0.49-0.72 (m, 4H), 1.81 (m, 1 H), 2.51 (s, 3H), 7.75 (m, 2H), 7.99 (dd, 1 H), 8.33 (d, 1 H), 8.51 (sa, 2H), 8.81 (sa, 2H), 8.92 (s, 1 H), 9.1 (t, 1 H).

EXAMPLE 3 M r5-ethyl-1- (2-methyl-6-quinolinyl) -1-pyrazole-4-carbonyl-uanidine hydrochloride 47. 6% yield 1H NMR (DMSO-de) d 1.11 (t, 3H), 2.89 (s, 3H), 3.0 (q, 2H), 7.86 (d, 1 H), 8.06 (d, 1 H), 8.34 -8.43 (m, 4H), 8.74-8.88 (m, 4H).

EXAMPLE 31 N r5-ethyl-1- (β-methyl-5-quinolinyl) -1H-pyrazole-4-carbonylguanidine hydrochloride 53. 9% yield 1 H NMR (DMSO-de) d 0.84 (t, 3H), 2.16 (s, 3H), 2.59 (2q, 2H), 7.61 (d, 1H), 7.72 (q, 1H), 7.99 (d , 1H), 8.32 (d, 1H), 8.5 (sa, 2H), 8.81 (sa, 2H), 9.07 (s + d, 2H).

EXAMPLE 31O r5-ethyl-1- (6-quinolinyl) -1 H-pyrazole-4-carbomT guanidine hydrochloride 63. 7% yield 1H NMR (DMSO-d6) d 1.11 (t, 3H), 3.04 (q, 2H), 7.91 (q, 1 H), 8. 08 (dd, 1H), 8.38 (s, 1 H), 8.42 (d, 1 H), 8.5 (sa, 2H), 8.8 (sa, 2H), 8.86 (d, 1H), 8.93 (s, 1H) , 9.21 (d, 1H).

EXAMPLE 32A f5-Cyclopropyl-1- (2-trifluoromethylphenyl) -1A-pyrazole-4-carboninguanidine hydrochloride monohydrate A mixture of 5-cyclopropyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxylic acid (1.00 g, 3.37 mmol) and thionyl chloride (0.739 ml, 10.1 mmol) was refluxed for 1 h under atmosphere of nitrogen, and concentrated in vacuo. The residue was treated with anhydrous toluene and the mixture was concentrated in vacuo (twice). A solution of the resulting thick oil in anhydrous tetrahydrofuran (2.5 ml) was added dropwise to a vigorously stirred mixture of guanidine hydrochloride (1.16 g, 12.0 mmol), sodium hydroxide (2 N aqueous, 12 ml, 24 mmol) and tetrahydrofuran. (6 ml) at 23 ° C. The resulting mixture was refluxed for 1 h, allowed to cool to room temperature and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo affording 1.1 g of a pale pink solid. A suspension of the solid in water (3.2 ml) was treated with concentrated hydrochloric acid (0.273 ml, 3.28 mmol) and stirred at room temperature for 1 h. The resulting suspension was filtered. The solid was dried with air and recrystallized from water. The resulting crystalline solid was dried with air affording 0.98 g (74% yield) of the title compound. APCIMS 338 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.57 (br s, 2 H), 0.72-0.74 (m, 2 H), 1.82-1.89 (m, 1 H), 7.71 (d, J = 8, 1 H), 7.80 (t, J = 8, 1 H), 7.86 (t, J = 7, 1 H), 7.97 (d, J = 7, 1 H), 8.36 (sa, 2H), 8.60 (s, 1 H), 8.62 (sa, 2H). The title compounds of examples 32B-32CCC were prepared using procedures analogous to that used for example 16A and example 32A.

EXAMPLE 32B ri- (2,3-dimethoxyphenyl) -3-methyl-1H-pyrazole-4-carbonylguanidine hydrochloride 82% APCIMS yield 304 [M + 1] + 1 H NMR (400 MHz, DMSO-de) d 2.43 (s, 3 H), 3.73 (s, 3 H), 3.85 (s, 3 H), 7.16 (m, 3 H) , 8.39 (sa, 2H), 8.64 (sa, 2H), 9.27 (s, 1 H), 12.12 (s, 1 H).

EXAMPLE 32C ri- (naphthalen-1-yl) -5-cyclopropyl-1H-pyrazole-4-carbonylguanidine hydrochloride 84% APCIMS yield 320 [M + 1] + 1 H NMR (400 MHz, DMSO-d6) d 0.40-0.70 (m, 4H), 1.90 (m, 1 H), .13 (d, J = 18.1 H), 7.60 (m, 3H), 8.06 (d, J = 8, 1 H), 8.13 (d, J = 8, 1 H), 8.39 (sa, H), 8.72 (m, 3H).

EXAMPLE 32D ri- (naphthalen-2-yl) -5-cyclopropyl-1 / -pyrazol-4-carbonylguanidine hydrochloride 83% APCIMS yield 320 [M + 1] + 1 H NMR (400 MHz, DMSO-de) d 0.38 (d, J = 4.8, 2H), 0.80 (d, J = 8, H), 2.24 (m, 1 H), 7.57 (m, 2H), 7.72 (d, J = 8.4, 1 H), 8.03 (m, 3H), 8.18 (s, 1 H), .38 (sa, 2H), 8.64 (s, 1 H), 8.70 (ss, 2H), 11.80 (s, 1 H).

EXAMPLE 32E H -naphthalen-2-yl) -3-methyl-1 H-pyrazole-4-carboning? Anidine hydrochloride 83% APCIMS yield 294 [M + 1] + 1 H NMR (400 MHz, DMSO-d6) d3.32 (s, 3H), 7.55 (m, 2H), 7.60-.10 (m, 4H), 8.30 ( s, 1 H), 8.40 (ss, 2H), 8.52 (ss, 2H), 9.80 (s, 1 H), 12.12 (s, H).

EXAMPLE 32F H - (o-biphenyl) -5-cyclopropyl-1 tf-pyrazol-4-carbonyl Hguanidine hydrochloride 72% yield APCIMS 346 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.25-0.70 (m, 4H), 1.12 (m, 1H), .00 (m, 2H), 7.27 (m, 3H), 7.49-7.87 (m, 4H), 8.30 (ss, 2H), 8.56 (ss, 2H), .59 (s, 1 H), 11.58 (s, 1 H).

EXAMPLE 32G ri- (5-quinolinyl) -5-isopropyl-1A-pyrazol-4-carbonylguanidine hydrochloride 74% yield APCIMS 323 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 1.15 (d, J = 6.8, 6H), 3.00 (m, H), 7.73 (s, 2H), 7.91 (d, J = 7.2, 1H), 8.04 (t, J = 8, 1 H), 8.38 (d, J = 8.4, 1 H), .51 (sa, 2H), 8.84 (sa, 2H), 8.96 (s, 1H) 9.12 (m, 1H), 12.01 (s, 1 H).

EXAMPLE 32H H -5-guinolinyl hydrochloride) -5- 7-propyl-1 H-pyrazole-4-carbon? Pguanidine 78% yield APCIMS 323 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.61 (t, J = 7.4, 6H), 1.33. (m, H), 2.73 (m, 2H), 7.69-7.78 (m, 3H), 7.91 (d, J = 7.6, 1 H), 8.03 (t, J = 7.2, 1 H), .35 (d) , J = 8, 1 H), 8.47 (sa, 2H), 8.81 (sa, 2H), 9.00 (s, 1 H), 9.11 (m, 1 H), 2.15 (s, 1H).

EXAMPLE 321 f1-phenyl-3-ethyl-1H-pyrazole-4-carbonnquanidine hydrochloride 63% yield APCIMS 258 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 1.22 (m, 3 H), 2.88 (m, 2 H), 7.38 (m, 1 H), 7.55 (m, 2 H), 7.75 (m , 2H), 8.37 (sa, 2H), 8.52 (sa, 2H), 9.71 (s, 1H), 12.10 (s, 1H). EXAMPLE 32J ri- (2-nitrophenyl) -5-cyclopropyl-1-pyrazol-4-carbonylguanidine hydrochloride 76% yield APCIMS 315 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.52 (br s, 2 H), 0.80 (d, J = 8.4, 2H), 2.04 (m, 1H), 7.81 (d, J = 7.6, 1H), 7.91 (sa, 2H), 8.16 (d, J = 8, 1H), 8.47 (sa, 2H), 8.67 (s, 1H), 8.72 (ss, 2H), 11.91 (s, 1H).

EXAMPLE 32K M - (2-rdimethylaminosulfonylphenyl) -5-cyclopropyl-1H-pi-razol-4-carboninguanidine hydrochloride 72% yield APCIMS 377 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.49 (br s, 2 H), 0.67 (d, J = 6, 2 H), 1.87 (m, 1 H), 2.62 (s, 6 H) ), 7.61 (d, J = 2, 1 H), 7.83 (m, 2H), 7.98 (m, 1 H), 8.40 (sa, 2H), 8.64 (s, 1 H), 8.68 (sa, 2H) , 11.81 (sa, 1 H).

EXAMPLE 32L H - (2-methanesulfonylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carbonylguanidine hydrochloride 68% yield APCIMS 348 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.40-0.60 (m, 4H), 1.89 (m, 1H), 3.30 (s, 3H), 7.73 (d, J = 6.4, 1 H), 7.88 (m, 2H), 8.11 (dd, J = 8, 1.6, 1H), 8.36 (sa, 2H), 8.64 (sa, 3H), 11.72 (s, 1H).

EXAMPLE 32M H - (2-f-methylamino-l-phenyl-phenyl) -5-cyclopropyl-1 H -pyrazole-4-carbonylguanidine hydrochloride 44% yield APCIMS 363 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.48-0.76 (m, 4H), 1.93 (m, 1H), 2.4 (s, 3H), 7.01 (s, 1H), 7.65 (m, 1H), 7.79 (m, 2H), 7.98 (m, 1H), 8.31 (sa, 2H), 8.53 (s, 1H), 8.57 (sa, 2H), 11.58 (s, 1H).

EXAMPLE 32N ri- (2-Ethylphenyl) -5-cyclopropyl-1-pyrazol-4-carbonylquinidine hydrochloride 48% yield APCIMS 298 [M + 1f 1 H NMR (400 MHz, DMSO-d 6) d 0.61 (d, J = 8.8, 2H), 0.71 (d, J = 8.4, 2H), 0.98 (t, J = 7.4, 3H), 2.26 (d, J = 7.2, 2H), 7.33 (m, 2H), 7.46 (m, 2H), 8.35 (sa, 2H), 8.59 (s, 1 H), 8.64 (sa, 2H), 11.70 (s) , 1 HOUR).

EXAMPLE 32O f1- (2-methylphenyl) -5-cyclopropyl-1 Y-pyrazole-4-carbonylguanidine hydrochloride 14% yield APCIMS 284 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.57 (br s, 2 H), 0.70 (d, J = 5.6, 2 H), 1.96 (s, 4 H), 7.20-7.60 (m, 4H), 8.40 (sa, 2H), 8.65 (s, 1H), 8.71 (sa, 2H), 11.81 (s, 1H).

EXAMPLE 32P ri- (2-chlorophenyl) -5-cyclopropyl-1H-pyrrazol-4-carbonylguanidine hydrochloride 74% yield APCIMS 304 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.55 (d, J = 3.6, 2 H), 0.72 (d, J = 7.2, 2 H), 1.90 (m, 1 H), 7.4 -7.8 (m, 4H), 8.36 (sa, 2H), 8.61 (s, 1 H), 8.63 (sa, 2H), 11.74 (s, 1 H).

EXAMPLE 32Q ri- (2-trifluoromethoxyphenyl) -5-cyclopropyl-1f / -pyrazol-4-carbonylguanidine hydrochloride 87% yield APCIMS 354 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.48 (m, 2 H), 0.74 (m, 2 H), 1.89 (m, 1 H), 7.4-7.8 (m, 4 H), 8.36 (sa, 2H), 8.62 (sa, 3H), 11.72 (s, 1 H).

EXAMPLE 32R f1- (2-fluorophenyl) -5-cyclopropyl-1-t-pyrazole-4-carbonylquinidine hydrochloride 79% yield APCIMS 287 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.49 (d, J = 4, 2 H), 0.75 (d, J = 6.8, 2 H), 1.94 (br s, 1 H), 7.4 -7.6 (m, 4H), 8.34 (sa, 2H), 8.58 (s, 1 H), 8.61 (sa, 2H), 11.71 (s, 1H).

EXAMPLE 32S f1 - (2,1, 3-benzothiadiazol-4-yl) -3-methyl-1 H-pyrazole-4-carboninguanidine 73% yield APCIMS 302 [M + 1] + 1 H NMR (400 MHz, DMSO-D6) d 2.49 (s, 3 H), 7.7-7.81 (m, 1 H), 7.98 (dd, J = 8.4, 0.8, 1 H), 8.13 (dd, J = 7.6, 0.6, 1 H), 9.36 (s, 1 H).

EXAMPLE 32T f1- (Indazol-7-yl) -5-cyclopropyl-1AV-pyrazole-4-carbonylguanidine hydrochloride 62% yield APCIMS 310 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.44 (dd, J = 7.6, 5.2, 2H), 0.67- 0.73 (m, 2H), 2.11 (m, 1 H), 7.26 (t, J = 10, 1 H), 7.53 (d, J = 8.8, 1 H), 7.94 (d, J = 9.6, 1 H), 8.25 (s, 1 H), 8.44 (sa, 2H), 8.79 (sa, 3H), 11.88 (s, 1 H).

EXAMPLE 32U f1 - (indazol-7-yl) -3-methyl-1 A7-pyrazole-4-carbonipguanidine hydrochloride 63% yield APCIMS 284 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 2.53 (s, 3 H), 7.23 (t, J = 7.8, 1 H), 7.57 (d, J = 7.6, 1 H), 7.78 (d, J = 8.0, 1 H), 8.23 (s, 1 H), 8.40 (sa, 2H), 8.51 (sa, 3H), 9.76 (s, 1 H), 12.15 (sa, 1 H).

EXAMPLE 32V ri- (benzothiazol-2-yl) -5-ethyl-1J-pyrazole-4-carbonylguanidine hydrochloride 85% yield APCIMS 315 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 1.29 (t, J = 7.2, 3H), 3.61 (q, J = 7.6, 2H), 7.44-7.56 (m, 2H), 7.96 (d, J = 8.4, 1H), 8.12 (d, J = 8.0, 1H), 8.43 (sa, 2H), 8.62 (sa, 2H) ), 8.84 (s, 1 H), 12.01 (s, 1 H).

EXAMPLE 32W H - (2-chloro-4-methylsulfonylphenyl) -5-cyclopropyl-1H-pyrazole-4-carbonylguanidine hydrochloride 89% yield APCIMS 382 [M + 1] + 1 H NMR 8400 MHz, DMSO-6) d 0.572 (dd, J = 5.6, 2.0, 2H), 0.76 (dd, J = 8.8, 2.0, 2H), 1.91 (m, 1 H ), 3.36 (s, 3H), 7.94 (d, J = 8.4, 1 H), 8.05 (dd, J = 8.4, 2.0, 1 H), 8.26 (s, 1 H), 8.36 (sa, 2H), 8.63 (sa, 2H), 8.67 (s, 1 H), 11.80 (s, 1H).

EXAMPLE 32X f1 - (2-Chloro-4-. {Methylsulfonylmethylene-sulfonyl} -phenyl) -5-cyclopropyl-1 / -pyrazol-4-carbonipguanidine hydrochloride 72% yield APCIMS 460 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.53 (m, 2 H), 0.77 (m, 2 H), 1.94 (m, 1 H), 3.23 (s, 3 H), 5.91 ( s, 2H), 7.96-8.00 (m, 1 H), 8.01-8.12 (m, 1 H), 8.30 (sa, 2H), 8.65 (sa, 2H), 8.66 (s, 1 H), 11.73 (d , J = 6.4, 1 H).

EXAMPLE 32Y ri- (2-Chloro-5- (dimethylaminosulfonyl phenyl) -5-cyclopropyl-1 ¥ -pyrazole-4-carboninguanidine hydrochloride 85% yield APCIMS 411 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.52 (s, 2 H), 0.74 (m, 2 H), 1.93 (m, 1 H), 2.45 (s, 6 H), 7.92- 8.08 (m, 3H), 8.35 (sa, 2H), 8.64 (sa, 3H), 11.73 (s, 1H).

EXAMPLE 32Z f1 - (2-Chloro-5-fdimethylaminosulfonyl}. Phenyl) -5-cyclopropyl-1 H-pyrazole-4-carboni Hguanidine hydrochloride 9% yield APCIMS 383 [M + 1] + H NMR (400 MHz, DMSO-d6) d 0.57 (d, J = 8.6, 2H), 0.78 (d, J = 8.0, 2H), 1.94 (m, 1 H), 7.14 (t, J = 51.0, 2H), 7.63 (s, 2H), 7.97 (m, 2H), 8.36 (s, 2H), 8.62 (s, 3H), 8.64 (s, 1 H), 11.73 (s, 1 HOUR).

EXAMPLE 32AA H - (2-chloro-5-fmethylaminosulfonyl> phenyl) -5-cyclopropyl-1 H-pyrazole-4-carboninguanidine hydrochloride 61% yield APCIMS 397 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.53 (m, 2 H), 0.72-0.76 (m, 2 H), 1.92 (m, 1 H), 2.43 (d, J = 5.2, 3H), 7.70 (d, J = 5.2, 1H), 7.93-7.99 (m, 3H), 8.35 (s, 2H), 8.60 (s, 2H), 8.61 (s, 1 H), 11.70 (s, 1H) ).

EXAMPLE 32BB M - (2,5-dichlorophenyl) -5-cyclopropyl-1 H -pyrazole-4-carbonylguanidine hydrochloride 84% yield APCIMS 338 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.58 (s, 2 H), 0.77 (d, J = 7.2, 2 H), 1.92 (m, 1 H), 7.70-7.77 (m, 2H), 7.90 (d, J = 2.4, 1H), 8.37 (sa, 2H), 8.62 (sa, H), 11.74 (s, 1H).

EXAMPLE 32CC H - (2,4-Dichlorophenyl-5-1 H-pyrazole-4-carbonylguanidine hydrochloride 62% yield APCIMS 338 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.54-0.56 (m, 2H), 0.73-0.78 (m, 2H), 1.90 (m, 1 H), 7.61-7.70 (m , 2H), 7.93 (s, 1H), 8.35 (sa, 2H), 8.60 (sa, 3H), 11.72 (s, 1 H).

EXAMPLE 32DD ri- (2,3-dichlorophenyl) -5-cyclopropyl-1A / -pyrazol-4-carbonylguanidine hydrochloride 44% yield APCIMS 339 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.56-0.58 (m, 2H), 0.76 (s, 2H), 1.93 (m, 1H), 7.57 (dt, J = 7.6, 2.0, 1 H), 7.67 (td, J = 8.0, 1.6, 1 H), 7.89 (td, J = 8.0, 1.6, 1 H), 8.42 (sa, 2H), 8.68 (sa, 3H), 11.86 ( s, 1 H).

EXAMPLE 32EE ri- (2-chloro-5-methylsulfonylphenyl) -5-cyclopropyl-1H-pyrazole-4-carbonylguanidine hydrochloride 86% yield APCIMS 382 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.57 (s, 2 H), 0.77 (d, J = 7.2, 2 H), 1.94 (m, 1 H), 3.36 (s, 3 H) ), 8.04 (d, J = 8.4, 1 H), 8.12 (d, J = 8.4, 1 H), 8.23 (s, 1 H) C 8.36 (sa, 2H), 8.61 (sa, 2H), 8.64 ( s, 1 H), 11.86 (s, 1 H).

EXAMPLE 32FF f1- (Benzimidazol-5-yl) -5-ethyl-1H-pyrazole-4-carbonylguanidine dihydrochloride 24% yield APCIMS 298 [M + 1] + 1 H NMR (400 MHz, DMSO-de) d 1.04 (t, J = 7.2, 3H), 2.88 (q, J = 7.2, 2H), 7.63 (d, J = 8.8, 1 H), 8.01 (sa, 2H) ), 8.47 (sa, 2H), 8.78 (sa, 2H), 8.86 (s, 1H), 9.55 (sa, 1H), 12.09 (s, 1H).

EXAMPLE 32GG f1 - (2-Chloro-4-fdimethylaminosulfonyl phenyl) -5-cyclopropyl-1 H-pyrazole-4-carboninguanidine hydrochloride 68% yield APCIMS 411 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 0.52 (d, J = 4.4, 2H), 0.75 (d, J = 8.4, 2H), 1.93 (sa, 1 H), 2.67 (s, 6H), 7.84-8.00 (m, 2H), 8.04 (s, 1 H), 8.37 (sa, 2H), 8.68 (sa, 3H), 11.82 (s, 1 H).

EXAMPLE 32HH H - (2-Chloro-4- (methylaminosulfonyl> phenyl) -5-cyclopropyl-1 H-pyrazole-4-carboninguanidine hydrochloride 26% yield APCIMS 397 [M + 1] + 1 h NMR (400 MHz, DMSO-de) d 0.55-0.58 (m, 2 H), 0.75-0.80 (m, 2 H), 1.93 (m, 1 H), 3.47 (s, 3 H) ), 7.82 (t, J = 4.8, 1 H), 7.88-8.01 (m, 2H), 8.05 (s, 1 H), 8.34 (sa, 2H), 8.57 (sa, 2H), 8.06 (s, 1 H), 11.66 (s, 1 H).

EXAMPLE 32II H - (Benzimidazol-5-yl) -5-cyclopropyl-1 tf-pyrazole-4-carboninquanidine hydrochloride 16% yield APCIMS 310 [M + 1f 1 H NMR (400 MHz, DMSO-d 6) d 0.37-0.41 (m, 2H), 0.75-0.82 (m, 2H), 2.19 (m, 1 H), 7.75 (d, J = 8.8 , 1 H), 7.91-7.98 (m, 2H), 8.05 (s, 1 H), 8.45 (sa, 2H), 8.70 (s, 1H), 8.76 (sa, 2H), 9.51 (s, 1H), 11.95 (s, 1H).

EXAMPLE 32JJ f1-Benzyl-3-methyl-1-f-pyrazol-4-carbonnquanidine hydrochloride 67% yield APCIMS 258 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 2.31 (s, 3 H), 5.29 (s, 2 H), 7.23-7.35 (m, 5 H), 8.47 (s, 2 H), 8.53 (sa, 1H), 8.55 (s, 1H), 11.73 (s, 1H).

EXAMPLE 32KK f1- (3-Chloro-ndazol-5-yl) -5-etl-1H-pyrazole-4-carbon-guanidine hydrochloride 66% yield APCIMS 332 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 1.03 (d, J = 10.4, 3H), 2.84 (d, J = 7.6, 2H), 7.49 (d, J = 8.4, 1H ), 7.72 (d, J = 8.8, 1H), 7.79 (s, 1H), 8.41 (sa, 2H), 8.73 (s, 2H), 8.76 (s, 1 H), 11.95 (s, 1 H), 13.69 (s, 1 H).

EXAMPLE 32LL Dihydrochloride [1- (1-methylbenzimidazol-6-yl) -5-ethyl-1 H-pyrazole-4-carbonylquinide 53% yield APCIMS 312 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 1.02 (m, 3 H), 2.84 (d, J = 7.6, 2 H), 4.03 (s, 3 H), 7.64 (d, J = 8.8, 1H), 8.00 (d, J = 8.4 1 H), 8.20 (s, 1H), 8.47 (sa, 2H), 8.78 (sa, 2H), 8.87 (s, 1 H), 9.50 (bs, 1 H), 12.12 (s, 1 H).

EXAMPLE 32MM Dihydrochloride [1- (2-methylbenzimidazol-5-yl) -5-ethyl-1 f / -pyrazol-4-carbonillquanidine 38% yield APCIMS 312 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 1.05 (br s, 3 H), 2.79 (s, 3 H), 2.88 (q, J = 7.6, 2 H), 7.60 (dd, J = 8.8, 1.6, 1 H), 7.93 (m, 2H), 8.46 (sa, 2H), 8.77 (sa, 2H), 8.85 (s, 1 H), 12.09 (s, 1 H).

EXAMPLE 32NN f1- (Benzothiazol-6-yl) -5-ethyl-1H-pyrazole-4-carbonylguanidine hydrochloride monohydrate 9. 5% yield APCIMS 315 [M + 1f 1 H NMR (CDC13) d 1.0-1.14 (t, 3H), 8.74 (s, 1H).

EXAMPLE 3200 H - (2-quinoxalinyl) -5-ethyl-1 A7-pyrazole-4-carbonipguanidine dihydrochloride 44% yield APCIMS 310 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 11.93 (s, 1 H), 9.44 (s, 1 H), 8.86 (s, 1 H), 8.64 (sa, 2H), 8.40 (sa, 2H), 8.16 (d, J = 8, 1 H), 8.043 (dd, J = 2.4, 8, 1H), 7.94-7.87 (m, 2H), 3.43 (q, J = 6, 2H) ), 1338 (t, J = 7, 3H).

EXAMPLE 32PP H - (2-benzimidacyl) -5-ethyl-1 H -pyrazole-4-carbonylguanidine dihydrochloride 44% yield APCIMS 298 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 12.15 (s, 1H), 8.97 (s, 1H), 8.73 (sa, 2H), 8.47 (sa, 2H), 7.56 (dd) , J = 3, 6, 2H), 7.22 (dd, J = 3.2, 6, 2H), 3.53 (q, J = 7, 2H), 1.24 (t, J = 7, 3H).

EXAMPLE 3200 f1 - (2-Trifluoromethyl-4-chlorophenyl) -5-cyclopropyl-1 A -pyrazol-4-carbonylguanidine hydrochloride 60% yield APCIMS 372 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 8.68 (br s, 3 H), 8.43 (br, 2 H), 8.14 (s, 1 H), 8.02 (d, J = 8, 1 H) , 7.84 (d, J = 9, 1H), 1.90 (m, 1H), 0.80 (d, J = 8, 2H), 0.693 (d, J = 4, 2H).

EXAMPLE 32RR f 1 - (2-Fluoro-6-trifluoromethylphenyl) -5-cyclopropyl-1 H -pyrazole-4-carbonillquanidine hydrochloride 71% yield APCIMS 356 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 8.71-8.44 (m, 5H), 8.00-7.90 (m, H), 1.82 (m, 1H), 0.89-0.70 (m, 4H).

EXAMPLE 32SS H- (2-trifluorometH-4-fluorophenyl) -5-cyclopropyl-1-pyrazol-4-carbonylguanidine hydrochloride 58% yield APCIMS 356 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 8.67 (br s, 3 H), 8.43 (br s, 2 H), 7.99 (d, J = 8, 1 H), 7.90-7.78 (m, 2H), 1.89 (m, 1H), 0.81-0.63 (m, 4H).

EXAMPLE 32TT f1- (1-Methylbenzimidaz-2-yl) -5-ethyl-1tf-pyrazole-4-carbonylguanidine hydrochloride 86% yield APCIMS 312 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 12.10 (s, 1 H), 8.96 (s, 1 H), 8.71 (br s, 2 H), 8.44 (br, 2 H), 7.69 (dd, J = 8.16, 2H), 7.40-7.29 (m, 2H), 3.68 (s, 3H), 3.03 (q, J = 7, 2H), 1.12 (t, J = 7, 3H).

EXAMPLE 32UU H - (2-quinolinyl) -5-etl-1-W-pyrazole-4-carbonillquanidine dihydrochloride 65% yield APCIMS 309 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 11.86 (s, 1 H), 8.79 (s, 1 H), 8.65 (sa, 2 H), 8.61 (d, J = 9, 1H), 8.38 (sa, 2H), 8.07 (d, J = 8, 1H), 8.01-7.96 (m, 2H), 7.83 (m, 1 H), 7.66 (t, J = 7, 1 H), 3.44 (q, J = 7, 2H), 1.31 (t, J = 7, 3H).

EXAMPLE 32W H - (2-Chloro-5-methylaminocarbonylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carbonillquanidine hydrochloride 57% yield APCIMS 359 [M-1] '1 H NMR (400 MHz, DMSO-de) d 11.71 (s, 1 H), 8.67 (m, 1 H), 8.61 (ss, 3 H), 8.36 (ss, 2 H), 8.04 ( d, J = 7, 1 H), 8.03 (s, 1 H), 7.84 (d, J = 8, 1 H), 2.60 (d, J = 4, 3 H), 1.94 (m, 1 H), 0.75 (d, J = 7, 2H), 0.57 (m, 2H).

EXAMPLE 32WW f1 - (4-Benzimidazolyl) -5-cyclopropyl-1 A / -pyrazole-4-carbonipguanidine dihydrochloride 22% yield APCIMS 310 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 9.19 (br s, 2 H), 8.84 (d, J = 2.1 H), 8.80 (s, 1 H), 8.45 (br, 2 H) ), 7.92 (m, 1H), 7.69-7.58 (m, 2H), 2.16 (m, 1 H), 0.72 (d, J = 9, 2H), 0.44 (d, J = 5, 2H).

EXAMPLE 32XX f1 - (2-Chloro-5-iodophenyl) -5-cyclopropyl-1-pyrazol-4-carbonyl-guanidine hydrochloride 81% APCIMS yield 430 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 8.66 (br s, 2 H), 8.64 (s, 1 H), 8.40 (br s, 2 H), 8.18 (d, J = 2, 1H), 7.94 (dd, J = 2, 8, 1 H), 7.45 (d, J = 8, 1H), 1.94 (m, 1 H), 0.84-0.72 (m, 2H), 0.68- 0.58 (m, 2H).

EXAMPLE 32YY f 1 - (2-Chloro-5-aminocarbonylphenyl) -5-cyclopropyl-1-t-pyrazole-4-carboninquanidine hydrochloride 45% yield APCIMS 347 [M + 1] + 1 H NMR (300 MHz, DMSO-d 6) d 8.65 (br s, 2 H), 8.62 (s, 1 H), 8.37 (br s, 2 H), 8.20 (s, 1 H), 8.10 ( s, 1 H), 8.02 (d, J = 8, 1 H), 7.87 (d, J = 9, 1 H), 7.68 (s, 1 H), 1.96 (m, 1 H), 0.80 (d, J = 8, 2H), 0.61 (d, J = 3, 2H). EXAMPLE 32ZZ f1 - (2-Chloro-5-dimethylaminocarbonylphenyl) -5-cyclopropyl-1 H-pyrazole-4-carbonyl Hguanidine hydrochloride 49% yield APCIMS 347 [M + 1] + 1 H NMR (300 MHz, DMSO-de) d 8.60 (br s, 3 H), 8.38 (br s, 2 H), 7.82 (d, J = 8, 1 H), 7.76 (d, J = 2, 1H), 7.66 (m, 1H), 2.99 (s, 3H), 2.93 (s, 3H), 1.96 (m, 1H), 0.79 (d, J = 9, 1 H), 0.60 (d, J = 4, 2H).

EXAMPLE 32AAA f-phenyl-4-cyclopropyl-1 / -pyrazol-3-carbonylguanidine hydrochloride 22% yield APCIMS 270 [M + 1f 1 H NMR (300 MHz, DMSO-d 6) d 9.56 (br s, 1 H), 8.45 (br s, 4 H), 7.74 (d, J = 8, 2 H), 7.56 (t, J = 8, 2H), 7.40 (t, J = 7, 1 H), 2.62 (m, 1 H), 0.99-0.94 (m, 4H).

EXAMPLE 32BBB f1- (1-Isoquinolyl-5-cyclopropyl-1H-pyrazole-4-carbonylguanidine dihydrochloride 69% yield APCIMS 321 [M + 1] + 1 H NMR (400 MHz, DMSO-d 6) d 11.99 (s, 1 H), 8.79 (s, 1 H), 8.77 (br s, 2 H), 8.51 (d, J = 6, 1 H), 8.49 (sa, 2H), 8.13 (d, J = 8, 1 H), 8.10 (d, J = 6, 1 H), 7.85 (dd, J = 7.8, 1H), 7.9-7.6 (sa , 1H), 7.69 (dd, J = 7, 8, 1H), 7.46 (d, J = 8, 1H), 2.05 (m, 1 H), 0.61-0.57 (m, 2H), 0.37-0.33 (m , 2H).

EXAMPLE 32CCC f1 - (2,3-dimethoxyphenyl) -5-cyclopropyl-1 H -pyrazole-4-carbonillquanidine hydrochloride 38% yield APCIMS 330 [M + 1] + H NMR (400 MHz, DMSO-d6) d 0.57 (d, J = 4.8, 2H), 0.72 (d, J = 8.4, 2H), 1.91 (m, 1H), 3.57 ( s, 3H), 3.86 (s, 3H), 6.97 (d, J = 8, 1H), 7.22 (m, 2H), 8.34 (sa, 2H), 8.56 (s, 1H), 8.65 (sa, 2H) , 11.67 (s, 1H).

EXAMPLE 33A N-tert-butoxycarbonyl-Ny-f5-isopropyl-1- (6-guinolinyl) -1A7-pyrazole-4-carbonylguanidine To a solution of S-isopropyl-1-β-quinoline-1H-pyrazole-carboxylic acid (336.7 mg, 1.2 mmol) in 5 ml of dimethylformamide, NN-diisopropylethylamine (0.42 ml, 2.39 mmol), benzotriazole hexafluorophosphate was added. -1-iloxitris (dimethylamino) phosphonium (BOP reagent) 582 ml, 1.32 mmol) and urea-butoxycarbonylguanidine (210 mg, 1.32 mmol). The resulting solution was stirred at room temperature for 2 h, then heated at 60 ° C for 2 h. The reaction mixture was then cooled to room temperature and concentrated to dryness in vacuo. The solid residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (sodium sulfate) and concentrated to dryness in vacuo. The solid residue was triturated with methanol (1.5 ml), filtered, washed with diethyl ether, and dried to yield the title compound as a white solid (114.3 mg, 22.5% yield). 1 H NMR (DMSO-de) d 1.27 (d, 6H), 1.42 (s, 9H), 3.28 (m, 1H), 7.62 (q, 1 H), 7.74 (q, 1 H), 8.08-8.15 (m , 4H), 8.47 (d, 1 H), 8.98 (d, 1 H), 9.21 (sa, 1H), 10.9 (sa, 1 H). The title compound of Example 33B was obtained using a procedure analogous to that used for Example 33A.

EXAMPLE 33B N-Ferro-butoxycarbonyl-N75-propyl-1- (6-guinolinyl) -1A7-pyrazole-4-carbonipguanidine 58. 9% yield 1 H NMR (DMSO-d 6) d 0.73 (t, 3 H), 1.24 (d, 2 H), 1.47 (s, 9 H), 3.08 (t, 2 H), 7.66 (q, 1 H), 7.86 (q, 1 H ), 8.18 (m, 3H), 8.51 (s + d, 2H), 9.01 (t, 1 H), 9.39 (ss, 1 H), 11.0 (ss, 1 H).

EXAMPLE 34A fS-isopropyl-l-fß-guinolini-1 / y-pyrazo-M-carbonylguanidine trifluoroacetate A solution of N-urea-butoxycarbonyl-N '- [5-γ-sopropyl-1- (6-quinolinyl) -1 H-pyrrazol-4-carbonyl] guanidine (114.3 mg, 0.27 mmoles) in 2 ml of dichloromethane containing 20% trifluoroacetic acid was stirred at room temperature overnight and was treated with ether. The resulting precipitate was filtered, yielding the title compound as a white solid (104.3 mg, 70% yield). 1 H NMR (DMSO-d 6) d 1.29 (d, 6H), 3.23 (m, 1H), 7.68 (q, 1H), 7.8 (dd, 1 H), 8.18-8.55 (m, 7H), 9.04 (t, 1 H), 11.1 (s, 1 H). The title compound of Example 34B was obtained using a procedure analogous to that used for Example 34A.

EXAMPLE 34B f5-propyl-1- (6-guinolinyl) -1 7-pyrazole-4-carbonylguanidine trifluoroacetate 81. 2% yield 1 H NMR (DMSO-de) d 0.72 (t, 3 H), 1.47 (d, 2 H), 2.97 (t, 2 H), 7.67 (t, 1 H), 7.87 (d, 1 H), 8.19-8.37 (m, 7 H) ), 8.53 (d, 1H), 9.03 (s, 1H), 11.1 (s, 1H).

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A compound that has the formula I Formula a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug wherein Z is bonded to a carbon and is a di-saturated diaza ring of five links having two contiguous nitrogens, said ring being optionally mono-, di- or trisubstituted with up to three substituents independently selected from R1, R2 and R3; or Z is bonded to a carbon and is a di-saturated diaza ring of five links, said ring being optionally mono- or disubstituted with up to two substituents independently selected from R4 and R5; wherein R1, R2, R3, R4 and R5 are each independently hydrogen, hydroxy alkyl (dd), alkyl (dd), alkylthio (dd), cycloalkyl (C3-C4), cycloalkyl (C3-C7) alkyl ( dd), alkoxy (dd), alkoxy (dd) alkyl (dd), mono-N- or di-N, N-alkyl (dd) carbamoyl, M or M-alkyl (dd), said alkyl moieties optionally having (dd) ) from one to nine fluorine atoms; said alkyl (dd) or cycloalkyl (C3-C4) being independently mono- or disubstituted with hydroxy, alkoxy (dd), alkyl (Crd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl, alkyl (dd), mono -N- or di-N, N-alkyl (dd) carbamoyl or mono-N- or di-N, N-alkyld (dd) aminosulfonyl and said cycloalkyl (C3-C4) optionally having from one to seven fluorine atoms; M being a partially saturated, fully saturated or fully unsaturated ring of between five and eight links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two partially saturated, fully saturated condensed rings or totally unsaturated from three to six links, independently considered, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; said optionally substituted M being on a ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, where one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with alkyl (dd) and further R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), formyl, alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl ( dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, thiol, alkyl (d-) djtio, alkyl (dd) sulfinyl, alkyl (dd) sulfo nyl, mono-N- or di-N, N-alkyl (dd) aminosulfonyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C5-C7) cycloalkenyl, said substituents R6, R7 and R8 are alkoxy (C1) -C4), (C1-C4) alkyl, alkanoyl (d-C7), alkyl (CrC4) thio, mono-No d-N, N-alkyl (dd) amino or (C3-C7) cycloalkyl optionally independently monosubstituted with hydroxy , alkoxy (dd) carbonyl, cycloalkyl (C3-C7), alkanoyl (C1-C4), alkanoyl (C1-C4) amino, alkanoyloxy (d-C4), alkoxy (C1-C4) carbonylamino, sulfonamido, alkyl (C1- C4) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, cyano, thiol, nitro, alkyl (CrC) thio, alkyl (dd) sulfinyl, (C 1 -C 4) alkylsulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms.
2. A compound according to claim 1, further characterized in that Z is R1 and R3 are each independently hydrogen, alkyl (dd), cycloalkyl (C3-C7, phenyl or phenylalkyl (dd), said alkyl (dd) being optionally substituted with one to nine fluorine atoms, said substituents R1 and R3 optionally mono or disubstituted independently with hydroxy, alkoxy (dd), alkyl (dd ^ io, alkyl (dd) sulfinyl or alkyl (d-C4) sulfonyl; and R2 is unsubstituted (C1-C4) alkyl or (C3-C7) cycloalkyl; or R2 is phenyl, phenylalkyl (dd), pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said R2 substituent optionally mono-, di or trisubstituted independently with halogen, alkyl (dd), alkoxy (dd), hydroxy, (C1-C4) alkoxycarbonyl, mono-N- or di-N, N-alkyl (dd) carbamoyl , mono-No di-N, N-alkyl (dd) amino, alkyl (dd) sulfonyl or sulfonamido, said alkyl (dd) or alkoxy (Crd) being optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts of the same.
3. A compound according to claim 2, further characterized in that R1 is alkyl (d-d) or cycloalkyl (C3-C7); R2 is phenyl, optionally mono- or disubstituted; and R3 is hydrogen or the pharmaceutically acceptable salts thereof.
4. A compound according to claim 2, further characterized in that the compound is [1- (2-chlorophenyl-) - 5-methyl-1H-pyrazole-4-carbonyl] guanidine; [5-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carbonyljguanidine; [5-ethyl-1-phenyl-1 H-pyrrazol-4-carbonyl] guanidine; [5-cyclopropyl-1- (2-trifluoromethylphenyl) -1 H-pyrrazol-4-carbonyl] guanidine; [5-cyclopropyl-1-phenyl-1 H-pyrazole-4-carbonyl] guanidine; or [5-cyclopropyl] -1- (2,6-dichlorophenyl) -1 H -pyrrazole-4-carbonyl] guanidine or the pharmaceutically acceptable salts thereof. 5. - A compound according to claim 3, further characterized in that R2 is 2-chlorophenyl; and R1 is methyl or the pharmaceutically acceptable salts thereof. 6. A compound according to claim 3, further characterized in that R2 is 2-trifluoromethylphenyl; and R1 is methyl or the pharmaceutically acceptable salts thereof. 7. A compound according to claim 3, further characterized in that R2 is phenyl; and R1 is ethyl or pharmaceutically acceptable salts thereof. 8. A compound according to claim 3, further characterized in that R2 is 2-trifluoromethylphenyl; and R1 is cyclopropyl or the pharmaceutically acceptable salts thereof. 9. A compound according to claim 3, further characterized in that R2 is phenyl; and R is cyclopropyl or the pharmaceutically acceptable salts thereof. 10. A compound according to claim 3, further characterized in that R2 is 2,6-dichlorophenyl; and R1 is cyclopropyl or the pharmaceutically acceptable salts thereof. 11. A compound according to claim 2, further characterized in that the compound is R1 is alkyl (dd) or cycloalkyl (C3-C7; R2 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopiranyl, benzothiophenyl) , benzodioxanil or benzodioxolílo, said R2 substituent optionally monosubstituted, and R3 is hydrogen or pharmaceutically acceptable salts thereof 12. A compound according to claim 1, further characterized in that the compound is [5-methyl-1- ( quinolin-6-yl) -1 H-pyrazole-4-carbonyl] guanidine; [5-methyl-1 - (naphthalene-1-yl) -1 H -pyrazole-4-carbonyljuanidine; [5-cyclopropyl-1 - ( quinolin-5-yl) -1 H-pyrazole-4-carbonyljguanidine; or [5-cyclopropyl-1- (quinolin-8-yl) -1 H -pyrazole-4-carbonyl] guanidine or pharmaceutically acceptable salts 13. A compound according to claim 11, further characterized in that R2 is naphthalenyl and R1 is methyl or the pharmaceutically acceptable salts thereof. 14. A compound according to claim 11, further characterized in that R2 is 5-quinolinyl and R1 is cyclopropyl or the pharmaceutically acceptable salts thereof. 15. A compound according to claim 11, further characterized in that R2 is 8-quinolinyl; and R1 is cyclopropyl or the pharmaceutically acceptable salts thereof. 16. A compound according to claim 11, further characterized in that R2 is 6-quinolinyl; and R1 is methyl or the pharmaceutically acceptable salts thereof. 17. A compound according to claim 2, further characterized in that R1 is hydrogen; R2 is phenyl, optionally mono- or di-substituted; and R is alkyl (d-d) or (C3-C7) cycloalkyl or the pharmaceutically acceptable salts thereof. 18. A compound according to claim 1, further characterized in that the compound is [3-methyl-1-phenyl-1H-pyrazole-4-carbonyljguanidine; [3-methyl-1- (naphthalen-1-yl) -1 H-pyrazole-4-carbonyl] guanidine; or [3-methyl-1- (isoquinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine or the pharmaceutically acceptable salts thereof. 19. A compound according to claim 17, further characterized in that R2 is phenyl; and R3 is methyl or the pharmaceutically acceptable salts thereof. 20. A compound according to claim 2, further characterized in that R1 is hydrogen; R2 is naphthalenyl, quinolinyl, isoquinolinyl, cynolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said substituent R2 being optionally monosubstituted; and R3 is alkyl (d-d) or (C3-C7) cycloalkyl or the pharmaceutically acceptable salts thereof. 21. A compound according to claim 20, further characterized in that R2 is 1-naphthalenyl; and R3 is methyl or the pharmaceutically acceptable salts thereof. 22. A compound according to claim 20, further characterized in that R2 is 5-isoquinolyl; and R3 is methyl or the pharmaceutically acceptable salts thereof. 23. - A compound according to claim 1, further characterized in that Z is R1 is hydrogen, alkyl (dd), cycloalkyl (C3-C7), phenyl or phenylalkyl (d-C4), said alkyl (dd) being optionally substituted with one to nine fluorine atoms, said substituents R1 being optionally mono- or disubstituted independently with hydroxy, alkoxy (dd), alkyl (Crd) thio, alkyl (C1-C4) sulfinyl or alkyl (dd) sulfonyl and R2 and R3 are each independently alkyl (dd) or cycloalkyl (C3-C7) not replaced; or R2 and R3 are each independently phenyl or phenylalkyl (dd), pyridyl or pyrimidinyl or a bicyclic ring consisting of two fused rings of five and / or six independently considered, optionally having one to four heteroatoms independently selected from nitrogen , sulfur and oxygen, said substituents R2 and R3 being optionally mono-, di- or trisubstituted independently with halogen, alkyl (dd), (C1-C4) alkoxy, hydroxy, alkoxy (Crd) carbonyl, mono-N- or di- , N, N-alkyl (Cid) carbamoyl, mono-No di-NN-(C1-C4) alkyl amino, (C1-C4) alkylsulfonyl or sulfonamido, said (C1-C4) alkyl or (C1-C4) alkoxy ) optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. 24. - A compound as recited in claim 1, the compound being [4-methyl-1-phenyl-1 H-pyrazole-3-carbonyl] guanidine or a pharmaceutically acceptable salt thereof. 25. A compound as cited in claim 23, wherein R3 is phenyl; R1 is methyl; and R2 is H or the pharmaceutically acceptable salts thereof. 26. A compound as cited in claim 23, wherein Z is R1 and R3 are each independently hydrogen, alkyl (Crd), cycloalkyl (C3-C7), phenyl or phenylalkyl (dd) optionally substituted with one to nine fluorine atoms, said substituents R1 and R3 being optionally mono or disubstituted independently with hydroxy, alkoxy (dd), alkyl (dd) thio, alkyl (dd) sulfinyl or alkyl (dd) sulfonyl; and R2 is unsubstituted alkyl (d-d) or cycloalkyl (C3-C7); or R2 is phenyl, phenylalkyl (dd), pyridyl or primidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, being said substituent R optionally mono-, di or trisubstituted independently with halogen, alkyl (dd), alkoxy (dd), hydroxy, alkoxy (dd) carbonyl, mono-N- or di-NN-alkyl (dd) carbamoyl, mono-N - or di-NN-alkyl (dd) amino, alkyl (dd) sulfonyl or sulfonamido, said alkyl (dd) or alkoxy (dd) being optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. 27. A compound as recited in claim 26, wherein R1 is alkyl (d-d) or cycloalkyl (C3-C7); R2 is phenyl, optionally mono- or disubstituted; and R3 is hydrogen or the pharmaceutically acceptable salts thereof. 28. A compound as recited in claim 26, wherein R is alkyl (d-d) or cycloalkyl (C3-C7); R 2 is naphthalenyl, quinolinyl, isoquinolinyl, cynolinyl, phthaiazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said R 2 being optionally mono-substituted; and R3 is hydrogen or the pharmaceutically acceptable salts thereof. 29. A compound as cited in claim 26, wherein R1 is hydrogen; R2 is phenyl, optionally mono- or disubstituted; and R3 is alkyl (d-d) or (C3-C7) cycloalkyl or the pharmaceutically acceptable salts thereof. 30. A compound as recited in claim 1, wherein the compound is [2-methyl-5-phenyl-2H-pyrazole-3-carbonyl] guanidine; or [2-methyl-5- (naphthalen-1-yl) -2H-pyrazole-3-carbonyl] guanidine or the pharmaceutically acceptable salts thereof. 31. - A compound as recited in claim 29, wherein R2 is phenyl; and R3 is mephyl or the pharmaceutically acceptable salts thereof. 32. A compound as recited in claim 26, wherein R1 is hydrogen; R 2 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said R 2 being optionally monosubstituted; and R3 is alkyl (d-d) or cycloalkyl (Ord-) or the pharmaceutically acceptable salts thereof. 33. A compound as recited in claim 32, wherein R2 is 1-naphthalenyl; and R3 is mephyl or the pharmaceutically acceptable salts thereof. 34. A compound as cited in claim 1, wherein Z is R4 is hydrogen, alkyl (dd), cycloalkyl (C3-C7), phenyl or phenylalkyl (dd), said alkyl (dd) being optionally substituted with one to nine fluorine atoms, said substituent R4 being optionally mono- or di-substituted independently with hydroxy, alkoxy (dd), alkyl (dd) thio, alkyl (dd) sulfinyl or alkyl (dd) sulfonyl and R5 is unsubstituted alkyl (dd) or cycloalkyl (C3-C7); or R5 is phenyl or phenylalkyl (dd), pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, being said substituent R5 optionally mono-, di- or trisubstituted independently with halogen, alkyl (dd), alkoxy (dd), hydroxy, alkoxy (dd) carbonyl, mono-N- or di-NN-alkyl (dd) carbamoyl, mono- N- or di-NN-alkyl (dd) amino, alkyl (dd) sulfonyl or sulfonamido, said alkyl (dd) or alkoxy (dd) being optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. 35.- A compound as cited in claim 1, wherein Z is R4 is hydrogen, alkyl (dd), (C3-C7) cycloalkyl, phenyl or phenylalkyl (dd), said alkyl (dd) being optionally substituted with one to nine fluorine atoms, said substituent R4 being optionally mono- or disubstituted independently with hydroxy, alkoxy (dd), alkyl (dd) thio, alkyl (dd) sulfinyl or alkyl (dd) sulfonyl and R5 is unsubstituted alkyl (dd) or cycloalkyl (C3-C7); or R5 is phenyl or phenyl (dd), pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said substituent R5 optionally mono-, di- or trisubstituted independently with halogen, alkyl (dd), alkoxy (dd), hydroxy, alkoxy (dd) carbonyl, mono-N- or di-NN-alkyl (dd) carbamoyl, mono- N- or di-NN-alkyl (C1-C4) amino, alkyl (dd) sulfonyl or sulfonamido, said alkyl (dd) or alkoxy (dd) being optionally substituted with one to nine fluorine atoms or pharmaceutically acceptable salts thereof . 36.- A compound as cited in claim 1, wherein Z is R4 is hydrogen, alkyl (dd), (C3-C7) cycloalkyl, phenyl or phenylalkyl (dd), said alkyl (dd) being optionally substituted with one to nine fluorine atoms, said substituent R4 being optionally mono- or disubstituted independently with hydroxy, alkoxy (dd), alkyl (dd) thio, (C 1 -C 4) alkylsulfinyl or alkyl (dd) sulfonyl and R 5 is unsubstituted alkyl (dd) or cycloalkyl (C 3 -C 7); or R5 is phenyl or phenylalkyl (dd), pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, being said substituent R5 optionally mono-, di- or trisubstituted independently with halogen, alkyl (dd), alkoxy (dd), hydroxy, alkoxy (dd) carbonyl, mono-N- or di-NN-alkyl (dd) carbamoyl, mono- N- or di-NN-alkyl (Crd) amino, (C 1 -C 4) alkylsulfonyl or sulfonamido, said alkyl (dd) or (C 1 -C 4) alkoxy optionally substituted with one to nine fluorine atoms or pharmaceutically acceptable salts of the same. 37.- A compound as cited in claim 1, wherein Z is R is hydrogen, alkyl (dd), (C3-C7) cycloalkyl, phenyl or phenylalkyl (dd), said alkyl (dd) being optionally substituted with one to nine fluorine atoms, said substituent R4 being optionally mono- or disubstituted independently with hydroxy, alkoxy (dd), alkyl (dd) thio, alkyl (dd) sulfinyl or alkyl (dd) sulfonyl and R5 is unsubstituted alkyl (dd) or cycloalkyl (C3-C7); or R5 is phenyl or phenylalkyl (Crd), pyridyl or pyrimidinyl or a bicyclic ring constituted by two fused rings of five and / or six links independently considered, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said substituent R5 optionally mono-, di- or trisubstituted independently with halogen, alkyl (dd), alkoxy (dd) hydroxy, alkoxy (dd) carbonyl, mono-N or di-N, N-alkyl (C1-C4) carbamoyl , mono-N- or di-NN-alkyl (dd) amino, alkyl (dd) sulfonyl or sulfonamido, said alkyl (dd) or alkoxy (Crd) being optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts of the same. 38. A compound as recited in claim 37, wherein R4 is alkyl (d-d) or cycloalkyl (C3-C7); and R5 is phenyl, optionally mono- or di-substituted or the pharmaceutically acceptable salts thereof. 39.- A compound as recited in claim 1, the compound being [5-methyl-2-phenyl-2H-1, 2,3-triazole-4-carbonyl] guanidine; [5-methyl-2- (3-methoxyphenyl) -2H-1, 2,3-triazole-4-carbonyl] guanidine; or [2 ~ (3-bromophenyl) -5-methyl-2H-1, 2,3-triazole-4-carbonyl] guanidine or the pharmaceutically acceptable salts thereof. 40.- A compound as cited in claim 38, wherein R5 is phenyl; and R 4 is methyl or the pharmaceutically acceptable salts thereof. 41. A compound as recited in claim 38, wherein R5 is 3-methoxyphenyl; and R 4 is methyl or the pharmaceutically acceptable salts thereof. 42. A compound as cited in rejoining 38, wherein R5 is 3-bromophenyl; and R 4 is methyl or the pharmaceutically acceptable salts thereof. 43. - A compound as recited in claim 37, wherein R4 is alkyl (d-d) or cycloalkyl (C3-C7); and R5 is naphthalenyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said substituents R5 being optionally monosubstituted. 44. A compound as recited in claim 1, wherein the compound [2-naphthalen-1-yl] -5-methyl-2H-1, 2,3-triazole-4-carbonyl] guanidine; [2-isoquinolino-5-yl) -5-methyl-2H-1, 2,3-triazole-4-carbonyl] guanidine; or [5-methyl-2- (quinolin-5-yl) -2H-1, 2,3-triazole-4-carbonyl] guanidine or the pharmaceutically acceptable salts thereof. 45. A compound as recited in claim 43, wherein R5 is 1-naphthalenyl; and R 4 is methyl or the pharmaceutically acceptable salts thereof. 46. A compound as recited in claim 43, wherein R5 is 5-isoquinolinyl; and R 4 is methyl or the pharmaceutically acceptable salts thereof. 47. A compound as recited in claim 43, wherein R5 is 5-quinolinyl; and R 4 is methyl or pharmaceutically acceptable salts thereof. The use of a compound according to claim 1 or a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug for the manufacture of a medicament for reducing tissue damage as a consequence of ischemia, in a mammal. 49.- The use as claimed in claim 48, wherein the tissue is the heart, brain, liver, kidney, lung, intestine, skeletal muscle, spleen, pancreas, nervous, spinal cord, retinal tissue, vascular tissue or intestinal tissue. 50.- The use as claimed in claim 49, wherein the medicament comprising the compound of formula I is provided from about 0.01 mg / kg to about 50 mg / kg to the mammal per day. 51.- The use as claimed in claim 50, in which the mammal is a woman or a man. 52. The use as claimed in claim 51, wherein said tissue is the cardiac tissue. 53. The use as claimed in claim 51, wherein said tissue is brain tissue. 54.- The use as claimed in claim 51, wherein said tissue is the liver tissue. 55.- The use as claimed in claim 51, wherein said tissue is the renal tissue. 56.- The use as claimed in claim 51, wherein said tissue is the lung tissue. 57. - The use as claimed in claim 51, wherein said tissue is the intestinal tissue. 58.- The use as claimed in claim 51, wherein said tissue is the skeletal muscle tissue. 59. The use as claimed in claim 51, wherein said tissue is the splenic tissue. 60.- The use as claimed in claim 51, wherein said tissue is the pancreatic tissue. 61.- The use as claimed in claim 51, wherein said tissue is the retinal tissue. 62.- The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered prophylactically. 63. The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered before surgery. 64.- The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered before cardiac surgery. 65. The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered during surgery. 66. - The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered during cardiac surgery. 67. The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered within twenty-four hours after surgery. 68.- The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered within twenty-four hours after cardiac surgery. 69. The use as claimed in claim 51, in which tissue damage as a consequence of ischemia is ischemic damage and occurs during organ transplantation. 70. The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered to prevent perioperative myocardial ischemic injury. 71. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. 72.- A pharmaceutical composition for the reduction of tissue damage as a consequence of ischemia, comprising a therapeutically effective amount of a compound of claim 1 or a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable vehicle. 73.- A compound, said compound being 5-methyl-2- (5-quinoline) -2H-1, 2,3-triazole-4-carboxylic acid, 5-methyl-2- (5-isoquinoline) -2 - / - 1, 2,3-triazole-4-carboxylic acid, 2- (1-naphthale -5-methyl-2H-1, 2,3-triazole-4-carboxylic acid, 5-cyclopropyl-1 - ethyl (2-trifluoromethylphenol) -1 H-pyrazole-4-carboxylate, ethyl 5-methyl-1- (6-quinolin) -1W-pyrrazole-4-carboxylate, Epoyl 5-methyl-1-naphthalene-1 / - / - pyrazole-4-carboxylate, ethyl 5-cyclopropyl-1- (quinolin-8-yl) -1H-pyrazole-1-carboxylate, 5-cyclopropyl- 1- (quinolin-5-yl) -1 - / - pyrazole-4-carboxylic acid ethyl ester, 5-ethyl-1- (quinolin-5-yl) -1H-pyrazoyl-4-carboxylate, 1- (isoquinoline) N-butyl-5-methyl-1- (6-quinoline) -1 - / - proprazole-4-carboxylic acid, -5-yl) -3-methyl-1-pyrazol-4-carboxylate, acid -5-methyl-1-naphthale1-pyrazol-4-carboxylic acid, 5-cyclopropyl-1 - (quinolin-8-yl) -1-pyrazol-4-carboxylic acid, 5-cyclopropyl-1-acid - (2-trifluoromethylphenii) -1 / - -pyrazol-4-carboxylic acid, 5-e-acid lime-1 - (quinolin-5-yl) -1 H-pyrazole-4-carboxylic acid, 5-cyclopropyl-1 - (quinolin-5-yl) -1 H -pyrazole-4-carboxylic acid or-1-acid (isoquinolin-5-yl) -3-methyl-1 / - / - pyrazol-4-carboxylic acid or a pharmaceutically acceptable salt of said compounds. 74. The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered before, during and after surgery. 75. - The use as claimed in claim 51, wherein the medicament comprising the compound of formula I is administered before, during and after cardiac surgery. 76.- A compound as cited in claim 1, wherein Z is R1 is cycloalkyl (C3-C), phenyl or phenylalkyl (dd), said cycloalkyl (C3-C7) being optionally substituted with one to three fluorine atoms, said substituent R1 being optionally mono- or di-substituted independently with alkoxy (dd), alkyl (dd) thio, alkyl (dd) sulfinyl or alkyl (Crd) sulfonyl and R2 is alkyl (Crd), cycloalkyl (C3-C4), M or M-alkyl (dd), optionally having all the alkyl (dd) moieties above mentioned from one to nine fluorine atoms; said alkyl (dd) or cycloalkyl (C3-C) being optionally mono- or disubstituted independently with hydroxy, alkoxy (dd), alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl, alkyl (dd), mono-N- or di-N, N-alkyl (dd) carbamoyl or mono-N- or di-NN-alkyl (dd) aminosulfonyl and said cycloalkyl (C3-C4) optionally having from one to seven fluorine atoms; M being a partially saturated, fully saturated or fully unsaturated ring of five to eight links, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two partially saturated, fully saturated condensed rings or fully unsaturated of three to six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said optionally substituted M being on a ring if the remainder is monocyclic, or on one or both rings if the the rest is bicyclic, carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, optionally substituted with alkyl (dd) and further R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), formyl, alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N or di-N, N-alkyl (dd) carbamoyl, cyano, thiol, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl, mono-N or di-N, N-alkyl ( dd) aminosulfonyl, alkenyl (C2-d), alkynyl (C2-d) or cycloalkenyl (C5-C7), said substituents R6, R7 and R8 are alkoxy (dd), alkyl (dd), alkanoyl (dd), alkyl ( dd) thio, mono-N- or dí-N, N-alkyl (dd) amino or cycloalkyl (C3-C7) optionally monosubstituted independently with hydroxy, alkoxy (dd) carbonyl, cycloalkyl (C3-C7), alkanoyl (dd) , alkanoyl (dd) amino, alkanoyloxy (dd), (C 1 -C 4) alkoxycarbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-C 1 -C 4 alkylamino, carbamoyl, mono-N- or di- N, N-alkyl (dd) carbamoyl, cyano, thiol, nitro, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (d-C4) sulfonyl or mono- -? - or di- ?,? -alkyl ( dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. 77. A compound as recited in claim 1, wherein the compound [1- (naphthalen-1-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine or a pharmaceutically acceptable salt of the same. 78. A compound as recited in claim 76, wherein R1 is cyclopropyl; and R2 is 1-naphthalenyl or a pharmaceutically acceptable salt thereof. 79. A compound as recited in claim 76, wherein R1 is (C3-C7) cycloalkyl; and R2 is a six-membered monocyclic aromatic ring optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; said ring R2 being optionally monosubstituted on carbon or on nitrogen with a fully saturated or fully unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl ( dd); said ring R2 being optionally mono- or disubstituted independently on carbon or the nitrogen with hydroxy, halogen, alkoxy (Crd), alkoxy (Crd) carbonyl, alkyl (dd), alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, suifonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-NN-alkyl (dd) amino, carbamoyl, mono-N- or di-NN-alkyl (dd) carbamoyl , cyano, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N or di-NN-alkyl (dd) aminosulfonyl; said alkoxy (dd), alkyl (dd), alkanoyl (Crd), alkyl (dd) thio, mono-N or di-N, N-alkyld (dd) amino optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl , alkanoyl (CrC), alkanoyl (dd) amino, alkanoyloxy (dd), alkoxy (dd) carbonylamino, sulfonamido, alkyl (C1-C4) sulfonamido, amino, mono-N or di-N, N-alkylal (dd) amino, carbamoyl, mono-N or di-NN-alkyl (dd) carbamoyl, alkyl (Crd) thio, alkyl (C1-C4) sulfinyl, alkyl (dd) sulfonyl or mono-N or di-NN-alkyl (dd) ) aminosulfonyl or optionally substituted with one to nine fluorine atoms or the pharmaceutically acceptable salts thereof. 80.- A compound as recited in claim 79, wherein R1 is cyclopropyl; and R2 is phenyl, optionally mono- or di-substituted independently with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (C1-) C4) sulfonamido, mono-N or di-NN-alkyl (dd) amino, carbamoyl, mono-N- or di-NN-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl or mono-N or di-NN-alkyl (dd) aminosulfonyl; said substituents being alkoxy (dd), alkyl (dd) mono-N- or di-NN-alkyl (dd) amino optionally monosubstituted with hydroxy, alkanoyl (dd) amino, alkyl (C 1 -C 4) sulfonamido, amino, mono-N - or di-NN-alkyl (dd) amino mono-N- or di-NN-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl or mono-No di-NN-alkyl (dd) amino sulfonyl or optionally substituted with one to five fluorine atoms, or a pharmaceutically acceptable salt thereof. 81. A compound as recited in claim 1, wherein the compound is [5-cyclopropyl-1- (2-trifluoromethylphenyl) -1 / - / - pyrazol-4-carbonyl] guanidine; [5-cyclopropyl-1-phenyl-1-pyrazol-4-carbonyl] guanidine; [5-cyclopropyl-1- (2,6-dichlorophenyl-1H-pyrazole-4-carbonyl] guanidine or a pharmaceutically acceptable salt thereof. 82. A compound as recited in claim 1, wherein the compound is (2-Chloro-4-methylsulfonylphenyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; [1- (2-chlorophenyl) -5-cyclopropyl-1 / - / - pyrazole-4-carbonyl] guanidine; [1- (2-trifluoromethyl) -4-fluorophenyl) -5-cyclopropyl-1 / - / - pyrazole-4-carbonyl] guanidine; [1- (2-bromophenyl) -5-cyclopropyl-1H-pyrrazol-4-carbonyl] guanidine; [1- (2-fluorophenyl) -5-cyclopropyl-1 H-pyrazole-4-carbonyl] guanidine; [1 - (2-chloro-5-methoxyphenyl) -5-cyclopropyl-1-pyrazol-4-carbonyl] guanidine; [1- (2-chloro-4-methylaminosulfonylphenyl) -5-cyclopropyl-1H-pyrrazol-4-carbonyl] guanidine; [1- (2,5-Dichlorophenyl-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; [1- (2,3-dichlorophenyl-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; [1 - (2-chloro-5-aminocarbonylphenyl) -5-cyclopropyl-1-pyrazol-4-carbonyl] guanidine; [1 - (2-chloro-5-aminosulfonylphenyl) -5-cyclopropyl-1-pyrazol-4 carbonyl] guanidine; [1 - (2-fluoro-6-trifluoromethyl-phenyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; [1 - (2-chloro-5-methylsulfonyl-phenyl) -5-cyclopropyl-1H -pyrazol-4-carbonyl] guanidine; [1- (2-chloro-5-dimethylaminosulfonylphenyl) -5-cyclopropyl-1-pyrazol-4-carbonyl] guanidine; [1- (2-trifluoromethyl-4) -chlorophenyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine; or a pharmaceutically acceptable salt thereof. 83. A compound as recited in claim 80, wherein R2 is 2-chloro-4-methylsulfonylphenyl or a pharmaceutically acceptable salt thereof. 84. A compound as recited in claim 80, wherein R2 is 2-chlorophenyl or a pharmaceutically acceptable salt thereof. 85. A compound as recited in claim 80, wherein R2 is 2-trifluoromethyl-4-fluorophenyl or a pharmaceutically acceptable salt thereof. 86. A compound as recited in claim 80, wherein R2 is 2-bromophenyl or a pharmaceutically acceptable salt thereof. 87. A compound as recited in claim 80, wherein R2 is 2-fluorophenyl or a pharmaceutically acceptable salt thereof. 88. A compound as recited in claim 80, wherein R2 is 2-chloro-5-methoxyphenyl or the pharmaceutically acceptable salts thereof. 89. A compound as recited in claim 80, wherein R2 is 2-chloro-4-methylaminosulfonylphenyl or the pharmaceutically acceptable salts thereof. 90. - A compound as recited in claim 80, wherein R2 is 2,5-dichlorophenyl or the pharmaceutically acceptable salts thereof. 91. A compound as recited in claim 80, wherein R2 is 2,3-dichlorophenyl or the pharmaceutically acceptable salts thereof. 92. A compound as recited in claim 80, wherein R2 is 2-chloro-5-aminocarbonylphenyl or pharmaceutically acceptable salts thereof. 93. A compound as recited in claim 80, wherein R2 is 2-chloro-5-aminosulfonylphenol or the pharmaceutically acceptable salts thereof. 94. A compound as recited in claim 80, wherein R2 is 2-fluoro-6-trifluoromethylphenyl or the pharmaceutically acceptable salts thereof. 95. A compound as recited in claim 80, wherein R2 is 2-chloro-5-methylsulfonylphenyl or the pharmaceutically acceptable salts thereof. 96. A compound as recited in claim 80, wherein R2 is 2-chloro-5-dimethylaminosulfonylphenyl or the pharmaceutically acceptable salts thereof. 97. - A compound as recited in claim 80, wherein R2 is 2-trifluoromethyl-4-chlorophenyl or the pharmaceutically acceptable salts thereof. 98. A compound as recited in claim 76, wherein R2 is a non-aromatic heterocyclic ring of five to six links having one to two heteroatoms independently selected from nitrogen, sulfur and oxygen or R2 is alkyl ( dd) unsubstituted, unsubstituted (C3-C7) cycloalkyl or phenylalkyl (dd), wherein said phenylalkyl (dd) is optionally mono- or disubstituted independently with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di -N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said substituents being alkoxy (dd), alkyl (dd), mono-N - or di-N, N-alkyl (CrC4) amino optionally monosubstituted with hydroxy, alkanoyl (dd) amino, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) ami no, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) carbamoyl or optionally substituted with one to five carbon atoms fluorine; or a pharmaceutically acceptable salt thereof. 99. A compound as recited in claim 76, wherein R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said R2 substituent being optionally substituted on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated ring or fully unsaturated of three to seven links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with alkyl (dd) and further R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (dd) , alkoxy (dd) carbonyl, alkyl (dd), formyl, alkanoyl ( dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (Crd) amino, carbamoyl, cyano , thiol, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl, mono-N- or di-N, N-alkyl (dd) aminosulfonyl, alkenyl (C2-d), alkynyl (C2-C) ) or (C5-C7) cycloalkenyl, said alkoxy substituents being R6, R7 and R8 (C1-C4), (C1-C4) alkyl, alkanoyl (dd), alkyl (C1-C4) thio, mono-N- or di -N, N-C 1 -C 4 alkylamino or (C 3 -C 7) cycloalkyl optionally independently monosubstituted with hydroxy, alkoxy (dd) carbonyl, cycloalkyl (C3-C7), alkanoyl (dd), alkanoyl (C1-C4) amino, alkanoyl (dd) oxy, alkoxy (C1-C4) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino , mono-N-od-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, thiol, nitro, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (Cr d) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 100. A compound as recited in claim 99, wherein R1 is (C3-C7) cycloalkyl, and R2 is a bicyclic ring constituted by two fused rings of five and / or six partially saturated links, fully saturated or totally unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said bicyclic ring R2 being optionally monosubstituted on carbon or nitrogen with a fully saturated or fully unsaturated ring of five to six links having up to three heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (dd) and said bicyclic ring being R2 optionally mono or disubstituted on carbon or the nitrogen with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amine, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said alkoxy (dd), alkyl (dd) being , alkanoyl (dd), alkyl (dd) thio, mono-N- or dí-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl, alkanoyl (Crd), alkanoyl (dd) amino, alkanoyl (dd) oxy, (C 1 -C 4) alkoxy carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N -alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, alkyl (dd) thio, alkyl (Crd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salt thereof. 101. A compound as recited in claim 100, wherein R1 is cyclopropyl; and R 2 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolyl, cynolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxyl, benzimidazole, pentazolyl, benzotriazolyl, benzotriazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiadiazolyl ring, said ring being bicyclic R2 optionally mono- or disubstituted independently on carbon or nitrogen with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (Crd), alkanoyl (dd) amine, alkoxy (dd) carbonylamino, sulfonamido, alkyl (C1) -C4) sulfonamido, mono-N- or di-N, N-(C1-C4) alkylamino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl, or mono-No di-N, N-alkyl (dd) aminosulfonyl, said substituents being alkoxy (d-C4), alkyl (dd), mono-N- or di-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy , alkanoyl (dd) amine, alkyl (dd) sulfonamido, amino, mono-N- or di -N, N-alkyl (dd) amino, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) amino-sulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 102. A compound as recited in claim 101, wherein R2 is a quinolinyl, isoquinolinyl, indazolyl or benzimidazolyl ring, said bicyclic ring R2 being optionally mono- or disubstituted independently on carbon or nitrogen with hydroxy, halogen, alkoxy ( dd), alkoxy (dd) carbonyl, alkyl (Crd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, mono-N- od-N, N-alkyl (dd) amino , carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said substituents being alkoxy (dd) or alkyl (dd) optionally monosubstituted with hydroxy, alkanoyl (dd) amine, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutic salt acceptable mind of it. 103. A compound as recited in claim 1, the compound being [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine; or [5-cyclopropyl-1- (quinolin-8-yl) -1 H-pyrazole-4-carbonyl] guanidine; or a pharmaceutically acceptable salt thereof. 104. A compound as recited in claim 1, the compound being [1- (8-bromoquinolin-5-yl) -5-cyclopropyl-1 / - / - pyrazole-4-carbonyl] guanidine; [1- (6-chloroquinolin-5-yl) -5-cyclopropyl-1 / - / - pyrazol-4-carbonyl] guanidine; [1- (indazol-7-yl) -5-cyc] ppropyl-1-1H-pyrazole-4-carbonyl] guanidine; [1- (benzimidazol-5-yl) -5-cyclopropyl-1 H-pyrazole-4-carbonyl] guanidine; [1 - (1-isoquinolin) -5-cyclopropyl-1 - / - pyrazole-4-carbonyl] guanidine; [5-cyclopropyl-1- (4-quinolin) -1-pyrazol-4-carbonyl] guanidine; or a pharmaceutically acceptable salt thereof. 105. A compound as recited in claim 102, wherein R2 is 8-bromoquinolin-5-yl or a pharmaceutically acceptable salt thereof. 106. A compound as recited in claim 102, wherein R2 is 6-chloroquinolin-5-yl or pharmaceutically acceptable salts thereof. 107. A compound as recited in claim 102, wherein R2 is indazol-7-yl or the pharmaceutically acceptable salts thereof. 108.- A compound as cited in claim 102, wherein R2 is benzimidazol-5-yl. 109. A compound as recited in claim 102, wherein R2 is 1-isoquinolyl or pharmaceutically acceptable salts thereof. 110. A compound as recited in claim 102, wherein R2 is 4-quinolinyl or the pharmaceutically acceptable salts thereof. 111. A compound as recited in claim 1, wherein Z is R 1 is alkyl (dd), (C 3 -C 7) cycloalkyl, phenyl or phenyl alkyl (dd), said alkyl (dd) being optionally substituted with one to nine fluorine atoms said substituent R1 being optionally mono- or disubstituted independently with alkoxy (dd), alkyl (dd) fio, alkyl (dd) sulfinyl or alkyl (dd) sulfonyl and R2 is a non-aromatic heterocyclic ring of five to six links having one to two heteroatoms independently selected from nitrogen, sulfur and oxygen or R2 is unsubstituted alkyl (dd) or unsubstituted cycloalkyl (dd); or R2 is phenyl alkyl (dd) or a bicyclic ring constituted by two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said R2 substituents being optionally substituted on carbon or nitrogen with up to three substituents selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of between three to seven links optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with alkyl (dd) and further R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl ( dd), formyl, alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (C) 1-C4) carbonylamine, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (C 1 -C 4) amino, carbamoyl, mono-N- or di-N, N-alkyl ( dd) carbamoyl, cyano, thiol, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl, mono-N- or di-N, N-alkyl (dd) aminosulfonyl, alkenyl (C2-C4), alkynyl (C2-C) aminosulfonyl, alkenyl (C2-C), alkynyl (C2-d) or cycloalkenyl (C5-C7), said alkoxy (dd), alkyl (dd), alkanoyl (d-C7), alkyl ( CrC) thio, mono-N- or di-N, N-alkyl (dd) amino or (C3-C7) cycloalkyl and substituents R6, R7 and R8 optionally monosubstituted independently with hydroxy, alkoxy (dd) carbonyl, cycloalkyl (C3) -C7), alkanoyl (C1-C4) amine, alkanoyloxy (dd), alkoxy (C1-C4) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dC) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, thiol, nitro, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or om ono-N-o di-N, N-alkyl (d-d) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 112. A compound recited in claim 111, wherein R1 is alkyl (d-d); and R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said bicyclic ring being R2 optionally monosubstituted on carbon or nitrogen with a ring of five to six links, fully saturated or fully unsaturated having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (dd) and said bicyclic ring R2 optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N - or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, alkyl (Crd) thio, alkyl (dd) sulfinyl, alkyl (dd) ) sulfonyl or mono-N- or di-N, N-alkyl (Crd) aminosulfonyl, said alkoxy (dd), alkyl (dd), alkanoyl (dd), alkyl (dd) thio, mono-N- or di- N, N-alkyl (dd) amino are optionally monosubstituted with hydroxy, alkoxy (Crd) carbonyl, alkanoyl (C1-C4), alkanoyl (dd) amino, alkanoyloxy (dd), alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) ) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salt thereof. 113.- A compound as cited in claim 112, wherein R 2 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cincholinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl, benzimidazolyl, pentazolyl, indolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiadiazolyl group, said bicyclic ring R2 being optionally mono- or di-substituted independently with hydroxy, halogen, (C1-C4) alkoxy, alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dC) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (C1-C4) sulfonamido, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl, or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said substituents being alkoxy (dd), (C 1 -C 4) alkyl, mono-N- or di-N, N-alkyl (C 1 -C 4) amino optionally monosubstituted with hydroxy, alkanoyl (dd) amine, alkyl (CrC4) sulfonamido, amino, mono-N- or di-N, N-al quil (dd) amino, mono-N- or di-N, N-C 1 -C 4 alkylcarbamoyl, alkyl (Crd) sulfonyl or mono-N- or di-N, N-alkyl (dd) amino-sulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 114. A compound as recited in claim 1, the compound being [1- (ndazoI-6-yl) -5-ethyl-1-p-arazoI-4-carbonyl] guanidine; [1- (ndazol-5-yl) -5-ethyl-1 H-pyrazol-4-carbonyl] guanidine; [1 - (benzimidazol-5-yl) -5-ethyl-1 H-pyrazole-4-carbonyl] guanidine; [1- (1-methylbenzimidazol-6-yl) -5-ethyl-1-pyrazol-4-carbonyl] guanidine; [1 - (5-quinolin-5) - /? - propyl-1 H -pyrazol-4-carbonyl] guanidine; [1- (5-quinolin-5) -5-isopropyl-1 - / - pyrazole-4-carbonyl] guanidine; [1-ethyl-1 - (6-quinolin-1 H-pyrazolo-4-carbonyl] guanidine; [1 - (2-methylbenzimidazol-5-yl) -5-ethyl-1-pyrazol-4-carbonyl] guanidine; [1- (1,4-benzodioxan-6-yl) -5-ethyl-1-pyrazol-4-carbonyl] guanidine; [1 - (benzotriazol-5-yl) -5-ethyl-1 / - / -pyrazol-4-carbonyl] guanidine; [1- (3-chloroindazol-5-yl) -5-etl-1H-pyrazole-4-carbonyl] guanidine; [1- (5-quinolin) -5-butyl -1 H-pyrazole-4-carbonyl] guanidine; [5-propyl-1- (6-quinoline) -1H-pyrazole-4-carbonyl] guanidine; [5-isopropyl-1- (6-quinoline) -1 - pyrazol-4-carbonyl] guanidine, or a pharmaceutically acceptable salt thereof - A compound as recited in claim 113, wherein R 1 is ethyl, and R 2 is indazol-6-yl or pharmaceutically acceptable salts thereof 116. A compound as recited in claim 113, wherein R 1 is efil, and R 2 is indazol-5-yl or the pharmaceutically acceptable salts thereof. the one cited in claim 113, wherein R1 is ethyl, and R2 e s benzimidazol-5-yl or the pharmaceutically acceptable salts thereof. 118. A compound as recited in claim 113, wherein R1 is ethyl; and R2 is 1-mehylbenzimidazole-6-yl or the pharmaceutically acceptable salts thereof. 119. A compound as recited in claim 113, wherein R1 is p-propyl; and R2 is 5-quinolinyl or the pharmaceutically acceptable salts thereof. 120. - A compound as recited in claim 113, wherein R1 is isopropyl; and R2 is 5-quinolinyl or the pharmaceutically acceptable salts thereof. 121. A compound as recited in claim 113, wherein R1 is ethyl; and R 2 is 6-quinolinyl or the pharmaceutically acceptable salts thereof. 122. A compound as recited in claim 113, wherein R1 is ethyl; and R2 is 2-methylbenzamidazol-5-yl or the pharmaceutically acceptable salts thereof. 123. A compound as recited in claim 113, wherein R1 is ethyl; and R 2 is 1,4-benzodioxan-6-yl or the pharmaceutically acceptable salts thereof. 124. A compound as recited in claim 113, wherein R 1 is ethyl; and R2 is benzotriazol-5-yl or the pharmaceutically acceptable salts thereof. 125. A compound as cited in claim 113, wherein R1 is efil; and R2 is 3-chloroindazol-5-yl or the pharmaceutically acceptable salts thereof. 126. A compound as recited in claim 113, wherein R1 is butyl; and R2 is 5-quinolinyl or the pharmaceutically acceptable salts thereof. 127. - A compound as recited in claim 113, wherein R1 is p-propyl; and R 2 is 6-quinolinyl or the pharmaceutically acceptable salts thereof. 128. A compound as recited in claim 113, wherein R1 is isopropyl; and R 2 is 6-quinolinyl or the pharmaceutically acceptable salts thereof. 129.- A compound as cited in claim 1, wherein R1 is alkyl (Crd), (C3-C7) cycloalkyl, phenyl or phenyl alkyl (dd), said alkyl (Crd) being optionally substituted with one to nine fluorine atoms, said substituent R1 being optionally mono- or disubstituted independently with alkoxy (dd), alkyl (dd) thio, alkyl (dd) sulfinyl or alkyl (dd) sulfonyl and R 2 is a non-aromatic heterocyclic ring of five to six links having one to two heteroatoms independently selected from nitrogen, sulfur and oxygen; or R2 is unsubstituted alkyl (d-d) or unsubstituted (C3-C) cycloalkyl; or R2 is phenyl alkyl (dd) or a bicyclic ring constituted by two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said R2 substituents being optionally substituted on carbon or nitrogen with up to three substituents selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of between three to seven links optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with alkyl (dd) and further R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl ( dd), formyl, alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or dí-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl , cyano, thiol, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (Crd) sulfonyl, mono-N- or di-N, N-alkyl (dd) aminosulfonyl, alkenyl (C2-C), alkynyl (C2) -d) or (C5-C7) cycloalkenyl, said substituents R6, R7 and R8 are alkoxy (dd), alkyl (CrC4), alkanoyl (d-C7), alkyl (C1-C4) fio, mono-No di-N , N-alkyl (dd) amino or (C3-C7) cycloalkyl optionally monosubstituted independently with hydroxy, alkoxy (dd) carbonyl, cycloalkyl (C3-C7), alkanoyl (CrC4) amine, alkanoyloxy (Crd), alkoxy (dd) carbonyl amino , sulfonamido, alkyl (C 1 -C 4) sulfonamido, amino, mono-N- or di-N, N-alquíl (dd) amino, carbamoílo, mono-N- or dí-N, N-alquil (dd) carbamoílo, cíano , thiol, nitro, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dC) sulfonyl or mono-N- or di-N, N -alkyl (dd) aminosulfonyl or optionally and substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 130.- A compound as cited in claim 129, wherein R1 is alkyl (d-d); and R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said bicyclic ring being R2 optionally monosubstituted on carbon or nitrogen with a fully unsaturated ring of 5 to 6 links having, optionally, from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring being optionally monosubstituted with alkyl (dd) and said bicyclic ring being R2 also optionally mono- or di-substituted on carbon or nitrogen with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) ) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N , N-alkyl (dd) aminosulfonyl, said alkoxy (dd), alkyl (dd), alkanoyl (dd), alkyl (dd) thio, mono-N- or di-N, N-alkyl (dd) amino being optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl, alkanoyl (dd), alkanoyl (dd) amino, alkanoyloxy (dd), alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or the pharmaceutically acceptable salt thereof. 131. A compound as recited in claim 130, wherein R2 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cinolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl, benzimidazolyl, indazolyl, indolyl, benzotriazolyl, benzoxazolyl ring , benzisoxazoli, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiadiazolyl, said bicyclic ring R2 being optionally mono- or disubstituted independently with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dC) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (Crd) sulfonyl, or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said substituents being (C 1 -C 4) alkoxy, alkyl (dd), mono-N- or di-N, N-alkyl (C1-C4) amino optionally monosubstituted with hydroxy, alkanoyl (dd) amino, alkyl (d) -d) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, mono-N- or di-N, N-alkyl (C1-C4) carbamoyl, alkyl (dd) sulfonyl or mono -N- or di-N, N-C 1 -C 4 alkylaminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 132. - A compound as recited in claim 1, wherein the compound is [1- (ndazol-7-yl) -3-methy1-1H-pyrrazol-4-carbonyl] guanidine; [1- (2,1, 3-benzothiadiazol-4-yl) -3-methyl-1 / - / - pyrazole-4-carbonyl] guanidine; [3- (methyl- (1-quinolin-5-yl) -1-pyrazol-4-carbonyl] guanidine, or a pharmaceutically acceptable salt thereof, 133. A compound as recited in claim 131, that R1 is methyl, and R2 is indazol-7-yl or a pharmaceutically acceptable salt thereof 134. A compound as recited in claim 131, wherein R1 is methyl, and R2 is 1, 2.3- benzothiadiazol-4-yl or a pharmaceutically acceptable salt thereof 135. A compound as recited in claim 131, wherein R 1 is methyl, and R 2 is quinolin-5-yl or a pharmaceutically acceptable salt thereof. .- A compound as cited in claim 1, wherein Z is R 4 is alkyl (dd), cycloalkyl (dd), phenyl or phenyl alkyl (dd), said alkyl (dd) being optionally substituted with one to nine fluorine atoms, said substituent R 4 being optionally mono- or disubstituted independently with alkoxy (dd) ), alkyl (dd) thio, alkyl (dd) sulfinyl 8 or alkyl (dd) sulfonyl and R5 is a non-aromatic heterocyclic ring of five to six links, having from one to two heteroatoms independently selected from nitrogen, sulfur and oxygen or R5 is unsubstituted alkyl (dd) or cycloalkyl (C3-C7) unsubstituted, or R5 is phenyl alkyl (dd) or a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, having one to four heteroatoms independently selected from nitrogen , sulfur and oxygen, said substituents R5 being optionally substituted on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having from one to three heteroatoms selected independently Among oxygen, sulfur and nitrogen optionally substituted with alkyl (dd) and additionally Rd, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), formyl, alkanoyl (dd) ), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono- N- or di-N, N-alkyl (dd) carbamoyl, cyano, thiol, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (C1-C4) sulfonyl, mono-N- or di-N, N- alkyl (dd) aminosulfonyl, alkenyl (C2-C), alkynyl (C2-d) or cycloalkenyl (C5-C7), said substituents R6, R7 and R8 are alkoxy (dd), alkyl (dd), alkanoyl (dd), alkyl (dd) thio, mono-N- or di-N, N-alkyl (dd) amino or (C3-C7) cycloalkyl optionally independently monosubstituted with hydroxy, alkoxy (dd) carbonyl, cycloalkyl (C3-C7), alkanoyl ( dd), alkanoyl (dd) amino, alkanoyloxy (dd), alkoxy (dd) car bonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyan, thiol, nitro, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 137. A compound as recited in claim 136, wherein R4 is alkyl (Crd); and R5 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered, independently having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring being bicyclic R5 bicyclic optionally monosubstituted on carbon or a fully saturated or fully unsaturated ring of five to six links, optionally having from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (dd) and said bicyclic ring R5 being optionally mono or disubstituted on carbon or the nitrogen with hydroxy, halogen, alkoxy (dd) ), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd), aanoyloxy (dd), alkanoyl (Cr d) amino, (C 1 -C 4) alkoxy carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono- N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl ( dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said alkoxy (dd), (C1-C4) alkyl, alkanoyl (dd), alkyl (C1-C4) thio, mono- N- or di-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl, alkanoyl (dd), alkanoyl (dd) amino, alkanoyloxy (C1-C4) alkoxy (dd) carbonyl mino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-n- or di-N, N-alquíl (d-C4) amino, carbamoílo, mono-N- or dí-N, N-aIquil (C1-C4) carbamoyl, alkyl (d-C4), alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (Crd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 138. A compound as recited in claim 137, wherein R5 is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cynolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl, benzimidazolyl, iodazolyl, ndolyl, benzotriazolyl ring. , benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl or benzothiadiazolyl, said bicyclic ring R5 being optionally mono or indeterminate independently with hydroxy, halogen, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, alkyl (dd), alkanoyl ( C1-C4) amino, (C1-C4) alkoxycarbonylamino, sulfonamido, alkyl (dd) sulfonamido, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl, or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said substituents being alkoxy (dd), alkyl (dd), mono-N- or di-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy, alkanoyl (dd) amin or, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 139.- The use of a compound or a prodrug of said compound as claimed in claim 1 or a pharmaceutically acceptable salt of said compound or of said prodrug for the preparation of a medicament for the prevention of myocardial tissue damage. in a human. 140.- A compound as cited in claim 1, wherein Z is R2 is alkyl (d-d), cycloalkyl (C3-C7), M or M-alkyl (d-d), any of said alkyl (d-d) residues having one to nine fluorine atoms optionally; said alkyl (dd) or (C3-C4) cycloalkyl optionally mono- or di-substituted independently with hydroxy, alkoxy (dd), alkyl (Crd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl, alkyl (C1-C4) , mono- N- or di-N, N-alkyl (dd) carbamoyl or mono-N- or di-N, N-C 1 -C 4 alkylaminosulfonyl and said cycloalkyl (C 3 -C 4) optionally from one to seven fluorine atoms; M being a partially saturated, fully saturated or fully unsaturated ring of five to eight links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two partially saturated fused rings, fully saturated or completely unsaturated of three to six links, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; said M being optionally substituted, on a ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8. Where one of R6, R7 and R8 is optionally a partially saturated, fully saturated or fully unsaturated ring of three to seven links, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with alkyl (dd) and optionally R6, R7 and R8 are optionally hydroxy, nitro, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), formyl, alkanoyl (dd), alkanoyloxy (Crd), alkanoyl (dd) amine, alkoxy (dd) ) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyld (dd) amino, carbamoyl, mono-N- or di-N, N -alkyl (dd) carbamoyl, cyan , thiol, alkyl (dd) thio, alkyl (Crd) sulfinyl, alkyl (dd) sulfonyl, mono-N- or di-N, N-alkyl (dd) aminosulfonyl, alkenyl (C2-d), alkynyl (C2-C) ) or (C5-C7) cycloalkenyl, said substituents R6, R7 and R8 are alkoxy (dd), alkyl (dd), alkanoyl (dd), alkyl (C1-C4) fio, mono-No di-N, N-alkyl (dd) amino or cycloalkyl (C3-C7) optionally monosubstituted independently with hydroxy, alkoxy (dd) carbonyl, cycloalkyl (C3-C7), alkanoyl (C1-C4), alkanoyl (dd) amino, alkanoyloxy (d-C4), alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (C1-) C4) carbamoyl, cyano, thiol, nitro, alkyl (dd) fio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with each other nine fluorine atoms; and R3 is alkyl (dd), (C3-C7) cycloalkyl, phenyl or phenyl alkyl (dd), said alkyl (dd) being optionally substituted with one or nine fluorine atoms, said substituent R3 being optionally mono- or disubstituted independently with alkoxy (dd), alkyl (dd) fio, (C 1 -C 4) alkylsulfinyl or alkyl (dd) sulfonyl or alkyl (dd) or a pharmaceutically acceptable salt thereof. 141. A compound as recited in claim 140, wherein R3 is alkyl (d-d); R 2 is phenyl, said phenyl being optionally monosubstituted on carbon with a fully saturated or fully unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (dd) ), said ring R2 also optionally being mono- or disubstituted independently on carbon with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono- or di-N, N-alkyl (dd) carbamoyl, cyano, alkyl (dd) thio , alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said alkoxy (dd), alkyl (CrC4), alkanoyl (d-C7), alkyl (dd) thio, mono-N- or di-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl, alkanoyl (dd), alkanoyl (dd) amino, alkanoyloxy (C1-C4), alkoxy (dd) carbonylamino, sulfonamido, alkyl (Crd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (CrC 4) sulfonyl or mono-N- or di-N, N-(C 1 -C 4) alkylsulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 142. A compound as recited in claim 140, wherein R3 is (C1-C4) alkyl; R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated rings independently considered, said bicyclic ring R2 being optionally monosubstituted on carbon with a fully saturated or fully unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (dd), said bicyclic ring R 2 being optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, alkoxy ( Crd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (Crd), alkanoyloxy (dd), alkanoyl (d-C4) amino, alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono- N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, alkyl (dd) fio, alkyl (dC) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said alkoxy (dd), alkyl (dd), alkanoyl (d-C7), alkyl (d) dd) thio, mono-N- or di-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl, alkanoyl (dd), alkanoyl (dd) amino, alkanoyloxy (dd), alkoxy (dd) ) carbonylamino, sulfonamido, alkyl (Crd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt of the same. 143. A compound as recited in claim 140, wherein R3 is alkyl (Crd); R2 is a monocyclic aromatic ring of five to six links having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; said bicyclic R2 ring being optionally monosubstituted on carbon with a fully saturated or fully unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (dd), said ring R2 also being optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, alkoxy (dd), alkoxy (dd) carbonyl, alkyl (dd), alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amino , alkoxy (dd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) ) carbamoyl, cyano, alkyl (dd) thio, alkyl (dd) suifinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl, said alkoxy (dd), alkyl (dd) being ), alkanoyl (dd), alkyl (dd) thio, mono-N- or di-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl, alkanoyl (dd), alkanoyl (dd) amino, alkanoyloxy (dd), alkoxy (Crd) carbonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N - or di-N, N -alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, alkyl (dd) fio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt thereof. 144. A compound as recited in claim 140, wherein R3 is alkyl (d-d); R2 is a bicyclic ring consisting of two fused rings of five and / or six partially saturated, fully saturated or fully unsaturated bonds independently considered, having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring being bicyclic R2 optionally monosubstituted on carbon with a fully saturated or totally unsaturated ring of five to six links, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, said ring optionally being monosubstituted with alkyl (dd) and said bicyclic ring being R2 optionally mono or disubstituted independently on carbon or nitrogen with hydroxy, halogen, alkoxy (dd) , (C 1 -C 4) alkoxycarbonyl, alkyl (dd), alkanoyl (dd), alkanoyloxy (dd), alkanoyl (dd) amine, alkoxy (dd) carbonylamino, sulfonamido, (C 1 -C 4) alkylsulfonamido, amino, mono- N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alkyl (dd) carbamoyl, cyano, (C 1 -C 4) alkylthio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (Crd) aminosulfonyl, said alkoxy (dd), alkyl (dd), alkanoyl (dd), alkyl (dd) fio, mono-N- being or di-N, N-alkyl (dd) amino optionally monosubstituted with hydroxy, alkoxy (dd) carbonyl, alkanoyl (dd), alkanoyl (dd) amino, alkanoyl (Crd) oxy, alkoxy (Crd) car bonylamino, sulfonamido, alkyl (dd) sulfonamido, amino, mono-N- or di-N, N-alkyl (dd) amino, carbamoyl, mono-N- or di-N, N-alky (d-C4) carbamoyl, alkyl (dd) thio, alkyl (dd) sulfinyl, alkyl (dd) sulfonyl or mono-N- or di-N, N-alkyl (dd) aminosulfonyl or optionally substituted with one to nine fluorine atoms, or a pharmaceutically acceptable salt of the same. 145.- A compound selected from the esters 5-cyclopropyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxylate, 5-methyl-1- (6-quinoline) -1H-pyrazole-4 -carboxylate, 5-methyl-1-naphthalenyl-1-pyrazol-4-carboxylate, 5-cyclopropyl-1- (quinolin-8-yl) -1 / - -pyrazol-4-carboxylate, 5-cyclopropyl- 1- (quinolin-5-H) -1 H-pyrazole-4-carboxylate, 5-ethyl-1- (quinolin-5-yl) -1-pyrazol-4-carboxylate and 1- (isoquinolin-5-yl) ) -3-methyl-1 - / - pyrazole-4-carboxylate, wherein said esters are benzyl, alkyl (dd) or cycloalkyl (d-Cs), said cycloalkyl (d-C8) being optionally monosubstituted with alkyl (dd) or a pharmaceutically acceptable salt of said compound. 146.- A compound selected from 5-methyl-2- (5-quinoline) -2H-1, 2,3-triazole-4-carboxylic acid, 5-methyl-2- (5-isoquinoline) -2 / - / -1, 2,3-triazole-4-carboxylic acid, 2- (1-naphthalenyl) -5-methyl-2H-, 2,3-triazole-4-carboxylic acid, 5-methyl-1- (6-) acid quinolin) -1H-pyrazole-4-carboxylic acid, 5-methyl-1-naphthalenyl-1 - / - pyrazole-4-carboxylic acid, 5-cyclopropyl-1- (quinolin-8-yl) -1H-pyrazole -4-carboxylic acid, 5-cyclopropyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxylic acid, 5-ethyl-1- (quinolin-5-yl) -1-pyrazol-4-acid carboxylic acid, 5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carboxylic acid and 1- (isoquinolin-5-yl) -3-methyl-1 - / - pyrazole-4- acid carboxylic acid or chlorides thereof or a pharmaceutically acceptable salt of said compounds or said chlorides. 147.- A pharmaceutical combination composition containing: a therapeutically effective amount of a composition that confers: a first compound, said first compound being a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and a second compound, said second compound being an aldose reductase inhibitor, and a pharmaceutical excipient, carrier or diluent. 148.- A pharmaceutical composition as recited in claim 147, wherein the inhibitor of aldose reductase is 3,4-dihydro-4-oxo-3 - [[5-trifluoromethyl) -2-benzothiazolyl] met L] -1-phthalazine acetic acid or a pharmaceutically acceptable salt thereof. 149. A pharmaceutical combination composition containing: a therapeutically effective amount of a composition containing: a first compound, said first compound being a compound of claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and a second compound, said second compound being an aldose reductase inhibitor; and a pharmaceutical excipient, vehicle or diluent. 150.- The use of a first compound, said first compound being a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, in combination with a second compound, said second compound an aldose reductase inhibitor for the manufacture of a medicament for reducing tissue damage as a consequence of ischemia in a mammal. 151. - The use as claimed in claim 150, wherein the inhibitor of aldose reductase is 3,4-dihydro-4-oxo-3 - [[5-trifluoromethyl] -2- benzothiazolyl] methyl-1-phthalazine acetic acid or a pharmaceutically acceptable salt thereof. 152.- The use of a first compound, said first compound being a compound according to claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, in combination with a second compound, said second compound an aldose reductase inhibitor, for the manufacture of a medicament for reducing tissue damage as a consequence of ischemia in a mammal. 153.- A case that includes: a. a first compound, said first compound being a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a second compound, said second compound being an aldose reductase inhibitor and a pharmaceutically acceptable excipient, vehicle or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. 154. A kit as claimed in claim 153, wherein the inhibitor of aldose reductase is 3,4-dihydro-4-oxo-3 - [[5-trifluoromethyl] -2- benzothiazole] methyl-1-phthalazine acetic acid or a pharmaceutically acceptable salt thereof. 155.- A box that includes: a. a first compound, said first compound being a compound of claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a second compound, said second compound being an aldose reductase inhibitor and a pharmaceutically acceptable excipient, carrier or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. 156. A pharmaceutical combination composition containing: a therapeutically effective amount of a composition that confers: a first compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; and a second compound, said second compound being an inhibitor of glycogen phosphorylase and a pharmaceutical excipient, carrier or diluent. 157.- A pharmaceutical composition as cited in claim 156 wherein the glycogen phosphorylase inhibitor is [(1 S) -benzyl- (2R) -hydroxy-3 - ((3S) -hydroxypyrrolidin-1-yl) -3-oxo-propyl] -amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1 S) -benzyl-3 - ((3S, 4S) -dihydroxypyrrolidin-1 -I) - (2R) 5-Chloro-1 H-indole-2-carboxylic acid-hydroxy-3-oxo-propyl] -amide, [(1S) - ((R) -hydroxy-d-methylcarbamoyl-methyl) -2-phenyl -etl] -amide of 5-chloro-1 H-indoI-2-carboxylic acid, [(1S) - ((R) -hydroxy-methoxy-methyl-carbamoyl) -methyl) -2-phenyl- ethyl] -amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) - ((R) -hydroxy - [(2-hydroxyethyl) -methyl-carbamoyl] -methyl] 5-Chloro-1H-indole-2-carboxylic acid-2-phenyl-ethyl] -amide, [(1 S) -benzyl-2- (3-hydroxy-pyrrolidin-1-yl) -2- oxo-ethyl] -amido of 5-chloro-1 H-indole-2-carboxylic acid, [2- (cis-3,4-dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] amide 5-chloro-1 H-indole-2-carboxylic acid, [(1S) -benzyl-3 - ((cis) -dih-droxip) 5-chloro-1 H-indole-2-carboxylic acid, (2R) -hydroxy-3-oxo-propyl] -idene (2R) -hydroxy-3-oxopropyl], [2 - ((3S, 4S) -dihydroxy-pyrrolidin-1) -l) -2-oxo-ethyl] amide of 5-chloro-1 H-indol-2-carboxylic acid, [(1S) -benzyl-2- (cis-3,4-dihydroxy-pyrrolidin-1- 5-chloro-1 H-indole-2-carboxylic acid yl) -2-oxo-ethyl] amide5-Chloro-1 H-indole-2-carboxylic acid [2- (1, 1-dioxo-thiazolin-3-yl) -2-oxo-ethyl] amide, [(1S) - (4-fluoro -benzyl) -2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1 S) -benzyl-2 - ((3RS) -hydroxy-piperidin-yl) -2-oxo-ethyljamide of 5-chloro-1 H-indole-2-carboxylic acid, [2-oxo-2 - ((1 RS) - 5-Chloro-1H-indol-2-carboxylic acid oxo-thiazolidin-3-yl] -etl] amide, [(IS) -benzyl-2- (3-hydroxy-azetidin-1-yl) 5-chloro-1 H-indol-2-carboxylic acid-2-oxo-ethyl] amide; or a pharmaceutically acceptable salt thereof. 158. A pharmaceutical combination composition that confers: a therapeutically effective amount of a composition that confers: a first compound of claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; and a second compound, said second compound being an inhibitor of glycogen phosphorylase and a pharmaceutical excipient, carrier or diluent. The use of a first compound, said first compound being a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, in combination with a second compound, said second compound an inhibitor of glycogen phosphorylase for the manufacture of a medicament for reducing tissue damage as a consequence of ischemia in a mammal. 160. The use as claimed in claim 159, wherein the inhibitor of glycogen phosphorylase is [(1S) -benzyl- (2R) -hydroxy-3 - ((3S) -hydroxypyrrolidin-1-) 5-Chloro-1 H-indole-2-carboxylic acid yl) -3-oxopropyl] -amide, [(1 S) -benzyl-3 - ((3S, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) - ((R) -hydroxy-dimethylcarbamoyl-methyl) -2-phenyl -ethyl] -amide of 5-chloro-1 H-indol-2-carboxylic acid, [(1S) - ((R) -hydroxy-methoxy-methyl-carbamoyl) -methyl 5-Chloro-1 H-indole-2-carboxylic acid-2-phenylethyl] -amide, [(1S) - ((R) -hydroxy - [(2-hydroxy-ethyl) -methi- carbamoyl] -methyl) -2-phenylethyl] -amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) -benzyl-2- (3-hydroxyimino-pyrrolidin) -1-l) -2-oxo-etl] -amide of 5-chloro-1 H-indol-2-carboxylic acid, [2- (cis-3,4-dihydroxy-pyrrolidin- 1-yl) -2-oxo-ethyljamide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) -benzyl-3 - ((cis) -dihydroxy-pyrrolid 5-Chloro-1H-indole-2-carboxylic acid (2R) -hydroxy-3-oxoproprim] amide, [2 - ((3S 4S) -dihydroxy-pyrroidin-1-yl) 2-oxo-etl] 5-chloro-1 H-indole-2-carboxylic acid amide, [(1 S) -benzyl-2- (cis-3,4-dihydroxy-pyrrolidin-1 - 5-Chloro-1H-indol-2-carboxylic acid yl) -2-oxo-ethyl] -amide, [2- (1,1-dioxo-thiazolidin-3-yl) -2-oxo-etl] amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) - (4-fluoro-benzyl) -2- (4-hydroxy-p-peridin-1-yl) -2-oxo -etl] amida of 5-chloro-1 H-indole-2-carboxylic acid, [(1 S) -benzyl-2 - ((3RS) -hydroxy-piperidin-yl) -2-oxo-ethyl-amide of 5-chloro-1 H-indole-2-carboxylic acid, [2-oxo-2 - ((1-RS) -oxo-thiazolidin-3-yl) -ethyl] -amide of 5-chloro-1 H -indole-2-carboxylic acid, 5-chloro-1 H-indole-2-carboxylic acid [(IS) -benzyl-2- (3-hydroxy-azetidin-1-yl) -2-oxo-ethyl] -amide; or a pharmaceutically acceptable salt thereof. 161. The use of a first compound, said first compound being a compound according to claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug in combination with a second compound, said second composed an inhibitor of glycogen phosphorylase, for the elaboration of a drug to reduce the damage in a tissue as a consequence of ischemia in a mammal. 162.- A case that includes: a. a first compound, said first compound being a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a second compound, said second compound being an inhibitor of glycogen phosphorylase and a pharmaceutically acceptable excipient, carrier or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. 163. A kit as claimed in claim 162, wherein the inhibitor of glycogen phosphorylase is: [(1S) -benzyl- (2R) -hydroxy-3 - ((3S) -hydroxypyrrolidin-1- 5-Chloro-1 H-indole-2-carboxylic acid yl) -3-oxopropyl] -amide, [(1 S) -benzyl-3 - ((3S 4S) -dihydroxy-pyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 5-chloro-1 H-indole -2-carboxylic acid, 5-chloro-1 H-indole-2-carboxylic acid [(1S) - ((R) -hydroxy-d-methylcarbamoyl-methyl) -2-phenyl-etl] -amide , [(1S) - ((R) -hydroxy-methoxy-methyl-carbamoyl) -methyl) -2-phenol-etl] -amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) - ((R) -hydroxy] - [(2-hydroxy-ethyl) -methyl] -carbamoyl] -methyl) -2-phenylethyl] -amide of 5-chloro-1 H -indole-2-carboxylic acid, [(1 S) -benzyl-2- (3-hydroxy-vinyl-pyrrolidin-1-yl) -2-oxo-ethyl] -amide of 5- cyclo-1 H-indole-2-carboxylic acid, [2- (cis-3,4-dihydroxy-pyrrolidin-1-yl) -2-oxo-ethyl-amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1S) -benzyl-3 - ((cys) -dihydroxypyrrolidol-1-yl) - (2R) -hydroxy-3-oxopropyl] amide of 5-doro-1 H acid -indole-2-carboxylic acid, [2 - ((3S 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxo-etl] -amido-5-chloro-1 H-indole-2-carboxylic acid, [ (1S) -benzyl-2- (cis-3,4-dihydroxy-pyrrolidin-1-yl) 5-Chloro-1 H-indole-2-carboxylic acid, 2-oxo-ethyl], [2- (1,1-dioxo-fiazolidin-3-yl) -2-oxo-ethyl] amide of the 5-chloro-1 H-indole-2-carboxylic acid, [(1S) - (4-fluoro-benzyl) -2- (4-hydroxy-p-peridin-1-yl) -2-oxo-etl ] amide of 5-chloro-1 H-indole-2-carboxylic acid, [(1 S) -benzyl-2 - ((3RS) -hydroxy-piperidin-yl) -2-oxo-ethyl] amide of 5-chloro-1 H-indole-2-carboxylic acid, [2-oxo-2 - ((1-RS) -oxo-thiazolidin-3-yl) -ethyl] -amide of 5-chloro-1 H-indole -2-carboxylic acid, 5-chloro-1 H-indole-2-carboxylic acid [(IS) -benzyl-2- (3-hydroxy-azetidin-1-yl) -2-oxo-etl] -amide]; or a pharmaceutically acceptable salt thereof. 164.- A case that includes: a. a first compound, said first compound being a compound of claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a second compound, said second compound being an inhibitor of glycogen phosphorylase and a pharmaceutically acceptable excipient, carrier or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. 165. A pharmaceutical combination composition containing: a therapeutically effective amount of a composition containing: a first compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; and a second compound, said second compound being a cardiovascular agent and a pharmaceutical excipient, vehicle or diluent. 166.- A pharmaceutical composition as cited in claim 165, wherein the cardiovascular agent is a β-blocker, a calcium channel blocker, an agent that produces the opening of the potassium channel, adenosine, adenosine agonists , an ACE inhibitor, a nitrate, a diuretic, a glucoside, a thrombolytic, a platelet inhibitor, aspirin, dipyridamole, potassium chloride, clonidine, prazosin or an A3 adenosine receptor agonist. 167. A pharmaceutical combination composition containing: a therapeutically effective amount of a composition containing: a first compound of claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; and a second compound, said second compound being a cardiovascular agent and a pharmaceutical excipient, vehicle or diluent. 168.- The use of a first compound, said first compound being a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, in combination with a second compound, said second compound being a cardiovascular agent for the manufacture of a medicament for reducing tissue damage as a consequence of ischemia in a mammal. 169. The use as claimed in claim 168, wherein the cardiovascular agent is a β-blocker, an agent that causes the opening of the potassium channel, adenosine, adenosine agonists, a channel blocker of calcium, an ACE inhibitor, a nitrate, a diuretic, a glucoside, a thrombolytic, a platelet inhibitor, aspirin, dipyridamole, potassium chloride, clonidine, prazosin, or an A3 adenosine receptor agonist. The use of a first compound, said first compound being a compound according to claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, in combination with a second compound, said second compound a cardiovascular agent, for the manufacture of a medicament for reducing damage in a tissue as a result of ischemia in a mammal. 171.- A case that contains: a. a first compound, said first compound being a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a second compound, said second compound being a cardiovascular agent and a pharmaceutically acceptable excipient, carrier or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect. 172.- A case as cited in claim 171, in which the cardiovascular agent is a β-blocker, a calcium channel blocker, an ACE inhibitor, a nitrate, a diuretic, a glucoside, a thrombolytic, a platelet inhibitor, aspirin, dipyridamole, potassium chloride, clonidine , prazosin or an A3 adenosine receptor agonist. 173.- A case containing: a. a first compound, said first compound being a compound of claim 76, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable excipient, carrier or diluent in a first unit dosage form; b. a second compound, said second compound being a cardiovascular agent and a pharmaceutically acceptable excipient, vehicle or diluent in a second unit dosage form; and c. means for containing said first and second dosage form wherein the amounts of the first and second compounds produce a therapeutic effect.