NZ737537B2 - Novel 5-ht2 antagonists - Google Patents

Novel 5-ht2 antagonists Download PDF

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NZ737537B2
NZ737537B2 NZ737537A NZ73753716A NZ737537B2 NZ 737537 B2 NZ737537 B2 NZ 737537B2 NZ 737537 A NZ737537 A NZ 737537A NZ 73753716 A NZ73753716 A NZ 73753716A NZ 737537 B2 NZ737537 B2 NZ 737537B2
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New Zealand
Prior art keywords
dihydro
methyl
pyrazole
carboximidamide
hydroxyphenyl
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NZ737537A
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NZ737537A (en
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Lars Pettersson
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Anamar Ab
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Priority claimed from EP15173111.4A external-priority patent/EP3109237A1/en
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Publication of NZ737537A publication Critical patent/NZ737537A/en
Publication of NZ737537B2 publication Critical patent/NZ737537B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to 1-amidino-3-aryl-2-pyrazoline derivatives of the general formula I The invention specifically relates to such derivatives which exhibit antagonizing activity towards serotonin 5-HT2B receptors. The present invention also relates to use of said compounds as a medicament and for the treatment of fibrosis, cardiovascular diseases, pain, IBD, and other inflammatory diseases, as well as pharmaceutical compositions comprising one or more of said compounds and methods of treatment. nt and for the treatment of fibrosis, cardiovascular diseases, pain, IBD, and other inflammatory diseases, as well as pharmaceutical compositions comprising one or more of said compounds and methods of treatment.

Description

/207231 T/EP2016/064446 WO PC NOVEL 5-HTz ANTAGONISTS Field of the invention The present invention relates to novel 5-HTz antagonists. The invention specifically relates to such derivatives which exhibit antagonizing activity towards serotonin 5-HTz~ receptors. The present invention also relates to use of said compounds as a medicament and for the treatment of fibrosis, cardiovascular diseases, IBD, pain, j 0 and other inflammatory diseases, as well as pharmaceutical compositions comprising one or more of said compounds and methods of treatment.
Background of the invention Serotonin (5-Hydroxytryptamine, 5-HT) is a well characterized neurotransmitter and vasoactive amine which has been implicated in common disorders involving central nervous, gastrointestinal, cardiovascular and pulmonary systems (for review see Berger, M. et -HT al. Annu Rev Med. (2009), 60, 355-366) . Peripheral is mainly 2 0 synthesized and released the enterochromaffin cells in the by gut.
When reaching the blood stream it is sequestered inside platelets.
-HT Under normal conditions the level of free in plasma is low and -HT strictly regulated specific transporters present on the -HT surface of e. platelets as well as degrading enzymes. Upon g. by -HT 5-HT activation platelets release and a local increase in concentration is observed. Over the evidence has gathered that years -HT has a significant role in the functioning of the mammalian body. For example it has been shown to regulate processes like -HT cardiovascular function, bowel motility and bladder control.
-HT and the receptor system have also been associated with the modulation of pain and more specifically, the 5-HT, receptors have been shown to an important role in the inflammatory play pain process (Cervantes-Duran C. et al. Neuroscience (2012) 232, 169) .
-HT Furthermore, several studies have shown that the system has an important role in the regulation of inflammation. The exact function -HT of on inflammation is recognized though, with only a few poorly and inconsistent published reports.
-HT A greater understanding of function has emerged with the 4 0 characterization of its, at least, 14 different human receptors PC T/EP2016/064446 which are into subfamilies on their structural and grouped based differences. Each exhibit pharmacological receptor unique distribution and shows various preference for different ligands. The receptors are all G protein-coupled with the exception of receptors, the 5-HT, which is a ligand-gated ion channel. Several of receptor, -HT's the 5-HT receptors have been linked to effects in inflammation.
The 5-HTz receptor family consists of 3 5-HT», 5-HTz~ and subtypes, j 0 5-HTz, . The 5-HTz receptors share significant sequence at the homology amino acid level and to the family of the G proteins. couple Gq An important role of 5-HTz receptors in inflammation has been shown in the kaolin/carrageenan-induced rat arthritis model in which the -HT, receptor antagonist ketanserin oedema formation and suppressed Also, mianserin, a receptor antagonist, has hyperalgesia. 5-HT»qz, been shown to inhibit cytokine production in human RA synovial membrane cultures.
The link between the 5-HT, receptor and inflammation is less 2 the involvement of 5-HT» 0 investigated, however, receptor signalling IL-6 in 5-HT-induced production of IL-IP, and TNF-o, in mouse cardiac fibroblasts has been shown (Jaffre F. et al. Circulation (2004) 969-74) 110(8), . The mRNA expression of the 5-HTz~ receptor on cells such and fibroblasts makes it inflammatory as macrophages 5-HTz~ for an important to investigate as target modulating in diseases such rheumatoid arthritis. The inflammatory response as -HT, use of N-benzylidene aminoguanidines as receptor antagonist for this purpose has been described in X02011012868AI.
The 5-HT» has been linked arterial receptor previously to pulmonary M. al. Pharmacol Ther. hypertension (PAH) (Thomas et (2013) 138(3), 409-17) and the of the 5-HTz~ knock-out mice shows phenotype receptor -HT its importance for heart development. It demonstrates that via the 5-HT, differentiation and of receptor regulates proliferation and adult heart. Furthermore, over-expression of the developing in mice leads cardiac HT, receptor to hypertrophy (Nebigil C. G. et al. Circulation. 3223 (2003) 107(25), 9) .
In with 5-HT and its 5-HT» and 5-HT» in agreement this, receptors, 4 have been in the of several fibrotic 0 particular, implicated etiology PC T/EP2016/064446 disorders carcinoid heart including retroperitoneal fibrosis, liver and fibrosis. Fibrosis is disease, systemic sclerosis, lung actually a feature of different of chronic respiratory many types diseases including IPF, PAH, COPD and asthma. A mechanistic link -HT between fibrosis and was first reported in the 1960s for a condition called carcinoid syndrome which is caused neuroendocrine carcinoid tumours that secrete vast of quantities HT. The syndrome is characterized tissue fibrosis that particularly affects cardiac valves but also impacts on other organs j 0 including and skin. agonism on the 5-HT» receptor lung Subsequently, has been implicated in fibrosis caused fenfluramine used in the treatment of obesity and psychiatric disorders. Fibrosis is characterized enhanced fibroblast/myofibroblast proliferation and activation which results in an altered extracellular matrix deposition which ultimately results in failure D. A. organ (Mann, and Oakley F. Biochim Acta. 905 .
Biophys (2013) 1832(7), 10) An important mediator of the fibrotic process is transforming growth factor TGF-P. This cytokine modulates a variety of beta, 2 In human 0 physiological processes through transcriptional regulation.
TGF-P is well-known for lung fibroblasts, inducing myofibroblast differentiation with increased levels of alpha-SMA in intracellular stress fibers as well as an increased matrix deposition. A lot of evidence a role of 5-HT in fibrosis although the exact support mechanism how 5-HT fibrosis is not defined. 5-HT has been promotes shown increase the mRNA levels of TGF-P via the 5-HTz~ to receptor and in models of sclerosis human dermal fibroblasts have systemic a -HT dose-dependent increase of TGF-P mRNA in response to as well as an increased expression of the 5-HTz~ receptor. This results in an increased mRNA expression of collagen lal, collagen la2 and fibronectin. The effects of 5-HT on matrix were blocked synthesis by -HTz~ or transfected 5-HTz~ siRNAs. The same a receptor antagonist by showed that selective 5-HT, receptor antagonists prevent study bleomycin-induced dermal fibrosis in vivo (Dees C. et al. J.
Exp.
Med. (2011) 961-72) . In other fibrotic diseases such as 208(5), liver fibrosis, treatment with 5-HT, receptor antagonists resulted in attenuated in an in vivo model of chronic liver fibrogenesis disease (Ebrahimkhani, M. R. et al. Nat Med. (2011) 1668— 17(12), -HT . Further for and fibrosis is found in patients 73) support 4 0 suffering from IPF that have an increased expression of 5-HT» and PC T/EP2016/064446 in the fibrotic Another identified HTz~ receptors lung. study strong fibroblast of 5-HTz~ in fibroblastic foci in expression receptor human samples from IPF patients. In addition, treatment with lung Terguride, a 5-HTzr, and 5-HTz~ receptor antagonist, reduces the expression of I collagen in TGF-Pl stimulated human type lung fibroblasts. This anti-fibrotic effect is also seen after treatment with and 5-HTz~ in the (BLM)— -HTzr, receptor antagonists bleomycin induced fibrosis model in mice (Konigshoff M. et al. Thorax. lung 949-55 and sabre A. et al . Eur Respir J. (2010);65(11), (2008) 32 426 (2), 36) antagonists HT~~ -HTz~ antagonists of variable structural classes have been Many described in the literature, such as in X02011012868AI. Two recent reviews on the enlist such their intended subject compounds, uses, and their state of development (Poissonnet, G. et al. Mini-Reviews in Medicinal Chemistry 325-330 and Brea, J. et al. (2004), 4(3), Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) 493-503) . These include the di-ureas (2010), 10(5), 2 SB206553 and the derivative EGIS-7625, the 0 SB215505, piperazine aminonaphthyl-pyrimidine MT-500 thioxanthene (RS127445), structures, the derivative terguride, tetrahydro-g-carbolines, ergot the thienopyrimidine PRX-08066, and quinoline derivatives. More recent of 5-HTz~ that also contain examples antagonists a guanidine are disclosed in US2009062363A1. moiety, Structurally related 5-HTz~ antagonists are N-benzylidene N-(2-chloro-3, amminoguanidines, such as 4-dimethoxybenzylidene- (X02011012868AI) amino) guanidine . — — — — — l kni di ar 2 azoli nes no 3 yl The class 1-amidinoarylpyrazolines was first compound reported in the 1950s describing synthetic preparative methods in which aryl Mannich were condensed with bases aminoguanidine (Scheme 1), .N N Ar N Ar 0 Scheme 1 PC T/EP2016/064446 F. L. and see: Scott, Reilly, J. Chemistry & Industry (London, United 907-8 and XIV. F.
Kingdom) (1952), Nitrogen systems. Scott, L. and Scott, M. T. Chimia 148-50. Some derivatives, (1958), 12, substituted at the or 5-position in the pyrazoline typically ring and/or at the amidine have later been developed into group, pharmacologically active compounds. These include 4-aryl-N- sulfonamides CB1-antagonists and channel modulators as potassium (X02001070700 Al and X02007125049AI), 4-heterocyclyl derivatives as — — — PAR 1 antagonists (X02005007157AI), N sulfonamides as 5 j 0 antagonists (X02008034863A2), and 5-aryl derivatives as necroptosis inhibitors P. G. et al. J. Med. Chem.
(Jagtap, (2007), 50(8), 1886-1895), as MAO-inhibitors A. et al. Bioorganic & (Sahoo, Medicinal Chemistry Letters 132 136 and M. et (2010), 20(1), Jagrat, al. Bioorganic & Medicinal Chemistry Letters 4296— (2011), 21(14), and as antimicrobials (Ferreras, J. A. et al. Bioorganic & 4300), Medicinal Chemistry Letters 6533 6537) (2011), 21(21), Also, the para-substituted I-amidinoarylmethylpyrazolines below have been reported as anti-inflammatory and analgesic agents, 2 with no mode of action described. (Abd-El al. Arch 0 however, G. et Pharm Res 807 (2012), 35(5), 821) .N NH R MeS- or MeSO2- Summary of the invention It has been identified that 1-amidinoarylpyrazolines are 5-HT» receptor antagonists with high potency and/or selectivity. In particular, it has been identified that certain substitution patterns enhance 5-HT, receptor binding. substituents e Specifically, in the ortho-position of the aromatic moiety confer an enhanced -HT, receptor binding affinity and thus an enhanced antagonistic potency. Furthermore, the compounds of the present invention, due to the presence of the pyrazoline ring, cannot undergo light induced cis/trans-isomerization of the benzyl imine double-bond, a characteristic of the above mentioned N-benzylidene-amminoguanidine compounds.
One objective problem of the present invention is to develop new 1-amidino aryl-pyrazolines as antagonists of the serotonin 5-HT receptors for the treatment of diseases, such as fibrosis, cardiovascular diseases, pain, IBD, and other inflammatory diseases.
In a first particular embodiment, the invention provides a compound of the general formula I wherein represents [Followed by page 6A] wherein R is selected from methyl, ethyl, iso-propyl, cyclopropyl, CF , hydroxy, methoxy, ethoxy, iso-propoxy, benzyloxy, OCF , SCH , S(O) CH , OC(O)OR , OC(O)R , NHCH , N(CH ) , NHC(O)H, 3 2 3 3 3 2 NHC(O)CH , NHC(O)NH , NHC(O)NHCH , NHC(O)N(CH ) , C(O)CH , 3 2 3 3 2 3 C(O)N(CH ) , Cl, Br, I, CN, and phenyl; R is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, CF , hydroxy, methoxy, ethoxy, iso-propoxy, OCF , SCH , S(O) CH , NH , NHCH , N(CH ) , NHC(O)H, NHC(O)CH , 3 2 3 2 3 3 2 3 NHC(O)NH , NHC(O)NHCH , NHC(O)N(CH ) , C(O)CH , C(O)N(CH ) , F, 2 3 3 2 3 3 2 Cl, Br, I, CN, and phenyl; R is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, CF , ethoxy, iso-propoxy, OCF , SCH , S(O) CH , NH , 3 3 3 2 3 2 NHCH , N(CH ) , NHC(O)H, NHC(O)CH , NHC(O)NH , NHC(O)NHCH , 3 3 2 3 2 3 NHC(O)N(CH ) , C(O)CH , C(O)N(CH ) , F, Cl, Br, I, CN, and 3 2 3 3 2 phenyl; R is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, CF , hydroxy, methoxy, ethoxy, iso-propoxy, OCF , SCH , S(O) CH , NH , NHCH , N(CH ) , NHC(O)H, NHC(O)CH , 3 2 3 2 3 3 2 3 NHC(O)NH , NHC(O)NHCH , NHC(O)N(CH ) , C(O)CH , C(O)N(CH ) , F, 2 3 3 2 3 3 2 Br, I, CN, and phenyl; R represents C -C alkyl or phenyl; 1 15 7 8 9 10 R , R , R , and R are independently selected from hydrogen and methyl; and X is selected from hydrogen, C -C alkyl, C -C cycloalkyl, C - 1 12 3 6 1 C fluoroalkyl, phenyl, 2-phenylethyl, benzyl, C(O)OCH CH , and 4 2 3 hydroxy; wherein said phenyl, 2-phenylethyl, and benzyl are optionally mono- or di-substituted by substituents independently selected from methyl, ethyl, methoxy, F, and Cl; pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, 40 [Followed by page 6B] with the proviso that when R is methyl and having the configuration as shown in formula Ib, R is not hydrogen; and 3 7 8 1 when X, R , R and R are simultaneously hydrogen, R is not methoxy.
In a second particular embodiment the invention provides use of a compound according to the first particular embodiment described above in the manufacture of a medicament for use in the treatment of fibrosis.
In a third particular embodiment the invention provides a pharmaceutical composition comprising a compound according to the first particular embodiment described above, admixed with one or more pharmaceutically acceptable excipients or carriers.
Detailed description of the invention The present invention relates to a compound of the general formula I I Brief description of the drawings Figure 1 provides a histogram with data showing effects by a compound of the invention on collagen production in normal human lung fibroblasts, suggesting an anti-fibrotic role.
[Followed by page 6C] Figure 2 provides a histogram with data showing anti-fibrotic effects by a compound of the invention in the bleomycin-induced pulmonary fibrosis model in mice. A compound of the invention in doses of 75 mg/kg bid and Nintedanib at doses of 30 mg/kg bid ameliorated bleomycin-induced pulmonary fibrosis and reduced the fibrotic area (A), inhibited myofibroblast differentiation (B), and reduced the hydroxyproline content (C).
Definitions The phrase “5-10 membered mono- or bicyclic aromatic or heteroaromatic ring system containing 0-4 heteroatoms independently selected from N, O, and S” represents, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, isoxazolyl, oxazolyl, oxadiazolyl, dioxazolyl, thiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridine, phthalazinyl, pteridinyl, benzofuranyl, iso benzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzisoxazolyl, furopyridinyl, oxazolopyridinyl, benzothiazolyl, [Followed by page 7] PC T/EP2016/064446 benzisothiazolyl, thienopyridine, ethylenedioxyphenyl It is understood that one of the is methylenedioxyphenyl. only rings aromatic when the is methylenedioxyphenyl or ring system ethylenedioxyphenyl.
The term "alkyl" represents a linear or branched alkyl having group the number of carbon atoms specifically indicated, e.g. Cj-Cjo one, three, four, five, six, seven, nine or ten carbon atoms, two, eight, including, but not limited to methyl, ethyl, n-propyl, isopropyl, j 0 sec-butyl, tert-butyl, butyl, isobutyl, pentyl, isopentyl, hexyl, nonyl-, decyl-, 2-methylbutyl, l-methylbutyl, heptyl, octyl, 2-dimethylpropyl, neo-pentyl, l-dimethylpropyl, ethylpropyl, 1, l, 2-methylpentyl, l-methylpentyl, methylpentyl, 3-pethylpentyl, l-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, ethylbutyl, 3, 2, 1, l-dimethylbutyl, 3-dimethylbutyl, 3-dimethylbutyl, or 2, 1, 1, dimethylbutyl.
The term -Cj~ alkyl" represents saturated, linear or branched 1-15 alkyl containing carbons, including, but not limited to group 2 n-butyl, iso-butyl, neo-butyl, 0 methyl, ethyl, n-propyl, iso-propyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or and isomers thereof. dodecyl, tridecyl, tetradecyl, pentadecyl The term "C,-Cj~ alkyl" represents saturated, linear or branched 1-16 not limited alkyl group containing carbons, including, but to n-butyl, iso-butyl, neo-butyl, methyl, ethyl, n-propyl, iso-propyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tetradecyl, or hexadecyl and isomers dodecyl, tridecyl, pentadecyl, thereof.
The term "C,-Cjz alkyl" linear or branched represents any saturated, 1-12 not limited alkyl group containing carbons, including, but to n-butyl, iso-butyl, neo-butyl, methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and isomers thereof.
The term "C,-C~ alkyl" linear or branched represents any saturated, alkyl containing carbons, including, but not limited to group n-butyl, iso-butyl, neo-butyl, methyl, ethyl, n-propyl, iso-propyl, 4 0 tert-butyl, and hexyl and isomers thereof. pentyl PC T/EP2016/064446 The term "C&-C~ cycloalkyl" or represents cyclopropyl, cyclobutyl cyclopentyl.
The term "C&-C~ cycloalkyl" represents cyclopropyl, cyclobutyl, and cyclohexyl. cyclopentyl, The term "Cj-C~ haloalkyl" represents methyl substituted with halogen atoms, substituted with halogen atoms, or n-propyl ethyl j 0 or substituted with halogen atoms. isopropyl The term "fluoroalkyl" represents an alkyl as defined group supra, substituted with one or more fluorine atoms.
The term fluoroalkyl" represents fluoroalkyl as defined C~ group with 1 to 4 carbon atoms. Examples of Cj-C~ fluoroalkyl supra, groups include substituted with fluorine atoms, n-propyl or ethyl substituted with fluorine atoms, and butyl substituted isopropyl with 1 to 9 fluorine atoms, and isomers thereof.
The term "fluoromethyl" with 1 all represents a methyl group to atoms substituted with fluorine atoms. of hydrogen Examples fluoromethyl include monofluoromethyl, difluoromethyl and trifluoromethyl.
The term "C,-Cj~ acyl" an defined in which represents alkyl as supra the carbon bound the rest of the is carbon to compound a carbonyl i.e. instead of two of the atoms, the carbon has a double hydrogen bound Examples of include oxygen. Cj Cj~ acyl groups C(0) CH~, -CO(CH, wherein n are integers from 1 to 14.
) CH„ In one of the invention, there is of the aspect provided a compound general formula I PC T/EP2016/064446 R R AR wherein -10 mono- AR represents a membered or bicyclic aromatic or heteroaromatic ring system containing heteroatoms independently selected from and S; N, 0, is selected from C, alkyl, C~-C~ cycloalkyl, Cj-C~ haloalkyl, OR OC R OC OR OC NR R SR S R S S ~ (0) ~ (0) ~ (0) ~ ~ (0) ~ (0) gR ~ (0) D'OR S(0)&NR NR NR NR C(0)NR C(0)OR, C(0)NR R, R, C(0)R, R, C(0)R, R, NR C OR, Cl, Br, CN, 4 fluorophenyl, 4 chlorophenyl, (0) F, I, phenyl, and 4-methoxyphenyl; or is part of said ring system when said ring system is bicyclic; R', R', OR', R', and R are independently selected from R, OC(0) OC OR OC NR R SR S R S S S R NR R (0) (0) (0) (0) gR (0) (0) gNR ~ ~ ~ ~ ~ D'OR ~ ~ ~F/Cl NRC(0)RNRC(0)NRRC(0)RC(0)OR C(0)NRRNRC(0)OR Br, CN, 4-fluorophenyl, 4-chlorophenyl, and 4-methoxyphenyl, wherein and R are positioned independently in of the free R, any 2 0 positions of the mono- or bicyclic aromatic or heteroaromatic ring system; R' R' and are independently selected from hydrogen, -Cj~ alkyl, C~-C~ cycloalkyl, benzyl, and Cj-C~ haloalkyl; phenyl, and R are independently selected from hydrogen, methyl, R, R, R, ethyl, n-propyl, iso-propyl, and n-butyl; or being selected such R' R' 4-, 5-, 6-, that and are connected to form a or 7-membered ring; — — — X is selected from hydrogen, alkyl, cycloalkyl, Cj Cj~ C~ C~ Cj Cj~ acyl CN, Cj-C~ fluoroalkyl, phenyl, benzyl, hydroxy, methoxy, ethoxy, OCH~CH~, 2 phenylethyl and benzyloxy, wherein said C(0) 2-phenylethyl and benzyl are optionally mono-, or phenyl, groups PC T/EP2016/064446 tri-substituted substituents selected from -C, by independently C, and and alkyl, Cj C~ alkoxy, Cj C~ fluoroalkyl, F, Cl, Br, I; pharmaceutically acceptable salts, tautomers, and prodrugs, stereoisomers thereof.
In one embodiment of this there is provided a compound of aspect, Formula wherein -10 AR represents a membered mono- or bicyclic aromatic or 1 0 heteroaromatic containing heteroatoms independently ring system selected from and N, 0, S; is selected from -C~ C~-C~ Cj-C~ haloalkyl, C, alkyl, cycloalkyl, OR OC R OC OR OC NR R SR S R S S (0) (0) (0) (0) (0) zR (0) ~ ~ ~ ~ ~ ~ ~ D'OR NR NR NR S(0)&NR R, R, C(0)R, C(0)NR R, C(0)R, C(0)OR, C(0)NR R, NR C 4 4 (0) OR, F, Cl, Br, I, CN, phenyl, fluorophenyl, chlorophenyl, and 4-methoxyphenyl; or is of said when said part ring system ring system is bicyclic; R', R', and R are selected from OR', R, R, independently OC (0) OR NR R SR R R NR R OC (0) OC (0) S (0) S (0) zR S (0) S (0) zNR ~ ~ ~ ~ ~ D'OR ~ ~ NR R NR NR R R OR NR R N R OR Cl C (0) C (0) C (0) C (0) C (0) C (0) F~ ~ ~ ~ ~ ~ ~ 4-fluorophenyl, 4-chlorophenyl, and 4-methoxyphenyl, Br, I, CN, wherein and R are positioned independently in of the free R, any of the mono- or aromatic or heteroaromatic positions bicyclic ring system; R and R are independently selected from -Cj~ C~-Cg hydrogen, C, alkyl, and Cj-C~ haloalkyl; cycloalkyl, phenyl, and R are selected from R, R, R, independently hydrogen, methyl, and n-butyl; or selected such ethyl, n-propyl, iso-propyl, being R' R' that and are connected to form a 4-, 5-, 6-, or 7-membered ring; X is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, neo-butyl, tert-butyl, butyl, cyclopropyl, cyclopentyl, CF~, CFzCF~, phenyl, benzyl, hydroxy, methoxy, ethoxy, phenylethyl and wherein said 2-phenylethyl and benzyl benzyloxy, phenyl, groups 4 0 are optionally mono- or di-substituted substituents independently PC T/EP2016/064446 selected from and methyl, ethyl, methoxy, ethoxy, iso-propyloxy, F, In one embodiment of this there is provided a compound of aspect, Formula wherein R R AR represents R" R" R" R" R" R R R R3 R3 R3 R" R" R" R R, R R R, R R, R, R R R, R N zN NH 0 S R R R R R R, R, R, R, R R R R R R R2 R4 R2 R4 R3, R3, I— R-~— R R R R, R, R, R, N~&N R, R, 1 0 wherein is selected from methyl, ethyl, iso-propyl, cyclopropyl, CF3, methoxy, ethoxy, iso-propoxy, benzyloxy, OC(0) OCH3CH3, OCF3, hydroxy, SCH3g S OC OR OC R NHCH3, N NHC NHC (0) gCH3, (0) ~ (0) ~ (CH3) 3, (0) H~ (0) CH3g NHC NHC NHCH3~ NHC N C C N Cl Br~ I (0) NHg~ (0) (0) (CH3) g~ (0) CH3~ (0) (CH3) g~ ~ CN, and phenyl; PC T/EP2016/064446 R is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, CF„ hydroxy, methoxy, ethoxy, iso-propoxy, OCF~, SCH~, S(0)HACH~, NH„ N NHC NHC NHC NHC NHCH3~ (CH3) (0) H~ (0) CH3~ (0) NHz~ (0) NHCH3~ NHC N N and (0) (CH, ) „C(0) CH„C (0) (CH, )„F, Cl, Br, I, CN, phenyl; is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, CF~, ethoxy, iso-propoxy, OCF~, SCH~, S (0) NHz, NHCH~, (CH~) HACH~, z, NHC NHC NHC NHC NHC N C (0) H~ (0) CH3~ (0) NHz~ (0) NHCH3~ (0) (CH3) (0) CH3~ C N and (0) (CH&) F, Cl, Br, I, CN, phenyl; is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, iso-propoxy, CF„ hydroxy, methoxy, ethoxy, OCF~, SCH~, S(0)HACH~, NH„ N NHC NHC NHC NHC NHCH3~ (CH3) z~ (0) H~ (0) CH3~ (0) NHz~ (0) NHCH3~ NHC N C C N and (0) (CH~) (0) CH~, (0) (CH~) F, Br, I, CN, phenyl; z, z, represents Cj-Cj~ alkyl or phenyl; and R are independently selected from hydrogen and R, R, R, R' R' or selected such that and are connected to form a methyl; being 2 5-, or 6-membered and 0 ring; — — — X is selected from hydrogen, Cj Cjz alkyl, C~ C~ cycloalkyl, Cj C~ fluoroalkyl, 2-phenylethyl, and phenyl, benzyl, C(0) OCHzCH~, hydroxy; wherein said 2-phenylethyl, and benzyl are optionally mono- phenyl, or di-substituted substituents selected from by independently methyl, ethyl, methoxy, F, Cl, with the proviso that when is methyl and having the configuration as shown in formula R R AR is not and hydrogen; when R and R are is not X, R, simultaneously hydrogen, methoxy.
PC T/EP2016/064446 In one embodiment of this there is of aspect, provided a compound Formula wherein R R AR is selected from the group R' R' R' R R R, R R, R, R, R R R R R, R, R R, R In one embodiment of this aspect, there is provided a compound of Formula wherein is selected from Cj-C~-alkyl, fluoromethyl, 1 0 methoxy, OC OCHzCH, and Br; hydroxy, benzyloxy, (0) Cl, R is selected from and hydrogen, F, Cl; is selected from fluoromethyl, and and hydrogen, F; is selected from and F. hydrogen, In one embodiment of this there is provided a compound of aspect, Formula wherein 2 0 X is selected from hydrogen, Cj Cjz alkyl, C~ C~ cycloalkyl, phenyl, fluoroalkyl, 2 and Cj C4 benzyl, phenylethyl, C(0) OCHzCH~, hydroxyl, wherein said 2-phenylethyl, and benzyl are optionally mono- phenyl, or di-substituted with substituents independently selected from fluoromethyl, and Cl. methyl, methoxy, F, -HT, receptor binding be obtained with a variety in High may large the X position in compounds of the invention, as determined in example 120.
PC T/EP2016/064446 In one embodiment of this there is of aspect, provided a compound Formula wherein R R AR is selected from the group R' R' R' wherein is selected from methyl, methoxy, isopropyl, CF~, hydroxy, j 0 OC and Br; benzyloxy, (0) OCH&CH&, Cl, R is selected from and hydrogen, F, Cl; is selected from and hydrogen, CF~, F; is selected from and hydrogen, F; and R are independently selected from and R, R, R, hydrogen, R' R' or selected such that and are connected to form a methyl; being 2 0 5 membered ring; X is selected from hydrogen, methyl, butyl, hexyl, dodecyl, 4-heptafluorobut-l-yl, cyclohexyl, cyclopropyl, phenyl, 2, 2, 3, 3, 4, 4, 2-trifluoroeth-l-yl, 4-trifluoromethylphenyl, 4-fluorophenyl, 2, 2, chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, benzyl, CHCHzCzH&, chlorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 4-dichlorobenzyl, 4-dichlorobenzyl, 4-methoxybenzyl, 5-dimethoxybenzyl, 3, 3, 3, dimethoxybenzyl, 3-chloromethoxybenzyl, 2-phenylethyl, C and (0) OCHzCH~, hydroxy, PC T/EP2016/064446 with the that when is and the proviso methyl having configuration shown in formula as Ib, R R, R is not and hydrogen; when R and R are is not X, R, simultaneously hydrogen, methoxy.
In one embodiment of this there is of aspect, provided a compound Formula wherein R R AR is selected from the group OH OMe Cl Cl In one embodiment of this there is provided a compound of aspect, Formula wherein represents PC T/EP2016/064446 R" R" R" R" R" R R R R3 R3 R3 R3 R" R" R" R R R R R R R R, R, R, R, R, N zN NH 0 S R2R3R4 R, R R R R R, R, I I R R R R R R R2 R4 R2 R4 R3, R3, ~— R-~— R R R R, R, R, R, R R, R N~&N R R, R R, R, R wherein is selected from methyl, ethyl, iso-propyl, cyclopropyl, CF3, hydroxy, methoxy, ethoxy, propoxy, OCF3, SCH3, S(0)2CH3, OC(0) OR, OC R NHCH3 N NHC NHC NHC NHC NHCH3 (0) (CH3) (0) H~ (0) CH3 (0) NH2 (0) ~ ~ 2 ~ ~ ~ ~ NHC N N and (0) (CH, ) „C(0) CH„C (0) (CH, ) „Cl, Br, I, CN, phenyl, benzyloxy; 1 R is selected from 0 hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, iso-propoxy, CF„ hydroxy, methoxy, ethoxy, OCF3, SCH3, S(0)2CH3, NH„ N NHC NHC NHC NHC NHCH3~ (CH3) (0) H~ (0) CH3~ (0) NH2~ (0) NHCH3~ NHC N N and (0) (CH, ) „C(0) CH„C (0) (CH, )„F, Cl, Br, I, CN, phenyl; is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, iso-propoxy, S N CF3, ethoxy, OCF3, SCH3, (0) 2CH3, NH2, NHCH3, (CH3) 2, NHC NHC NHC NHC NHC N C (0) H~ (0) CH3~ (0) NH2~ (0) NHCH3~ (0) (CH3) (0) CH3~ C N and (0) (CH3) F, Cl, Br, I, CN, phenyl; PC T/EP2016/064446 is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl, CF„ hydroxy, methoxy, ethoxy, iso-propoxy, OCF~, SCH~, S(0)HACH~, NH„ N NHC NHC NHC NHC NHCH3~ (CH3) (0) H~ (0) CH3~ (0) NHz~ (0) NHCH3~ NHC N C C N and (0) (CH~) (0) CH~, (0) (CH~) F, Br, I, CN, phenyl; z, z, represents Cj-Cj~ alkyl or phenyl; and R are independently selected from and R, R, R, hydrogen R' R' or selected such that and are connected to form a methyl; being 1 0 5-, or 6-membered and ring; X is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclopentyl, CF&, CFzCF~, phenyl, phenylethyl, benzyl, and wherein said 2-phenylethyl, and benzyl is hydroxy; phenyl, mono- or di-substituted substituents independently optionally by selected from and methyl, ethyl, methoxy, F, Cl, with the proviso that when is methyl and having the configuration as shown in formula R R, R is not hydrogen; and when R and R are simultaneously is not methoxy.
X, R, hydrogen, In one embodiment of this aspect, there is provided a compound of Formula wherein R R AR is selected from the group PC T/EP2016/064446 R' R' S R, R, R R R, R R, R R R R R, R, R R, R In one embodiment of this aspect, there is provided a compound of Formula wherein is selected from Cj-C~-alkyl, fluoromethyl, methoxy, Cl, and Br; hydroxy, R is selected from hydrogen, and Cl; is selected from hydrogen, fluoromethyl, and F; and j 0 is selected from hydrogen and F.
In one embodiment of this aspect, there is provided a compound of Formula wherein R R AR is selected from the group R' R' wherein is selected from methyl, iso-propyl, methoxy, Cl, CF&, hydroxy, and Br; R is selected from hydrogen, and Cl; PC T/EP2016/064446 is selected from and hydrogen, CF~, F; is selected from and hydrogen, F; and R are independently selected from and R, R, R, hydrogen, R' R' or selected such that and are connected form methyl; being to a -membered ring; j 0 X is selected from CHCH, hydrogen, methyl, benzyl, C,H„ chlorobenzyl, 2-chlorobenzyl, 4-dichlorobenzyl, 2, 3, dichlorobenzyl, 4-methoxybenzyl, 5-dimethoxybenzyl, 3, 3, dimethoxybenzyl, 3-chloromethoxybenzyl, 2-phenylethyl, and hydroxyl, with the proviso that when is methyl and having the configuration as shown in formula Ib, R R, R is not hydrogen; and R' R' R' 2 0 when X, and are simultaneously hydrogen, is not methoxy.
In one embodiment of this there is of aspect, provided a compound Formula wherein is hydrogen or methyl; and R, R, and R are hydrogen.
In one embodiment of this there is of aspect, provided a compound Formula wherein X is It is understood that said I, benzyl. to be is mono- or di-substituted substituents benzyl optionally by iso- independently selected from methyl, ethyl, methoxy, ethoxy, and Cl. propyloxy, F, PC T/EP2016/064446 In one embodiment of this there is of aspect, provided a compound Formula wherein R is and methyl; R', R', and R are hydrogen.
In one embodiment of this there is provided a compound of aspect, Formula wherein is methyl and having the configuration as shown in formula Ia R R, R In one embodiment of this there is of aspect, provided a compound Formula said selected from: I, compound being 3-(2-Methoxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Hydroxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Bromophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; -dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Chlorophenyl)-4, -dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Methylphenyl)-4, 2 3-(2, 5-Difluorophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; -dihydro-lH-pyrazole-l-carboximidamide; 3-(2-1sopropylphenyl)-4, 3-(Naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(Benzo[b]thiophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; -dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Fluorophenyl)-4, — — — — — — — 1H 3 (2 (Trifluoromethyl)phenyl) 4, 5 dihydro pyrazole carboximidamide; 3-(Benzofuranyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — 4 1H 3 (2 Methoxyphenyl) methyl 4, 5 dihydro pyrazole carboximidamide; 3-(2-Chlorophenyl)-N-methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Hydroxyphenyl)-N-methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; PC T/EP2016/064446 N-Benzy1(2-chlorophenyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Benzyl(2-hydroxyphenyl) -4, 5-dihydro-1H-pyrazole carboximidamide; 5-methyl(naphthalenyl) -4, 5-dihydro-1H-pyrazole carboximidamide; 3-(2-Chlorophenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2, 6-Difluorophenyl) methyl-4, 5-dihydro-1H-pyrazole 1 0 carboximidamide; ethyl-4, 5-dihydro-1H-pyrazole 3-(2-Chlorophenyl) carboximidamide; -Methyl(3-methylbenzofuranyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — — 5 Methyl 3 2 5 1H pyrazole— (3 yl) 4, methylbenzo[bjthiophen dihydro 1-carboximidamide; 3-(2-Chlorophenyl)-4, 6a-tetrahydrocyclopentaIcjpyrazole-l(3aH) , 6, carboximidamide; 3-(2-Aminophenyl) -4, 5-dihydro-1H-pyrazolecarboximidamide; — — — — 2 0 3 (2 Hydroxyphenyl)-4, 4 dimethyl 5-dihydro-lH-pyrazole-l carboximidamide; 3-(2-Chloromethoxyphenyl) -4, 5-dihydro-1H-pyrazole carboximidamide; — — — — — — — — — 3 Chloro 6 5 1H (2 hydroxyphenyl) 4, dihydro pyrazole carboximidamide; — — — 3-(2-Hydroxyphenyl) 4-methyl 5-dihydro-lH-pyrazole-l (S) 4, carboximidamide; — — — — — — — — — — 4 1H 1 (R) 3 (2 Hydroxyphenyl) methyl 4, 5 dihydro pyrazole carboximidamide; — — — — — — — — — — 4 1H 1 (S) 3 (2 Hydroxyphenyl) methyl 4, 5 dihydro pyrazole carboximidamide; — — — 3-(2-Hydroxyphenyl) 4-methyl 5-dihydro-lH-pyrazole-l (R) 4, carboximidamide; -N, 4-dimethyl-4, 5-dihydro-lH-pyrazole-l 3-(2-Methoxyphenyl) carboximidamide; 3-(2-Hydroxyphenyl) -N, 4-dimethyl-4, 5-dihydro-lH-pyrazole-l carboximidamide; — — — — — — — — — — — N 3 (2 methoxyphenyl) 4 methyl 5 1H Benzyl dihydro pyrazole carboximidamide; RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 N-Benzy1(2-hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Hydroxy(2-methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — — — N H 3 4 methyl 5 1H (2 hydroxyphenyl) 4, ydroxy dihydro pyrazole carboximidamide; 3-(5-Fluoromethoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide 3-(5-Fluorohydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole 1 0 carboximidamide; methyl-4, 5-dihydro-1H-pyrazole 3-(3-Fluoromethoxyphenyl) carboximidamide; methyl-4, 5-dihydro-1H-pyrazole 3-(3-Fluorohydroxyphenyl) carboximidamide; — — — — 3 (4 Fl uoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(4-Fluorohydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; 3-(5-Chloromethoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole 2 0 carboximidamide; 3-(5-Chlorohydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; 3-(3-Chloromethoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; -dihydro-lH-pyrazole-l- (3-Chlorohydroxyphenyl)methyl-4, carboximidamide; — — — — — — — N (4 Chlorobenzyl) 3 (2 hydroxyphenyl) methyl-4, 5 dihydro-1H— pyrazolecarboximidarnide; — — — — — — — — — — N (2 Chlorobenzyl) 3 (2 hydroxyphenyl) 0 methyl 5 dihydro pyrazolecarboximidarnide; N-(2, 4-Dichlorobenzyl) (2-hydroxyphenyl) methyl-4, 5-dihydro-1H- pyrazolecarboximidarnide; N-(3, 4-Dichlorobenzyl) (2-hydroxyphenyl) methyl-4, 5-dihydro-1H- pyrazolecarboximidarnide; — — — — — — (4-rnethoxybenzyl) methyl 1H— 3 (2 Hydroxyphenyl) 4, 5 dihydro pyrazolecarboximidarnide; — — — — — — — 3-(2 r( 5-dihydro-lH- N 4 Dimethoxybenzyl) hydroxyphenyl) methyl 4, 1 carboximidarnide; pyrazole — — — — — — — — — — N 4 1H— (3, 5 Dimethoxybenzyl) 3 (2 hydroxyphenyl) methyl 4, 5 dihydro 4 pyrazolecarboximidarnide; RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 N-(3-chloromethoxybenzyl)(2-hydroxyphenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; 3-(2-Hydroxyphenyl)methyl-N-((R)-l-phenylethyl)-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(2-Hydroxyphenyl)methyl-N-((S)-l-phenylethyl)-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(2-hydroxyphenyl)methyl-N-phenethy1-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2, 4-Dimethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- j 0 carboximidamide; 3-(2, 4-Dihydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — 3 Methoxy 4 (trifluoromethyl)phenyl) 4 methyl 5 (2 4, dihydro pyrazolecarboximidamide; — — — — — — — — — — — 3 2 H 4 (tri fluoromethyl) 4 methyl 5 dihydro ( ydroxy phenyl) 4, pyrazolecarboximidamide; 3-(IH-Indo1yl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; and 4-Methyl(quinolinyl)-4, 5-dihydro-lH-pyrazole-l- 2 carboximidamide.
In one embodiment of this there is of aspect, provided a compound Formula said compound selected from: I, being 3-(2-Hydroxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Bromophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Chlorophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Meth 1 hen 1 5-dj.hydro-lH-pyrazole-l-carboxj. mj. damj. y p y ) , 3-(2-1sopropylphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; — — — — — 3 1-y 1 4 5-dihydro-1H-pyrazolecarboximidamide; (Naphthalen , — — — — — — 3 (Benzo[b]thio hen 7 -y 1 4 5-dihydro-1H-pyrazolecarboximidamide; — — — — — — — 3 (2 (Trifluoromethyl)phenyl) 4, 5 dihydro pyrazole carboximidamide; 3-(Benzofuranyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Chlorophenyl)-N-methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; WO 20i6/20723i PC T/EP2016/064446 3-(2-Hydroxyphenyl)-N-methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Benzy1(2-chlorophenyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Benzy1(2-hydroxyphenyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; -methyl(naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 4-Methyl(naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l- j 0 carboximidamide; 3-(2-Chlorophenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; -Methyl(3-methylbenzofuranyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 5-Methyl(3-methylbenzo[b]thiophenyl)-4, 5-dihydro-lH-pyrazole- 1-carboximidamide; — — — — 3 Chloro hen 4 6a-tetrahydrocyclopenta[c]pyrazole-l(3aH) (2 1) ) 5, 6, p y , carboximidamide; (R)(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- 2 carboximidamide; 3-(2-Methoxyphenyl)-N, 4-dimethyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Hydroxyphenyl)-N, 4-dimethyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — — — N 4 1H 3 (2 methoxyphenyl) methyl 4, 5 Benzyl dihydro pyrazole carboximidamide; N-Benzy1(2-hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Hydroxy(2-methoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; N-Hydroxy(2-hydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; 3-(5-Fluoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide 3-(5-Fluorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(3-Fluoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(3-Fluorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- 4 0 carboximidamide; PC T/EP2016/064446 -A-methyl-4, 3-(4-Fluoromethoxyphenyl) 5-dihydro-1H-pyrazole carboximidamide; 3-(4-Fluorohydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; (5-Chlorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(3-Chloromethoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; 3-(3-Chlorohydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole 1 0 carboximidamide; — — — — — — — — — — N (4 Chlorobenzyl) 3 (2 hydroxyphenyl) 4 methyl 4 5 I dihydro pyrazolecarboximidarnide; — — — — — — — dihydro-1H— N (2 Chlorobenzyl) 3 (2 hydroxyphenyl) methyl-4, 5 pyrazolecarboximidarnide; — — — -A-methyl-4, 5-dihydro-1H- N (2 4 -Dichlorobenzyl) Di h (2-hydroxyphenyl) pyrazolecarboximidarnide; N-(3, 4-Dichlorobenzyl) (2-hydroxyphenyl) methyl-4, 5-dihydro-1H- pyrazolecarboximidarnide; — — — — — — — — — — 3 N rnethoxybenzyl) 4 methyl 5 (2 Hydroxyphenyl) (4 4, dihydro 2 0 pyrazolecarboximidarnide; — — — — — — — 3-(2 5-dihydro-lH- N (3, 4 Dimethoxybenzyl) hydroxyphenyl) 4 methyl 4, pyrazolecarboximidarnide; — — — — — — — 3-(2 r( 5-dihydro-lH- N (3, 5 Dimethoxybenzyl) hydroxyphenyl) methyl 4, 1 carboximidarnide; pyrazole N-(3-chloromethoxybenzyl) methyl-4 (2-hydroxyphenyl) dihydro-1H-pyrazolecarboximidamide; — — — — — — — — -4 1H— 3 (2 Hydroxyphenyl) methyl N-((R) 1 phenylethyl) -4, 5 dihydro pyrazolecarboximidarnide; — — — — — — — — — — — 3 (2 Hydroxyphenyl) 4 methyl N 1 phenylethyl) 4 5 ((S) I dihydro pyrazolecarboximidarnide; 3-(2-hydroxyphenyl) methyl-N-phenethy1-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — r( 1H— 3 (trifluorornethyl)phenyl) 4 methyl 5 (2 4, &(ethoxy dihydro pyrazolecarboximidarnide; — — — — — 3-(2-H drox methyl 1H— (tri phenyl) 4, 5 dihydro y y fluorornethyl) pyrazolecarboximidarnide; — — — — (1H-Indol 4-methyl 5-dihydro-lH-pyrazole-l- 3 3-yl) 0, carboximidamide.
RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 In one embodiment of this there is of aspect, provided a compound Formula said selected from: I, compound being 4-Methyl(naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — 3 chloro 2 enyl)methyl-4, 5-dihydro-lH-pyrazole-l- (S) (3 hydroxyph carboximidamide; (R)(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Benzy1(3-chloromethoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-Benzy1(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; (R)-N-Benzy1(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; (S)-N-Benzyl(3-chloro-2— hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-Butyl(3-chloromethoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-Butyl(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)-N-hexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-hexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl )-N-dodecylmethyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-dodecy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)-N-cyclohexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-cyclohexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)-N-cyclopropy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl )-N-cyclopropylmethyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH- 40 pyrazolecarboximidamide; WO 20i6/20723i PC T/EP2016/064446 3-(3-Chloromethoxyphenyl)-N-cyanomethyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-cyanomethyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(2, 4-Heptafluorobutyl)(2-methoxyphenyl)methyl-4, 2, 3, 3, 4, 4, dihydro-1H-pyrazolecarboximidamide; N-(2, 4-Heptafluorobutyl)(2-hydroxyphenyl)methyl-4, 2, 3, 3, 4, 4, dihydro-1H-pyrazolecarboximidamide; 3-(2-Methoxyphenyl)methyl-N-(2, 2-trifluoroethyl)-4, 5-dihydro- 1H-pyrazolecarboximidamide; 3-(2-Hydroxyphenyl)methyl-N-(2, 2-trifluoroethyl)-4, 5-dihydro- 1H-pyrazolecarboximidamide; 3-(2-Methoxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Hydroxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — 3 4 methyl N (trifluoromethyl)phenyl) (2 Methoxyphenyl) (4 4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — 3 4 methyl N (trifluoromethyl)phenyl) (2 Hydroxyphenyl) (4 4, dihydro-1H-pyrazolecarboximidamide; N-(4-Fluorophenyl)(2-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(4-Fluorophenyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(4-Chlorophenyl)(2-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(4-Chlorophenyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; — — — — — — — — — — 3 N 4 methyl 5 (2 (Benzyloxy)phenyl) (4 methoxyphenyl) 4, dihydro pyrazolecarboximidamide; 3-(2-Hydroxyphenyl)-N-(4-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; — — — — — — — — 3 Chloro 2 N 4 heptafluorobutyl) 4 (3 methoxyphenyl) (2, 2, 3, 3, 4, 4, methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide; — — — — — — — — 3 Chloro 2 N 4 fluorobutyl) 4 (3 hydroxyphenyl) (2, 2, 3, 3, 4, 4, hepta methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide; — — — — — — — — — — 2 N 4 3 (3 Chloro methoxyphenyl) (4 fluorophenyl) methyl 4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — — 3 Chloro 2 N fluorophenyl) 4 methyl (3 hydroxyphenyl) (4 4, 40 dihydro-1H-pyrazolecarboximidamide; PC T/EP2016/064446 3-(3-Chloromethoxyphenyl)-N-(4-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-(4-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — 3 Chloro 2 4 methyl N (trifluoromethyl)phenyl) (3 methoxyphenyl) (4 -dihydro-lH-pyrazole-l-carboximidamide; — — — — — — — — — 2 4 N 3 (3 Chloro hydroxyphenyl) methyl (4 (trifluoromethyl)phenyl) -dihydro-lH-pyrazole-l-carboximidamide; 3-(3-Chloromethoxyphenyl)-N-(2-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-(2-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — — 3 Chloro 2 N fluorobenzyl) 4 methyl (3 methoxyphenyl) (4 4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — — 3 Chloro 2 N 4 methyl (3 (4 4, hydroxyphenyl) fluorobenzyl) dihydro-1H-pyrazolecarboximidamide; — — — — — — — chloro 2 4 methyl Ethyl((3 (3 ((ethoxycarbonyl)oxy)phenyl) 4, — — — — 1H 1 yl)(imino) methyl) carbamate; dihydro pyrazol Ethyl ((3-(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolyl) carbamate. (imino) methyl) In one embodiment of this there is of aspect, provided a compound Formula said compound selected from: I, being 4-Methyl(naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Hydroxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Bromophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Chlorophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Methylphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(2-Isopropylphenyl) -4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(Naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; 3-(Benzo[b]thiophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide; — — — — — — — 3 (Trifluoromethyl)phenyl) 5 1H (2 4, dihydro pyrazole carboximidamide; — — — — 3 (Benzo furan 3 4 5-dihydro-1H-pyrazolecarboximidamide; 3-(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; WO 20i6/20723i PC T/EP2016/064446 3-(2-Chlorophenyl)-N-methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Hydroxyphenyl)-N-methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Benzy1(2-chlorophenyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Benzy1(2-hydroxyphenyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; -methyl(naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l- j 0 carboximidamide; 3-(2-Chlorophenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; -Methyl(3-methylbenzofuranyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 5-Methyl(3-methylbenzo[b]thiophenyl)-4, 5-dihydro-lH-pyrazole- 1-carboximidamide; — — — — 3 Chloro hen 4 6a-tetrahydrocyclopenta[c]pyrazole-l(3aH) (2 1) ) 5, 6, p y , carboximidamide; (R)(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- 2 carboximidamide; 3-(2-Methoxyphenyl)-N, 4-dimethyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Hydroxyphenyl)-N, 4-dimethyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — — — N 4 1H 3 (2 methoxyphenyl) methyl 4, 5 Benzyl dihydro pyrazole carboximidamide; N-Benzy1(2-hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Hydroxy(2-methoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; N-Hydroxy(2-hydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; 3-(5-Fluoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide 3-(5-Fluorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(3-Fluoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(3-Fluorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- 4 0 carboximidamide; PC T/EP2016/064446 -A-methyl-4, 3-(4-Fluoromethoxyphenyl) 5-dihydro-1H-pyrazole carboximidamide; 3-(4-Fluorohydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; (5-Chlorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(3-Chloromethoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide; 3-(3-Chlorohydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole 1 0 carboximidamide; — — — — — — — — — — N (4 Chlorobenzyl) 3 (2 hydroxyphenyl) 4 methyl 4 5 I dihydro pyrazolecarboximidarnide; — — — — — — — dihydro-1H— N (2 Chlorobenzyl) 3 (2 hydroxyphenyl) methyl-4, 5 pyrazolecarboximidarnide; — — — -A-methyl-4, 5-dihydro-1H- N (2 4 -Dichlorobenzyl) Di h (2-hydroxyphenyl) pyrazolecarboximidarnide; N-(3, 4-Dichlorobenzyl) (2-hydroxyphenyl) methyl-4, 5-dihydro-1H- pyrazolecarboximidarnide; — — — — — — — — — — 3 N rnethoxybenzyl) 4 methyl 5 (2 Hydroxyphenyl) (4 4, dihydro 2 0 pyrazolecarboximidarnide; — — — — — — — 3-(2 5-dihydro-lH- N (3, 4 Dimethoxybenzyl) hydroxyphenyl) 4 methyl 4, pyrazolecarboximidarnide; — — — — — — — 3-(2 r( 5-dihydro-lH- N (3, 5 Dimethoxybenzyl) hydroxyphenyl) methyl 4, 1 carboximidarnide; pyrazole N-(3-chloromethoxybenzyl) methyl-4 (2-hydroxyphenyl) dihydro-1H-pyrazolecarboximidamide; — — — — — — — — -4 1H— 3 (2 Hydroxyphenyl) methyl N-((R) 1 phenylethyl) -4, 5 dihydro pyrazolecarboximidarnide; — — — — — — — — — — — 3 (2 Hydroxyphenyl) 4 methyl N 1 phenylethyl) 4 5 ((S) I dihydro pyrazolecarboximidarnide; 3-(2-hydroxyphenyl) methyl-N-phenethy1-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — — r( 1H— 3 (trifluorornethyl)phenyl) 4 methyl 5 (2 4, &(ethoxy dihydro pyrazolecarboximidarnide; — — — — — 3-(2-H drox methyl 1H— (tri phenyl) 4, 5 dihydro y y fluorornethyl) pyrazolecarboximidarnide; — — — — (1H-Indol 4-methyl 5-dihydro-lH-pyrazole-l- 3 3-yl) 0, carboximidamide; — — — — — — — — — — — — 2 r) 1H (S) 3 (3 chloro hydroxyphenyl) methyl 4, 5 dihydro pyrazole 4 carboximidamide; RECTIFIED SHEET (RULE 91) ISA/EP WO 20i6/20723i PC T/EP2016/064446 (R)(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; N-Benzy1(3-chloromethoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-Benzyl(3-chlorohydr oxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; (R)-N-Benzy1(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; (S)-N-Benzy1(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-butyl(3-chloromethoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-Butyl(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl )-N-hexylmethyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-hexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)-N-dodecy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-dodecy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)-N-cyclohexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl )-N-cyclohexylmethyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)-N-cyclopropy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-cyclopropy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH- pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl )-N-cyanomethyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(2, 4-Heptafluorobutyl)(2-methoxyphenyl)methyl-4, 2, 3, 3, 4, 4, dihydro-1H-pyrazolecarboximidamide; N-(2, 4-Heptafluorobutyl)(2-hydroxyphenyl)methyl-4, 2, 3, 3, 4, 4, 40 dihydro-1H-pyrazolecarbo ximidamide; WO 20i6/20723i PC T/EP2016/064446 3-(2-Methoxyphenyl)methyl-N-(2, 2-trifluoroethyl)-4, 5-dihydro- 1H-pyrazolecarboximidamide; 3-(2-Hydroxyphenyl)methyl-N-(2, 2-trifluoroethyl)-4, 5-dihydro- 1H-pyrazolecarboximidamide; 3-(2-Methoxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; 3-(2-Hydroxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide; — — — — — — — — 3 4 methyl N (trifluoromethyl)phenyl) (2 Methoxyphenyl) (4 4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — 3 4 methyl N (trifluoromethyl)phenyl) (2 Hydroxyphenyl) (4 4, dihydro-1H-pyrazolecarboximidamide; N-(4-Fluorophenyl)(2-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(4-Fluorophenyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(4-Chlorophenyl)(2-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; N-(4-Chlorophenyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; — — — — — — — — — — 3 (2 (Benzyloxy)phenyl) (4 methoxyphenyl) methyl 4, 5 dihydro pyrazolecarboximidamide; 3-(2-Hydroxyphenyl)-N-(4-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide; — — — — — — — — 2 N 4 3 (3 Chloro methoxyphenyl) (2, 2, 3, 3, 4, 4, heptafluorobutyl) methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide; — — — — — — — — 2 N 4 3 (3 Chloro hydroxyphenyl) (2, 2, 3, 3, 4, 4, heptafluorobutyl) methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide; — — — — — — — — — — 3 Chloro 2 N fluorophenyl) 4 methyl (3 methoxyphenyl) (4 4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — — 2 N 4 3 (3 Chloro hydroxyphenyl) (4 fluorophenyl) methyl 4, dihydro-1H-pyrazolecarboximidamide; 3-(3-Chloromethoxyphenyl)-N-(4-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-(4-chlorophenyl) methyl-4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — 2 4 N 3 (3 Chloro methoxyphenyl) methyl (4 (trifluoromethyl)phenyl) -dihydro-lH-pyrazole-l-carboximidamide; — — — — — — — — — 3 Chloro 2 4 methyl N (trifluoromethyl)phenyl) (3 hydroxyphenyl) (4 40 5-dihydro-lH-pyrazole-l-carboximidamide; PC T/EP2016/064446 3-(3-Chloromethoxyphenyl)-N-(2-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; 3-(3-Chlorohydroxyphenyl)-N-(2-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — — 3 Chloro 2 N fluorobenzyl) 4 methyl (3 methoxyphenyl) (4 4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — — — — 2 N 4 3 (3 Chloro hydroxyphenyl) (4 fluorobenzyl) methyl 4, dihydro-1H-pyrazolecarboximidamide; — — — — — — — chloro 2 4 methyl Ethyl((3 (3 ((ethoxycarbonyl)oxy)phenyl) 4, — — — — 1 0 1H 1 carbamate; yl)(imino) methyl) dihydro pyrazol Ethyl ((3-(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- 1 carbamate. yl)(imino) methyl) pyrazol In another of the invention, there is provided a compound of aspect the general formula I R R AR wherein -10 2 0 AR represents a membered mono- or bicyclic aromatic or heteroaromatic containing heteroatoms independently ring system selected from and N, 0, S; is selected from -C~ C~-C~ Cj-C~ haloalkyl, C, alkyl, cycloalkyl, 2 5 OR OC R OC OR OC NR R SR S R S S (0) (0) (0) (0) (0) zR (0) ~ ~ ~ ~ ~ ~ ~ D'OR S R NR R NR C R NR C NR R C R C OR C NR R (0) zNR (0) (0) (0) (0) (0) ~ ~ ~ ~ ~ ~ NR C 4 fluorophenyl, 4 chlorophenyl, (0) OR, F, Cl, Br, I, CN, phenyl, and 4-methoxyphenyl; or is of said when said is bicyclic; part ring system ring system R', OR', R', and R are independently selected from R, R, OC(0) OC OR OC NR R SR S R S S S R NR R (0) (0) (0) (0) zR (0) (0) zNR ~ ~ ~ ~ ~ D'OR ~ ~ NR C R NR C NR R C R C OR C NR R N R C OR Cl (0) ~ (0) ~ (0) ~ (0) ~ (0) ~ (0) ~ F~ 4-fluorophenyl, 4-chlorophenyl, and 4-methoxyphenyl, Br, I, CN, R', R', wherein and are positioned independently in of the free PC T/EP2016/064446 of the mono- or aromatic or heteroaromatic positions bicyclic ring system; R and R are independently selected from -Cj~ C~-Cg hydrogen, C, alkyl, and Cj-C~ haloalkyl; cycloalkyl, phenyl, and R are selected from R, R, R, independently hydrogen, methyl, and n-butyl; or selected such ethyl, n-propyl, iso-propyl, being R' R' that and are connected to form a 4-, 5-, 6-, or 7-membered ring; X is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, neo-butyl, tert-butyl, butyl, cyclopropyl, cyclopentyl, CF~, CFzCF~, phenyl, benzyl, hydroxy, methoxy, ethoxy, phenylethyl and wherein said 2-phenylethyl and benzyl benzyloxy, phenyl, groups are mono- or di-substituted substituents independently optionally by selected from and methyl, ethyl, methoxy, ethoxy, iso-propyloxy, F, Cl; and 2 and 0 pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers thereof.
In one embodiment of this there is provided a compound of aspect, Formula wherein R R AR represents PC T/EP2016/064446 R' R' R' R' R' R2 R4 R2 R4 R3, R3, R3 R3 R3 R' R' R' R R R R R R R, R, R, NH 0 S R2 R4 R, R, R R, R R R R R, R, R R2 R3 R4 R R, R R R, R ~— ~— R R R R R, R, R R R R, R, R, N~zN R R, R R, R, R, R, R~g wherein and R are in of the free R, R, positioned independently any of the mono- or aromatic or heteroaromatic positions bicyclic ring system; is selected from methyl, ethyl, iso-propyl, cyclopropyl, CF3, hydroxy, methoxy, ethoxy, propoxy, OCF3, SCH3, S(0)3CH3, OC(0) OR, R N NHC NHC NHC OC (0) NH3~ NHCH3~ (CH3) (0) H~ (0) CH3~ (0) NH3~ ~ 3~ NHC NHC N N and (0) NHCH3, (0) (CH3) C (0) CH3, C (0) (CH3) F, Cl, Br, I, CN, 3, 3, phenyl; R', R', and are selected from independently hydrogen, methyl, iso- ethyl, iso-propyl, cyclopropyl, CF3, hydroxy, methoxy, ethoxy, N NHC NHC propoxy, OCF3, SCH3, S (0) 3CH3, NH3, NHCH3, (CH3) (0) H, (0) CH3, NHC NHC NHC N N Cl (0) NH3~ (0) NHCH3~ (0) (CH3) C (0) CH3~ C (0) (CH3) F~ Br~ 3~ 3~ ~ I, CN, phenyl; represents Cj-Cj3 alkyl phenyl; PC T/EP2016/064446 and R are selected from R, R, R, independently hydrogen, methyl R' R' and or selected such that and are connected ethyl; being to form a 5-, or 6-membered and ring; X is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclopentyl, CF&, CFzCF~, phenyl, phenylethyl, benzyl, and wherein said and is hydroxy; phenyl, 2-phenylethyl, benzyl mono- or di-substituted substituents independently optionally by selected from and Cl. methyl, ethyl, methoxy, F, In one embodiment of this there is provided a compound of aspect, Formula wherein AR is selected from I, phenyl, naphtyl, benzothiophenyl, indolyl and benzofuranyl. quinolinyl, In one embodiment of this there is provided a compound of aspect, Formula wherein R R, R 2 is selected from the 0 group R' R' R R, R R, R R R R R, R, R R, R R R, R R, R, R R, R HN o wherein R' — is selected from methyl, iso propyl, CF~, hydroxy, methoxy, NH&, F, Cl, and Br; R, R, and R are independently selected from hydrogen, CF„ hydroxy, methoxy, F, and Cl; PC T/EP2016/064446 and R are selected from R, R, R, independently hydrogen, methyl R' R' and or selected such that and are connected ethyl; being to form a 5-membered ring; X is selected from hydrogen, methyl, benzyl, CHCH&C&H&, chlorobenzyl, 2-chlorobenzyl, 4-dichlorobenzyl, 2, 3, -dimethoxybenzyl, dichlorobenzyl, 4-methoxybenzyl, 3, 3, dimethoxybenzyl, 3-chloromethoxybenzyl, 2-phenylethyl, and hydroxy.
In one embodiment of this there is provided a compound of aspect, Formula wherein R R AR is selected from the group R" R" wherein 2 is selected from 0 methyl, iso-propyl, CF„ hydroxy, methoxy, NH„ F, Cl, Br; R is selected from and Cl. hydrogen, CF&, hydroxy, methoxy, F, In one embodiment of this there is of aspect, provided a compound Formula wherein R R AR is selected from the group PC T/EP2016/064446 wherein is selected from methyl, iso-propyl, CF~, hydroxy, methoxy, NH&, F, Cl, and Br; and R is selected from hydrogen and F.
In one embodiment of this aspect, there is provided a compound of Formula wherein R R, R is selected from the group N HN wherein is selected from methyl, iso-propyl, CF~, hydroxy, methoxy, NH&, F, and Br.
In one embodiment of this there is provided a compound of aspect, Formula wherein R R, R PC T/EP2016/064446 represents wherein is selected from methyl, iso-propyl, CF&, hydroxy, methoxy, OC OC OC OC CH and NHz, F, Cl, Br, (0) CHz, (0) Ph, (0) (CHz) zCHq, (0) (CHq) OC and (0) OCH~CH~, R is selected from Cl and Br. hydrogen, F, In another aspect of the invention there is provided a compound of formula I for use as a medicament.
In another of the invention there is provided a compound of aspect formula for use in treatment of fibrosis, cardiovascular diseases, IBD, or other inflammatory diseases. pain, Typically, fibrosis is selected from systemic sclerosis, skin fibrosis, liver heart intestinal fibrosis, fibrosis, kidney fibrosis, fibrosis, lung fibrosis fibrosis and fibrosis including idiopathic pulmonary (IPF) 2 0 associated with arterial hypertension and fibrosis pulmonary (PAH), associated with transplantation, stenosis, or keloid surgery, scarring. said cardiovascular disease is selected from Typically, atherosclerosis and hypertension. said is selected Typically, pain from and associated with diseases. migraine pain inflammatory said IBD is selected from Crohn's disease and ulcerous Typically, colitis In another of the invention there is provided a compound of aspect formula for use in treatment of inflammatory diseases I, joint including RA and OA.
In another of the invention there is provided use of a aspect compound of formula in the manufacture of a medicament useful in treatment of fibrosis, cardiovascular diseases, IBD or other pain, inflammatory diseases. said fibrosis is selected from Typically, systemic sclerosis, skin fibrosis, liver fibrosis, heart fibrosis, kidney fibrosis, intestinal fibrosis, fibrosis including lung PC T/EP2016/064446 fibrosis and fibrosis associated with idiopathic pulmonary (IPF) arterial and fibrosis associated with pulmonary hypertension (PAH), transplantation, stenosis, or keloid scarring. surgery, Typically, said cardiovascular disease is selected from atherosclerosis and hypertension. said is selected from migraine and Typically, pain associated with inflammatory diseases. said IBD is pain Typically, selected from Crohn's disease and ulcerous colitis.
In another of the invention there is provided use of a aspect 1 0 compound of formula in the manufacture of a medicament useful in treatment of inflammatory diseases including RA and OA. joint In another of the invention there is provided a method of aspect treating fibrosis, cardiovascular diseases, IBD, or other pain, inflammatory diseases comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need thereof. said fibrosis is selected from systemic Typically, sclerosis, skin fibrosis, liver fibrosis, heart fibrosis, kidney fibrosis, intestinal fibrosis, fibrosis including idiopathic lung 2 fibrosis and fibrosis associated with 0 pulmonary (IPF) pulmonary arterial and fibrosis associated with hypertension (PAH), or keloid transplantation, surgery, stenosis, scarring. Typically, said cardiovascular diseases are selected from atherosclerosis and hypertension. said is selected from migraine and Typically, pain associated with diseases. sais IBD is pain inflammatory Typically, selected from Crohn's disease and ulcerous colitis.
In another of the invention there is provided a method of aspect treating inflammatory diseases including RA and comprising joint OA, administering a therapeutically effective amount of a compound of formula I in need thereof. to a patient In another of the invention there is provided a aspect pharmaceutical composition comprising a compound according to Formula admixed with one or more pharmaceutically acceptable excipients or carriers. said excipients are selected from Typically, group comprising filling agents, lubricants, flavours, colourings, sweetenings, buffers, acidifying diluents, and agents, preservatives. said compositions are administered Typically, orally, 4 0 oral inhalation, intramuscularly, intravenously, PC T/EP2016/064446 or via intraperitoneally, subcutaneously, implants, rectally, intranasally, transdermally; preferably orally.
The compounds of the invention be used in the and may prophylaxis treatment as such, or in a form of a pharmaceutical preferably composition. While it is possible for the active ingredient to be administered alone, it is preferable for it to be present in a formulation or the pharmaceutical composition. Accordingly, invention provides a pharmaceutical formulation comprising a compound according to the invention, and a pharmaceutically j 0 acceptable diluent, excipient or carrier (collectively referred to "carrier" herein as materials) . Pharmaceutical compositions of the invention take the form of a pharmaceutical formulation as described below. Thus, the present invention relates to a pharmaceutical composition containing at least one compound of formula I together with conventional excipients. compositions for oral administration include suspensions Exemplary (including nanosuspensions) which can contain, for example, microcrystalline cellulose for bulk, alginic acid or imparting 2 sodium 0 alginate as a suspending agent, methylcellulose as a and sweeteners or such those viscosity enhancer, flavoring agents as known in the and immediate release tablets which can art; contain, for microcrystalline cellulose, dicalcium example, phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose, lactose other and/or and/or excipients, binders, extenders, and lubricants such those known in the disintegrants, diluents, as art. Suitable binders include natural such starch, gelatin, sugars as glucose or beta-lactose, corn sweeteners, natural and synthetic such as acacia, tragacanth or sodium gums alginate, carboxymethylcellulose, waxes, and the like. polyethylene glycol, include without limitation Disintegrators starch, methylcellulose, xanthan and the like. The of formula agar, bentonite, gum, compounds I can also be delivered through the oral cavity sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze- dried tablets are forms which be used. exemplary may Exemplary compositions include those formulating the present with compound(s) fast diluents such dissolving as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations be may high molecular weight excipients such as celluloses (avicel) or PC T/EP2016/064446 Such formulations can also include an polyethylene glycols (PEG) . aid mucosal adhesion such cellulose excipient to as hydroxy propyl methyl cellulose sodium carboxy methyl (HPC), hydroxy propyl (HPMC), cellulose maleic anhydride Gantrez), and (SCMC), copolymer (e.g. to control release such as agents polyacrylic copolymer (e.g.
Carbopol 934) . Lubricants, flavors, coloring and glidants, agents, stabilizers also for of fabrication and may be added ease use.
Lubricants used in these forms include sodium oleate, sodium dosage stearate, magnesium stearate, sodium benzoate, sodium acetate, j 0 sodium chloride, and the like. For oral administration in liquid non- form, the oral components can be combined with oral, drug any toxic, pharmaceutically acceptable inert carrier such as ethanol, water, and the like. glycerol, The pharmaceutical formulations according to the invention include those suitable for oral, parenteral [including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular], inhalation (including fine particle dusts or mists which be generated means of various of metered dose may by types 2 nebulizers or insufflators, 0 pressurized aerosols), rectal, intraperitoneal, topical (including dermal, buccal, sublingual, and intraocular) administration, the most suitable route although for the condition and disorder of the may depend upon, example, recipient.
Formulations of the invention suitable for oral present administration discrete units such may be presented as as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous for example liquid, as elixirs, tinctures, suspensions (including nanosuspensions) or an oil-in-water emulsion or water-in-oil syrups; as liquid a liquid emulsion. The active ingredient also be presented as a bolus, electuary or paste.
A tablet be made compression or moulding, optionally with one may by or more tablets accessory ingredients. Compressed may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or optionally mixed with a granules, 4 0 binder, lubricant, inert diluent, lubricating, surface active or PC T/EP2016/064446 Moulded tablets made in dispersing agent. may be by moulding a suitable machine mixture of the moistened with a powdered compound an inert liquid diluent. The tablets be coated or may optionally scored and be formulated so as to provide slow or controlled release of the active ingredient therein. The present compounds can, for be administered in a form suitable for immediate example, release or extended release. Immediate release or extended release can be achieved the use of suitable pharmaceutical compositions comprising the present particularly in the case of compounds, or, 1 0 extended release, the use of devices such as subcutaneous implants or osmotic The present compounds can also be pumps. administered liposomally. Preferred unit formulations are dosage those containing an effective as hereinbefore recited, or an dose, fraction thereof, of the active ingredient. appropriate It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention include other conventional in the art having regard to the agents of formulation in question, for example those suitable for oral type administration include flavouring may agents.
The formulations in unit form may conveniently be presented dosage and of the methods well known in the art of may be prepared by any All methods include the of the active pharmacy. step bringing ingredient into association with the carrier which constitutes one or more In the formulations are accessory ingredients. general and into association the prepared by uniformly intimately bringing active with carriers or divided solid ingredient liquid finely carriers or both and then, if the product into necessary, shaping the desired formulation.
The of the invention can also administered in compounds present be the form of such small unilamellar liposome delivery systems, as vesicles, unilamellar vesicles, and multilamellar vesicles. large Liposomes can be formed from a variety of phospholipids, 1, dipalmitoylphosphatidylcholine, ethanolamine phosphatidyl phosphatidylserine, phosphatidylinositol, (cephaline), diphosphatidylglycerol (cardiolipin) phosphatidylcholine (lecithin) .
PC T/EP2016/064446 Formulations for administration include and non- parenteral aqueous sterile solutions which contain anti-oxidants, aqueous injection may buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and and aqueous non-aqueous sterile suspensions (including nanosuspensions) which include and thickening agents. The may suspending agents formulations in unit-dose or multi-dose may be presented containers, for example sealed ampoules and vials, and be stored in a freeze-dried condition the addition of (lyophilised) requiring only 1 0 the sterile liquid carrier, for example saline or water-for- injection, immediately prior to use. Extemporaneous injection solutions and suspensions be from sterile may prepared powders, and tablets of the kind described. granules, previously Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for suitable example, non-toxic, parenterally acceptable diluents or solvents, such as ethanol, 3-butanediol, water, Ringer's polyethylene glycol, 1, solution, an isotonic sodium chloride solution, or other suitable or wetting and including synthetic dispersing suspending agents, 2 mono- or and oleic 0 diglycerides, fatty acids, including acid, polysorbates, Cremaphor. compositions for nasal, aerosol or inhalation Exemplary administration include solutions in saline, which can contain, for alcohol or other suitable example, benzyl preservatives, absorption enhance other or promoters to bioavailability, and/or solubilizing such those known in the art. dispersing agents as Formulations for rectal administration be presented as a with the usual carriers such as cocoa butter, synthetic suppository esters or Such carriers are glyceride polyethylene glycol. typically solid dissolve in the at ordinary temperatures, but liquefy and/or rectal cavity to release the drug.
Formulations for topical administration in the mouth, for example buccally or include lozenges comprising the active sublingually, in flavoured basis such sucrose and acacia or ingredient a as tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and or sucrose and acacia. glycerine Exemplary PC T/EP2016/064446 for administration include carrier compositions topical a topical such Plastibase (mineral oil with as gelled polyethylene) .
The amount of active ingredient which is required to achieve a therapeutic effect will, of course, with the particular vary the route of administration, the under treatment, compound, subject the and medical condition including type, species, age, weight, sex, of the and the renal and hepatic function of the subject subject, and the particular disorder or disease treated, as well as its being j 0 severity. An ordinarily skilled veterinarian or clinician physician, can readily determine and prescribe the effective amount of the drug required to counter or arrest the of the prevent, progress condition.
Oral of the present invention, when used for the indicated dosages effects, will between about 0. 01 of weight range mg per kg body per to about 100 0. 01 of day (mg/kg/day) mg/kg/day, preferably mg per kg body weight to 10 and most preferably per day (mg/kg/day) mg/kg/day, 0. 1 to 5. 0 for adult humans. For oral administration, the mg/kg/day, 2 are in the form of tablets or other 0 compositions preferably provided forms of in discrete units presentation provided containing 0. 01, 1. 2. 10. 15. 25. and 0. 05, 0.1, 0.5, 0, 5, 5. 0, 0, 0, 0, 50. 0, 100, 500 milligrams of the active ingredient for the adjustment symptomatic of the to the patient to be treated. A medicament dosage typically contains from 01 of the active about 0. mg to about 500 mg Furthermore, for the ingredient. preferred compounds present invention can administered in intranasal form via of be topical use suitable intranasal vehicles, or via transdermal routes, those using forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal the administration of delivery system, dosage will, course, be continuous rather than intermittent the throughout dosage regimen.
In another of the invention there is provided a aspect pharmaceutical composition comprising a compound of general formula and an additional therapeutic (I) agent.
Compounds of general formula be administered as the sole (I) may pharmaceutical or in combination with one or more additional agent 4 0 therapeutic where the combination causes no unacceptable agents PC T/EP2016/064446 adverse effects. This combination includes pharmaceutical administration of formulation which a single pharmaceutical dosage contains a compound of general formula and one or more additional therapeutic as well as administration of the agents, compound of general formula and each additional therapeutic in its own separate pharmaceutical formulation. For agent dosage of formula and example, a compound general (I) a therapeutic agent be administered to the patient together in a single oral may dosage composition such as a tablet or or each be capsule, agent may j 0 administered in separate formulations. dosage Where separate formulations are the compound of general dosage used, formula and one or more additional therapeutic be (I) agents may administered at essentially the same time concurrently) or at (e.g. times separately staggered (e.g. sequentially) In particular, the compounds of the present invention be used in fixed or separate combination with effectors of nuclear receptors, transcription factors, G protein coupled ion channels, receptors, 2 or 0 integrins, kinases, enzymes.
In the of the invention in particular, compounds present may be used fixed or separate combination with: glucocorticoid receptor agonists e. triamcinolone, prednisone, prednisolone or budesonide; mineralocorticoid receptor antagonists e.g. spironolactone, or canrenone; PPAR GFT eplerenone agonists e.g. rosiglitazone, 505, or FXR saroglitazar, pioglitazone farglitazar; agonists e.g. obeticholic acid, Px 102 or ursodeoxycholic acid; PXR agonists e. pregnenolone 160-carbonitrile; NR4AI agonists e. g. cytosporone B; Nrf2 activators e. bardoxolone XNT P-catenin inhibitors g. methyl; / ICG-001; chemokine bindarit; LPA e.g. antagonists e.g. antagonists BMS 986020 or SAR e.g. 100842; prostacyclin analogues e.g. (+/ beraprost sodium, iloprost or treprostinil; ATI receptor antagonists e. losartan; ETA receptor antagonists e. atrasentan, g. g. ambrisentan, bosentan or macitentan; CCR5 antagonists e. maraviroc; CCR2 antagonists e. RS-504393; CXCR4 antagonists e. g. g.
AMD3100; PARI inhibitors SCH S1P e.g. 79797; ligands e.g. fingolimod (FTY720); PTGER agonists e. rutaprost PTGFR g. (R) (prodrug); antagonists e. AL-8810; LXA4 agonists e. BML-111; RXFPI g. g. 4 0 agonists; 5-HT2A or 5-HT2B receptor antagonists e. g. sarpogrelate; PC T/EP2016/064446 P2X7 A-438079; KCa3. 1 IKCal blockers TRAM- antagonists e.g. / e.g.
Ca2+ Channel blockers Na-K-Cl 34; T-type e.g. efonidipine; cotransporter inhibitors e. torsemide; integrin inhibitors g. DVP6 e. CXHM 12; integrin inhibitors e. Galectin 3 g. DVPI g. c8; antagonists e. TD139; TGF-P or inhibitors e. pirfenidone or g. p38 g.
F-351; tyrosine kinase inhibitors e. nintedanib, imatinib or nilotinib; kinase inhibitors baricitinib e.g. sorafenib, dasatinib, or tanzisertib; PI3K mTOR inhibitors e. GSK2126458; MK2 inhibitors e. MMI 0100; IGFII antagonists e. PXS 64 or PXS 25; PKC5 g. g. j 0 inhibitors e. rottlerin; MAPK inhibitors e. SB239063 or g. p38 g. 167653; RHO kinase inhibitors e. Y-27632; FAK inhibitors e. g. g. 562271; ALK5 inhibitors e. SB-431542; SMAD3 inhibitors e. SIS-3; g. g.
TGFPI inhibiting e. disitertide; PDE inhibitors e. peptides g. g. pentoxifylline or CTP 499; PDE5 inhibitors e. sildenafil; NADPH oxidase inhibitors e. GKT 137831; TAFI inhibitors e. UK 082; g. g. 396, cathepsin B inhibitors e. VBY 376; inhibitors e. g. caspase g. emricasan; LOXL2 inhibitors e. P-aminopropionitrile; TGM2 antagonists e. NTU281; prolyl hydroxylase inhibitors e. HOE 077 g. g. or pyridine-2, 4-dicarboxylate; inhibitors of BMP1 or BMP1-like 2 UK-421045; elastases ONO-5046; EPRS 0 proteinases e.g. neutrophil e.g. inhibitors TNKS1 inhibitors ACE e.g. halofuginone; e.g. XAV939; inhibitors ATX inhibitors GXJ-A-23; AT1 e.g. enalapril; e.g. receptor antagonists e. losartan; 5LO inhibitors e. zileuton; g. g.
HMG-CoA reductase inhibitors (statins) e. atorvastatin, rosuvastatin or fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin; PAI1 TM5275; FKBP12 binders antagonists e.g. e.g. sirolimus; S100A9 binders transfer cofactor e.g. paquinimod; methyl e. ademetionine; immunomodulatory compounds e. thalidomide or g. g. pomalidomide; mitochondria-targeted antioxidants e. mitoquinone; vitamin derivatives e. pyridoxamine or D-tocopherol; purine antagonists e. azathioprine; ROS scavengers or anti-oxidants e. g. g.
N-acetylcysteine, alpha lipoic acid or D-tocopherol; microtubules colchicine; chelators D-penicillamine; disrupters e.g. copper e.g.
HSP47 inhibitors or BET alkylators e.g. cyclophosphamide; expression inhibitors e. or interferon lb. g. (+) JQ 1; The invention will now described in more detail the present be by which are included in order disclose certain following examples, to PC T/EP2016/064446 embodiments of the invention, not in limit the but any way to scope of the invention.
Preparation of compounds of the invention The novel compounds of the present invention can be prepared by known methods described in organic chemistry textbooks March's (e.g.
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th or in the literature X02006/072351 and Edition, Wiley) (see e.g.
X. et al. J. Med. Chem. 2002, 2695 2707) . Thus, the Du, 45, pyrazoline can be formed reacting aromatic Mannich bases ring by j 0 with hydrazine to 3-Arpyrazolines with hydrazine give (b), derivatives such as aminoguanidines, NNHC(NH)NHX (X=H, H, alkyl, or to 1-amidinoArpyrazolines or benzyl, phenyl, OH) give (d), with semicarbazides, NHX, to the corresponding HzNNHC(S) give thiocarbonyl derivatives which can be transformed to the final (c), products (Scheme . The ring-forming condensation reactions (d) 2) hydrazine or hydrazine derivatives are performed in using typically solvents at elevated temperatures, e. in alcohols such as polar g.
MeOH or EtOH at reflux temperatures. 2 The 3-Arpyrazolines can further reacted in one or several 0 (b) be with that the amidino-group the steps reagents provide to give amidinoarylpyrazolines Methods described in the (d) . literature are e. reactions with MeSC(NH)NHX, or its salts, at elevated temperature in or with amidino-pyrazole or with pyridine di-Boc-protected amidino-pyrazole in THE room at temperature followed TEA M. al. by deprotection by (Bernatowicz, S. et Tetrahedron Vol. No. 3389-3392, In other Letters, 34, 21, 1993) . methods the thiocarbonyl derivatives are first generated (c) by iso- reaction with e. iso-thiocyanates, XN=C=S, protected thiocyanate BzNCS, cleaved basic or other (e.g. by hydrolysis), forms of activated imidazolyl-based thiocarbonyl derivatives, e.g.
This is followed activation S-methylation, reagents. by by e.g.
MeI, and reaction with an amine (HzN-X) to the final using give amidinoarylpyrazolines . See also Scheme 5 for the analogous preparation of the hydrazine starting materials.
"-NHX" In reaction where is included in both the substrate sequences "-NHX" and the at least one is -NHz. reagent, PC T/EP2016/064446 R9 R9 9 R' R' R R' , 10 R7 10 R" R" ~ N N.
NH .
AR Jt tt S (d) (~) (c) R, R R R R R Scheme 2 Alternatively, aryl-vinylketones (e) can be used as starting materials in the reactions with the hydrazine derivatives (Scheme 3) .
R' 1o R" R" p N X R, R, R R, R, R AR Scheme This allows for a broader of the pyrazoline substitution range ring pattern for the R9 and R10 substituents. 4-R7, R8- Another method (X02013/006308A2), suitable for 4, disubstituted 1-amidinoArpyrazolines is react aryl- (k) to alkylketones containing a leaving-group in the P-position other (LG) than amino groups, such as halo or tosylate, with hydrazine or hydrazine derivatives analogous to the reactions above (Scheme 4) . 1o R R R R" R" .N N.
R AR R AR R, R, R, R, Scheme 4 The hydrazine derivatives HzNNHC(NH) NHX and HzNNHC(S) NHX (X is as defined in general formula I) are either commercially available or can be prepared known methods, see e. US 4, 107, 326. Thus, by g. thiosemicarbazides, which can be prepared reacting hydrazine with XN=C=S, iso-thiocyanates, can be activated S-methylation and further reacted with amines (XNHz) or ammonia to give the PC T/EP2016/064446 derivatives NHX In these aminoguanidine HzNNHC (NH) (Scheme 5) . reactions the three N —, and =NH) are groups (HzNNH NHX, interchangeable, e. hydrazine can be reacted with an S-methylated urea derivative MeSC(NH)NHX.
N2H4 .N N. N N.
H2N X H2N X tt H2N X-NCS Scheme 5 The aromatic starting materials used in the reaction with hydrazine 1 0 derivatives are either commercially available or can be prepared Mannich- several methods described in the literature. The aromatic bases can be prepared from alkyl-arylketones in Mannich-type reactions using formaldehyde or an equivalent reagent, such as 1, dioxolane, and a dialkylamine or its salt, e. dimethylammonium iodide, or alternatively using a preformed iminium species, such as the Eschenmoser salt HzCNMezl.
Several synthetic routes, which can be found in organic chemistry March's textbooks (e. Advanced Organic Chemistry: Reactions, 2 0 Mechanisms, and Structure, 7th Edition, Wiley), exist for the preparation of aryl-vinylketones, some of which are listed below: aldol-condensations of arylketones with aldehydes or ketones; elimination of amine from N-alkylated Mannich-bases; elimination reactions via other functionalized arylketones, such as bromo or seleno derivatives; addition or substitution reactions with alkenyl or alkynyl nucleophiles to aromatic carbonyl compounds aldehydes or (e.g.
Xeinreb amides) optionally followed by reduction of o, triple bonds and/or oxidation of benzylic alcohols; Xittig-type reactions, Xadsworth-Horner-Eommons reactions; Friedel-Crafts acylation or Fries rearrangements; metal-catalyzed acylations of aromatic precursors, e. Suzuki reaction using arylboronic acids and acyl chlorides; and, reaction of aromatic acyl derivatives with nucleophilic alkenes. 3-Ar Yet another method (X02013/006308A2) for the preparation of pyrazolines is the metal-catalyzed of a 3-halopyrazoline coupling with arylboronic acid derivatives (Scheme . (h) (g) 6) PC T/EP2016/064446 9 9 9 R" R R R R' R7 &o R" R" AR .N N.
R, R, R N PG N NHX CI N PG AR AR NH NH R2 R9 R4 R, R, R Scheme 6 The 3-halopyrazoline can be prepared condensation of hydrazine with acrylic starting materials to give a 3-oxo-pyrazolidine, the salt of which is chlorinated and then optionally reacted at NH with an electrophilic reagent, such as a protecting (PG) reagent or group 1 0 reagents that provide the amidino-group.
In the preparative examples column chromatography separations were 040-0. performed using Merck SiO& 60 (0. 063 mm) silica gel. NMR spectra were recorded on Varian Mercury or on Bruker UltraShield machines (frequencies and solvents as indicated) . The chemical names of the compounds were generated using Chemdraw (Cambridgesoft) .
Example 1 3-(2-Methoxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide 2 0 exemplified its hydrochloride salt .N~NH t HCI — — — — — — 3 (Di me ami no) I (2 me opan I one thol th oxyph encl Three drops (ca 70 of HCl (aq. conc. was added to a mixture of mg) ) 3-dioxolane 2-hydroxy-acetophenone (1.36 10.0 mmol), 1, (2. 96 g, g, 40. 0 mmol), and dimethylamine hydrochloride (1.02 12.5 mmol) . The 90'C reaction mixture was stirred at in a sealed vial for 3.5 h.
After cooling, the reaction mixture was diluted with water (15 mL) and then washed with EtOAc (2 x 5 mL) . The product was extracted with EtOAc (2 x 10 mL) after addition of aq. NaOH (2 M, 10 mL) and the organic phase was then dried (NazS04) and concentrated at reduced pressure to give the crude product (1.98 96-:), which was used without further purification in the next step.
PC T/EP2016/064446 H NMR (CDC13g 400 MHz) 6 2 27 6H) 2 70 2H) 3 18 2H) (sg g (tg g (tg 7. 7. 45 7. 3. 90 (s, 3H), 6. 96 (d, 1H), 00 (t, 1H), (t, 1H), 68 (d, — — — — — — — — lH l carboximidamide 3 (2 Methoxyphenyl) 4, 5 dihydro pyrazole hydrochl de Aminoguanidine 1. was hydrochloride (111 mg, 00 mmol) added to a — — — — — — solution of 1 1 one 3 (dimethylamino) (2 methoxyphenyl)propan (207 1. in EtOH (96-:, 2 The reaction mixture was stirred mg, 00 mmol) mL) . j reflux for 2 h and the solvent was then allowed 0 at temperature to The residue was silica column evaporate. purified by chromatography The eluted was (EtOAc:MeOH:AcOH, 100:0:1, 66:33:1). product addition of collected filtration and precipitated by EtOAc, by washed with EtOAc and pentane to the title compound as an off- give white solid 24-:) (60 mg, .
HNMR(CD30Dg400MHZ)6361(tg2H)g3 86(sg3H)g3 97(tg2H) 6. 98 (t, 1H), 7. 08 (d, 1H), 7. 43 (t, 1H), 7. 91 (d, 1H) .
The in 2-16 were from the following compounds Examples prepared 2 0 corresponding acetophenone derivatives the same method as described above.
Comparative Example 2 3-Phenyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its hydrochloride salt .N~NH t HCI H NMR (CD&OD, 400 MHz) 6: 3.58 2H), 4. 08 2H), 7. 44 7.53 (m, (t, (t, 7. 88 2H) . 3H), (d, 3 0 Example 3 3-(2-Hydroxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its hydrochloride salt N+NH H NMR (CD&OD, 400 MHz) 6: 3.68 2H), 4. 02 2H), 6. 94 7. 00 (t, (t, (m, 7. 7. 2H), 38 (t, 1H), 59 (d, 1H) PC T/EP2016/064446 Example 3-(2-Bromophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its 2-trifluoroacetate salt by 2, 2, N NH F3CCO2H Isolated TEA-salt after HPLC as purification by (Cj8/MeCN/HZO/I-: TEA) HNMR((CD3)ZSOg400MHZ)6360(tg2H)g404(tg2H)g7 1H), 7.51 (t, 1H), 7.73 7.79 (m, 6H) .
Example 5 -dihydro-lH-pyrazole-l-carboximidamide 1 0 3-(2-Chlorophenyl)-4, its 2-trifluoroacetate salt exemplified by 2, 2, N NH F3CCO2H TEA-salt Isolated as after purification HPLC (Cj8/MeCN/HZO/I-: TEA) H NMR 400 61 4 04 7 46 (CD3) ZSOg MHZ) 6 3 (tg 2H) (tg 2H) ( g g ( 1H), 7. 52 1H), 7.59 1H), 7. 85 4H), 7. 88 1H) . (t, (d, (s, (d, Example 6 3-(2-Methylphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide 2 0 exemplified its 2-trifluoroacetate salt by 2, 2, N NH F3CCO2H Isolated as TEA-salt after purification HPLC (Cj8/MeCN/HZO/I-: TEA) 2 5HNMR((CD3)ZSOg400MHz)6256(sg3H)g3 54(tg2H)g3 96( 7.31 7. 7. 57 7. 78 2H), 39 (m, 3H), (d, 1H), (s, 4H) Example 7 3-(2, 5-Difluorophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide its 2-trifluoroacetate salt exemplified by 2, 2, ~.N NH F3CCO2H PC T/EP2016/064446 Isolated TEA-salt after HPLC as purification by (Cj8/MeCN/HzO/I-: TEA) HNMR((CD3)gSOg400MHZ)6352(tg2H)g400(tg2H)g7 2H), 7. 87 (s, 4H), 8. 01 (m, 1H) .
Example 8 -dihydro-lH-pyrazole-l-carboximidamide 3-(2-1sopropylphenyl)-4, its 2-trifluoroacetate salt exemplified by 2, 2, .N NH2 F3CCO2H Isolated as TEA-salt after purification HPLC (Cj8/MeCN/HzO/I-: TEA) H NMR 400 MHz) 6: 1.20 3.50 2H), 3.52 ( (CD&) &SO, (d, 6H), (t, (m, 7. 7. 43 7. 7. 67 1H), 3. 99 (t, 2H), 30 (t, 1H), 50 (m, 3H), (s, 4H) . 1 5 Example 9 3-(Naphthalen-l-yl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its hydrochloride salt . NH2 NH HCI H NMR 400 77 4. 7. 7. 61 (CD&OD, MHz) 6: 3. (t, 2H), 09 (t, 2H), 55 (m, 2H), 7. 66 1H), 7. 82 1H), 7. 96 1H), 8. 03 1H), 9. 04 (t, (d, (d, (d, 1H) .
Example 10 3-(Benzo[b]thiophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its hydrochloride salt N+NH2 H NMR 400 74 4. 11 7. 7.7. 57 (CD&OD, MHz) 6: 3. (t, 2H), (t, 2H), 50 (m, 2H), 7. 67 7. 75 2H), 8. 05 1H) (m, (d, Example 11 3-(2-Eluorophenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its hydrochloride salt PC T/EP2016/064446 . NH~ NH HCI 400 MHZ)6', HNMR(CD30Dg 364(tg2H)g4 07(tg2H) 724(ddt 1H) 7.29 7. 54 8. 07 1H) . (t, 1H), (m, 1H), (t, Comparative Example 3-(Naphthalenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its hydrochloride salt N NH NH HCI NMR (CD&OD, 400 MHz) 6: 3.65 2H), 4. 08 2H), 7. 57 (m, 2H), (t, (t, 7. 85 7. 97 (m, 3H), 8.11 1H), 8. 19 1H) . (d, (s, Example 13 — — — 5-dihydro-lH-pyrazole-l- 3 (2 (Trifluoromethyl)phenyl) 4, carboximidamide exemplified its hydrochloride salt . NHz H NMR (CDqOD, 400 MHz) 6: 3.55 2H), 4. 12 2H), 7. 68 7.7. 78 (t, (t, (m, 7. 86 1H) 3H), (d, Example 3-(Benzofuranyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide its salt exemplified by hydrochloride .N NHz H NMR 400 4. 7. 41 (CDqOD, MHz) 6: 3.59 (t, 2H), 05 (t, 2H), (m, 2H), 7. 32 58 (d, 1H), 8. (s, 1H), 8. 33 (d, 1H) .
Comparative Example 3-(4-Methoxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its 2, 2, 2-trifluoroacetate salt RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 .N NH F3CC03H 400 MHz) 6: 3.46 3 83 3 97 ( (C 3) 3SO, (t, 2H), (s 3H) (t 2H), 7. 05 2H), 7. 66 4H), 7. 81 2H) . (d, (s, (d, Comparative Example 3-(3, 4-Dimethoxyphenyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide 2-trifluoroacetate exemplified by its 2, 2, salt F3CC03H H NMR 400 46 82 82 (cD3) &so, MHz) 6: 3. (t, 2H), 3. (s, 3H), 3. (s, 3. 98 2H), 7. 05 1H), 7.29 1H), 7. 55 1H), 7.71 3H), (t, (d, (d, (s, 4H) .
Example 17 — — — — — — — — — 3 (2 Hydroxyphenyl) 4 methyl 5 1H dihydro pyrazole carboximidamide exemplified its hydrochloride salt N+NH — — — — — — — — 2 l 2 l one 0 3 no) (2 hydr opan (Di methyl ami oxyphenyl ) methyl pr 1-(2- Prepared the method described in Example 1 by using propanone as starting material 1.49 77-:) . hydroxyphenyl) (yield H NMR (CDC13, 400 MHz) 6: 1.23 2. 25 2. 34 1H), (d, 3H), (s, 6H), (dd, 2. 74 91 7. 47 85 (dd, 1H), 3. (m, 1H), 6. (t, 1H), 6. 99 (d, 1H), (t, 7. 81 1H), (d, 1H) — — — — — — — — — 4 di lH azol 3 (2 Hydr ) 4, 5 hydr o pyr e oxyphenyl methyl carboximi dami ochloride de hydr the method described in 1. from Prepared by Example Recrystallized MeOH-Etzo 767 (30-:) of the title to give mg compound.
H NMR (CD30D, 400 MHz) 6: 1.33 3.76 1H), 4. 11 1H), (d, 3H), (dd, (t, 4. 23 7. 7. (m, 1H), 6. 96 (t, 1H), 6. 98 (d, 1H), 36 (t, 1H), 65 (d, PC T/EP2016/064446 The were from the following compounds prepared corresponding derivatives the same method described above. arylketone by as Example 18 3-(2-Methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide exemplified its 2-trifluoroacetate salt by 2, 2, N NH F3CCO2H Isolated TEA-salt after HPLC as purification by (Cj8/MeCN/HzO/I-: TEA) NMR 400 MHz) 6: 1.10 3.61 3.86 ( (CD&) &SO, (d, 3H), (m, 1H), (s, 3H), 4. 04 4. 21 (m, 2H), 7. 03 1H), 7. 16 1H), 7. 50 1H), (t, (d, (t, 7.76 (m, 5H) .
Example 19 — — — — — — — — — 3 (2 Chlorophenyl) N methyl 4, 5 1H dihydro pyrazole carboximidamide exemplified its hydroiodide salt N-Methylhydrazinecarboximi dami de hydr oi odi de MeI (17.03 120 mmol) was added to a solution of hydrazine- carbothioamide (9.11 100 mmol) in MeOH (40 mL) . The reaction 60'C mixture was stirred at for 1 h. Some of the solvent (ca 10 mL) was then evaporated to remove any residual MeI. After cooling, a solution of MeNH& in MeOH (15.0 mL, 9. 8 147 mmol) was added and 60-70'C the reaction mixture was stirred overnight at and then concentrated at reduced pressure. The residue was crystallized from i-PrOH i-PrOH (40 mL), collected filtration, washed with (10 mL), EtOAc (10 mL), and pentane (10 mL) to give the title compound (16.13 75-:) as off-white crystals.
H NMR 400 2.
(CDgOD, MHz) 6: 86 (s, 3H) — — — — — — — — — 3 Chlor N methyl 5 lH (2 ophenyl) 4, pyrazole di hydro carboximi dami de oi odi de hydr PC T/EP2016/064446 the method described for 1 Prepared by Example using 1-(2- methylhydrazinecarboximidamide and hydroiodide chlorophenyl)ethanone as starting materials.
H NMR 400 MHZ) 6; 2 88 3H) 3 60 2H) 4 02 ( (CD3) zSOg (sg g (tg g (tg 7. 42 7. 7. 2H), 63 (m, 3H), 89 (d, 1H), 8. 00 (s, 3H) Example 3-(2-Hydroxyphenyl)-N-methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide its 2-trifluoroacetate salt exemplified by 2, 2, F3CCO2H the method described above.
Prepared by HNMR((CD3)zSOg400MHZ)6288(dg3H)g3 57(tg2H)g3 93( 2H), 6. 94 1H), 6. 98 1H), 7.36 1H), 7. 68 1H), 7. 96 (t, (d, (t, (d, 1H), 8. 12 1H), 9.70 1H) (s, (s, (s, Example 21 -dihydro-lH-pyrazole-l- N-Benzy1(2-chlorophenyl)-4, carboximidamide .N N N Ben azi necarboxi mi dami de oi odi de zylhydr hydr Mel 703 12 mmol) was added to a solution of hydrazine- carbothioamide (911 10 mmol) in MeOH (10 mL) . The reaction 60'C mixture was stirred in a sealed vial at for 75 min and then in 70'C vial at for 20 min. After PhCH, 07 10 opened cooling, NH, (1. mmol) was added and the reaction mixture was stirred overnight at 55'C and then concentrated at reduced pressure to an oil. The give product was crystallized dropwise addition of EtzO with vigorous stirring and was collected filtration to give the title compound (2. 848 97-:) as a pale orange solid.
H NMR (CD&OD, 400 MHz) 6: 4. 13 and 4. 45 (two isomers, 1:2) (2 s, 2H), 7.28 7 48 . (m, 5H) PC T/EP2016/064446 — — — — — — — — — N chl or di lH azol Benz@1 3 (2 ) 4, 5 hydr o pyr e ophenyl carboxi mi dami Prepared the method described for Example 1 by using benzylylhydrazinecarboximidamide hydroiodide and 1-(2-chlorophenyl) ethanone as starting materials.
HNMR((CD3)zSOg400MHZ)6342(tg2H)g4 05(tg2H)g446(s 7. 34 7. 44 7. 62 2H), (m, 8H), (m, 1H) .
Example — — — — — — — — — 1 N 1H 0 3 (2 hydroxyphenyl) 4, 5 Benzyl dihydro pyrazole carboximidamide its 2-trifluoroacetate salt exemplified by 2, 2, F3CCO2H Prepared the method described above.
HNMR((CD3)zSOg400MHZ)6283(tg2H)g4 30(tg2H)g4 60(dg 2H), 6. 93 1H), 7. 00 1H), 7.30 7. 44 (m, 6H), 8. 10 2H), (d, (t, (s, 8. 34 1H), 8. 50 1H), 10.56 1H) . (d, (s, (s, 2 0 Example 23 -dihydro-lH-pyrazole-l- -methyl(naphthalen-l-yl)-4, carboximidamide exemplified its hydrochloride salt N NH2 5 M NaOH (0.2 mL, 1 was added to a solution of Aq. eq) — — — — — — amino- (naphthalen 1 but 2 en 1 one (196 1.0 mmol) and yl) mg, guanidine hydrochloride 111 1.0 mmol) in 96-: EtOH (2 mL) . The 80-90'C reaction mixture was stirred at for 1 h and was then cooled to room temperature, acidified with 1.5 HCl/EtOH 1.5 eq (1 M, mL), and then heated again at boiling point to reduce the volume to approx. 2 mL. The product was purified column chromatography (Si02, EtOAc-AcOH, 99:1, then EtOAc-MeOH-AcOH, 99:99:2) and crystallized from MeOH-EtOAc to give the title compound (175 61-:) .
PC T/EP2016/064446 H NMR (CD&OD, 400 MHz) 6: 1.43 3.37 1H), 4. 00 2H), (d, 3H), (dd, (dd, 4. 76 7. 7. 62 7. 67 7. 7. (m, 1H), 55 (m, 2H), (t, 1H), 83 (d, 1H), 96 (d, 1H), 8. 03 (d, 1H), 9. 02 (d, 1H) .
The following compounds were from the corresponding o, P— prepared unsaturated aryl-ketone derivatives the same method as described above.
Example — — — — — — — — — — j 4 1 1H 0 Methyl 3 yl) 4, 5 (naphthalen dihydro pyrazole carboximidamide exemplified by its hydrochloride salt . NH2 H NMR 400 1.24 79 4. 25 4.
(CD&OD, MHz) 6: (d, 3H), 3. (m, 1H), 36 (m, 2H), 7. 54 7. 64 7.76 1H), 7. 95 1H), 8. 01 1H) . (m, 3H), (d, (d, (d, Example 25 3-(2-Chlorophenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide exemplified its hydrochloride salt . NH2 Methyl dimethylphosphonate (682 5. 5 mmol) was added to a solution of LiHMDS in THE (11 mL, 1.0 M, 11.0 mmol) at 0 Methyl 2-chlorobenzoate (853 5. 0 mmol) was then added dropwise maintaining the internal temperature of the reaction below 5 The reaction mixture was stirred at 0 for 2 h and then partitioned between NH, Cl (aq. sat. and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic phases were dried over sodium (2-(2- sulfate and concentrated to get the crude dimethyl chlorophenyl)oxoethyl)phosphonate (1.2 which was used in the next step without further purification.
K&CO& (276 2. 0 mmol) was added to a solution of the crude phosphonate (279 1.0 mmol) and acetaldehyde (88 2. 0 mmol) in mg, mg, THE-water.
The reaction mixture was stirred for 2h and was then partitioned between diluted with EtzO and NH~C1 (aq. sat. . The PC T/EP2016/064446 was and the was extracted with organic layer separated aqueous layer The combined were dried over sodium sulfate and EtzO. organic layers concentrated to the crude 1-(2-chlorophenyl)butenone (150 which was used in the next without further purification. mg), step 5M NaOH 1 0. 5 mmol) was added to a solution of the crude Aq. (0. mL, — — — — — — 1 chlorophenyl)but 2 en 1 one 0. 5 mmol) and amino- (2 (90 mg, in 96-: EtOH The guanidine hydrochloride 55 mg, 0. 5 mmol) (2 mL) . 80-90'C reaction mixture was stirred at for 1 h and was then cooled to room temperature, acidified with 1.2 HC1/EtOH 0. 6 eq (1 M, mL), j 0 and then heated at boiling to reduce the volume to again point 2 mL. The product was purified column approx. by chromatography EtOAc-AcOH, 99:1, then EtOAc-MeOH-AcOH, 99:99:2) to the (SiO&, give title compound (27 20-:) .
HNMR((CD3)zSOg400MHZ)6125(dg3H)g3 1(dg2H)g3 1(ddt 4. 7. 46 7. 52 7. 7. 87 1H), 83 (m, 1H), (t, 1H), (t, 1H), 59 (d, 1H), (d, 1H), 96 (s, 4H) The were from the following compounds prepared corresponding aromatic Me-ester derivatives the same method as described above.
Example 26 6-Difluorophenyl)methyl-4, 5-dihydro-lH-pyrazole-l- 3-(2, carboximidamide exemplified its hydrochloride salt N+NH2 NH HCI H NMR (CD&OD, 400 MHz) 6: 1.36 3.18 2H), 3.81 1H), (d, 3H), (d, (dd, 4. 74 7. 14 7. (m, 1H), (t, 2H), 55 (m, 1H) .
Example 3-(2-Chlorophenyl)ethyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified its hydrochloride salt N NH2 H NMR (CD&OD, 400 MHz) 6: 0. 95 (t, 3H), 1.77 (m, 2H), 3.41 (d, 2H), 3.84 4. 69 7. 42 7. 48 7.53 (dd, 1H), (m, 1H), (t, 1H), (t, 1H), (d, PC T/EP2016/064446 Example -Methyl(3-methylbenzofuranyl)-4, 5-dihydro-lH-pyrazole-l- carboximidamide exemplified its hydrochloride salt N NHz / X 0 NH H NMR 400 1 2 (CDgOD, MHz) 6: 39 (dg 3H) 59 (sg 3H) 3 33 (d, 2H) 3.82 1H), 4. 74 1H), 7.33 1H), 7. 43 1H), 7. 50 (dd, (m, (t, (t, (d, 7. 69 1H) . 1H), (d, Example 29 -Methyl(3-methylbenzo[b]thiophenyl)-4, 5-dihydro-lH-pyrazole- 1-carboximidamide exemplified its hydrochloride salt N NHz / X S NH H NMR (CD3) zSOg 400 MHZ) 6; 1 27 (dg 3H) 2 63 (sg 3H) 3 27 (dg ( g g 3.86 4. 84 7. 46 7. 88 78. 00 1H), (dd, 1H), (m, 1H), (m, 2H), (m, 6H) Example 30 — — — — — 2 0 3 Chlorophenyl) 6a 1(3aH)— (2 4, 5, 6, tetrahydrocyclopenta[c]pyrazole carboximidamide exemplified its hydrochloride salt .N NHz NH HCI — — — — — Ch1 or t l en l me than one (2 ophen pl ) (cycl open yl ) 2-Chlorobenzoyl chloride 5 (8. 48. 4 mmol) was added to aluminium 47g, chloride 7. 53.2 mmol) suspended in mL) After 5 10g, dry CH, C1, (50 min the was decanted from the excess and resulting complex A1C1~ O'C. cooled A solution of 48. 4 in to cyclopentene (3.30g, mmol) dry mL) was then added dropwise over a period of 0. 5 hr.
CH, C1, (50 Upon completion of the addition, the mixture was added to crushed ice with stirring. After separation of the the vigorously phases, aqueous was extracted several times with The combined phase CH, Clz. fractions were washed with and organic NaHCO~, (aq. sat. ) water, PC T/EP2016/064446 brine and dried. Removal of the solvent an oil which was yielded to The resultant mixture was immediately added triethylamine (30 mL) . then heated at reflux for 48 hr. Concentration at reduced pressure yielded an oil which was diluted with ether and washed with HC1 sat. and brine. After concentration (aq. 1M), NaHCO~, (aq. ) drying, at reduced pressure yielded crude (2-chlorophenyl)(cyclopenten methanone 45-:), which was in the next without yl) (4. 5g, used step further purification. — — — — — 1 0 3 Chlor 6a tetr ta azole l (3aH)— (2 ophenyl) 4, 5, 6, ahydr ocycl open (c]pyr carboximi dami de ochloride hydr Aminoguanidine hydrochloride 8. 4 mmol) was added to a (0. 92g, solution of crude (2-chlorophenyl)(cyclopentenyl) methanone 8. 4 mmol) in EtOH (95-:, 20 mL) was added and then 5 M (1.72g, aq.
NaOH 7 1 (NaC1 . The reaction mixture was (1. mL, eq. ) precipitates) — 'C — — stirred at 80 90 (reflux) for 30 60 min, TLC (EtOAc AcOH, 99:1, EtOAc-MeOH-AcOH, 99:99:2). The reaction mixture was cooled to room temperature and acidified with 1.1 HC1/EtOH (1 11 mL), and eq. M, then heated under reflux to reduce water content and volume to again 2 2 mL. After the was column 0 about cooling product purified by EtOAc-AcOH, then EtOAc-MeOH-AcOH, chromatography (SiO&, 99:1, the title 2-:) 99:99:2) to give compound (80mg, 3. .
H NMR 400 MHz) 6: 1.30 1H), 1.57 1H), 1.68 ( (CD&) &SO, (m, (m, (m, 1.84 1. 4. 4. 7. 47 1H), (m, 1H), 90 (m, 2H), 60 (t, 1H), 93 (m, 1H), 7. 7. 7. 74 7. 91 (t, 1H), 53 (t, 1H), 60 (d, 1H), (d, 1H), (s, 4H) .
Example 31 -dihydro-lH-pyrazole-l-carboximidamide 3-(2-Aminophenyl)-4, its salt exemplified by hydrochloride . NH2 — — — — — — 3 no) l (2 ni tr opan l one (Di ophenyl) pr methyl ami HC1 (35-: 2 was solution of aq. 0. mL) added to a paraformaldehyde (1.43 48 mmol), dimethylamine hydrochloride (11.64 143 mmol) g, g, 2-nitro-acetophenone and (18.17 110 mmol) in ethanol (10 mL) . The reaction mixture was refluxed for 5 hours. The yellowish solution was diluted with cold acetone (50 mL) and chilled for several hours PC T/EP2016/064446 O'C.
The were washed with acetone at crystals filtrated, (2x20 mL), dissolved in water and then extracted in (20 mL), ethyl acetate (2x35 mL) . The was treated with potassium carbonate aqueous layer (pH=10) and extracted in acetate (5x35 mL) . The organic ethyl phases were dried over sodium sulfate and concentrated at reduced pressure to the crude title compound as oil 77-:), which was used give (8.7g, in the next without further step purification. — — — — — — — — 3 kni 5 di o lH azol e l carboxi mi dami de (2 ) 4, hydr pyr nophenyl j 0 hydrochl ori de Aminoguanidine hydrochloride 6. 3 mmol) was added to a (0.70g, — — — — — — solution of 3 (dimethylamino) 1 1 one (2 nitrophenyl)propan (1.40g, 6. 3 mmol) in EtOH (95-:, 20 mL) . NaOH 1.26 6. 3 mmol) was (aq. 5M, mL, then added (NaC1 and the reaction mixture was stirred precipitates) at 80 90 for 60 min. After cooling to room temperature the reaction mixture was acidified with 1.1 HC1/EtOH 7 eq (1 M, mL), heated under reflux for 0. 5 and then concentrated at again hr, reduced pressure. The residue was dissolved in EtOH (30 ml) and then NH&C1 25. 2 mmol) and iron 63. 0 mmol) were added. The (1.32g, (3.53g, 2 reaction mixture was stirred reflux for cooled room 0 at 5 h, to filtered and The temperature, through celite, evaporated to dryness. was column the title product purified by chromatography to give compound 10-:) . (150mg, HNMR(CD30Dg400MHZ)6361(tg2H)g3 1H) 95(tg2H)g6 76(tg 91 7.24 7. 6. (d, 1H), (t, 1H), 36 (d, 1H) Example 32 4-dimethyl-4, 5-dihydro-lH-pyrazole-l- 3-(2-Hydroxyphenyl)-4, carboximidamide its 3-trifluoroacetate salt exemplified by 3, 3, .N~~NH2 F3CCO2H — — — — — — — — 2 (4, 4 Dimethyl 4, 5 dihydro lH pyrazol 3 phenol Hydrazine hydrate (647 12. 9 mmol) was added to a solution of — — — — — — — 1 2 1 one 2. chloro (2 hydroxyphenyl) 2, (550 mg, 59 dimethylpropan mmol) and NEtz (522 mg, 5. 16 mmol) in EtOH (abs. 20 mL) . The 130'C reaction mixture was stirred in a sealed vial at for 22 h.
After cooling, the reaction mixture was concentrated at reduced PC T/EP2016/064446 pressure and partitioned between water and Et,O. The organic phase was concentrated at reduced pressure and the residue (0.52 was purified silica column (heptane-EtOAc, 5:1) to by chromatography 37-:) give the title compound as pale yellow crystals (180 .
H NMR (cDc13g 400 MHz) 6: 1.50 3.30 2H), 6. 86 1H), (s, 6H), (s, (t, tert 7. 01 1H), 7.23 1H), 7. 54 1H) (d, (t, (d, (((tert — — — — — Butyl butoxycarbonyl)imino) (3 (2 hydroxyphenyl) 4, — — — — — — dimethyl 4, 5 lH l yl)methyl) carbamate dihydro pyrazol 1 0 tert-Butyl (((tert-butoxycarbonyl) imino) (1H-pyrazolyl) methyl)— carbamate (260 8.41 mmol) was added to a solution of 2 (4, — — — — — — 1H 41 in dimethyl 4, 5 3 yl) phenol (160 mg, 8. mmol) dihydro pyrazol THE (1.2 mL) . The reaction mixture was stirred overnight and then concentrated reduced The residue was silica at pressure. purified by column chromatography (heptane EtOAc, 10:1, 5:1) to give the title 37-:) compound (136 mg, .
H NMR (CDC13g 400 MHz) 6: 1.52 18H)g 1 57 6H)g 3 94 2H) (sg (sg (sg 6. 88 1H), 7. 02 1H), 7. 30 1H), 7. 58 1H), 9. 92 (broad (t, (d, (t, (d, s, 1H), 33 (s, 1H) . — — — — — — — — — 3 (2 4, 4 di me thyl 4, 5 di hydro lH pyrazol e Hydroxypnenyl carboxi mi dami ochl ori de hydr de Trifluoroacetic acid (1.8 mL) was added to a solution of tert-butyl — — — — 4-dimethyl (tert-butoxycarbonyl) imino) (3 (2 hydroxyphenyl) 4, 4, dihydro-1H-pyrazol 1 methyl) carbamate (136 3.14 mmol) in yl) mg, CH&C13 (1.8 mL) . The reaction mixture was stirred at room temperature for 2. 5 h and was then concentrated at reduced pressure. The residue was triturated with Et,O (5 mL) to crystallize the material, which was collected filtration, washed with and dried to the by Et30 give title compound as off white crystals (99 91-') H NMR 400 MHZ) 6; 1 34 6H) 3 83 2H) 6 90 ( (CD3) 3SOg (sg g (sg g (tg 6. 97 7.30 7.39 7. 89 9. 90 1H) . 1H), (d, 1H), (m, 2H), (s, 4H), (s, Example 33 3-(2-Chloromethoxyphenyl) -4, 5-dihydro-1H-pyrazole carboximidamide its salt exemplified by hydrochloride . NH3 RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 — — — — — — — — l (2 ch1 or o 6 me thoxyphenyl 3 (di me thyl ami no) propan l one Prepared (240 41-:) the method as described for Example 1. mg, by H NMR 400 2.27 2 75 2 (CDC13g MHz) 6: (s, 6H)g (tg 2H)I 99 (tg 2H) 82 82 7.26 3. (s, 3H), 6. (d, 1H), 6. 98 (t, 1H), (t, 1H) — — — — — — — — Chl or di lF. azole 3 (2 o 6 4, 5 hydr o methoxyphenyl) pyr 12 was solution of Hydrazine hydrate (0. mL, 5. mmol) added to a — — — — — (2-chloro 6 methoxyphenyl) 3 (dimethylamino)propan-1 one (240 1 0 8. 83 mmol) in EtOH (95-: 4 mL) . The reaction mixture was stirred at reflux temperature for 5 h. After cooling, the reaction mixture was concentrated reduced the crude an oil at pressure to give product as (210 which was used in the next without further mg) step purification. — — — — — — — — — 3 (2 Chl or o 6 4, 5 di hydr o lF. azol e me thoxyphenyl ) pyr carboxi mi dami de hydrochl ori de Methyl carbamimidothioate hydroiodide (260 1.19 mmol) was added to a solution of 3-(2-chloromethoxyphenyl) -4, 5-dihydro-1H- 2 0 pyrazole (210 1.00 mmol) in pyridine (1 mL) under argon. The reaction mixture was stirred at 110 for 1.5 h. After cooling, the reaction mixture was concentrated reduced and the at pressure residue was partitioned between CH, Clz and water. NaOH 1M) was (aq. added to basic reaction and the product was extracted with .
CH, C1, The organic phase was washed with water, dried and (NazSOq) concentrated reduced The residue was dissolved at pressure. (210 mg) in EtOAc mL) and HC1/MeOH 0. 91 mL) was added to precipitate (5 (1M, HCl-salt. the product as the Additional EtOAc (5 mL) was added and after stirring for 5 min the crystals were collected filtration, washed with EtOAc and dried to give the title compound as white crystals (200 69-:) .
H NMR 400 34 4. 07 (CD&) zSO, MHz) 6: 3. (t, 2H), 3.83 (s, 3H), (t, 2H), 7. 16 (d, 1H), 7. 18 (d, 1H), 7.49 (t, 1H), 7. 87 (s, 4H) .
Example 34 -r(, 3-(2-Chlorohydroxyphenyl) 5-dihydro-1H-pyrazole carboximidamide exemplified its hydrochloride salt RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 N+NH, A solution of 1M BBrz in MeOH (2. 63 mL, 2. 63 mmol) was added to a solution of 3-(2-chloromethoxoxyphenyl)-4, 5-dihydro-lH-pyrazole- 1-carboximidamide hydrochloride (190 0. 66 mmol) in CH, C1, (10 mL) under Ar. The reaction mixture was stirred at room temperature overnight. MeOH (20 mL) was added and after 10 min stirring the reaction mixture was concentrated at reduced pressure. Water (10 mL) and EtOAc (20 mL) was added to the residue and after adding KHCO, sat. to basify the mixture, the product was extracted into (aq. , ) j 0 the organic phase. The phases were separated and the aqueous phase was extracted with EtOAc (2 x 15 mL) . The combined organic phases were dried (NazSO~) and concentrated at reduced pressure. The residue was dissolved in MeOH (1 mL), 1M HC1 in MeOH (0.5 mL) was added and the product was precipitated addition of EtOAc (10 mL) . The product was collected filtration, washed with EtOAc and dried to give the title compound as beige crystals (95 52-:) .
HNMR((CD3)zSOg400MHZ)6361(tg2H)g4 05(tg2H)g6 98(dg 7. 00 7.30 7. 82 10.64 1H) . 1H), (d, 1H), (t, 1H), (s, 4H), (s, 2 0 Example 35 (S)(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide (isomer N+NH Example 36 -dihydro-lH-pyrazole-l- (R)(2-Hydroxyphenyl)methyl-4, carboximidamide (isomer 2) PC T/EP2016/064446 N+NH The enantiomers were separated and purified SFC (Supercritical Fluid Chromatography) using an @my-C column (20mm x 250mm, 5um) with MeOH/COz (40-:) as eluent (DEA was added as a modifier) with 50 mL/min flow rate and UV-detection at 280nm wavelength.
The racemate compound HCl-salt (8.43 was dissolved in methanol (50 mg/mL) and injected in 0. 8 mL (40 volumes. The combined fractions of each enantiomer (isomer 1 at 1.22 min and isomer 2 at j 0 1.77 min) were concentrated at reduced pressure and dried in a 40'C vacuum oven at to give the title products as off-white crystals.
The final analysis was performed SFC (Amy-C column, 4. 6mm x 250mm, 5um) . The eluent was MeOH/COz (40-:) (DEA was added as a modifier) with 4 mL/min flow rate.
For isomer 1: (S)-configuration (determined X-ray crystallography, see Ex. 37); Yield 3. 90 (46-:).
Chemical 220 nm): 100-: (purity Enantiomeric excess: 100 For isomer 2: (R)-configuration (determined X-ray crystallography, see Ex. 38); Yield 3.50 (41-:) Chemical 220 nm): 100-: (purity Enantiomeric excess: 99. 8 HNMR((CD3)zSOg400MHZ)6116(dg3H)g3 1H)g3 56(ddt 89( 4. 14 6. 14 (broad 6.59 6. 77 1H), (m, 1H), s), 4H), (t, 1H), (d, 1H), 7. 12 7. 54 1H) (t, 1H), (d, Example 37 (S)(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide exemplified its hydrochloride salt N+NH PC T/EP2016/064446 Example 38 (R)(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide exemplified its hydrochloride salt N+NH j 0 The isolated enantiomers isomer-1 and isomer-2, respectively, were dissolved in EtOH and the HC1-salts were precipitated addition of 40'C HCL/EtzO (sat. . The solvents were then removed at under a nitrogen stream to leave the final material as off-white solid. i-PrOH Samples of each enantiomer were recrystallized from to give crystals suitable for X-ray crystallography.
Data collection For both isomers, plate-shaped crystals measuring approx. 0. 1 x 0. 1 x 0. 02 mm were mounted in nylon loops using paraffin oil at room 2 0 temperature. The paraffin oil was used to the crystal to stick help MAX- to the Data were collected at 100 K at station 1911-3 of loop. lab (2 0. 8 with a 225mm marCCD detector. All data A), equipped were integrated using the program XDS and scaled using XSCALE. isomer (isomer-1) R S (isomer 2) unit cell 7.58, 8.30, 18.86 7.57, 8.29, 18.86 resolution 75 77 78 81 (A) 0. (0. 0.75) 0. (0. 0.78) observations, 6820 5622 unique reflections, 2694 2344 possible 2611 (60. 0) 89. 8 (91.1) completeness 2. 5 multiplicity 6. (6.5) PC T/EP2016/064446 The statistics take into account that Friedel were not pairs merged before refinement.
Structure solution and refinement For both isomers the was identified as primitive space group orthorhombic XDS and more specifically identified as by P2j2j2j using the XPREP Both structures were solved program (Bruker AXS) . using SHELXS and refined SHELXL in combination with the using graphical user interface SHELXLE . For the S isomer (isomer-1) the R 1 0 configuration of the compound together with one chloride ion was found the atom from direct methods in SHELXS. The Flack using peaks parameter from SHELXL was around 1 9+ 0. after refining the R (0. 1) conformation, which indicates that the absolute configuration was wrong. Thus the S isomer was built instead (Flack parameter of 1+ -: -: 0. . The final R factor is 4. 6 for 2540 Fo & and 5. 0 for 1) 4o(Fo) all 2590 reflections to 0. 77 A resolution.
For the R isomer (isomer-2) the space group P2, 2,2, was given to XPREP, since this had been found for the previous isomer space group 2 and the cell dimensions were identical. The R conformation of the with one chloride ion was found compound together correctly by SHELXS from the start. The Flack from SHELXL was around parameter 0 (-0. 1 0. after refining the R conformation, which indicates that the absolute structure is correct. The final R-factor is 7. 5 for 2268 Fo & and 10.2 for all 2410 reflections 78 4o(Fo) to 0. resolution.
H NMR 400 MHz) 6: 1.18 3.70 1H), 4. 10 ( (CD&) &SO, (d, 3H), (dd, (t, 4. 13 92 7. 01 7. 7. 1H), (m, 1H), 6. (t, 1H), (d, 1H), 35 (t, 1H), 68 7. 87 (d, 1H), (s, 4H), 9. 95 (s, 1H) Example 39 4-dimethyl-4, 5-dihydro-lH-pyrazole-l- 3-(2-Methoxyphenyl)-N, carboximidamide its salt exemplified by hydroiodide — — — — — — — — 3 (Di me ami no) l (2 me 2 me thyl opan l one ) pr thol th oxyph encl PC T/EP2016/064446 1-(2- HC1 conc. was mixture of (aq. 0. 85 mL) added to a — — — 1 one 144 dioxolane methoxyphenyl)propan (23. 6 mmol), 1, 3 (42. 8 578 and dimethylamine hydrochloride (14.7 180 mmol) . mmol), g, g, 85'C The reaction mixture was stirred at in a sealed vial for 4 h.
After the reaction mixture was mixed with EtOAc mL) cooling, (300 and stirred for 30 min to the Mannich-base as an HC1- precipitate salt. The were collected filtration, washed with EtOAc crystals by and and dried to 31 (84-:) of white crystals. The crystals EtzO give were partitioned in water (250 mL) and (250 mL) and extracted CH&Clz 1 0 into the organic after addition of NaOH 50 mL) . The phase (aq. 5M, was extracted with (100 mL) and the combined aqueous phase CH, C1, organic were washed with water, dried and phases (NazSO~) concentrated at reduced pressure to the title compound as a give yellow oil (23.2 73-:), which was used without further pale purification in the next step.
H NMR (CDC13g 400 MHz) 6 1 15 3H) 2 20 6H) 2 29 1H) (dg g (sg g (ddt 2. 67 94 68 (dd, 1H), 3. (m, 1H), 3.88 (s, 3H), 6. (d, 1H), 6. 98 (t, 7. 42 7. 1H), (t, 1H), 55 (d, 1H) . — — — — — — — — — 2 4 di lH azole 0 3 (2 Methoxyphenyl) methyl 4, 5 hydr o car ho thi oami de 50-:, NaOH (aq. 1.7 mL, ca 32 mmol) was added to a solution of 3-(dimethylamino)(2- thiosemicarbazide (440 4. 82 mmol) and 1 one 07 4. 82 in MeOH methoxyphenyl)propan (1. mg, mmol) (60 mL) under Ar. The reaction mixture was stirred reflux for at temperature 1. h and was then concentrated reduced The residue was at pressure. partitioned in water and CH&Clq. The organic phase was washed with water and concentrated at reduced pressure to give the crude product 1 which was silica column (heptane- (1. purified by chromatography the title oil EtOAc, 10:4) to give compound as a yellow (940 mg, 78-:) H NMR 400 MHz) 6: 1.16 3.87 3. 93 4. 07 (CDClz, (d, 3H), (s, 3H), (m, 2H), 4. 47 1H), 6. 96 1H), 7. 00 1H), 7. 42 1H), 7. 65 (t, (d, (t, (t, (d, 1H) .
— — — — — — — — — Methyl 3 (2 methoxyphenyl) 4 methyl 4, 5 dihydro lH pyrazole carbimidothi oate hydr oi odide Methyl iodide (Mel) (1.06 7.50 mmol) was added to a solution of 3-(2-methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- PC T/EP2016/064446 carbothioamide 73 in MeOH The reaction (930 mg, 3. mmol) (5 mL) . 70'C mixture was stirred in sealed vial for 4 h. After a at cooling, the solvent was evaporated at reduced pressure to a final give volume of 1 mL. mL) was added and the mixture was approx. Et&0 (10 stirred for 1 h to the which were vigorously precipitate product, collected filtration, washed with and dried to the by EtzO, give title (S-methylisothiouronium derivative iodide compound salt) as crystals 32 90-:) . This material was used without further beige (1. purification in the next step. — — — — — — — — — 3 4 dimethyl 5 lH (2 Methoxyphenyl) N, 4, pyrazole di hydro carboximi dami de oi odi de hydr MeNHz 0 M in MeOH, 1.6 3.2 mmol) was added to a solution of (2. mL, methyl 3-(2-methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carbimidothioate hydroiodide 1.07 mmol) in MeOH mL) . The (0.42g, (3 70'C reaction mixture was stirred at in a seal vial for 3.5 h. After the reaction mixture was concentrated at reduced pressure cooling, to give the title compound (0. 40 quant. .
H NMR (CDClz, 400 MHz) 6: 1.20 3H), 3.23 3H), 3.87 3H), (d, (d, (s, 97 4. 20 4. 7. 01 3. (m, 1H), (m, 1H), 53 (t, 1H), 6. 96 (d, 1H), (t, 1H), 7. 45 (t, 1H), 7. 65 (d, 1H) Example 40 -N, 4-dimethyl-4, 5-dihydro-1H-pyrazole 3-(2-Hydroxyphenyl) carboximidamide BBr, in 28 4. 28 mmol) was added to a solution of CH, C1, (4. mL, 1M, — — — — — — — — 4 dimethyl 5 1H (2 methoxyphenyl) N, 4, dihydro pyrazole carboximidamide hydroiodide 40 1.07 mmol) in mL) . (0. CH, C1, (10 The reaction mixture was stirred at room temperature for 20 h. After addition of MeOH (50 mL) and stirring for 10 min, the solution was concentrated at reduced pressure. The residue was dissolved in water, basified with KHCO~ sat. and concentrated at reduced (aq. ), pressure. The residue was purified silica column by chromatography MeOH:NH~ 30:5:1) to the title compound 15 (CHzClz. (aq. ), give (0. 60-:) .
PC T/EP2016/064446 H NMR 400 MHz) 6: 1.17 2. 83 3.64 ( (CD&) &SO, (d, 3H), (s, 3H), (dd, 97 4. 94 7.29 1H), 3. (t, 1H), 09 (m, 1H), 6. 85 (t, 1H), 6. (d, 1H), (t, 1H), 7. 65 (d, 1H), ca 8 (very broad s), 3H) .
Example N-Benzy1(2-methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide Benzylamine (132 1.23 mmol) was added to a solution of methyl (2-methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l-carbimido- thioate hydroiodide (0.400 1.02 mmol) in MeOH mL) . The mg, (3 reaction mixture was stirred at reflux for 2. 5 h. After cooling, the reaction mixture was partioned in NaOH 1M, 10 mL) and CH, C1, (aq. , mL) . The organic was washed with water and concentrated at (20 phase reduced pressure. The residue was purified silica column :MeOH:NH& 45:5:1) to the title chromatography (CH, C1, (aq. ), give compound (235 71-:) .
H NMR (CDC13g 400 MHz) 1 14 3H) 3 66 1H) 3 86 3H) (dg g (ddt g (sg 97 4. 14 4. 46 97 3. (m, 1H), (dd, 1H), (s, 2H), 6. 93 (d, 1H), 6. (t, 7.26 7. 32 7.41 7. 62 1H), (t, 1H), (m, 5H), (d, 1H) .
Example — — — — — — — — — — — N 4 1H 3 (2 hydroxyphenyl) methyl 4, 5 Benzyl dihydro pyrazole carboximidamide BBr, in CH, C1, (2. 92 mL, 1M, 2. 92 mmol) was added to a solution of benzy1(2-methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide (235 1.07 mmol) in CH&Clz (10 mL) . The reaction mixture was stirred at room temperature for 20 h. After addition of MeOH (30 mL) and the solution was concentrated at reduced pressure.
The residue was partitioned in water (10 mL) and CH, C1, (10 mL), basified with KHCO~ sat. and separated. The aqueous phase was (aq. , ) PC T/EP2016/064446 extracted with and the combined were CH, C1, (10 mL) organic phases washed with water dried and concentrated (10 mL), (NazSO~), at reduced pressure. The residue was purified silica column :MeOH:NH~ 40:5:1) to the title chromatography (CH, C1, (aq. ), give compound 15 67-:) H NMR (CDClz, 400 MHz) 6: 1.35 3.75 1H), 3.86 1H), (d, 3H), (m, (dd, 97 4. 46 7. 01 7.26 7. 40 3. (t, 1H), (s, 2H), 6. 95 (t, 1H), (d, 1H), (m, 7H) . 43 Example N-Hydroxy(2-methoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide N QH — — — — — — — — — — — 3 4 methyl N (tetrahydro 2H 2 (2 Methoxyphenyl) ( pyran yl) oxy) 4, — — — — di o lH azole l carboximi dami de hydr pyr Prepared the method described in Example 41 0-(tetrahydro- by using 2H-pyranyl)hydroxylamine instead of methylamine. The crude 2 0 product was purified silica column MeOH, by chromatography (CHzClz. 50:1) to the title compound (295 75-:) . give mg, H NMR (CDClz, 400 MHz) 6: 1.10 1.52 1.90 3. (2d, 3H), (m, 6H), 4 04 92 . 05 (m, 5H), 3 . 85 (s, 3H), 5 . (m, 1H), 6 . (d, 1H), 6 . 96 (t, 7. 34 7. 62 1H), (t, 1H), (d, 1H) .
— — — — — — — — — — — N 4 lH Hydroxy 3 (2 methoxyphenyl) methyl 4, 5 dihydro pyrazole ear boximi dami Dowex 50x8-400 1.7 250 was solution (H form, meq/mL, mg) added to a — — — — — — — — — — of 3 4 methyl N 2H 2 (2 methoxyphenyl) yl)oxy)— ((tetrahydro pyran — — — — — 1H 1 carboximidamide in 4, 5 (295 mg, 0. 89 mmol) dihydro pyrazole The reaction mixture was stirred room CH, C1, (5 mL) . at temperature for 20 h. in EtOH was and after 15 min NHz (5M, 5 mL) added stirring the solution is filtration and concentrated reduced separated by at pressure. The residue was purified silica column by chromatography MeOH, 10:1) to the title compound 36-:) .
(CHzClz. give (80 mg, H NMR (CDClz, 400 MHz) 6: 1.12 3.45 1H), 3.86 (d, 3H), (m, (s, 3H), 87 7. 7. 64 3. 3. 98 (m, 2H), 6. 93 (d, 1H), 6. 98 (t, 1H), 36 (t, 1H), (d, 1H) .
PC T/EP2016/064446 Example N-Hydroxy(2-hydroxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide exemplified its hydrobromide salt N OH Prepared the method described in Example 40. After concentrating the reaction mixture in MeOH the crude product HBr-salt was purified j 0 silica column chromatography (EtOAc:MeOH:AcOH, 100:10:1) to give the title compound (62 61-:) .
HNMR((CD3)zSOg400MHZ)6118(dg3H)g3 65(ddt 1H)g400( 1H), 4. 09 1H), 6. 93 1H), 6. 98 1H), 7.35 1H), 7. 67 (m, (t, (d, (t, 1H), 8. 18 2H), 9.80 1H), 10.04 1H), 11.17 1H) . (d, (s, (s, (s, (s, Example 45 meth 3-(5-Fluoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide N+NH2 oxyphenyl — — — — — — l Fl uor 2 l one (5 o pr opan — — — Mel 12 7. was mixture of 1 fluoro (1. 88 mmol) added to a (5 1 one 02 and 26 hydroxyphenyl) propan (1. 6. 06 mmol) K&CO& (1. g, g, in DMF The reaction mixture was stirred room 9.09 mmol) (10 mL) . at for 20 min and was then in water and temperature partitioned (30 mL) The was washed with water x 20 Et&0 (40 mL) . organic phase (2 mL), dried and concentrated at reduced pressure to the (NazSO~), give crude title an oil 04 91-:) compound as (1. .
H NMR (CDClz, 400 MHz) 6: 1.16 2. 99 2H), 3.89 (t, 3H), (q, (s, 3H), 6. 91 (dd, 1H), 7 . 14 (ddd, 1H), 7 . 41 (dd, 1H) — — — — — — — — — — 3 (Dimethylamino) l (5 fluoro 2 methoxyphenyl) 2 methylpr opan l one HC1 conc. 052 was mixture of 1-(5-fluoro (aq. 0. mL) added to a — — — 1 one 67 dioxolane methoxyphenyl)propan (1.58 8. mmol), 1, 3 (2. 58 PC T/EP2016/064446 34. and 10. 8 mmol), dimethylamine hydrochloride (0.883 8 mmol) . g, g, 85'C The reaction mixture was stirred in sealed vial for 4 h. at a After the reaction mixture was mixed with EtOAc mL) and cooling, (40 stirred for 2 h to the crude product HCl-salt, which was precipitate collected filtration, washed with EtOAc, and dried. The solid material 95 was partitioned in water mL) and (1. (30 CH&Clz (50 The mixture was basified addition of and mL) . by KHCO~ (aq. sat. ) the product was extracted into the organic The phase. aqueous phase was extracted with mL) and the combined organic CH, C1, (25 phases 1 0 were washed with water dried and concentrated at (30 mL), (NazSO~), reduced pressure to the title compound as an oil 45 70-:) . give (1.
H NMR (CDClz, 400 MHz) 6: 1.15 2. 21 2. 29 1H), (d, 3H), (s, 6H), (dd, 2. 72 7. 13 7.29 (dd, 1H), 3.69 (m, 1H), 6. 90 (dd, 1H), (ddd, 1H), 1H) . (dd, — — — — — — — — — — — Fl or 2 me th en 4 me th di l H z o1 3 (5 u o oxyph yl yl 4, 5 o a e ) hydr pyr rboxi mi dami ca de Aminoguanidine was hydrochloride (673 mg, 6. 06 mmol) added to a — — — — — — — solution of 3 (dimethylamino) 1 fluoro 2 (5 methoxyphenyl) 2 1 one 45 in EtOH (96-:, 12 The 0 (1. 6. 06 mmol) mL) . methylpropan g, reaction mixture was stirred at reflux temperature for 20 h and was then concentrated to a volume of approx. 3.5 mL. EtOAc (35 mL) was added and the reaction mixture was stirred for 15 min to precipitate the crude HCl-salt, which was collected filtration, product by washed with and dried. The solid material 92 was EtOAc, (0. dissolved in water and was basified addition of (25 mL) by KHCO, (aq. sat. and concentrated to dryness at reduced pressure. CH, C1, (40 mL) was added to the residue and after 5 min stirring the mixture was filtered. The filtrate was concentrated reduced the title an foam 40-:) pressure to give compound as orange (0. 60 .
H NMR 400 MHz) 6 1 15 3 66 3 84 (CDC13g (dg 3H)g (ddt 1H)g (sg 3H) 4. 00 (m, 1H), 4. 14 (dd, 1H), 6. 86 (dd, 1H), 7. 05 (ddd, 1H), 7. 40 (dd, 1H) .
Example 46 3-(5-Fluorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide exemplified its hydrobromide salt PC T/EP2016/064446 N+NH2 in 4 was solution of 3-(5- BBr, CH, C1, (4. 0 mL, 1M, mmol) added to a fluoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide 25 1. in The reaction (0. 0 mmol) CH&Clz (12 mL) . mixture was stirred room for 20 h. After addition of at temperature MeOH the solution was concentrated reduced MeOH (10 mL) at pressure. was The solution was concentrated reduced (10 mL) again added. at and the residue was from MeOH pressure recrystallized at (3 mL) . j The were collected filtration, washed with 0 yellowish crystals by and dried the title 19-:) EtzO, to give compound (60 mg, .
H NMR 400 MHz) 6: 1.18 3.69 4. 05 4. 18 ( (CD&) &SO, (d, 3H), (dd, 1H), (m, 2H), 6. 98 (dd, 1H), 7 .21 (dt, 1H), 7 . 62 (dd, 1H), 7 . 75 4H), .01 (s, 1H) .
Example 47 3-(3-Fluoromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide F N .
. NH2 the method described in 45.
Prepared by Example Yield: (55-:). 500 mg H NMR (CDClz, 400 MHz) 6: 1.20 3.82 1H), 3. 96 (d, 3H), (dd, (d, 3H), 4. 00 (m, 1H), 4. 38 (t, 1H), 6. 61 (s, 3H), 7. 04 (dt, 1H), 7. 17 (ddd, 1H), 7.41 1H) Example 48 3-(3-Fluorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide its salt exemplified by hydrobromide . NH2 PC T/EP2016/064446 r(6.
Prepared the method described in Example Yield: 156 mg (42-:).
HNMR((CDn)gSOg400MHZ)6119(d3H)371(dd 1H)405418 2H), 6. 94 1H), 7.36 (ddd, 1H), 7. 50 1H), 7. 80 4H), (m, (dt, (d, (s, 9. (s, 1H) Example 9 3-(4-Fluoromethoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide .N .NH~ r(5.
Prepared the method described in Example Yield: 470 (75-:).
H NMR 400 1.14 73 (CDC1:, MHz) 6: (d, 3H), 3. (dd, 1H), 3.85 (s, 3H), 4. 02 (m, 1H), 4. 26 (t, 1H), 6. 13 (s, 3H), 6. 66 (dd, 1H), 6. 70 (dt, 7 . 64 1H) . 1H), (dd, Example 50 2 0 3-(4-Fluorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide its hydrobromide salt exemplified by N~NHp NH HBr the method described in r(6.
Prepared by Example (25'-.
Yield: 90 . mg ) HNMR((CD3)gSOg100MHZ)6117(dg3H)g3 03)17 67(ddt 1H)g1 2H), 6. 77 6. 83 2H), 7. 65 7. 80 (rn, 10.36 1H) . (m, (m, 5H), (s, Example 51 methyl-4, zole-l- 3-(5-Chloromethoxyphenyl) 5-dihydro-lH-pyra. carboximidamide RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 . NHz Prepa. red the method described in Example 45.
Yield: 520 (27-:). 5HNMR((cD3)3sog 400 MHZ)6105(dg3H)g3 51(ddt 1H)f385(s 1-7. 3.88 4. 00 7. 7 (broad 7. 15 3H), (m, 1H), (t, 1H), s, 3H), (d, 1H), 7. 45 1H), 7.79 1H) . (d, (d, Example 52 — — — — — — — — — — — j 0 3 Chloro 2 4 methyl 5 1H (5 hydroxyphenyl) 4, dihydro pyrazole carboximidamide exemplified its hydrobromide salt N. NHz the method described in 46.
Prepared by Example Yield: 90 (38-') . 400 MHZ)6'116(dg3H)g3 05 4 22 HNMR((CD3)3SOg 66(ddt 1H)g4 6. 97 7. 35 7. 77 10.5 (broad (m, 2H), (d, 1H), (d, 1H), (s, 4H), s, Example 53 3-(3-Chloromethoxyphenyl) methyl-4, 5-dihydro-1H-pyrazole carboximidamide Cl N the method described in 45.
Prepared by Example (54-:-) Yield: 520 .
H NMR (CDC13g 400 MHz) 6, 17 3 71 1H)g 3 82 3H) (dg 3H)g (ddt (sg 3. 92 1H), 4. 24 1H), 5.25 7. 10 1H), 7. 44 (m, (t, (s, 3H), (t, (dd, 1H), 7 . 51 (clcl, 1H) RECTIFIED SHEET (RULE 91) ISA/EP PC T/EP2016/064446 Example 3-(3-Chlorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide exemplified its hydrobromide salt CI .N NH2 NH HBr Prepared the method described in Example 46.
Yield: 135 (36-:).
H NMR (CD&) &SO, 400 MHz) 6: 1.21 (d, 3H), 3.77 (dd, 1H), 4. 05 (t, 4. 13 7. 02 7.59 7. 90 9.89 1H), (m, 1H), (t, 1H), (m, 2H), (s, 4H), Example 55 -dihydro-lH- N-(4-Chlorobenzyl)(2-hydroxyphenyl)methyl-4, pyrazolecarboximidamide exemplified its hydrochloride salt i. N N — — — — — — — — — 3 (2 Hydr 4 4, 5 di hydr o lH azol e ) pyr oxyphenyl methyl 2 0 carbo thi oami de BBrz in CH&Clz (87 mL, 1M, 87 mmol) was added during 30 min to a -dihydro-lH- solution of methyl 3-(2-methoxyphenyl)methyl-4, pyrazolecarbothioamide (7.20 28. 9 mmol) in CH, C1, (80 mL) . The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to and then MeOH (80 mL) was added during 30 min. The mixture was concentrated at reduced pressure to dryness. MeOH (100 mL) was again added and the mixture was concentrated at reduced pressure. The residue was stirred in MeOH (60 mL) for 30 min to give a suspension. The solid material was collected filtration, washed with cold MeOH and dried to give the title compound (4. 1 60-:) .
H NMR 400 1.16 97 4. 15 (CD&) &SO, MHz) 6: (d, 3H), 3.86 3. (m, 2H), 1H), 6. 91 1H), 6. 95 1H), 7. 32 1H), 7. 63 1H), (t, (t, (d, (t, (d, 9.75 1H) .
PC T/EP2016/064446 — — — — — — — — — 4 di lH azol Methyl 3 (2 hydr ) 4, 5 hydr o pyr e oxyphenyl methyl carbimi dothi oi odi oate hydr de 3-(2- Mel 724 5. 10 mmol) was added to a solution of methoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l-carbothioamide 00 4. 25 mmol) in MeOH mL) . The reaction mixture was stirred (1. (6 70'C in a sealed vial at for 4 h and was then allowed to cool to room MeOH was and the temperature to give a suspension. (6 mL) added mixture was stirred for 10 min. The solid material was collected filtration, washed with cold MeOH mL) and dried to the title (5 give compound 00 64-:).
HNMR((CD3)zSOg400MHZ)6;121(dg3H)g2 69(sg3H)g3 79(ddt 4. 20 4. 94 7. 40 1H), 33 (m, 2H), 6. (t, 1H), 6. 99 (d, 1H), (t, 1H), 7. 67 10.22 (broad s, 1H), (s, 1H) . — — — — — — — — — — j N Chl or 4 di (4 ) 3 (2 hydr ) 4, 5 hydr o obenzyl oxyphenyl methyl azole l carboximi dami ochl oride de hydr 4-Chlorobenzylamine 156 1.10 was solution of (0. mmol) added to a 3-(2-hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- methyl carbimidothioate hydroiodide 400 1.06 mmol) in MeOH mL) . (0. (3 2 The reaction mixture was stirred reflux for 2. h. After 0 at 5 cooling, the reaction mixture was partitioned in CH, C1, (20 mL) and water (10 mL) and the mixture was basified addition of KHCO~ (aq. sat. . by , ) The organic phase was washed with water and the aqueous phase was extracted with The combined were CH, C1, (10 mL) . organic phases concentrated reduced The residue was silica at pressure. purified by column the chromatography (CH, C1, :MeOH:NH~ (aq. 45:5:1) to give base 61-:) product (0.21 as a glass. This was dissolved in MeOH (2 mL) and HC1 in MeOH (1.75 mL, 0. 55 M, 1.0 mmol) was added followed addition of EtOAc and the HC1— (10 mL) Et&0 (10 mL) to precipitate which was collected filtration, washed with and dried salt, by EtzO the title 13 34-:) to give compound (0. .
H NMR 400 MHz) 6: 1.19 3.77 4. 10 4. 21 ( (CD&) &SO, (d, 3H), (dd, 1H), (m, 2H), 4. 59 2H), 6. 91 1H), 7. 02 1H), 7. 34 1H), (s, (t, (d, (t, 7. 44 7. 72 22 79 10. 4H), (d, 1H), 8. (s, 2H), 8. (s, 1H), 03 (s, (q», 1H) .
Example 56 N-(2-Chlorobenzyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide its salt exemplified by hydrochloride PC T/EP2016/064446 NH CI the method described in The salt-formation Prepared by Example 55. addition of HC1/MeOH was in followed by performed CH, Clz by repeated of the solvents reduced evaporation to dryness at pressure.
Yield: 18 0. (47:) .
H NMR 400 MHz) 6: 1.21 3.81 1H), 4. 13 4. 25 ( (CD&) &SO, (d, 3H), (dd, 4. 92 7. 04 7. 32 7. 43 (m, 2H), 63 (d, 2H), 6. (t, 1H), (d, 1H), (m, 4H), 7.51 (d, 1H), 8.25 (s, 2H), 8. 68 (t, 1H), 10.06 (s, 1H) .
Example 57 N-(2, 4-Dichlorobenzyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide NH Cl the method described in without salt- Prepared by Example 55 formation.
Yield: 183 (49-:) H NMR (CDClz, 400 MHz) 6: 1.37 3.80 1H), 3. 94 1H), (d, 3H), (m, (dd, 4. 02 (t, 1H), 4. 57 (s, 2H), 6. 96 (t, 1H), 7. 03 (d, 1H), 7.26 (dd, 1H), 7.30 7. 37 (m, 2H), 7. 40 1H), 7. 58 1H) . (d, (d, 2 5 Example 58 N-(3, 4-Dichlorobenzyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide its salt exemplified by hydrochloride Prepared the method described in Example 55.
Yield: 0. 17 (41:).
H NMR (CD&) &SO, 400 MHz) 6: 1.19 3H), 3.76 (m, 1H), 4. 10 4. 22 ( (d, 4. 92 7. 02 7. (m, 2H), 59 (s, 2H), 6. (t, 1H), (d, 1H), 35 (t, 1H), PC T/EP2016/064446 7.41 7. 64 7. 75 22 10.02 (d, 1H), (m, 3H), 8. (s, 2H), 8. 80 (s, 1H), (s, 1H) .
Example 59 3-(2-Hydroxyphenyl)-N-(4-methoxybenzyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt .N N j the method described in 0 Prepared by Example 55.
Yield: 11 (29-:) 0. .
H NMR (CD&OD, 400 MHz) 6: 1.32 3.74 3.80 1H), 3.79 (d, 3H), (m, (s, 4. 12 4. 23 4. 52 7. 3H), (t, 1H), (m, 1H), (s, 2H), 6. 90 00 (m, 4H), 7.28 7. 40 7. (m, 3H), 66 (d, 1H) .
Example 60 N-(3, 4-Dimethoxybenzyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt Prepared the method described in Example 56.
Yield: 0.25 (62:) ~ H NMR (CD&) &SO, 400 MHz) 6: 1.18 3H), 3.73 3H), 3.73 3.78 ( (d, (s, 3.76 4. 09 4. 20 4. 48 6. 89 6. 95 (m, 1H), (s, 3H), (m, 2H), (d, 2H), 7. 01 1H), 7. 07 1H), 7. 34 1H), 7.71 1H), (m, 3H), (d, (s, (t, (d, 8. 14 2H), 8. 68 1H), 9. 99 1H) . (s, (t, (s, Example 61 N-(3, 5-Dimethoxybenzyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt PC T/EP2016/064446 the method described in Prepared by Example 56.
Yield: 24 (60-:) 0. .
H NMR 400 MHz) 6: 1.19 3.70 3.80 3.74 ( (CD&) &SO, (d, 3H), (m, 1H), 6H), 4. 10 4. 20 (m, 2H), 4. 50 2H), 6. 44 1H), 6. 58 (s, (d, (s, (s, 2H), 6. 92 1H), 7. 01 1H), 7. 34 1H), 7.71 1H), 8. 14 (t, (d, (t, (d, 2H), 8.71 1H), 9. 98 1H) . (s, (t, (s, j 62 0 Example N-(3-chloromethoxybenzyl)(2-hydroxyphenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide N Cl the method described in without salt- Prepared by Example 55 formation.
Yield: 20 (54-:).
H NMR 400 MHz) 6: 1.34 3.80 3. 92 (CDClz, (d, 3H), (m, 1H), (d, 1H), 4. 03 1H), 4. 47 2H), 6. 88 1H), 6. 94 1H), 7. 00 (t, (s, (d, (t, (d, 7.25 7. 7.41 1H), 35 (m, 3H), (s, 1H) Example 63 -dihydro-lH- 3-(2-Hydroxyphenyl)methyl-N-((R)-l-phenylethyl)-4, pyrazolecarboximidamide exemplified its hydrochloride salt Prepared the method described in Example 56.
Yield: 0. 040 (11-:) H NMR 400 6:(diastereomeric 1.23 and 1.
(CDClz, MHz) mixture, 1:1) 35 (broad s and d, 3H), 1.71 3H), 1.87 (broad s, 1H), 3.88 and 3. 96 PC T/EP2016/064446 4. 20 4. 43 49 7. (2m, 1H), (m, 2H), 5.35 5. (m, 1H), 6. 95 (t, 1H), 08 7.23-7. 40 7. 46 7.51 29 (d, 1H), (m, 5H), (d, 1H), (d, 1H), 8. (broad 9.26 and 9.36 1H) . s, 2H), (2s, Example 64 3-(2-Hydroxyphenyl)methyl-N-((S)-l-phenylethyl)-4, 5-dihydro-lH- pyrazolecarboximidamide its salt exemplified by hydrochloride the method described in Prepared by Example 56.
Yield: (10-:). 0. 036 H NMR 400 MHz) 6: (diastereomeric mixture, 1: 1.32 (CD&OD, 1) (d, 3H), 1.66 and 1.66 (2d, 3H), 3.80 (m, 1H), 4. 14 1H), 4. 23 (m, 1H), 4. 7.28 7. 46 7. 67 93 (m, 1H), 6. 93 6. 99 (m, 2H), (m, 6H), (d, 1H) Example 65 -dihydro-lH-pyrazole-l- 3-(2-hydroxyphenyl)methyl-N-phenethy1-4, carboximidamide exemplified its hydrochloride salt the method described in Prepared by Example 56.
Yield: 105 (29-:) 0. .
H NMR 400 MHz) 6: 1.17 2. 89 3.55 ( (CD&) &SO, (d, 3H), (t, 2H), (m, 2H), 73 4. 4. 19 92 7. 04 7.23 3. (m, 1H), 03 (m, 2H), 6. (t, 1H), (d, 1H), 7.27 7. 37 7.71 18 26 (m, 1H), (m, 5H), (d, 1H), 8. (s, 2H), 8. (t, .04 1H), (s, 1H) .
Example 66 3-(2, 4-Dimethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide PC T/EP2016/064446 N+NH2 the method described in 45.
Prepared by Example Yield: 1.10 (69-:) H NMR (CDC13g 400 MHz) 6 1 14 3 66 1H)g 3 84 3H) (dg 3H)g (ddt (sg 3.84 (s, 3H), 3. 99 (m, 1H), 4. 16 (t, 1H), 5. 69 (s, 3H), 6. 47 (d, 1H), 6. 52 (dd, 1H), 7. 60 1H) .
Example — — — — — — — — — j 4 4 1H 0 3 (2, Dihydroxyphenyl) methyl 4, 5 dihydro pyrazole carboximidamide its salt exemplified by hydrobromide N+NH2 Prepared the method described in Example 46 8 of BBr, . by using eq.
The crude was silica column product purified by chromatography and then from EtOH (EtOAc:MeOH:AcOH, 80:20:1) recrystallized (abs. .
Yield: 47 (12-:).
HNMR(CD30Dg400MHZ)6134(dg3H)g3 1H) 74(ddt 1H)g401(tg 4. 11 (m, 1H), 6.39 1H), 6. 43 1H), 7. 45 1H) . (s, (d, (d, Example 68 — — — — — — — — — 3 (2 Methoxy 4 (trifluoromethyl)phenyl) 4 methyl 4, 5 dihydro pyrazolecarboximidamide exemplified its hydrochloride salt N+NH2 F NH HCI HC1- Prepared the method described in Example 45 isolated as the salt without free-basing.
Yield: 0. 34 (36-:) H NMR 400 MHz) 6: 1.10 3.66 3. 96 ( (CD3) &SO, (d, 3H), (dd, 1H), (s, 3H), 4. 11 (m, 1H), 4. 22 1H), 7.41 1H), 7. 46 1H), 7. 94 (t, (d, (s, 4H), 7. 99 1H) . (s, (d, PC T/EP2016/064446 Example 69 — — — — — — — — — 3 4 (trifluoromethyl)phenyl) 4 methyl 5 (2 Hydroxy 4, dihydro pyrazolecarboximidamide exemplified its hydrochloride salt N+NH2 F NH HCI the method described in 46.
Prepared by Example Yield: 22 (53-:) 0. .
NMR 400 MHz) 6: 1.17 3.69 4. 10 4. 23 ( (CD&) &SO, (d, 3H), (m, 1H), (m, 2H), 7.26 1H), 7.28 1H), 7.79 4H), 7. 95 1H), (d, (s, (s, (d, .63 1H) .
Example 3-(1H-Indo1yl)methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide exemplified by its hydrochloride salt N~NH2 NH HCI — — — — — — — — — — from 1 indol 2 2 en 1 one the Prepared (1H 3 yl) methylprop by method described in 23.
Example Yield: 23 (36-:).
H NMR 400 MHz) 6: 1.33 3.72 1H), 3. 90 4. 02 ( (CD&) &SO, (d, 3H), (d, 7. 14 7.21 7. 46 7. 87 (m, 2H), (t, 1H), (t, 1H), (d, 1H), (s, 4H), 8. 03 (s, 1H), 8. 37 (d, 1H), 11.99 (s, 1H) .
Example 71 4-Methyl(quinolinyl)-4, 5-dihydro-lH-pyrazole-l-carboximidamide N NH2 Prepared from 2-methyl(quinolinyl)propenone the method described in Example 23. After completing the reaction the PC T/EP2016/064446 reaction mixture was concentrated reduced and the at pressure residue was stirred with for min. The was CH, C1~ (25 mL) 5 product isolated filtration and concentration of the filtrate at reduced pressure followed crystallization from EtOAc mL) . The by (20 crystals were collected filtration, washed with and dried to by EtzO the title compound 29 56-:) . give (0.
NMR (CDClz, 400 MHz) 6: 1.34 3.63 1H), 3. 90 1H), (d, 3H), (m, (dd, 4. 04 48 7. 7. 45 7.51 (t, 1H), 6. (broad s, 1H), 30 (m, 2H), (d, 1H), 19 75 (m, 1H), 8. (d, 1H), 8. (broad s, 1H), 9.06 (s, 1H) .
Example (S)*(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole- 1-carboximidamide its salt exemplified by hydrochloride Cl N . NH2 Example 73 (R)*(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole- 1-carboximidamide 2 0 exemplified its hydrochloride salt Cl N NH2 The enantiomers were separated and purified SFC (Supercritical Fluid Chromatography) using an @my-C column (20mm x 250mm, 5um) with EtOH/COz (40-:) as eluent (NH, 0. was added as a modifier) with 50 mL/min flow rate and UV-detection at 215nm wavelength.
HBr-salt The racemate compound (154 was dissolved in methanol (50 mg/mL) and injected in 0. 4 mL (20 volumes. The combined fractions of each enantiomer (isomer 1 at 2. 47 min and isomer 2 at 3.05 min) were concentrated at reduced pressure and then redissolved in EtOH. The HC1-salt of each enantiomer was precipitated addition of a saturated solution of HC1 in EtOH, followed 40'C evaporation of the solvent and drying in a vacuum oven at to give the title product.
PC T/EP2016/064446 The final chiral was SFC (@my-C 4. 6mm analysis performed by column, x The eluent was (40-:) was 250mm, 5um) . EtOH/COz (NH, 0. added as a modifier) with 4 mL/min flow rate.
The chemical was determined HPLC water/MeCN, 0. purity by (C18, TFA) For isomer 1: (S)*-configuration (based on biological activity and absolute configuration of Ex. 37); j 0 Yield 62 Chemical (240 nm): 99.3-:; purity Enantiomeric excess: 97.2.
For isomer 2 (R)*-configuration (based on biological activity and absolute configuration of Ex. 38); Yield 65 Chemical (240 nm): 99.4-:; purity Enantiomeric excess: 98.8.
Example N-Benzy1(3-chloromethoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide Cl N N Prepared essentially the same methods as described in Example 39 and Example 41. — — — — — — — — — — l ch1 or o 2 me 3 (di me ami no) 2 me thylpr opan l one (3 ) th oxyph encl thy' For the starting material 1-(3-chloromethoxyphenyl)propan-l-one, see DE 102005014089 Al.
Yield: 45. 3 (68-:) .
H NMR 400 1.16 2. 20 2. 28 (CDClz, MHz) 6: (d, 3H), (s, 6H), (dd, 1H), 2. 70 1H), 3.54 1H), 3.88 7. 11 1H), 7.35 (dd, (m, (s, 3H), (t, (dd, 7. 48 1H) . 1H), (dd, 3-(3-Chloromethoxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- carbothioamide Yield: 27. 5 (99:) PC T/EP2016/064446 H NMR (CDClz, 400 MHz) 6: 1.18 3.83 3.89 1H), (d, 3H), (s, 3H), (m, 4. 52 7. 12 7. 48 7. 3. 99 (dd, 1H), (dd, 1H), (t, 1H), (dd, 1H), 50 (dd, meth oxyphenyl — — — — — — — — — chl or 2 4 di Methyl 3 (3 o 4, 5 hydr o ) methyl azole l carbimi dothi oi odi oate hydr de Yield: (80-:) 33.0 ~ NMR 400 MHz) 6: 1.14 2. 64 3.83 ( (CD&) &SO, (d, 3H), (s, 3H), (s, 73 4. 17 4. 3H), 3. 3.88 (m, 1H), 3.83 (s, 3H), (m, 1H), 39 (t, 1H), 7. 32 7. 7. 82 1 7 broad (t, 1H), 58 (m, 2H), 9. 9. (2 s, 2H) — — — — — — — — — — — N Benzyl 3 (3 chl or o 2 4 methyl 4, 5 di hydr o methoxyphenyl) azole l carboximi dami de Yield: 2. 80 (77:).
H NMR 400 MHz) 6: 1.17 3.74 3.81 (CDClz, (d, 3H), (dd, 1H), (s, 3H), 3.86 (m, 1H), 4. 22 1H), 4. 48 2H), 7. 08 1H), 7.28 (tt, (t, (s, (t, 1H), 7. 32 7. 43 (m, 5H), 7.49 (dd, 1H) .
Example 75 — — — — — — — — — — — 2 0 N 3 chloro 2 hydroxyphenyl) 4 methyl 5 (3 4, Benzyl dihydro pyrazolecarboximidamide exemplified its hydrochloride salt CI N HCl-salt Prepared the method described in Example 40, followed by by precipitation.
Yield: 1.20 (40-:) H NMR 400 MHz) 6: 1.22 3.89 4. 08 4. 20 (CD&) &SO, (d, 3H), (m, 1H), (m, 2H), 4. 62 2H), 7. 01 1H), 7.31 (m, 1H), 7.36 7. 43 (m, 4H), (s, (t, 7. 55 7. 63 (m, 2H) .
Example 76 — — — — — — — — — — — — (R)* 1H— N 3 (3 chloro 2 hydroxyphenyl) 4 methyl 4, 5 Benzyl dihydro pyrazolecarboximidamide exemplified its hydrochloride salt CI -N N 3 5 ancl PC T/EP2016/064446 Example — — — — — — — — — — — — (S)* N 2 4 3 (3 chloro hydroxyphenyl) methyl 4, 5 Benzyl dihydro pyrazolecarboximidamide exemplified its hydrochloride salt CI N The enantiomers were and SFC separated purified by (Supercritical Fluid an Amy-C column (20mm x 250mm, 5um) with Chromatography) using (40-:) eluent was modifier) with EtOH/COz as (NH, 0. added as a 50 mL/min flow rate and UV-detection 210nm at wavelength. j The racemate HC1-salt was dissolved in methanol 0 compound (1.00 and in mL volumes. The combined (27 mg/mL) injected 0. 3 (8 mg) fractions of each enantiomer (isomer 1 at 1.82 min and isomer 2 at 2. 38 min) were concentrated at reduced pressure and then redissolved in EtOH. The HC1-salt of each enantiomer was precipitated by addition of saturated solution of HC1 in followed a EtOH, by 40'C of the solvent and in vacuum oven evaporation drying a at to the title product. give The final chiral was SFC (Amy-C 4. 6mm analysis performed by column, x The eluent was (35-:) 1-: was 250mm, 5um) . EtOH/COz (NH, 0. added as a 2 0 modifier) with 4 mL/min flow rate.
The chemical purity was determined HPLC (C18, water/MeCN, 0.
TFA) For isomer 1 (R)*-configuration on and absolute (based biological activity configuration of Ex. 38); Yield 404 Chemical 3-:; purity (240 nm): 98.
Enantiomeric excess: &95.
For isomer 2: (S)*-configuration on and absolute (based biological activity of Ex. configuration 37); Yield 364 Chemical 4-:; purity (240 nm): 99.
Enantiomeric excess: 99.6.
PC T/EP2016/064446 The 78-91) were the following compounds (Examples prepared by methods described in 74 the amines or Example using corresponding aniline as nucleophiles. Demethylations to phenol derivatives give were performed the method described in Example using 40, optionally followed HC1-salt precipitation.
Example N-butyl(3-chloromethoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt CI .
N~N~ Yield: 0. 34 (81-:) .
H NMR 400 1.10 1.
(CD&) &SO, MHz) 6: 0. 90 (t, 3H), (d, 3H), 33 (m, 2H), 1.52 2H), 3.29 2H), 3.72 1H), 3.79 4. 02 (m, (t, (dd, (s, 3H), 1H), 4. 27 1H), 7.27 1H), 7. 66 1H), 7. 78 1H), (m, (t, (t, (dd, (dd, 8. 14 3H) Example 79 N-Butyl(3-chlorohydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt N. .
Yield: 0. 13 (40-:) .
H NMR 400 1.24 1.43 (CD&OD, MHz) 6: 0. 99 (t, 3H), (d, 3H), (m, 2H), 1.64 2H), 3.3 2H, in solvent 3.62 1H), 4. 02 (m, (t, peak), (dd, (t, 1H), 4. 31 1H), 6. 45 1H), 7.28 1H), 7.36 1H) . (m, (t, (d, (d, Example 80 -dihydro-lH- 3-(3-Chloromethoxyphenyl)-N-hexy1methyl-4, pyrazolecarboximidamide Cll N.
Yield: (91-') 0. 30 'H — NMR (CDC1„400 MHz) 6: 0. 89 1.24 1.26 1.38 (t, 3H), (d, 3H), (m, 65-1. 4H), 1.43 (m, 2H), 1. 84 (m, 2H), 3.63 2H), 3.85 3H), (q, (s, 4. 05 4. 16 (m, 2H), 4. 71 1H), 6. 32 (broad s, 1H), 7. 15 1H), (t, (t, 7 . 51 (broad 1H), 7 . 52 1H), 7 . 72 (broad 2 H) . d, (dd, s, PC T/EP2016/064446 Example 3-(3-Chlorohydroxyphenyl)-N-hexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt N. .
Yield: 82 (30-:) .
H NMR 400 1.26 1.32 1.46 (CD&OD, MHz) 6: 0. 93 (t, 3H), (d, 3H), (m, 1.66 2H), 3.31 2H, in solvent 3.66 1H), 6H), (m, (t, peak), (dd, 4. 04 1H), 4. 28 1H), 6. 58 1H), 7.33 1H), 7.41 (t, (m, (t, (d, (d, Example 82 -dihydro-lH- 3-(3-Chloromethoxyphenyl)-N-dodecy1methyl-4, pyrazolecarboximidamide exemplified its hydrochloride salt Cl N N Yield: 31 (70-:) 0. .
H NMR (CD&OD, 400 MHz) 6: 0. 90 1.21 1.23 1.45 (t, 3H), (d, 3H), (m, 1.67 34 in solvent 71 18H), (m, 2H), 3. (t, 2H, partly peak), 3. (dd, 1H), 3.86 (s, 3H), 4. 15 (m, 1H), 4. 27 (t, 1H), 7.22 (t, 1H), 7.59 1H), 7.71 1H) (d, (d, Example 83 3-(3-Chlorohydroxyphenyl)-N-dodecy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide its salt exemplified by hydrochloride Cl N N Yield: 135 (40-:) .
H NMR 400 1.21 1.22 1.45 (CD&OD, MHz) 6: 0. 90 (t, 3H), (d, 3H), (m, 18H), 1.65 (m, 2H), 3.28 2H, partly in solvent peak), 3.57 (dd, 1H), 4. 00 1H), 4. 35 1H), 6. 32 1H), 7.23 1H), 7.30 (t, (m, (t, (d, 1H) Example 84 3-(3-Chloromethoxyphenyl)-N-cyclohexy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide PC T/EP2016/064446 Yield: 0. 16 (44-:) H NMR (CDClz, 400 MHz) 6: 1.10 1.35 (m, 3H), 1.17 (d, 3H), 1.50 (m, 1.64 1.73 2. 06 3.75 3. 2H), (m, 1H), (m, 2H), (t, 2H), (m, 1H), 3. 95 3.83 4. 39 7. 11 7. 45 (m, 2H), (s, 3H), (t, 1H), (t, 1H), (dd, 7.49 1H) 1H), (dd, Example 85 3-(3-Chlorohydroxyphenyl)-N-cyclohexy1methyl-4, 5-dihydro-lH- j 0 pyrazolecarboximidamide Yield: 90 (59-:) H NMR 400 1.18 1. 1.23 1.42 (CD&OD, MHz) 6: 30 (m, 1H), (d, 3H), (m, 4H), 1.69 1H), 1.83 2H), 1.98 2H), 3.47 1H), 3.62 (m, (m, (m, (m, 1H), 4. 01 1H), 4. 29 1H), 6. 42 1H), 7.27 1H), (dd, (t, (m, (t, (d, 7. 32 1H) Example 86 3-(3-Chloromethoxyphenyl)-N-cyclopropy1methyl-4, 5-dihydro-lH- 2 0 pyrazolecarboximidamide exemplified its hydrochloride salt Yield: 0. 35 ~ (87:) H NMR (CD&OD, 400 MHz) 6: 0. 78 2H), 0. 95 2H), 1.20 (m, (m, (d, 3H), 2. 67 4. 14 4. 25 65 (m, 1H), 3. (dd, 1H), 3.85 (s, 3H), (m, 1H), (dd, 7.22 7. 7. 70 1H), (t, 1H), 58 (dd, 1H), (dd, 1H) Example 3-(3-Chlorohydroxyphenyl)-N-cyclopropy1methyl-4, 5-dihydro-lH- pyrazolecarboximidamide its salt exemplified by hydrochloride Yield: 65 mg (20-:) PC T/EP2016/064446 H NMR (CD&OD, 400 MHz) 6: 0. 76 2H), 0. 93 2H), 1.25 (m, (m, (d, 3H), 2. 62 62 4. 4. 26 (m, 1H), 3. (dd, 1H), 00 (t, 1H), (m, 1H), 6. 56 (t, 1H), 7.33 (dd, 1H), 7.39 (dd, 1H) .
Example 88 3-(3-Chloromethoxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH- pyrazolecarboximidamide its salt exemplified by hydrochloride Yield: 30 (28-:) H NMR (CD&OD, 400 MHz) 6: 1.26 3H), 3.84 (dd, 1H), 3.89 3H), (d, (s, 4. 23 4. 41 7. 24 7. 37 7. 44 7. 52 (m, 1H), (t, 1H), (t, 1H), (m, 3H), 7. 61 7.76 (t, 2H), (d, 1H), (d, 1H) .
Example 89 — — — — — — — — — — — 3 (3 Chloro 2 hydroxyphenyl) 4 methyl N phenyl 4, 5 dihydro pyrazolecarboximidamide exemplified its hydrochloride salt Yield: (37-:) 80 mg .
H NMR 400 MHz) 6: 1.37 3. 90 4. 22 (CD&OD, (d, 3H), (dd, 1H), (m, 2H), 6. 93 1H), 7.33 7. 40 (m, 3H), 7. 46 7.53 (m, 3H), 7.59 1H) (t, (d, Example 90 3-(3-Chloromethoxyphenyl)-N-cyanomethyl-4, 5-dihydro-lH- pyrazolecarboximidamide CI N N Yield: 105 (36-:) .
H NMR 400 MHz) 6: 1.06 3.57 1H), 3.78 ( (CD&) &SO, (d, 3H), (dd, (s, 4. 10 7.23 7. 7. 61 3H), 3.86 (m, 1H), (t, 1H), (t, 1H), 53 (s, 2H), (dd, 1H), 80 (dd, 1H) .
Example PC T/EP2016/064446 3-(3-Chlorohydroxyphenyl)-N-cyanomethyl-4, 5-dihydro-lH- pyrazolecarboximidamide Cl N N Yield: 0. 13 (18-:) H NMR (CD&) &SO, 400 MHz) 6: 1.17 (d, 3H), 3.67 (m, 1H), 3.85 3. 96 6. 98 7.51 7. 57 7. 96 9. 97 (m, 2H), (t, 1H), (m, 2H), (s, 2H), (s, Example 92 — — — — — — — — N 4 Heptafluorobutyl) 3 (2 methoxyphenyl) 4 methyl (2, 2, 3, 3, 4, 4, 4, dihydro-1H-pyrazolecarboximidamide exemplified its hydrochloride salt N~CF NH F 1 5 N 4 carbamothi benzami de ( (2, 2, 3, 3, 4, 4, heptaf1 uorobu tel) opal) A solution of benzoyl isothiocyanate (2. 63 16.1 mmol) in acetone mL) was added to a solution of (5 2, 2, 3, 3, 4, 4, heptafluorobutylamine (3.20 16.1 mmol) in acetone (45 mL) . After 50'C stirring at for 8 h the reaction mixture was concentrated at 2 0 reduced pressure to give the title compound as pale yellow crystals (5. 9 quant. .
H NMR (CDC13g 400 MHz) 6 4 59 2H)g 7 55 2H)g 7 67 1H) (dt's (tg (tg 7. 87 2H), 9.15 1H), 11.19 1H) . (d, (s, (s, 2 5 l 4 thi ourea (2, 2, 3, 3, 4, 4, Heptaf1 uorobu tel) A solution of NaOH (16.2 mL, 2M) was added to a solution of 4 heptafluorobutyl) carbamothioyl) benzamide . 83 ((2, 2, 3, 3, 4, 4, (5 16.1 mmol) in MeOH (40 mL) . The reaction mixture was stirred at 65 C for 3 h. After cooling, the reaction mixture was neutralized with HC1 (conc. 2. 7 mL) and concentrated at reduced pressure to aq. , approximately half the volume. The formed crystals were collected filtration, washed with water, and dried to give the title compound (1.40 34-:) .
PC T/EP2016/064446 H NMR 400 MHz) 6: 4. 50 (broad 2H), 7.23 (broad 1H), (CD&) &SO, t, s, 7. 82 01 (broad s, 1H), 8. (t, 1H) . — — — — l 4 2 sothi our oni um i odi (2, 2, 3, 3, 4, 4, Heptaf1uor obutyl) methyli de A solution of 1 4 thiourea 40 (2, 2, 3, 3, 4, 4, heptafluorobutyl) (1. 42 and MeI 10. in MeOH was stirred . mmol) (1.53 8 mmol) (10 mL) 70'C in sealed vial for 4 h. After the reaction at a cooling, mixture was concentrated reduced the title at pressure to give brown solid 17 compound as a (2. quant. ) .
H NMR 400 MHz) 6: 2. 66 4. 43 2H), 9.50 (broad (CD&) &SO, (s, 3H), (t, s, 1H), 9.75 (broad s, 1H), 10.07 (broad s, 1H) (2, 2, 3, 3, 4, 4, 4 Hep t afl u or oh u t amino) (hydr a zi n me t h ani mi ni um ( yl ) yl ) iodide — — — A solution of 1 4 (2, 2, 3, 3, 4, 4, heptafluorobutyl) methylisothiouronium iodide 17 42 and (2. 5. mmol) hydrazine hydrate (0.407 8. 13 mmol) in MeOH (20 mL) was stirred at reflux temperature for 3 h. After cooling, the reaction mixture was concentrated reduced the title brown at pressure to give compound as 2 0 oil which solidifies on standing (2. 10 quant. g, ) H NMR 400 4. 19 20 (CD&) &SO, MHz) 6: (t, 2H), 6. (broad s, 6H) — — — — — — — — N 4 Heptaf1 uor 3 (2 4 methyl (2, 2, 3, 3, 4, 4, 4, obutyl) methoxyphenyl) — — — — di hydr o lH azole l carboximi dami de hydr ochloride NaOH (aq. 50-:, 0. 7 mL, ca 13 mmol) was added to a solution of 4 heptafluorobutyl) amino) (hydrazinyl) methaniminium ( (2, 2, 3, 3, 4, 4, — — — iodide (650 1.69 mmol) and 3 (dimethylamino) 1 methoxyphenyl)methylpropanone (375 1.69 mmol) in MeOH mg mg, (20 mL) . The reaction mixture was stirred at reflux temperature for 3 h and was then concentrated at reduced pressure. The residue was partitioned in water and CH&Clq. The organic phase was washed with water and concentrated at reduced pressure. The residue was purified silica column chromatography (CHzClz-MeOH-NH~, 160:10:1) to give the base of the title compound as a yellow oil (240 34-:) . This HCl-salt was dissolved in EtOAc (5 mL) and the was precipitated addition of 2M HC1/EtzO, collected filtration, and dried to give the title compound (230 30-:) .
PC T/EP2016/064446 H NMR 400 MHz) 6: 1.11 3.72 1H), 3.87 (CD&) &SO, (d, 3H), (dd, (s, 4. 13 4. 29 4. 41 7. 7. 18 3H), (m, 1H), (t, 1H), (t, 2H), 06 (t, 1H), 55-8. (d, 1H), 7. 52 (dt, 1H), 7. 80 (dd, 1H), 8. 70 (2 broad s, 3H) .
Example 93 N-(2, 4-Heptafluorobutyl)(2-hydroxyphenyl)methyl-4, 2, 3, 3, 4, 4, dihydro-1H-pyrazolecarboximidamide its exemplified by salt hydrochloride N~CF NH F j 0 Prepared the method described in Example followed HC1-salt by 40, by precipitation.
Yield: 140 (72-:).
H NMR (CD&) &SO, 400 MHz) 6: 1.19 3H), 3.75 (m, 1H), 4. 13 4. 23 (m, 4. 37 6. 93 7. 02 7.36 7. 72 2H), (dq, 2H), (t, 1H), (d, 1H), (dt, 1H), 8. 55 (broad 8. 63 (broad 10.09 1H) . (dd, 1H), s, 2H), s, 1H), (s, Example 94 3-(2-Methoxyphenyl)methyl-N-(2, 2-trifluoroethyl)-4, 5-dihydro- 1H-pyrazolecarboximidamide its salt exemplified by hydrochloride Prepared the methods described in Example 92 by using 2, 2, trifluoroethanamine as starting material.
Yield: 0. 67 (49-:).
H NMR (CD&) &SO, 400 MHz) 6: 1.11 3H), 3.71 (dd, 1H), 3.87 3H), (d, (s, 4. 12 4. 23 4. 37 7. 05 7. 17 7.51 (m, 1H), (m, 3H), (t, 1H), (d, 1H), 7. 82 8. 60 8. 72 1H) (dt, 1H), (dd, 1H), (s, 2H), (s, Example 95 3-(2-Hydroxyphenyl)methyl-N-(2, 2-trifluoroethyl)-4, 5-dihydro- 1H-pyrazolecarboximidamide exemplified its hydrochloride salt HC1-salt Prepared the method described in Example 40, followed by by precipitation.
PC T/EP2016/064446 Yield: 180 (69-:) mg .
H NMR 400 MHz) 6: 1.19 3.76 1H), 4. 12 4. 23 (CD&) &SO, (d, 3H), (m, (m, 2H), 4. 30 2H), 6. 92 (t, 1H), 7. 03 (d, 1H), 7.35 (dt, 1H), 7.73 54 75 10. (dd, 1H), 8. (s, 2H), 8. (s, 1H), 09 (s, 1H) .
Example 96 3-(2-Methoxyphenyl)methyl-N-phenyl-4, 5-dihydro-lH-pyrazole-l- carboximidamide its salt exemplified by hydrochloride j 0 Prepared the methods described in Example 92 aniline as by using starting material.
Yield: 0. 34 (41:) H NMR (CD&) &SO, 400 MHz) 6: 1.15 3H), 3.83 (m, 1H), 3.88 ( (d, (s, 4. 15 4. 36 7. 05 7. 19 7. 3H), (m, 1H), (t, 1H), (t, 1H), (d, 1H), 7.38 7. 46 7. 54 7. 89 8. 06 10.06 (m, 3H), (m, 3H), (dd, 1H), (s, 2H), Example 97 -dihydro-lH-pyrazole-l- 3-(2-Hydroxyphenyl)methyl-N-phenyl-4, 2 0 carboximidamide the method described in 40.
Prepared by Example Yield: 13 (58-:).
H NMR 400 MHz) 6: 1.40 3.78 3. 92 (CDClz, (d, 3H), (m, 1H), (dd, 1H), 4. 06 1H), 4. 73 (broad s, 2H), 6. 94 7. 07 (m, 5H), 7.29 7. 37 (m, 4H), 00 (broad s, 1H) Example 98 — — — — — — — — 3 (2 Methoxyphenyl) 4 methyl N (4 (trifluoromethyl)phenyl) 4, dihydro-1H-pyrazolecarboximidamide exemplified its salt hydrochloride PC T/EP2016/064446 the methods described in 92 Prepared by Example using aniline material. (trifluoromethyl) as starting Yield: 0. 14 (24-:) .
H NMR 400 MHz) 6: 1.15 3.83 3. 94 1H), 3.89 ( (Cpz) &SO, (d, 3H), (m, 4. 16 4. 41 7. 7. 19 (s, 3H), (m, 1H), (broad t, 1H), 05 (t, 1H), (d, 7. 52 7. 57 7. 81 7. 37 1H), (dt, 1H), (d, 2H), 88 (m, 3H), 8. (s, 2H), .43 (broad s, 1H) .
Example 99 — — — — — — — — j 0 3 (2 Hydroxyphenyl) 4 methyl N (4 (trifluoromethyl)phenyl) 4, dihydro-1H-pyrazolecarboximidamide exemplified its hydrochloride salt the method described in followed HCl-salt Prepared by Example 40, by precipitation.
Yield: 95 (4' . mg ) 24-4.
NMP, 4pp MHz) 6: 1.38 3. 90 4. 36 (Cp, Op, (d, 3H), (m, 1H), (m, 2H), 6. 95 7. 00 (m, 2H), 7.38 1H), 7. 58 2H), 7.71 1H), (t, (d, (d, 7. 81 2H) .
Example 100 N-(4-Fluorophenyl)(2-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt Prepared the methods described in Example 92 by using fluoroaniline material. as starting Yield: 16 (50-:).
H NMR 400 MHz) 6: 1.14 3.83 3.88 ( (Cpz) &SO, (d, 3H), (m, 1H), (s, 3H), 4. 14 (m, 1H), 4. 36 1H), 7. 05 1H), 7. 18 1H), 7. 32 (t, (t, (d, 2H), 7. 40 (dd, 2H), 7.51 (dt, 1H), 7. 88 (dd, 1H), 8. 03 2H), (t, (s, 09 (s, 1H) Example 101 PC T/EP2016/064446 N-(4-Eluorophenyl)(2-hydroxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide the method described in 40.
Prepared by Example Yield: 165 (56-:) mg H NMR 400 MHz) 6: 1.19 3. 65 3.79 3.88 ( (CD&) &SO, (d, 3H), (dd, 1H), (m, 1H), 3.89 1H), 5. 89 2H), 6. 82 (dd, 2H), 6. 92 1H), (t, (s, (t, 6. 94 1H), 7. 04 2H), 7. 27 (dt, 1H), 7.53 (dd, 1H), 9.85 (d, (t, (s, Example N-(4-Chlorophenyl)(2-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide exemplified its hydrochloride salt Prepared the methods described in Example 92 by using chloroaniline material. as starting Yield: 25 (43-:).
H NMR 400 MHz) 6: 1.14 3.85 1H), 3.88 ( (CD&) &SO, (d, 3H), (m, (s, 4. 15 4. 7. 7. 18 7. 3H), (m, 1H), 36 (t, 1H), 05 (t, 1H), (d, 1H), 38 7. 48 7. 7. 87 12 10.15 (d, 2H), 56 (m, 3H), (dd, 1H), 8. (s, 2H), (s, Example 103 -dihydro-lH- N-(4-Chlorophenyl)(2-hydroxyphenyl)methyl-4, pyrazolecarboximidamide Prepared the method described in Example 40.
Yield: 155 (77-:).
H NMR (CD&) &SO, 400 MHz) 6: 1.19 3H), 3. 65 (dd, 1H), 3.79 3.88 ( (d, 3. 90 6. 02 6. 84 6. 92 (m, 1H), (t, 1H), (s, 2H), (d, 2H), (t, 1H), 6. 94 7.25 7. 27 7. 54 9.83 (d, 1H), (d, 2H), (dt, 1H), (dd, 1H), (s, PC T/EP2016/064446 Example — — — — — — — — — — 3 (2 (Benzyloxy)phenyl) (4 methoxyphenyl) methyl 4, 5 dihydro pyrazolecarboximidamide NH r — — — — l l one (2 (Ben zyl oxy) phenyl pr opan 1-(2- bromide 4 400 is solution of Benzyl (68. mmol) added to a 1 one 400 and hydroxyphenyl)propan (60. 0 mmol) K&CO& (111.0 800 g, g, in DMF The reaction mixture is stirred room mmol) (400 mL) . at 1 for 20 h and is then in Et20 and water 0 temperature partitioned (1 L) The is washed water x dried (1 L) . organic phase by (2 300 mL), and concentrated reduced the title (NazSO~), at pressure to give oil 98-:) compound as a yellow (94. 0 .
H NMR 400 MHz) 6: 1.13 3.00 5. 17 (CDClz, (t, 3H), 2H), (s, 2H), 7. 7. 7. 7. 46 7. 70 00 05 (m, 2H), 33 (m, 6H), (dd, 1H) . — — — — — — — — l me ami 2 me l one (2 (Ben zyl oxy) phenyl) 3 (di thyl no) thylpr opan meth 1-(2- Prepared the method described in Example 1 using (benzyloxy)phenyl)propanone as starting material.
Yield: 39.0 (66-:) H NMP, 400 1 2 2 31 (CDC13g MHz) Q 09 (dg 3H) 08 (sg 6H) (ddt 1H) oxyphenyl — 2. 63 1H), 3.69 1H), 5. 15 2H), 7. 00 7. 05 2H), 7. (dd, (m, (s, (m, 7. 46 7.59 1H) . (m, 6H), (dd, — — — — — — — — — — 2 5 3 (2 (Ben zyl N (4 4 5 di hydr o oxy) phenyl) ) 4, methyl azole l carboximi dami de Prepared the methods described in Example 92 using methoxyaniline (to give hydrazinyl((4- 1-(2- methoxyphenyl) amino) methaniminium iodide) and — — — — — — (benzyloxy)phenyl) 3 (dimethylamino) 2 1 one as methylpropan starting materials.
Yield: 0.51 (45-:).
H NMR 400 1.17 72 (CDClz, MHz) 6: (d, 3H), 3. (m, 1H), 3.80 (s, 3H), 3. 93 1H), 4. 17 1H), 4. 90 (broad 2H), 5. 13 2H), 6. 87 (m, (t, s, (s, 6. 93 7. 04 7. 34 7. 45 7. 67 1H) (d, 2H), (m, 4H), (m, 6H), (dd, Example PC T/EP2016/064446 3-(2-Hydroxyphenyl)-N-(4-methoxyphenyl)methyl-4, 5-dihydro-lH- pyrazolecarboximidamide — — — — — — Hydrogenation of 3 (2 (benzyloxy) phenyl) N (4 methoxyphenyl) methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide 1.16 (480 mg, mmol) in MeOH was atm. with 10-:) (25 mL) performed at H, Pd/C (50 mg, as for 1 h mL The reaction mixture was catalyst (26 Hz consumed) . filtered and the filtrate was concentrated reduced at pressure to the title 37 98-:) give compound (0. . 1 0 NMR (CDClz, 400 MHz) 6: 1.38 3.73 3.85 1H), 3.80 (d, 3H), (m, (s, 3H), 3. 95 (dd, 1H), 08 (t, 1H), 6. 89 (d, 2H), 6. 93 6. 98 (m, 3H), 7. 03 (d, 1H), 7.31 (dt, 1H), 7.35 (dd, 1H) . 106-117) The following compounds (Examples were prepared the methods described in 92 1-(3-chloromethoxyphenyl)— Example using 3-(dimethylamino)methylpropanone and the amine corresponding or aniline derivatives materials. as starting Demethylations to give phenol derivatives were performed using the method described in Example 40, optionally followed HC1-salt precipitation.
Example 106 — — — — — — — — 3 (3 Chloro 2 methoxyphenyl) N (2, 2, 3, 3, 4, 4, 4 heptafluorobutyl) -dihydro-lH-pyrazole-l-carboximidamide methyl-4, exemplified its hydrochloride salt Cl N N CF3 NH F Yield: 0.27 (38-:) .
H NMR (CD&OD, 400 MHz) 6: 1.23 3.76 1H), 3.87 (d, 3H), (dd, (s, 3H), 4. 15 4. 7.24 7. 61 7. 72 38 (m, 4H), (t, 1H), (dd, 1H), (dd, 1H) .
Example — — — — — — — — 2 N 4 3 (3 Chloro hydroxyphenyl) (2, 2, 3, 3, 4, 4, heptafluorobutyl) methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide its exemplified by hydrochloride salt PC T/EP2016/064446 Cl .N N CF3 NH F Yield: 0. 12 (51-:) .
H NMR (CD&OD, 400 MHz) 6: 1.35 3H), 3.83 (dd, 1H), 4. 17 4. 35 (m, 6. 99 7. 52 7. 63 1H) . 4H), (t, 1H), (d, 1H), (d, Example 108 — — — — — — — — — — 3 Chloro 2 methoxyphenyl) N (4 fluorophenyl) 4 methyl (3 4, dihydro-1H-pyrazolecarboximidamide Yield: 0.33 (42-:) H NMR (CDClz, 400 MHz) 6: 1.21 3.77 1H), 3.86 (d, 3H), (dd, (s, 3H), 4. 25 4. 92 7. 04 7. 10 3.88 (m, 1H), (t, 1H), 90 (s, 2H), 6. (m, 4H), 7. 44 7. 54 (t, 1H), (dd, 1H), (dd, 1H) .
Example 109 — — — — — — — — — — 3 (3 Chloro 2 hydroxyphenyl) N (4 fluorophenyl) 4 methyl 4, dihydro-1H-pyrazolecarboximidamide Yield: 0. 14 (49-:) H NMR 400 1. 77 92 (CDClz, MHz) 6: 39 (d, 3H), 3. (m, 1H), 3. (dd, 1H), 4. 07 1H), 4. 66 2H), 6. 89 6. 95 7. 02 2H), 7.27 (t, (s, (m, 3H), (t, (dd, 1H), 7. 40 (dd, 1H), 10.64 1H) .
Example 110 — — — — — — — — — — 3 Chloro 2 methoxyphenyl) N (4 chlorophenyl) 4 methyl (3 4, dihydro-1H-pyrazolecarboximidamide exemplified its hydrochloride salt PC T/EP2016/064446 Yield: 197 (40-:) .
H NMR (CD&OD, 400 MHz) 6: 1.26 3H), 3.84 (dd, 1H), 3.89 3H), (d, (s, 4. 23 4. 41 7. 24 7.39 7. 52 (m, 1H), (t, 1H), (t, 1H), (d, 2H), (d, 2H), 7. 61 1H), 7. 75 1H) (dd, (dd, Example 111 3-(3-Chlorohydroxyphenyl)-N-(4-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide Yield: 0. 12 (74') .
H NMR (CDClz, 400 MHz) 6: 1.39 3.77 1H), 3. 91 1H), (d, 3H), (m, (dd, 4. 4. 67 94 7.26 7. 06 (t, 1H), (s, 2H), 6. 89 6. (m, 3H), 30 (m, 3H), 7. 40 10. (dd, 1H), 60 (s, 1H) .
Example 112 — — — — — — — — — 3 (3 Chloro 2 methoxyphenyl) 4 methyl N (4 (trifluoromethyl)phenyl)— -dihydro-lH-pyrazole-l-carboximidamide Yield: 0.27 (27-:) H NMR (CDClz, 400 MHz) 6: 1.22 3.78 1H), 3.86 (d, 3H), (dd, (s, 3H), 4. 27 4. 7. 7. 11 3. 90 (m, 1H), (t, 1H), 96 (s, 2H), 09 (d, 2H), (t, 7. 45 7. 54 7. 1H), (dd, 1H), (dd, 1H), 56 (d, 2H) . 2 113 Example — — — — — — — — — Chloro 2 4 N 3 (3 hydroxyphenyl) methyl (4 (tri fluoromethyl) phenyl)— -dihydro-lH-pyrazole-l-carboximidamide PC T/EP2016/064446 Yield: 0. 17 (72:) ~ NMR &00 1.40 79 94 (CDCj MHz) 6: (d, 3H), 3. (m, 1H), 3. (dd, 1H), 4. 09 1H), 4. 75 (broad 2H), 6. 93 1H), 7. 08 2H), 7.29 (t, s, (t, (d, 7. 42 7. 58 10.55 (broad 1H) (dd, 1H), (dd, 1H), (d, 2H), s, Example 114 3-(3-Chloromethoxyphenyl)-N-(2-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide exemplified its j 0 hydrochloride salt 0 CI Yield: 0. 18 (22-:).
HNMR(CD30Dg400MHZ)6127(dg3H)g3 84(ddt 1H)g3 90(sg3H) 4. 24 1H), 4. 42 1H), 7.24 1H), 7. 45 7. 54 7. (m, (t, (t, (m, 3H), 7. 66 2H), 7.76 1H) (m, (dd, Example 115 3-(3-Chlorohydroxyphenyl)-N-(2-chlorophenyl)methyl-4, dihydro-1H-pyrazolecarboximidamide Yield: 80 (67-:) .
NMR 400 1.41 4.
(CDClz, MHz) 6: (d, 3H), 3.80 (m, 1H), 00 (dd, 1H), 4. 16 1H), 4. 67 (broad 2H), 6. 92 1H), 7. 00 1H), 7. 05 (t, s, (t, (dt, 1H), 7.23 1H), 7.28 1H), 7.39 7. 43 2H), 10.58 (dd, (dt, (dd, (m, (broad s, 1H) Example 116 — — — — — — — — — — 3 Chloro 2 methoxyphenyl) N (4 fluorobenzyl) 4 methyl (3 4, dihydro-1H-pyrazolecarboximidamide exemplified its hydrochloride salt PC T/EP2016/064446 Cl .N N Yield: 40 (49-:) 0. .
H NMR 400 MHz) 6: 1.22 3.75 3.86 (CD30D, (d, 3H), (dd, 1H), (s, 3H), 4. 17 (m, 1H), 4. 32 (dd, 1H), 4. 58 2H), 7. 13 2H), 7.22 (s, (t, (t, 1H), 7. 42 (dd, 2H), 7.59 (dd, 1H), 7. 72 (dd, 1H) Example 117 — — — — — — — — — — 2 N 4 3 (3 Chloro hydroxyphenyl) (4 fluorobenzyl) methyl 4, dihydro-1H-pyrazolecarboximidamide Cl & N N Yield: 0. 15 (51-:) .
HNMR(CD30Dg400MHZ)6123(dg3H)g3 63(ddt 1H)g4 05(tg 1H) 4. 35 4. 52 6. 37 7. 11 7.25 (m, 1H), (s, 2H), (t, 1H), (t, 2H), (dd, 7. 34 7. 40 2H) . 1H), (dd, 1H), (dd, Example 118 — — — — — — — Ethyl chloro 2 4 methyl ((3 (3 ((ethoxycarbonyl)oxy)phenyl) 4, — — — — 1H 1 carbamate yl)(imino) methyl) dihydro pyrazol Cl N N~O~ NH 0 2 0 A solution of Etoc cl (250 2 . 31 mmol) in mL) was (0) mg, cHzcL3 (5 solution of 3-(3-chlorohydroxyphenyl)methyl-4, added to a dihydro-1H-pyrazolecarboximidamide 2. 10 hydrobromide (700 mg, and 4. 62 in The reaction mmol) NEt3 (470 mg, mmol) CH3CL3 (25 mL) . mixture was stirred at room temperature overnight and was then concentrated at reduced pressure. The residue was purified silica column then C13-MeOH 20:1) to the chromatography (CH3C13, CH, give title 46-:) compound (380 mg, .
H NMR (CDC13g 400 MHz) 6 1 24 1 33 1 36 3H) (dg 3H)g (tg 3H)g (tg 3.72 (m, 1H), 3. 93 (dd, 1H), 4. 12 (t, 1H), 4. 15 2H), 4. 33 (q, (q, PC T/EP2016/064446 7. 7. 45 7. 70 2H), 6. 60 (s, 1H), 30 (t, 1H), (dd, 1H), 53 (dd, 1H), 8. (s, 1H) .
Example 119 — — — — — — — — — Ethyl chloro 2 4 methyl 5 ((3 (3 hydroxyphenyl) 4, dihydro 1 carbamate yl)(imino) methyl) pyrazol NH 0 — — — — — — — Ethyl chloro 2 (ethoxycarbonyl) 4 methyl ( (3 (3 ( oxy) phenyl) 4, — — — — dihydro 1H pyrazol 1 (imino) methyl) carbamate (120 0. 30 mmol) yl) mg, was dissolved in MeONa/MeOH (0.03 10 mL, 0. 30 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2 M HC1/Et~0 and then concentrated at reduced pressure. The residue was purified silica column chromatography (heptane:EtOAc, 2:1) to give the title compound (85 87-:) as a white solid.
H NMR (CDClz, 400 MHz) 6: 1.34 3H), 1.36 3H), 3.79 (m, 1H), (t, (d, 4. 03 4. 11 2H), 4. 18 2H), 5. 96, (broad 1H), 6. 94 1H), (m, (m, s, (t, 7.29 7. 45 8. 91 (broad 10.30 1H) . (dd, 1H), (dd, 1H), s, 1H), (s, 2 0 12 0 Example -HT~~ receptor binding (performed at Eurofins Panlabs Taiwan, Ltd. to human receptor protein expressed in CHO-Kl cells was determined in a ligand displacement 'H-lysergic acid diethylamide assay using as radioligand and ketanserine as a standard reference (LSD) compound. Data is presented as displacement of radioligand at indicated compound concentrations, see Table 1 and Table 2.
PC T/EP2016/064446 Table -HT, receptor binding (-: displacement)) Compound 0. 001 0. 01 0. 1 uM 10 UM uM uM uM (Ex. No) 89 101 75 53 13 82 17 100 100 18 89 101 89 22 89 102 23 68 86 102 27 25 88 31 21 32 28 33 37 23 52 37 72 38 98 102 104 12 30 85 68 48 85 28 78 50 87 51 31 52 72 53 40 87 100 81 101 57 21 78 58 52 60 28 PC T/EP2016/064446 27 72 31 72 71 20 72 21 73 83 101 103 77 28 78 85 80 13 82 51 23 82 85 101 87 100 88 53 88 100 27 22 78 21 80 12 17 77 12 70 100 27 78 101 55 102 102 17 104 33 77 105 106 106 57 107 51 100 108 101 109 72 104 110 83 80 101 112 77 119 50 PC T/EP2016/064446 Table 2.
Comparative compounds.
-HT, receptor binding displacement) Compound 0. 01UM 0. 1 UM 1 uM 10 UM (Ex. No) 38 88 12 18 13 The results show a clear positive effect of ortho-substituents in the aromatic on 5-HT~~ ring receptor binding.
Example -HT, Eurofins Panlabs receptor antagonism (performed at Taiwan, Ltd. was determined in CHO-Kl cells human receptor ) expressing 1 0 protein as inhibition of 5-HT nM) stimulated IP-1 accumulation measured HTRF SB 206553 was standard by quantitation. used as a reference The is compound. antagonistic response expressed as inhibition of the 5-HT induced effect.
The results demonstrated antagonistic effects in accordance potent with Table receptor binding potencies, see 3.
Table 3.
-HT~~ (-:) antagonism Ex. No 0. 0001 UM 0. 001 UM 0. 01 UM 0. 1 UM 1 uM 10 UM 72 107 38 103 103 116 17 31 70 100 103 21 10 104 113 22 28 88 108 110 38 23 27 75 100 102 73 87 98 Example 122 -HT, receptor agonism (performed at Eurofins Panlabs Taiwan, Ltd. was determined in the same model as described above in Ex. 117. without prior stimulation with 5-HT. The agonistic response is expressed as of the IP 1 accumulation induced 5 HT (1 uM) stimulation.
PC T/EP2016/064446 The results demonstrated the absence of effects of all the agonistic all concentrations Table 4. tested compounds at tested, see Table 4.
-HTz~ agonism (-:) Ex. No 0. 0001 uM 0. 001 uM 0. 01 UM 0. 1 UM 1 UM 10 UM — — — 8 8 13 21 13 22 10 Example 123 TNF-o, LPS-induced Reduction of plasma levels in the acute inflammation in mice was used to determine the in vi vo anti- inflammatory of the compounds. properties Method Mice (BALB/c, female, 20 8 were treated with approx. mice/group) the test compound or 30 in water) 30 min prior perorally (10 mg/kg LPS treatment in to (10 ug saline, intraperitoneally, serotype 055:B5) . Alternatively, the test compound was administered -: subcutaneously in the neck or 30 in PEG400 in saline) (10 mg/kg min prior to LPS treatment. Blood samples were collected 90 min TNF-o, after LPS treatment and plasma concentrations were determined in ELISA. duplicates by Test compounds 1: 3-(2-Hydroxyphenyl)-4, 5-dihydro-lH-pyrazole-l- Compound carboximidamide hydrochloride (Ex 3) 2: 3-(2-Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l- Compound carboximidamide hydrochloride (Ex 17) RS127445: as reference compound (5-HTz~ selective antagonist) Results Anti-inflammatory effects determined as reduction of TNF-o, plasma levels were demonstrated for both Compound 1 and Compound 2. administered dose-dependently reduced Compound 1, per orally (p. o.
TNF-o, plasma levels. Compound 2 also reduced TNF-o, levels with o.
PC T/EP2016/064446 administration and demonstrated dose-dependent effects with subcutaneous administration. with the reference (s.c. Compared compound RS127545, Compound 2 showed or higher anti- equal inflammatory effects. Results are shown in Table 5. SEM is to be understood as standard error mean.
Table Experiment No Treatment SEM TNF-o, and admin. (pg/mL) (pg/mL) vehicle (control) 2211 p. Compound 1, 10 mg/kg 5767 2658 (water) Compound 1, 30 mg/kg 3992 1437 vehicle 2868 (control) 8866 o. Compound 10 4139 907 p. 2, mg/kg (water) Compound 30 4062 2319 2, mg/kg 3 vehicle (control) 5749 1670 s.c.
Compound 2, 10 mg/kg 2708 1199 (PEG400/saline) 1397 Compound 2, 30 mg/kg RS127445, 10 3215 1397 mg/kg Example 124 Effects on collagen production in normal human fibroblasts. lung Normal human fibroblasts were cultured in FGM-2 lung (NHLF, Lonza) full medium manufacturer's instructions. When (+EBS) according to cells were onto 24-well tissue culture confluent, seeded plates at 100. cells/well wells until 000 (4 per condition), reaching confluence. Once cells were confluent were serum starved they in serum free FGM-2 medium. After 16 hours the serum free overnight medium was removed and cells were treated with (R)(2- hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide 2 1 and 10 (vehicle The cells 0 (Example 36, Compound 3) at pM ddH&0) . were then stimulated with human recombinant TGF-Pl alone or ng/mL in combination with 1 or 10 5-HT. All stimuli were in pM pM prepared serum free FGM-2 media mL volume/well) . Unstimulated cells received serum free FGM-2 medium alone. After 48 hours the -80'C. were collected and stored supernatants at Collagen production was in I analyzed supernatants using procollagen type C-peptide ELISA Bio Cell was (PIP) (Takara 4MK1010) . viability tested using a LDH (Abeam gAb102526) assay Results Normal human fibroblasts increased the of lung production collagens stimulation with TGF-Pl and 5-HT. Treatment with upon 5 ng/mL PC T/EP2016/064446 reduced the of This Compound 3 significantly production collagens. result an anti-fibrotic role for Results are suggests Compound 3. presented in Figure l Example 125 Anti fibroti c effects of in the bleomycin induced fibrosis pulmonary model in mice.
Pulmonary fibrosis was induced in female C57BL/6 mice intratracheal instillation of bleomycin in saline 0. 5 (50 uL, 1 0 . Treatment was initiated at the of intratracheal mg/mL) day instillation and continued to 28. The mice day (8 animals/group) were orally treated twice with 25 or 75 (R)(2- daily mg/kg Hydroxyphenyl)methyl-4, 5-dihydro-lH-pyrazole-l-carboximidamide (Example Compound dissolved in ddH&0. Nintedanib at 30 36, 3) mg/kg in o. twice was used as a positive control. Vehicle- ddH, O, p. daily, treated bleomycin-challenged mice and vehicle-treated non-fibrotic mice served as controls. The animals were sacrificed after 28 days and the fibrotic area of the lung was determined histological evaluation of Sirius Red-stained sections according to standard 2 The content of tissue was measured the 0 protocol. collagen lung using and the number of was hydroxyproline collagen assay myofibroblasts quantified staining for D-smooth muscle actin -SMA) in paraffin by (o, embedded sections.
Results in of 75 bid and Nintedanib of Compound 3 doses mg/kg at doses 30 mg/kg bid ameliorated bleomycin-induced pulmonary fibrosis and reduced the fibrotic area inhibited myofibroblast (A), differentiation and reduced the content No (B), hydroxyproline (C) . in of the outcomes were statistically significant changes any observed with in of 25 bid.
Compound 3 doses mg/kg n mice for all indicates with 8 groups. significant changes 0. 05 as compared to vehicle-treated, bleomycin-challenged mice.
Results are in 2. presented Figure 512461NZPR 305309912

Claims (1)

1. A compound of the general formula I wherein 10 represents 305309912
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