NZ711522B2 - 6-(5-hydroxy-1h-pyrazol-1-yl)nicotinamide derivatives and their use as phd inhibitors - Google Patents

6-(5-hydroxy-1h-pyrazol-1-yl)nicotinamide derivatives and their use as phd inhibitors Download PDF

Info

Publication number
NZ711522B2
NZ711522B2 NZ711522A NZ71152214A NZ711522B2 NZ 711522 B2 NZ711522 B2 NZ 711522B2 NZ 711522 A NZ711522 A NZ 711522A NZ 71152214 A NZ71152214 A NZ 71152214A NZ 711522 B2 NZ711522 B2 NZ 711522B2
Authority
NZ
New Zealand
Prior art keywords
hydroxy
pyrazolyl
pyridinyl
methylbenzonitrile
mmol
Prior art date
Application number
NZ711522A
Other versions
NZ711522A (en
Inventor
Jason W Brown
Melinda Davis
Anthony Ivetac
Benjamin Jones
Andre A Kiryanov
Jon Kuehler
Marion Lanier
Joanne Miura
Sean Murphy
Xiaolun Wang
Original Assignee
Takeda Pharmaceutical Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Priority claimed from PCT/US2014/031918 external-priority patent/WO2014160810A1/en
Publication of NZ711522A publication Critical patent/NZ711522A/en
Publication of NZ711522B2 publication Critical patent/NZ711522B2/en

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The present invention provides compounds of formula (I) which are useful as inhibitors of PHD, pharmaceutical compositions thereof, methods for treatment of conditions associated with HIF, processes for making the compounds and intermediates thereof.

Description

/031918 6-(5-HYDROXY-1H-PYRAZOLYL)NICOTINAMIDE DERIVATIVES AND THEIR USE AS PHD INHIBITORS FIELD OF THE INVENTION The present invention relates to medicinal chemistry, pharmacology, and medicine.
BACKGROUND OF THE INVENTION The t invention relates to novel compounds, s, and compositions capable of decreasing HIF prolyl hydroxylase (PHD) enzyme activity, thereby increasing the stability and/or activity and/or levels of hypoxia ble factor (HIF).
HIF mediates changes in gene expression in response to changes in cellular oxygen concentration. HIF is a heterodimer having an oxygen-regulated subunit (HIF-Ot) and a constitutively expressed subunit (HIP—[3). In cells with adequate oxygen HIF—oc is hydroxylated at ved proline es by propyl-hydroxylases (PHD) resulting in its rapid degradation. Prolyl hydroxylases, PHDs, exist in a number of isoforms and function as oxygen sensors and in the regulation of cell metabolism in response to oxygen content in cells. Due to PHD’s central role in oxygen sensing, PHD inhibitors are useful in ng cardiovascular disorders, such as ischemic events, hematological disorders, such as anemia, pulmonary disorders, brain disorders, and kidney disorders. There is a need for treatment of such conditions and others described herein with compounds that are PHD inhibitors. The present invention es inhibitors of PHD. n inhibitors of calpain are described in W02008/080969, lipoxygenase inhibitors are disclosed in US4698344 and microicidal activity is disclosed in US4663327, MtSK inhibitors are disclosed in W02007/020426, and tors of PHD are described in US2010/035906 and USZOlO/0093803.
SUMMARY OF THE INVENTION The present invention es a nd of formula I T3 HO 0 R5 / '\>_N \ R1\N \ / \ N N R2 4 Wherein R1 is selected from the group consisting of optionally substituted C1_6 alkyl, optionally substituted C3_g cycloalkyl, and optionally substituted C3_6 heterocyclyl; R2 is selected from the group ting of hydrogen, C3_g cycloalkyl, and optionally substituted C1_4 alkyl; R1 and R2 er with the nitrogen to which they are attached form a 4 to 12 membered, saturated, ring optionally having 1 or 2 additional ring heteroatoms independently selected from the group N, O, and S and optionally substituted on any of the ring carbon atoms with l to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amino, C142 substituted amino, optionally substituted C3_6 heterocyclyl, C1_9 amide, ally substituted C1_6 alkyl, and C1_4 alkoxy and substituted on any additional ring nitrogen by a substituent independently selected from the group consisting of hydrogen, optionally substituted C3_g cycloalkyl, and optionally substituted C1_6 alkyl; R3, each time taken, is independently selected from the group consisting of hydrogen, hydroxyl, amino, C1_g alkylamino, cyano, halo, optionally substituted C1_6 alkyl, and C1_4 alkoxy; R4 is selected from the group consisting of hydrogen, cyano, halo, methyl, ethyl, y, and trifluoromethyl; R5 is selected from the group ting of EJEl El E; Jr W,R63 d G is carbon; A is selected from the group consisting ofN, O, S, CR6 and NR6; E is selected from the group consisting of N, O, S, and CR6; provided that only one ofA and E can be 0 or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, each time taken, is independently selected from the group consisting of en, cyano, halo, C3_g cycloalkyl, optionally substituted C1_6 alkyl, C1_4 alkoxy, and trifluoromethyl; R7 is ed from the group consisting of cyano and ethyl; or a pharmaceutically acceptable salt thereof. [0005a] In a particular aspect, the present invention provides a nd of formula 3 or a pharmaceutically able salt thereof, wherein q is 0, 1, or 2; s is 0, 1, or 2; R3, which occurs at every open valency of a pyridinyl moiety depicted in a 3, each time taken is independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-8 alkylamino, cyano, halo, C1-6 alkyl, and C1-4 alkoxy; R4 is selected from the group consisting of hydrogen, cyano, halo, methyl, ethyl, methoxy, and trifluoromethyl; R5 is selected from the group consisting of the formulae G is carbon; A is selected from the group consisting of N, O, S, CR6 and NR6; E is selected from the group consisting of N, O, S, and CR6; provided that only one of A and E can be O or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, which is at every open valency in the formulae for R5, each time taken is independently selected from the group consisting of hydrogen, cyano, halo, C3-8 cycloalkyl, C1-6 alkyl, C1-4 alkoxy, and trifluoromethyl; R7 is selected from the group consisting of cyano and ethyl; R8, which occurs at every open valency of a ring moiety ed in formula 3, each time taken is independently selected from the group consisting of hydrogen, cyano, halo, C1-4 alkyl, C1-4 alkoxy, and trifluoromethyl; and [FOLLOWED BY PAGE 3a] R9 is selected from the group consisting of hydrogen, C1-6 alkyl optionally tuted with 1 to 3 fluoro, and C3-8 lkyl.
The present invention also es pharmaceutical compositions, comprising: a compound of formula I or a pharmaceutically acceptable salt thereof and a ceutically acceptable ent.
The compounds of the invention are inhibitors of PHD they are useful for the treatment of conditions associated with HIF, including cardiovascular disorders. Thus, the present invention es for the use of the compounds of the invention as a medicament, including for the manufacture of a medicament. The present invention also provides methods of treating the conditions associated with HIF, comprising: administering to a patient in need thereof an effective amount of the compounds of the invention.
The present invention also provides processes from making PHD inhibitors and ediates thereof.
DETAILED DESCRIPTION OF THE INVENTION The term “C1-3 alkyl” refers to a straight or branched alkyl chain of one to three carbon atoms.
The term “C1-4 alkyl” refers to a straight or branched alkyl chain of one to four carbon atoms.
The term “optionally substituted C1-4 alkyl” refers to a C1-4 alkyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of optionally substituted C1-4 alkoxy, C1-4 thioalkoxy, C1-9 amide, C1-7 amido, amino, C1-8 alkylamino, C1-5 oxycarbonyl, C1-5 carbonyloxy, C1-8 sulfonyl, cyano, optionally substituted C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, ally tuted C3-6 heterocyclyl, optionally substituted C1-10 heteroaryl, and optionally substituted C5-10 aryl.
More particularly “optionally tuted C1-4 alkyl” refers to a C1-4 alkyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of C1-4 alkoxy, C1-9 amide, amino, C1-8 alkylamino, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, C3-6 heterocyclyl ally substituted on any ring nitrogen by C1-4 alkyl, C1-10 heteroaryl, and optionally substituted phenyl.
[FOLLOWED BY PAGE 3b] Even more particularly nally substituted C1-4 alkyl” refers to a C1-4 alkyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of C1-4 alkoxy, cyano, C3-8 cycloalkyl, halo, hydroxy, C3-6 heterocyclyl optionally substituted on any ring en by C1-4 alkyl, and optionally substituted phenyl.
The term “C1-6 alkyl” refers to a straight or branched alkyl chain of one to six carbon atoms.
[FOLLOWED BY PAGE 4] The term “optionally substituted C1_6 alkyl” refers to a C1_6 alkyl optionally substituted with l to 7 substituents independently selected from the group consisting of amino, C1_g alkylamino, optionally substituted C1_4 alkoxy, C1_4 thioalkoxy, C1_9 amide, C1_7 amido, C1_5 oxycarbonyl, C1_5 carbonyloxy, C1_g sulfonyl, cyano, optionally tuted C3_g cycloalkyl, halo, y, oxo, optionally substituted C1_10 heteroaryl, optionally substituted C3_6 heterocyclyl, and optionally substituted C540 aryl.
More particularly “optionally substituted C1_6 alkyl” refers to a C1_6 alkyl optionally substituted with l to 7 substituents independently selected from the group consisting of C1_4 alkoxy, C1_9 amide, amino, C1_g alkylamino, C1_5 oxycarbonyl, cyano, C3_g cycloalkyl, halo, hydroxy, C3_6 heterocyclyl optionally substituted on any ring nitrogen by C1_4 alkyl, CHO heteroaryl, and optionally substituted phenyl.
Even more particularly “optionally substituted C1_6 alkyl” refers to a C1_6 alkyl optionally substituted with l to 7 substituents independently selected from the group consisting of C1_4 alkoxy, cyano, C3_g cycloalkyl, halo, hydroxy, C3_6 heterocyclyl optionally tuted on any ring nitrogen by C1_4 alkyl, and ally substituted phenyl.
The term “C1_g sulfonyl” refers to a sulfonyl linked to a C1_6 alkyl group, C3_g cycloalkyl, or an optionally substituted phenyl.
The term “C14 alkoxy” refers to a C14 alkyl, that is methyl and ethyl, attached through an oxygen atom.
The term “C1_4 alkoxy” refers to a C1_4 alkyl attached through an oxygen atom.
The term “optionally substituted C1_4 alkoxy” refers to a C1_4 alkoxy optionally substituted with l to 6 substituents ndently selected from the group consisting of C1_4 alkoxy, C1_9 amide, C1_5 oxycarbonyl, cyano, ally substituted C3_g cycloalkyl, halo, y, optionally substituted C1_10 heteroaryl, and ally substituted C5_10 aryl. While it is understood that where the optional substituent is C1_4 alkoxy or hydroxy then the tuent is generally not alpha to the alkoxy attachment point, the term “optionally substituted C1_4 alkoxy” includes stable moieties and ically includes trifluoromethoxy, difluoromethoxy, and fluoromethoxy.
More particularly “optionally substituted C1_4 alkoxy” refers to a C1_4 alkoxy optionally substituted with l to 6 substituents independently ed from the group consisting of C1_4 , cyano, C3_g lkyl, halo, hydroxy, and optionally substituted phenyl. Even more particularly “optionally substituted C1_4 alkoxy” refers to trifluoromethoxy, romethoxy, and fluoromethoxy.
The term “C1_9 amide” refers to a -C(O)NRaRb group in which Ra is selected from the group consisting of hydrogen and C1_4 alkyl, and Rb is selected from the group consisting of hydrogen, C1_3 alkyl, and optionally substituted phenyl.
The term “C1_7 amido” refers to a -NHC(O)Rc group in which Rc is selected from the group consisting of en, C1_6 alkyl, and optionally substituted .
The term “C1_5 carbamoyl” refers to an O- or N—linked carbamate substituted with a terminal C1_4 alkyl.
The term “C1_5 ureido” refers to a urea optionally tuted with a C1_4 alkyl.
The term “C1_g alkylamino” refers to a -NRdRJe group in which Rd is a C1_4 alkyl and Re is selected from the group consisting of hydrogen and C1_4 alkyl.
The term “€5-10 aryl” refers to a clic and polycyclic unsaturated, conjugated hydrocarbon haVing five to ten carbon atoms, and includes cyclopentyldienyl, phenyl, and naphthyl.
More particularly “C5_10 aryl” refers to phenyl.
The term “optionally substituted C540 aryl” refers to a C540 aryl optionally substituted with l to 5 substituents independently selected from the group consisting of optionally substituted C1_4 alkyl, optionally substituted C1_4 alkoxy, C1_4 thioalkoxy, amino, C1_g alkylamino, C1_9 amide, C1_7 amido, C1_5 oxycarbonyl, C1_5 carbonyloxy, C1_g yl, C1_5 carbamoyl, C1_6 sulfonylamido, aminosulfonyl, C140 aminosulfonyl, C1_5 , cyano, halo, and hydroxyl.
More particularly “optionally substituted C540 aryl” refers to a C540 aryl ally substituted with l to 5 substituents independently ed from the group consisting of C1_4 alkyl, C1_4 alkoxy, cyano, halo, y, amino, trifluoromethyl, and trifluoromethoxy.
Even more particularly “optionally substituted C540 aryl” refers to phenyl optionally substituted with l to 5 substituents independently selected from the group consisting of C1_4 alkyl, C1_4 alkoxy, cyano, halo, trifluoromethyl, and trifluoromethoxy.
The term “C1_5 oxycarbonyl” refers to an bonyl group (—COZH) and C1_4 alkyl ester thereof.
The term “C1_5 carbonyloxy” refers to a yloxy group (—OZCRf), in which Rf is selected from the group consisting of hydrogen and C1_4 alkyl, for example, acetoxy.
The term “C3_g cycloalkyl” refers to clic or bicyclic, saturated or partially (but not fully) unsaturated alkyl ring of three to eight carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. It is understood that the term includes benzofused cyclopentyl and cyclohexyl.
WO 60810 The term “optionally tuted C3_g cycloalkyl” refers to a C3_g cycloalkyl optionally substituted with l to 6 tuents independently selected from the group consisting of optionally substituted C1_4 alkyl, optionally substituted C1_4 alkoxy, C1_9 amide, C1_7 amido, amino, C1_g alkylamino, C1_5 oxycarbonyl, cyano, C3_g cycloalkyl, C3_g lkoxy, halo, hydroxy, nitro, oxo, optionally substituted C1_10 heteroaryl, and optionally substituted phenyl.
More particularly “optionally substituted C3_g cycloalkyl” refers to a C3_g cycloalkyl optionally substituted with l to 3 substituents independently selected from the group consisting of C1_4 alkoxy, halo, hydroxy, and C1_4 alkyl optionally substituted with C1_4 alkoxy, halo, and hydroxy.
The term “C3_g cycloalkoxy” refers to a C3_g cycloalkyl attached through and oxygen.
The terms en” and “halo” refers to a chloro, fluoro, bromo or iodo atom.
The term “C3_6 heterocyclyl” refers to a 4 to 8 membered monocyclic or bicyclic, saturated or partially (but not fully) unsaturated ring haVing three to six carbons and one or two heteroatoms selected from the group consisting of nitrogen, , and sulfur and the ring optionally es a carbonyl to form a lactam or lactone. It is understood that where sulfur is included that the sulfur may be either -S-, -SO-, and -SOz-. It is also under that the term includes spirofused bicyclic systems. For example, but not limiting, the term includes azetidinyl, pyrrolidinyl, piperidinyl, zinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, and the like. It is understood that a C3_6 heterocyclyl can be attached as a substituent through a ring carbon or a ring nitrogen atom.
More particularly “C3_6 heterocyclyl” is selected from the group consisting of azetidinyl, idinyl, dinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and tetrahydrofuryl.
The term “optionally substituted C3_6 heterocyclyl” refers to a C3_6 heterocyclyl ally substituted on the ring carbons with l to 4 substituents independently selected from the group consisting of optionally substituted C1_4 alkyl, optionally substituted C1_4 alkoxy, C1_9 amide, C1_7 amido, amino, C1_g alkylamino, C1_5 oxycarbonyl, cyano, optionally substituted C3_g cycloalkyl, C3_g cycloalkoxy, halo, hydroxy, nitro, oxo, and optionally tuted phenyl; and optionally substituted on any ring nitrogen with a substituent independently ed from the group consisting of optionally substituted C1_4 alkyl, C3_g cycloalkyl, optionally substituted C3_6 cyclyl, optionally substituted C140 heteroaryl, and optionally substituted phenyl.
WO 60810 2014/031918 More particularly “optionally substituted C3_6 heterocyclyl” refers to a C3_6 heterocyclyl optionally substituted on the ring carbons with l to 4 substituents independently ed from the group consisting of C1_4 alkyl, C1_4 alkoxy, halo, and hydroxy and optionally substituted on any ring nitrogen with a C1_4 alkyl.
The term “€1-10 heteroaryl” refers to a five to en membered, monocyclic or clic fully unsaturated, ring or ring system with one to ten carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For example, but not ng, the term includes furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, azepinyl, diazepinyl, benzazepinyl, iazepinyl, uryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, benzopyrazinyl, benzopyrazolyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinazolyl, thienopyridyl, imidazopyridyl, quinolyl, isoquinolyl benzothiazolyl, and the like. It is understood that a C1_10 heteroaryl can be attached as a tuent through a ring carbon or a ring en atom where such an attachment mode is available, for example for a pyrrolyl, indolyl, imidazolyl, pyrazolyl, azepinyl, triazolyl, pyrazinyl, etc.
More particularly “C1_10 heteroaryl” is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridyl, and pyrimidyl.
The term “optionally substituted C140 heteroaryl” refers to a C140 aryl optionally substituted with l to 5 substituents on carbon independently selected from the group consisting of amino, C1_g alkylamino, C1_9 amide, C1_7 amido, C1_5 carbamoyl, C1_6 sulfonylamido, aminosulfonyl, C140 aminosulfonyl,C1_5 ureido, optionally substituted C1_4 alkyl, optionally substituted C1_4 alkoxy, cyano, halo, yl, oxo, nitro, C1_5 carbonyloxy, C1_5 oxycarbonyl, and C1_g sulfonyl and optionally substituted with a tuent on each nitrogen ndently selected from the group consisting of optionally substituted C1_4 alkyl, C1_g sulfonyl, optionally substituted C3_6 heterocyclyl, and optionally substituted phenyl.
More particularly “optionally substituted C1_10 heteroaryl” refers to a C140 heteroaryl ally substituted with l to 3 substituents on carbon independently ed from the group consisting of amino, C1_g mino, C1_9 amide, C1_4 alkyl, C1_4 alkoxy, cyano, halo, hydroxyl, oxo, trifluoromethyl, and trifluoromethoxy and optionally substituted on a ring nitrogen with a C1_4 alkyl.
Even more particularly “optionally substituted C140 heteroaryl” refers to a C1_10 heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, diazolyl, pyridyl, pyrimidyl, and triazolyl each optionally substituted with l to 3 substituents independently selected from the group consisting of C1_4 alkyl, C1_4 , cyano, halo, trifluoromethyl, and trifluoromethoxy and optionally substituted on a ring nitrogen with a methyl.
The term “oxo” refers to an oxygen atom doubly bonded to the carbon to which it is attached to form the carbonyl of a ketone or aldehyde. For e, a ne radical is contemplated as an oxo substituted C1_10 heteroaryl.
The term “optionally substituted ” refers to a phenyl group optionally substituted with l to 5 substituents independently selected from the group consisting of C1_4 alkyl, C1_4 alkoxy, C1_9 amide, amino, C1_g alkylamino, C1_5 oxycarbonyl, cyano, halo, hydroxyl, nitro, C1_g sulfonyl, and trifluoromethyl.
More particularly “optionally substituted phenyl” refers to a phenyl group optionally substituted with l to 5 substituents ndently selected from the group consisting of C1_4 alkyl, C1_4 alkoxy, C1_9 amino, C1_g alkylamino, C1_5 oxycarbonyl, cyano, halo, yl, nitro, and trifluoromethyl.
The term “C1_6 sulfonylamido” refers to a )2—Rg group wherein Rg is selected from the group consisting of C1_6 alkyl and optionally substituted phenyl.
The term “aminosulfonyl” refers to a —S(O)2NH2.
The term “€1-10 aminosulfonyl” refers to a -S(O)2NRhRi group wherein Rh is selected from the group consisting of hydrogen and C1_4 alkyl and R is selected from the group consisting of C1_4 alkyl, and optionally substituted phenyl.
The term “C142 substituted amino” refers to a —NRJ-Rk group in which Rj is selected from the group consisting of hydrogen and optionally tited C1_4 alkyl and Rk is selected from the group consisting of optionally substituted C1_4 alkyl, and C3_g cycloalkyl.
The term “C1_4thioalkoxy” refers to a C1_4 alkyl attached through a sulfur atom.
The term “pharmaceutically acceptable salt” refers to salts of pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and e those described in Journal of Pharmaceutical Science, 66, 2—19 (1977).
An example is the hydrochloride salt.
The term ituted,” including when used in “optionally substituted” refers to one or more hydrogen radicals of a group are replaced with non-hydrogen radicals (substituent(s)). It is tood that the substituents may be either the same or different at every tuted position. Combinations of groups and substituents envisioned by this invention are those that are stable or chemically feasible.
WO 60810 The term “stable” refers to compounds that are not substantially altered when subjected to conditions to allow for their production. In a non-limiting example, a stable compound or chemically feasible nd is one that is not substantially altered when kept at a temperature of 40 0C or less, in the absence of re or other chemically reactive conditions, for about a week.
It is understood that, where the terms defined herein mention a number of carbon atoms, the mentioned number refers to the mentioned group and does not include any carbons that may be present in any optional substituent(s) thereon.
The skilled n will appreciate that certain of the compounds of the t invention exist as isomers. All stereoisomers of the compounds of the invention, including geometric isomers, omers, and diastereomers, in any ratio, are contemplated to be within the scope of the present invention.
The skilled artisan will appreciate that certain of the nds of the present invention exist as tautomers. All tautomeric forms the compounds of the invention are contemplated to be within the scope of the present invention. In particular it is understood that compounds of formula I and embodiments related thereto can exist in either the hydroxy form depicted in formula I, l, 2, 3, 4, and 5 or the keto forms depicted below: O 0 ’N>\I0 T3 R o T3 5 R5 El, and _N H R4 Ea)_</;4\>7N>X:[_N N Compounds of the invention also include all ceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the predominant atomic mass. Isotopes suitable for inclusion in compounds of formulaI include, for example, isotopes of hydrogen, such as 2H and 3H; isotopes of carbon, such asllC, 13 C and 14C; isotopes of nitrogen, such as13N and 15N; isotopes of oxygen, such as 15O, 17O and 18O; isotopes of sulfur, such as 35$; isotopes of fluorine, such as 18F; and es of iodine, such as 123 I and 12SI. Use of isotopic variations (e.g., deuterium, 2H) may afford r metabolic stability. Additionally, certain isotopic variations of the compounds of the invention may incorporate a ctive isotope (e.g., tritium, 3H, or 14C), which may be useful in drug and/or substrate tissue distribution studies.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, may be useful in Positron on aphy (PET) studies for examining substrate receptor occupancy.
Isotopically—labeled compounds may be prepared by processes analogous to those described elsewhere in the disclosure using an appropriate isotopically-labeled reagent in place of a non—labeled reagent.
The terms “compounds of the invention” and “a compound of the invention” and the like include the embodiment of formulae 1, l, 2, 3, 4, or 5 and the other more particular embodiments encompassed by formula I, l, 2, 3, 4, or 5 described herein and exemplified compounds described herein and a pharmaceutically acceptable salt of each of these embodiments.
It is understood that a variable R6 is at every open valency in the formulae: O )3 0R7 / N / / / E \ /N 6/ so \N /N / / \A That is, from left to right, the first, second, third, fourth and fifth formula above have 4 R6 groups; the last formula has 2 to 4 R6 groups depending on A and E.
Likewise, for the variable R3, it occurs at every open valency of the pyridinyl moiety depicted in the formulae 1, l, 2, and 3.
In the same manner, for the variable R8, it occurs at every open valency of the ring moiety depicted in the ae 3 and 5 and for the variable R10, it occurs at every open valency of the ring moiety depicted in the formula 4.
One embodiment of the present invention provides a compound of formula 1 wherein R1 is selected from the group consisting of optionally substituted C1_6 alkyl, ally substituted C3_g cycloalkyl, and optionally substituted C3_6 heterocyclyl; R2 is selected from the group consisting of hydrogen and C1_4 alkyl, R1 and R2 together with the nitrogen to which they are attached form a 4 to 8 ed, saturated, ring optionally having an additional ring heteroatom selected from the group N, O, and S and ally substituted on any of the ring carbon atoms with l to 5 substituents ndently selected from the group ting of cyano, halo, hydroxy, amino, C1_9 amide, C1_4 alkyl, C1_4 alkoxy, hydroxymethyl, and romethyl and optionally tuted on any optional additional ring nitrogen by optionally substituted C1_4 alkyl, R3, each time taken, is ndently selected from the group consisting of hydrogen, hydroxyl, amino, C1_g alkylamino, cyano, halo, optionally substited C1_6 alkyl, and C1_4 R4 is selected from the group consisting of hydrogen, cyano, halo, methyl, ethyl, methoxy, and trifluoromethyl; R5 is selected from the group ting of R6 R R6 R6 R6 R6 X ‘Mlj7 /\‘\N X ' V" Cfarfi/\’ \ \ \N /N /N / /G\A R6 Gis carbon; A is selected from the group consisting of N, O, S, CR6 and NR6; E is selected from the group consisting of N, O, S, and CR6; provided that only one ofA and E can be 0 or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, each time taken, is independently ed from the group ting of hydrogen, cyano, halo, optionally substituted C1_6 alkyl, C1_4 alkoxy, and trifluoromethyl; R7 is selected from the group consisting of cyano and cyanomethyl; or a pharmaceutically acceptable salt thereof.
One embodiment of the t invention provides a compound of formula 2 T3 HO 0 R5 / —\>‘N \ R1\N \ / \ _N N R2 4 Wherein R1 and R2 together with the nitrogen to which they are attached form a 4 to 12 membered, saturated, ring optionally having 1 or 2 additional ring heteroatoms independently ed from the group N, O, and S and optionally substituted on any of the ring carbon atoms with l to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amino, C142 substituted amino, optionally substituted C3_6 heterocyclyl, C1_9 amide, optionally substituted C1_6 alkyl, and C1_4 alkoxy and substituted on any additional ring nitrogen by a substituent independently selected from the group consisting of hydrogen, optionally substituted C3_g cycloalkyl, and optionally substituted C1_6 alkyl; R3, each time taken, is ndently selected from the group consisting of hydrogen, hydroxyl, amino, C1_g alkylamino, cyano, halo, optionally tuted C1_6 alkyl, and C1_4 alkoxy; R4 is selected from the group consisting of hydrogen, cyano, halo, methyl, ethyl, methoxy, and trifluoromethyl; R5 is selected from the group consisting of R6 R R6 R6 R6 R6 7 O X /\/’\N X ,I X \ \ \N /N /N / /G‘A R6 G is carbon; A is ed from the group consisting of N, O, S, CR6 and NR6; E is selected from the group consisting of N, O, S, and CR6; provided that only one ofA and E can be 0 or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, C3_g cycloalkyl, optionally substituted C1_6 alkyl, C1_4 alkoxy, and trifluoromethyl; R7 is ed from the group consisting of cyano and cyanomethyl; or a pharmaceutically acceptable salt thereof.
One embodiment of the present invention provides a nd of formula 3 R3 HO My!“ \0 R5 N ‘ / —N N /N\\(all) S 3 R9 R8 Wherein q is 0, l, or 2; s is 0, l, or 2; R3, each time taken, is independently selected from the group consisting of hydrogen, hydroxyl, amino, C1_g alkylamino, cyano, halo, optionally substituted C1_6 alkyl, and C1_4 alkoxy; R4 is selected from the group consisting of hydrogen, cyano, halo, methyl, ethyl, methoxy, and trifluoromethyl; R5 is selected from the group consisting of 3:33o if; byCameRES/j G is carbon; A is selected from the group ting of N, O, S, CR6 and NR6; E is selected from the group consisting of N, O, S, and CR6; ed that only one ofA and E can be 0 or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, C3_g cycloalkyl, optionally substituted C1_6 alkyl, C1_4 alkoxy, and trifluoromethyl; R7 is selected from the group consisting of cyano and cyanomethyl; R8, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, C1_4 alkyl, C1_4 , and trifluoromethyl; R9 is ed from the group ting of hydrogen, C1_6 alkyl optionally substituted with l to 3 fluoro, and C3_g cycloalkyl; or a pharmaceutically acceptable salt thereof.
One embodiment of the present invention provides a compound of a 4 {131:55/R3 wherein q is 0, l, or 2; s is 0, l, or 2; R3, each time taken, is independently selected from the group consisting of hydrogen, hydroxyl, amino, C1_g alkylamino, cyano, halo, optionally substituted C1_6 alkyl, and C1_4 alkoxy; R4 is selected from the group consisting of en, cyano, halo, methyl, ethyl, methoxy, and trifluoromethyl; R5 is selected from the group consisting of 3:33o if; byCameRES/j G is carbon; A is selected from the group consisting of N, O, S, CR6 and NR6; E is selected from the group consisting of N, O, S, and CR6; provided that only one ofA and E can be 0 or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, C3_g lkyl, optionally substituted C1_6 alkyl, C1_4 alkoxy, and trifluoromethyl; R7 is selected from the group consisting of cyano and cyanomethyl; R10, each time taken, is independently selected from the group consisting of en, cyano, halo, hydroxy, amino, C142 substituted amino, optionally substituted C3_6 cyclyl, C1_9 amide, optionally substituted C1_6 alkyl, and C1_4 alkoxy and substituted on any additional ring nitrogen by a substituent independently selected from the group consisting of hydrogen, optionally substituted C3_g cycloalkyl, and optionally tuted C1_6 alkyl; or a pharmaceutically acceptable salt thereof.
One embodiment of the present invention provides a compound of formula 5 T3 HO O R (NJ—QM 5 / \ Nlj\N/ O\,\) R4 Wherein R3, each time taken, is ndently selected from the group consisting of hydrogen, hydroxyl, amino, C1_g alkylamino, cyano, halo, optionally substituted C1_6 alkyl, and C1_4 alkoxy; R4 is ed from the group consisting of hydrogen, cyano, halo, methyl, ethyl, methoxy, and trifluoromethyl; R5 is ed from the group consisting of R6 R R6 R6 R6 R6 O X 7 L)/\/’\N ,I X ‘ i)X V \ [j to, Gis carbon; A is selected from the group consisting of N, O, S, CR6 and NR6; E is ed from the group consisting of N, O, S, and CR6; provided that only one ofA and E can be O or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, C3_g cycloalkyl, optionally substituted C1_6 alkyl, C1_4 alkoxy, and romethyl; R7 is selected from the group consisting of cyano and cyanomethyl; R8, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, C1_4 alkyl, C1_4 , and trifluoromethyl; or a ceutically acceptable salt thereof. (a) One embodiment relates to compounds of formula I, l, 2, 3, 4, or 5 wherein R5 is is, R7 (b) One embodiment relates to compounds of embodiment (a) wherein R7 is cyano. (ba) One embodiment relates to compounds of embodiment (b) wherein one of R6 is 3-methyl and each other R6 is independently selected from the group consisting of hydrogen, fluoro, and methyl, depicted below: CH 3 (bb) One embodiment relates to compounds of embodiment (b) wherein one of R6 is 3—methyl, one of R6 is fluoro, and each other R6 is en depicted below: (be) One embodiment relates to compounds of ment (b) wherein one of R6 is 3-methyl and each other R6 is en depicted below: (c) One embodiment relates to compounds of embodiment (a) wherein R7 is cyanomethyl. (ca) One embodiment relates to compounds of embodiment (c) wherein R6, each time taken, is independently selected from the group consisting of en, cyano, halo, and C1_6 alkyl. (cb) One embodiment relates to compounds of embodiment (c) wherein R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, fluoro, and methyl. (d) One embodiment relates to compounds of formula I, l, 2, 3, 4, or 5 wherein R5 is selected from the group consisting of Rf’ :3, O /§:P and /NJ (da) One embodiment relates to compounds of embodiment (d) n R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, and C1_6 alkyl. (db) One embodiment relates to compounds of embodiment (d) wherein R6, each time taken, is ndently selected from the group consisting of hydrogen, cyano, fluoro, and (e) One embodiment relates to compounds of formula I, l, 2, 3, 4, or 5 wherein R5 is M/ N (ea) One embodiment relates to compounds of ment (e) wherein R6, each time taken, is independently selected from the group ting of hydrogen, cyano, halo, and C1_6 alkyl. (eb) One embodiment relates to compounds of embodiment (e) wherein R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, fluoro, and methyl. (f) One embodiment relates to nds of embodiment (e) wherein at least one of R6 is methoxy. (fa) One embodiment relates to compounds of embodiment (f) wherein R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, and C1_6 alkyl. (lb) One ment relates to compounds of embodiment (e) wherein R6, each time taken, is independently selected from the group ting of hydrogen, cyano, fluoro, and methyl. (g) One embodiment s to compounds of formula I, l, 2, 3, 4, or 5 wherein R5 is ii)N (ga) One embodiment relates to nds of embodiment (g) wherein R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, and C1_6 alkyl. (gb) One embodiment relates to compounds of embodiment (e) wherein R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, fluoro, and methyl. (h) One embodiment relates to compounds of formula I, l, 2, 3, 4, or 5 wherein R5 is /é:®\AI\R6E (i) One embodiment relates to compounds of embodiment (h) wherein G and A are N and E is CR6. (j) One embodiment relates to compounds of embodiment (h) wherein G, A, and E are (ja) One embodiment s to compounds of embodiments (h), (i), or (j) wherein R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, halo, and C1_6 alkyl. (jb) One embodiment relates to compounds of embodiments (h), (i), or (j) wherein R6, each time taken, is independently selected from the group consisting of hydrogen, cyano, fluoro, and methyl. (k) One embodiment relates to compounds of formulaI or 1 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), 0), Ga), (jb), and (k) wherein R1 is optionally tuted C1_6 alkyl. (1) One embodiment relates to compounds of formulal or 1 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), 0), Ga), (jb), and (k) wherein R1 is C1_6 alkyl optionally substituted with l to 7 substituents independently selected from the group consisting of C1_4 alkoxy, C1_9 amide, amino, C1_g alkylamino, C1_5 oxycarbonyl, cyano, optionally tuted C3_g cycloalkyl, halo, hydroxy, C3_6 heterocyclyl optionally substituted on any ring en by C1_4 alkyl, C140 heteroaryl, and ally substituted phenyl. (n) One embodiment relates to compounds of formulaI or 1 and ments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), 0), Ga), (jb), and (k) n R1 is C1_6 alkyl optionally substituted with l to 7 substituents independently selected from the group ting of C1_4 , amino, C1_g alkylamino, cyano, C3_g cycloalkyl, halo, hydroxy, C3_6 heterocyclyl optionally substituted on any ring nitrogen by C1_4 alkyl. (m) One embodiment relates to compounds of formula I or 1 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), (j), (ja), (jb), and (k) wherein R1 is C1_6 alkyl optionally substituted with l to 3 substituents independently selected from the group consisting of C1_4 alkoxy, amino, cyano, C3_g cycloalkyl, hydroxy, C3_6 heterocyclyl optionally substituted on any ring nitrogen by C1_4 alkyl. (0) One embodiment relates to compounds of formulaI or 1 and embodiments (a), (b), (b3), (bb), (b0), (C), (03), (0b), (d), (d3), (db), (6), (63), (6b), (0, (fa), (fb), (g), (h), (i), (j), 03), (jb), and (k) wherein R1 is C1_6 alkyl substituted with C3_6 cyclyl optionally substituted on any ring nitrogen by C1_4 alkyl. (p) One embodiment relates to compounds of formulaI or 1 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), 0), Ga), (jb), and (k) wherein R1 is C1_6 alkyl substituted with optionally substituted C3_g cycloalkyl. (q) One embodiment relates to compounds of formulaI or 1 and embodiments (a), (b), (be), (bb), (be), (C), (ea), (eb), (d), (d3), (db), (e), (ea), (eb), (f), (fa), (fb), (g), (h), (i), 0'), Ga), (jb), and (k) wherein R1 is C1_6 alkyl substituted with l to 3 hydroxy. (r) One embodiment relates to compounds of formula I or 1 and embodiments (a), (b), (be), (bb), (be), (C), (ea), (eb), (d), (d3), (db), (e), (ea), (eb), (f), (fa), (fb), (g), (h), (i), 0), Ga), (jb), and (k) wherein R1 is optionally substituted C3_g lkyl. (s) One embodiment relates to nds of formula I or 1 and embodiments (a), (b), (be), (bb), (be), (C), (ea), (eb), (d), (d3), (db), (e), (ea), (eb), (f), (fa), (fb), (g), (h), (i), 0'), Ga), (jb), and (k) wherein R1 is optionally substituted C3_6 heterocyclyl. (t) Another embodiment relates to compounds of a I or 1 and embodiments (a), (b), (ba), (bb), (be), (C), (ea), (eb), (d), (d3), (db), (e), (ea), (eb), (f), (fa), (fb), (g), (h), (i), (j), (ja), (jb), (k), (l), (m), (n), (o), (p), (q), (r), and (s) wherein R2 is hydrogen. (u) Another embodiment relates to compounds of formula I, l, 2, 3, 4, or 5 and embodiments (a), (b), (ba), (bb), (be), (c), (ca), (cb), (d), (da), (db), (e), (ea), (eb), (f), (fa), (ib), (g), (h), (i), 0), Ga), (jb), (k), (1), (in), (n), (0), (p), ((1), (r), (S), and (0 wherein each R3 iS hydrogen.
(V) Another embodiment relates to compounds of formula I, l, 2, 3, 4, or 5 and embodiments (a), (b), (ba), (bb), (be), (c), (ca), (cb), (d), (da), (db), (e), (ea), (eb), (f), (fa), (ib), (g), (h), (i), 0), Ga), (jb), (k), (1), (in), (n), (0), (p), ((1), (i), (S), (t), and (11) wherein R4 is (w) Another embodiment relates to compounds of formula I, l, or 2 and embodiments (a), (b), (be), (bb), (be), (C), (ea), (eb), (d), (d3), (db), (e), (ea), (eb), (f), (fa), (ib), (g), (h), (i), (j), (ja), (jb), (u), and (V) wherein R1 and R2 together with the nitrogen to which they are attached form a 4 to 12 membered, ted, ring optionally having 1 or 2 additional ring heteroatoms independently selected from the group N, O, and S and optionally substituted on any of the ring carbon atoms with l to 5 substituents independently selected from the group consisting of cyano, halo, y, CH2 substituted amino, ally substituted C3_6 heterocyclyl, and optionally substituted C1_6 alkyl, and substituted on any additional ring nitrogen by a substituent independently selected from the group ting of hydrogen, optionally substituted C3_g cycloalkyl, and optionally substituted C1_6 alkyl. (x) r embodiment relates to compounds of formula I, l, or 2 and embodiments (a), (b), (be), (bb), (be), (C), (ea), (eb), (d), (d3), (db), (e), (ea), (eb), (f), (fa), (ib), (g), (h), (i), (j), (ja), (jb), (u), and (V) wherein R1 and R2 together with the en to which they are attached form a 4 to 12 membered, saturated, ring having 1 additional ring heteroatom independently selected from the group N, O, and S and optionally substituted on any of the ring carbon atoms with l to 5 substituents independently selected from the group consisting of cyano, halo, y, amino, CH2 substituted amino, optionally substituted C3_6 heterocyclyl, C1_9 amide, optionally substituted C1_6 alkyl, and C1_4 alkoxy and optionally substituted on any additional ring nitrogen by a substituent selected from the group consisting of hydrogen, optionally tuted C3_g cycloalkyl, and optionally substituted C1_6 alkyl. (y) Another embodiment relates to compounds of formula I, l, or 2 and ments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), and (V) wherein R1 and R2 together with the nitrogen to which they are attached form a clic 4 to 8 membered, saturated, ring having 1 additional ring heteroatom independently selected from the group N, O, and S and optionally substituted 0 on any of the ring carbon atoms with l to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amino, CH2 substituted amino, optionally substituted C3_6 heterocyclyl, C1_9 amide, optionally substituted C1_6 alkyl, and C1_4 alkoxy and optionally substituted on any additional ring nitrogen by a substituent selected from the group consisting of en, optionally substituted C3_g cycloalkyl, and ally substituted C1_6 alkyl. (2) Another embodiment s to compounds of a I, l, or 2 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), and (V) wherein R1 and R2 together with the nitrogen to which they are attached form a monocyclic 4 to 8 membered, saturated, ring having 1 additional ring N and optionally substituted on any of the ring carbon atoms with l to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amino, €1.12 substituted amino, optionally substituted C3_6 cyclyl, C1_9 amide, optionally substituted C1_6 alkyl, and C1_4 alkoxy and substituted on the additional ring nitrogen by a substituent selected from the group consisting of hydrogen, optionally substituted C3_g cycloalkyl, and ally substituted C1_6 (aa) Another embodiment relates to compounds of a I, l, or 2 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (6b), (0, (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), and (V) wherein R1 and R2 together with the nitrogen to which they are attached form a monocyclic 4 to 8 membered, ted, ring having 1 additional ring N and substituted on the additional ring nitrogen by a C1_6 alkyl. (ab) Another embodiment s to compounds of formula 3 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (eb), (f), (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), and (V) wherein R9 is C1_6 alkyl. (ac) Another ment relates to compounds of formulae 3, 4, and 5 and embodiments (a), (b), (ba), (bb), (bc), (c), (ca), (cb), (d), (da), (db), (e), (ea), (eb), (f), (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), (V), and (ab) wherein s is l and q is l. (ad) Another embodiment relates to compounds of formulae 3 and 5 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (eb), (f), (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), (V), (ab), and (ac) wherein one of R8 is C1_6 alkyl and each other R8 is hydrogen. (ae) Another embodiment relates to compounds of formulae 3 and 5 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (eb), (f), (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), (V), (ab), and (ac) n each R8 is hydrogen. (af) Another embodiment relates to compounds of formula 4 and embodiments (a), (b), (b3), (bb), (b0), (C), (ca), (0b), (d), (d3), (db), (6), (ea), (eb), (f), (fa), (fb), (g), (h), (i), (j), (ja), (jb), (u), (V), (ab), and (ac) n each R10 is hydrogen. (ay) Another embodiment relates to a pharmaceutically able salt of each of the above embodiments. (az) Another embodiment relates to a pharmaceutically acceptable salt of each of the exemplified nds.
It is understood that when R1 and R2 together with the nitrogen to which they are attached form a 4 to 12 membered, ted, ring optionally having 1 or 2 additional ring atoms independently selected from the group N, O, and S and optionally substituted on any of the ring carbon atoms with l to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amin, C142 tuted amino, optionally tuted C3_6 heterocyclyl, C1_9 amide, optionally substituted C1_6 alkyl, and C1_4 alkoxy and substituted on any additional ring nitrogen by a substituent independently selected from the group consisting of hydrogen, optionally substituted C3_g cycloalkyl, and ally substituted C1_6 alkyl that the ring formed by R1 and R2 together with the nitrogen to which they are attached can be monocyclic or bicyclic, including spiro, fused, and bridged systems.
The compounds of the invention can be prepared by a variety of procedures, some of which are described below. All substituents, unless otherwise indicated, are as previously d. The products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like. The procedures may require tion of certain groups, for e hydroxy, amino, or carboxy groups to ze ed ons. The selection, use, and removal of protecting groups are well known and appreciated as standard practice, for example T.W.
Greene and P. G. M. Wuts in Protective Groups in Organic Chemistry (John Wiley and Sons, 1991). It is tood that formula I encompasses formulae 1, 2, 3, 4, and 5 and that the procedures below are also amenable to preparing compounds of formulae 1, 2, 3, 4, and 5.
Scheme A R3 HO LC‘LO R5 —»kLCELLit/r: Scheme A depicts the ion of an riate compound of formula (a) to give a compound of formula I. An appropriate compound of formula (a) is one in which R3, R4, and R5 are defined in formula I or give rise to R3, R4, and R5 as defined in formula I and Q gives rise to -NRaR2 to a desired final t of formula 1. Typical groups Q are hydroxyl or a g group, such as chloro, bromo, or imidazolyl, an activating moiety, a mixed anhydride of another carboxylic acid, such as formic acid, acetic acid, or represents the other part of a symmetrical anhydride formed from two compounds of formula (a). The preparation of compounds of formula (a) is readily appreciated in the art. A compound of formula (a) is reacted in an amide forming reaction with an amine of formula HN(R1)(R2) in which R1 and R2 are defined in formula I or give rise to R1 and R2 as defined in formula I.
For example, standard amide forming conditions can be used, such as those using coupling agents, including those used in peptide couplings, such as 2—(lH—7—azabenzotriazol— l-yl)- l, 1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride. If necessary or desired, an additive such as 4—(dimethylamino)pyridine, l— hydroxybenzotriazole, and the like may be used to facilitate the reaction. Such reactions are generally carried out using a base, such as N—methylmorpholine or triethylamine, in a wide variety of suitable solvents such as romethane, dimethylformamide (DMF), N- methylpyrrolidone (NMP), dimethylacetamide (DMA), tetrahydrofuran (THF), and the like.
Such amide forming ons are well understood and appreciated in the art.
Scheme B R0 /R3 NR2 N(b) NH2 (H C3 )2N R4 Scheme B the coupling of an appropriate compound of formula (b) and an appropriate compound of formula (c) to give a compound of formula I. An appropriate compound of formula (b) is one in which R1, R2, and R3 are defined in formula I or give rise to R1, R2, and R3 as defined in formula I. An appropriate compound of formula (c) is one in which R is H or preferably a C1_4 alkyl and R4 and R5 are defined in formula I or gives rise to R5 as defined in a I. For convenience the N,N—dimethylamino-acrylate is ed but any suitable leaving group on the acrylate can be used. The preparation of compounds of formula (b) and (c) is readily iated in the art.
For example, a compound of formula (b) and (c) are ed in a solvent, such as a lower alcohol, e. g., methanol, ethanol, or isopropanol, optionally in the presence of an acid, such as hydrochloric acid. Typically, a base is later added and the reaction continued to give a compound of formula 1. Suitable bases include organic , such as Hunig’s base, triethylamine, and the like. The reaction can optionally be heated if necessary under either the acidic or basic conditions.
Scheme C R3 OPg ”ELQ: _. NELQvilli:R3 Scheme C depicts coupling of an appropriate compound of formula (d) and an appropriate onic acid or boronic ester to give a compound of formula I. An appropriate compound of formula (d) is one in which R1, R2, R3, and R4 are defined in formulaI or give rise to R1, R2, R3, and R4 as defined in formula I, X is a leaving group, such as halo, in particular chloro and bromo, and Pg is an appropriate protecting group, such a methyl. The selection and removal of suitable protecting groups is well known in the art. An appropriate onic acid or boronic ester is one in which R5 is as defined in formula I or give rise to R5 as defined in formula 1. Such reactions are generally known as a Suzuki reaction and are well known in the art. While a Suzuki reaction is depicted in Scheme C it is understood that other carbon—carbon bond g coupling reactions can be used to e compounds of WO 60810 2014/031918 formula I. In a step, not shown, the product of compound (d) from the —carbon bond forming reaction depicted in Scheme C is deprotected to tive a compound of formula I.
It will be recognized by one of ordinary skill in the art that a compound of formula I can be elaborated in a variety of ways to r give nds of formula 1. Such reactions include hydrolysis, oxidation, reduction, alkylation, esterification, amidation, ation, and the like.
Also, in an optional step, not shown, the compounds of formula I can be converted to a pharmaceutically acceptable salt by methods well known and appreciated in the art.
The following examples are intended to be illustrative and non-limiting, and represent ic embodiments of the present invention.
Proton nuclear magnetic resonance (NMR) spectra were obtained for many of the nds in the following examples. Characteristic chemical shifts (8) are given in parts- per-million downf1eld from tetramethylsilane using conventional abbreviations for designation of major peaks, including s (singlet), d (doublet), t (triplet), q et), m (multiplet), and br (broad). The following abbreviations are used for common ts: CDCl3 oform—a0, DMSO-d6 (deuterodimethylsulfoxide), CD3OD (methanol-d4)), and THF-d8 (deuterotetrahydrofuran). Other abbreviations have their usual meaning unless otherwise indicated, for example, HOBT is 1-hydroxybenzotriazole, EDC is 1-(3- dimethylaminopropyl)ethylcarbodiimide, generally used as its hloride salt, DMSO is dimethylsulfoxide, etc. The mass spectra, unless otherwise indicated, were recorded using either electrospray ionization (EST) or atmospheric pressure chemical ionization.
The examples below were carried out in appropriate vessels and were typically stirred. Where indicated, ts of certain preparations and examples are purified by mass- triggered HPLC (e.g., Pump: WatersTM 2525; MS: ZQTM; Software: MassLynxTM), flash chromatography, or preparative thin layer chromatography (TLC). Reverse phase chromatography can be carried out using a variety of systems, including on a column (GeminiTM 5p C18 110A, AxiaTM, ID30 x 75 mm, 5 u) under acidic ions, eluting with acetonitrile (ACN) and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively, or 0.1% formic acid (FA) in v/v) water/methanol or under basic conditions, eluting with water and 20/80 (v/v) water/acetonitrile mobile phases, both containing 10 mM NH4HCO3; or (XSelectTM C18, 5 u, ID30x75mm) under acidic conditions, eluting with ACN and water mobile phases containing 0.1% FA or under basic conditions, eluting with 0.1% ammonium hydroxide in water (pH=9.5-10) and 0.1% ammonium hydroxide in ACN (pH=9.5-10). After isolation by chromatography, the solvent is removed and the product is obtained by ating product containing fractions (e.g., GeneVacTM), rotary evaporator, evacuated flask, lyophilization, etc.
Preparation 1 (2-ethoxyoxoethyl)zinc(II) e Combined THF (60.0 mL), zinc (19.61 g, 300 mmol), and (I) chloride (2.97 g, .0 mmol) under nitrogen. The d sion was heated to reflux for 40 minutes, cooled to ambient temperature, and ethyl 2-bromoacetate (6.64 mL, 60 mmol) was added . The reaction was stirred for an additional 1h at ambient temperature and was left overnight without stirring. The top clear layer was cannulated into a separate flask under nitrogen to give the title compound (approximately 1M concentration) which used in the next step without further purification.
Preparation 2 ethyl 2-(2-methoxypyridinyl)acetate ed 4—bromo—2—methoxypyridine (654 [11, 5.32 mmol), (2—ethoxy—2— oxoethyl)zinc(H) bromide (5850 [11, 5.85 mmol), and Pd(PPh3)4 catalyst (615 mg, 0.532 mmol) in THF (15.2 mL) and heated to 120°C in a microwave for 5 minutes. The reaction was filtered through a course glass frit, concentrated to an oil and d via flash chromatography (100g silica gel using a 5% to 50% EtOAc in heptane gradient). The appropriate fractions were combined and concentrated to acquire ethyl 2-(2-methoxypyridin- 4—yl)acetate (400 mg, 38.5 % yield) as a colorless oil. MS m/z [M+H]+ 196.1.
Preparation 3 ethyl 3-(dimethylamino)(2-methoxypyridinyl)acrylate Combined ethyl ethoxypyridinyl)acetate (320 mg, 1.639 mmol) and 1,1- diethoxy-N,N—dimethylmethanamine (2079 [11, 12.13 mmol) and heated to 100°C for 1h then cooled to ambient temperature with stirring overnight. The reaction was concentrated in vacuo to afford a brown oil. The oil was ioned between EtOAc and water (200 mL). The aqueous phase was back—extracted with EtOAc (2X20 mL) and the c layers were combined, washed with brine (100 mL), dried over sodium sulfate, and concentrated to an oil in vacuo. The oil was purified by flash chromatography (100g basic silica using a 5% to 50% EtOAc in heptanes gradient) to give the title compound as a light yellow oil. MS m/z [M+H]+ 251.1.
Preparation 4 6-(5-hydroxy(2-methoxypyridinyl)-lH-pyrazol-l-yl)nicotinic acid Combined 6-hydrazinylnicotinic acid (167 mg, 1.090 mmol), ethyl 3- (dimethylamino)(2-methoxypyridinyl)acrylate (300 mg, 1.199 mmol), 2-propanol (3632 [11), and hydrochloric acid (1.85% aqueous, 2.15 mL, 1.090 mmol). The reaction was stirred at room temperature. After 1 hour Hunig’s base (949 [11, 5.45 mmol) was added to the suspension which became a yellow solution. The reaction was washed with EtOAc (2X15 mL) and the aqueous phase was concentrated in vacuo, yielding a yellow solid. The solid was triturated with 1N HCl (50 mL), collected by filtration, and washed with water. The solid was then slurried in ol (2 x 60 mL) and diethyl ether (2 x 60 mL), the dried under vacuum to give the title compound. MS m/z [M+H]+ 313.0.
Preparation 5 methyl 3-(dimethylamino)(4-methoxyphenyl)acrylate Combined methyl ethoxyphenyl)acetate (3.58 mL, 22.20 mmol) and 1,1- dimethoxy-N,N—dimethylmethanamine (11.89 mL, 89 mmol) and heated to 100°C for 14h.
The reaction was concentrated in vacuo to afford a light yellow oil which was purified by flash chromatography (100g basic silica using a 5% to 50% EtOAc in heptanes gradient to give the title compound (361 mg, 6.91%) as a colorless oil. MS m/z [M+H]+ 236.1.
Preparation 6 azinylnicotinic acid A suspension of 6—chloronicotinic acid (30.0 g, 189 mmol) in 1,4—dioxane (29.0 mL) was treated with hydrazine hydrate (134 mL, 1.51 mol) and heated to 90°C overnight. The mixture was cooled to ambient temperature and then in ice for 30 min. Precipitate formation was induced by etching the side of the flask and the precipitate was filtered and re—suspended in EtOH (500 mL) with vigorous ng. The resulting suspension was filtered. The precipitate was ved in water (300 mL) and HCl (6N) was added until pH = 1. The pH was then adjusted to 5 with NaOH (50%, aq.) and the resulting suspension was stirred for 1h.
The solids were collected by filtration and dried in vacuum to give the title compound (16.65 g, 57.7 % yield) as an off—white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 6.70 (d, 1 H) 7.86 (dd, J=8.97, 2.15 Hz, 1 H) 8.32 (br. s., 1 H) 8.52 (d, J=1.77 Hz, 1 H). MS m/z [M+H]+ 154.
Preparation 7 4-cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid Combined 6-hydrazinylnicotinic acid (6.00 g, 39.2 mmol) and ethyl 2-(4- cyanophenyl)-3 -(dimethylamino)acrylate (10.05 g, 41.1 mmol) and 2-propanol (80 mL) and treated with 1.85% hydrochloric acid (77 mL, 39.2 mmol). The reaction was stirred at room temperature for 16h, then Hunig’s base (34.1 mL, 196 mmol) was add to the suspension which became homogeneous. The mixture was stirred for 3h. The reaction e was washed with isopropyl acetate (2 x 150 mL). The combined organic layers were extracted with water (40 mL) and the combined aqueous layers were concentrated in vacuo to give a solid. The solid was triturated with 1N HCl (300 mL), ed and washed with water (20 mL), then slurried in ethanol (350 mL) and granulated overnight. The solid was collected by filtration and dried in vacuum to give the title compound (9.20 g, 77 % yield) as a tan solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 7.79 (d, J=8.34 Hz, 2 H) 8.14 (br. s., 2 H) 8.47 (d, J=7.07 Hz, 1 H) 8.71 (br. s., 2 H) 8.97 (s, 1 H) 13.44 (br. s., 1 H) 13.60 (br. 5., 1 H). MS [M+H] 307. ation 8 ethyl 2-(4-cyano-1H-pyrazolyl)acetate Combined 1H-pyrazolecarbonitrile (0.432 g, 4.64 mmol) in acetone (9.28 mL), ium carbonate (1.924 g, 13.92 mmol) and ethyl 2-bromoacetate (1.027 mL, 9.28 mmol). The reaction mixture was stirred at room ature ght, then concentrated in vacuo, diluted with EtOAc (10 mL), washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to give a residue. The residue was d using flash column chromatography on silica gel (EtOAc in heptane, 10-50% gradient) to give a white solid. The solid was suspended in heptane and then filtered and dried to give the title compound (0.4314 g, 51.9 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.21 (t, J=7.20 Hz, 3 H) 4.17 (q, J=7.07 Hz, 2 H) 5.19 (s, 2 H) 8.11 (s, 1 H) 8.57 (s, 1 H). MS m/z [M+H]+ 180.
Preparation 9 ethyl 2-(4-cyano-1H-pyrazolyl)(dimethylamino)acrylate Combined ethyl 2-(4-cyano-1H-pyrazolyl)acetate (0.427 g, 2.383 mmol) with 1,1- diethoxy-N,N—dimethylmethanamine (1.403 g, 9.53 mmol) and heated in a closed vial at 100°C for 2.5h. The e was concentrated in vacuo and purified using flash column chromatography on NH silica gel (30 g SiO2, EtOAc in heptane, 10-50% gradient) to give the title compound (0.4942 g, 89 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO—d6) ppm 1.12 (t, 3 H) 1.91 — 2.43 (m, 3 H) 2.70 — 3.29 (m, 3 H) 4.03 (q, J=7.07 Hz, 2 H) 7.59 (s, 1 H) 8.14 (s, 1 H) 8.56 (s, 1 H). MS m/z [M+H]+ 235 Preparation 10 ethyl 3-(dimethylamino)(4-fluorophenyl)acrylate Combined ethyl 2—(4-fluorophenyl)acetate (500 mg, 2.74 mmol) in 1,1-dimethoxy- N,N—dimethylmethanamine (1.837 mL, 13.72 mmol) and DMF (2 mL) and heated at 100°C for 5 h. The reaction was then diluted with EtOAc (50 mL), washed with saturated aqueous um chloride (50 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes to give the title compound (223 mg, 34.2 % yield) as a clear, colorless oil. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.10 (t, J=7.1 Hz, 3 H) 2.64 (s, 6 H) 3.98 (q, J=7.1Hz, 2 H) 7.06 — 7.15 (m, 4 H) 7.49 (s, 1 H).
Preparation 11 methyl 2-(4-cyanofluorophenyl)—3-(dimethylamino)acrylate The title compound was prepared in a manner similar to Example Preparation 10 using methyl 2-(4-cyanofluorophenyl)acetate to give the title compound. 1H NMR (400 MHz, 6) 5 ppm 2.73 (br. s., 6 H) 3.54 (s, 3 H) 7.11 (dd, J=8.1, 1.5 Hz, 1 H) 7.25 (dd, J=11.1, 1.5 Hz, 1 H) 7.63 (s, 1 H) 7.77 (t, J=7.7 Hz, 1 H).
Preparation 12 ethyl 3-(dimethylamino)(4-(trifluoromethyl)phenyl)acrylate The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-(trifluoromethyl)phenyl)acetate and 1,1-diethoxy-N,N—dimethylmethanamine to give the title compound. 1H NMR (400 MHz, chloroform-d) 5 ppm 1.21 (t, J=7.1 Hz, 3 H) 2.71 (s, 6 H) 4.14 (q, J=7.2 Hz, 2 H) 7.31 (d, J=7.8 Hz, 2 H) 7.53 (d, J=7.8 Hz, 2 H) 7.61 (s, 1 H).
Preparation 13 ethyl 3-(dimethylamino)(4-oxopyridin-1(4H)-yl)acrylate The title compound was prepared in a manner similar to e Preparation 10 using ethyl 2-(4-oxopyridin-1(4H)-yl)acetate and ethoxy-N,N—dimethylmethanamine to give the title compound. MS m/z 237 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.16 (t, J=7.1 Hz, 3 H) 2.86 (br. s, 6 H) 4.06 (q, J=7.1 Hz, 2 H) 6.01 — 6.11 (m, 2 H) 7.43 — 7.47 (m, 2 H) 7.48 (s, 1 H).
Preparation 14 tert-butyl yanophenyl)acetate Combined 3—bromobenzonitrile (1500 mg, 8.24 mmol), 0.5 M (2—(tert—butoxy)—2— oxoethyl)zinc(H) chloride (24.72 mL, 12.36 mmol), 2'-(dicyclohexylphosphino)—N,N— yl-[1,1'-biphenyl]amine (324 mg, 0.824 mmol) and Pd(dba)2 (237 mg, 0.412 mmol) in THF (25 mL) and heated at 100° in an oil bath for 14 h. The reaction solution was concentrated onto Celite® and chromatographed on a 120 g silica gel column eluted with 0 to 50% EtOAc in s to give the title compound (1.537 g, 86 % yield) as a yellow oil. MS m/z 218 [M+H]+. 1H NMR (400 MHz, chloroform-d) 5 ppm 1.45 (s, 9 H) 3.56 (s, 2 H) 7.40 — 7.46 (m, 1 H) 7.49 — 7.54 (m, 1 H) 7.54 — 7.59 (m, 2 H).
Preparation 15 ethyl 2-(3-cyanophenyl)acetate ed tert—butyl 2—(3 —cyanophenyl)acetate (500 mg, 2.301 mmol), ethanol (10 mL) and 4 N HCl in dioxane (0.288 mL, 1.151 mmol) and the solution heated at 60°C for 22 h. The solution was concentrated in vacuo to give the title compound a yellow oil which was used without further purification. MS m/z 190 [M+H]+. 1H NMR (400 MHz, chloroform—d) 5 ppm 1.23 — 1.31 (m, 3 H) 3.65 (s, 2 H) 4.17 (q, J=7.1Hz, 2 H) 7.40 — 7.47 (m, 1 H) 7.51 — 7.56 (m, 1 H) 7.56 — 7.62 (m, 2 H).
Preparation 16 ethyl 2-(3-cyanophenyl)(dimethylamino)acrylate WO 60810 The title compound was prepared in a manner similar to e Preparation 10 using ethyl 2-(3 -cyanophenyl)acetate and 1,1-diethoxy-N,N—dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.12 (t, J=7.1 Hz, 3 H) 2.67 (s, 6 H) 4.00 (q, J=7.1Hz, 2 H) 7.42 — 7.45 (m, 1 H) 7.45 — 7.50 (m, 1 H) 7.53 — 7.55 (m, 1 H) 7.57 (s, 1 H) 7.64 (dt, J=7.1, 1.7 Hz, 1 H).
Preparation 17 methyl 2-(4-(methylsulfonyl)phenyl)acetate Combined 2-(4-(methylsulfonyl)phenyl)acetic acid (1 g, 4.67 mmol) in DCM (15 mL) and MeOH (5 mL) and slowly added TMS-diazomethane (2 M in hexanes) (3.50 mL, 7.00 mmol) and the on was stirred at 20°C for 3 h. The reaction was quenched with acetic acid (0.134 mL, 2.334 mmol), let stir for 15 min, then concentrated in vacuo to give the title compound which was used without r purification. MS m/z 229 [M+H]+.
Preparation 18 methyl 3-(dimethylamino)(4-(methylsulfonyl)phenyl)acrylate The title compound was prepared in a manner similar to Example Preparation 10 using methyl 2-(4-(methylsulfonyl)phenyl)acetate to give the title compound. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.68 (br. s., 6 H) 3.22 (s, 3 H) 3.53 (s, 3 H) 7.36 (d, J=8.6 Hz, 2 H) 7.61 (s, 1 H) 7.80 (d, J=8.6 Hz, 2 H).
Preparation 19 ethyl 3-(dimethylamino)(2-oxopyridin-1(2H)-yl)acrylate Combined ethyl 2-(2-oxopyridin-1(2H)-yl)acetate (500 mg, 2.76 mmol), 1,1- xy-N,N—dimethylmethanamine (2031 mg, 13.80 mmol) and DMF (2 mL) and heated at 100°C for 15 h. The reaction mixture was diluted with xylenes and concentrated onto Celite® then purified on a 30 g NH silica column (Moritex) eluted with 0 to 100% EtOAc in hexanes to give the title compound (551 mg, 85 % yield) as a light yellow solid. MS m/z 237 . 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.13 (br. s., 3 H) 2.77 (br. s., 6 H) 3.94 — 4.08 (m, 2 H) 6.17 (td, J=6.7, 1.3 Hz, 1 H) 6.36 (dt, J=9.0, 1.1 Hz, 1 H) 7.35 — 7.45 (m, 2 H) 7.47 (s, 1 H).
Preparation 20 1-(2-methoxyethyl)cyclopropanamine ed 3—methoxypropanenitrile (2.00 g, 23.50 mmol) and THF (75 mL) at 0°C then added titanium(IV) isopropoxide (7.57 mL, 25.9 mmol) followed by dropwise addition of ethylmagnesium bromide (49.4 mL, 49.4 mmol). The solution d for 30 min at 20°C and then boron trifluoride etherate (5.96 mL, 47.0 mmol) was added at 20°C (solution warmed up and turned black). The mixture stirred 40 min and was then quenched at 0°C with 12 mL 15% aqueous sodium hydroxide solution. The reaction was concentrated in vacuo to give a residue which was diluted with water to about 100 mL and extracted 6 x 100 mL with chloroform. Extracts 3-6 were dried over magnesium sulfate and concentrated in vacuo to give the title nd (1.2 g, 44% yield) as a brown oil. 1H NMR (400 MHz, chloroform-d) ppm 0.39 — 0.45 (m, 2 H) 0.53 — 0.60 (m, 2 H) 1.68 (t, J=6.4 Hz, 2 H) 3.36 (s, 3 H) 3.59 (t, J=6.4 Hz, 2 H).
Preparation 21 6-chloro-N—(3-methoxypropyl)nicotinamide Combined 6—chloronicotinic acid (6.0 g, 38.1 mmol), HOBT (2.57 g, 19.04 mmol) and EDC (10.95 g, 57.1 mmol) in CHzClz (100 mL) the Hunig’s base (9.98 mL, 57.1 mmol) and 3-methoxypropanamine (5.85 mL, 57.1 mmol) were added and stirred at 20°C for 22 h. The reaction mixture was concentrated in vacuo to give a residue which was taken up in EtOAc (250 mL) and washed with saturated aqueous ammonium chloride (250 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on an 330 g silica gel column eluted with 10 to 80% EtOAc in hexanes to give the title nd (6.6 g, 76 % yield) as a white solid. MS m/z 229, 231 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.76 (quin, J=6.7 Hz, 2 H) 3.24 (s, 3 H) 3.27 — 3.35 (m, 2 H) 3.38 (t, J=6.3 Hz, 2 H) 7.65 (dd, J=8.3, 0.8 Hz, 1 H) 8.23 (dd, J=8.3, 2.5 Hz, 1 H) 8.73 (t, J=5.3 Hz, 1 H) 8.82 (dd, J=2.5, 0.8 Hz, 1 H).
Preparation 22 6-hydrazinyl-N—(3-methoxypropyl)nicotinamide A solution of 6—chloro—N—(3—methoxypropyl)nicotinamide (6.6 g, 28.9 mmol) and ine (4.53 mL, 144 mmol) in isopropanol (100 mL) was heated at 80°C for 21 h. More hydrazine (3 mL) was added and heating continued at 80°C for 24 h. The reaction was then concentrated in vacuo to give a tan oil which was entrated from toluene to give the title compound as its hydrochloride salt as a white solid in quantitative yield. MS m/z 225 [M+H]+. 1H NMR (400 MHz, 6) 5 ppm 1.66 — 1.78 (m, 2 H) 3.18 — 3.30 (m, 5 H) 3.35 (t, J=6.3 Hz, 2 H) 6.68 (d, J=8.8 Hz, 1 H) 7.87 (dd, J=8.8, 2.3 Hz, 1 H) 7.99 (br. s., 1 H) 8.20 (t, J=5.6 Hz, 1 H) 8.49 (dd, J=2.4, 0.6 Hz, 1 H).
Preparation 23 ium 4-(ethoxycarbonyl)(5-((3- methoxypropyl)carbamoyl)pyridinyl)-1H-pyrazololate A mixture of 6-hydrazinyl-N—(3 -methoxypropyl)nicotinamide hydrochloride (7.5 g, 28.8 mmol), diethyl 2-(ethoxymethylene)malonate (14 mL, 69 mmol), and ium carbonate (9.94 g, 71.9 mmol) in water (150 mL) and ethanol (25 mL) and stirred at 25°C for 3 h and then at 60°C for 18 h. The mixture was cooled to 20°C to give a precipitate which was collected by filtration and washed with water to give the title compound (8.14 g, 73.2 % yield) as a yellow solid. MS m/z 349 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.19 (t, J=7.1 Hz, 3 H) 1.77 (quin, J=6.7 Hz, 2 H) 3.25 (s, 3 H) 3.27 — 3.34 (m, 2 H) 3.38 (t, J=6.3 Hz, 2 H) 4.02 (q, J=7.1 Hz, 2 H) 7.52 (s, 1 H) 8.10 (dd, J=8.8, 2.5 Hz, 1 H) 8.42 (dd, J=8.8, 0.5 Hz, 1 H) 8.48 (t, J=5.6 Hz, 1 H) 8.78 (dd, J=2.4, 0.6 Hz, 1 H).
Preparation 24 5-hydroxy(5-((3-methoxypropyl)carbamoyl)pyridinyl)-1H- pyrazolecarboxylate A mixture of potassium 4-(ethoxycarbonyl)(5-((3- methoxypropyl)carbamoyl)pyridinyl)-1H-pyrazololate (3.0 g, 7.76 mmol), ted aqueous um chloride (100 mL), and 4 N aqueous HCl (1.941 mL, 7.76 mmol) was stirred for 2 h to give a yellow solid. The solid was collected by filtration, rinsed with water and dried in a lyophilizer to give the title compound (2.228 g, 82 % yield) as a yellow solid.
MS m/z 349 [M+H]+.
Preparation 25 ethyl oxy(5-((3-methoxypropyl)carbamoyl)pyridinyl)- 1H-pyrazolecarboxylate [01 85] Combined ethyl 5 —hydroxy(5-((3 -methoxypropyl)carbamoyl)pyridinyl)-1H- pyrazolecarboxylate (2.2 g, 6.32 mmol), MeOH (5 mL), and DCM (50 mL) and added 2.0 M TMS-diazomethane in hexanes (4.42 mL, 8.84 mmol) (over about 10 minutes) and stirred at 20°C for 20 min. The reaction was then quenched with acetic acid (0.145 mL, 2.53 mmol) and concentrated in vacuo to give a e which was purified on an 80 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title nd (2.0 g, 87 % yield) as a white solid. MS m/z 363 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.30 (t, J=7.1 Hz, 3 H) 1.78 (quin, J=6.6 Hz, 2 H) 3.25 (s, 3 H) 3.30 — 3.37 (m, 2 H) 3.39 (t, J=6.3 Hz, 2 H) 4.14 (s, 3 H) 4.27 (q, J=7.1 Hz, 2 H) 7.79 (dd, J=8.5, 0.6 Hz, 1 H) 8.03 (s, 1 H) 8.39 (dd, J=8.5, 2.4 Hz, 1 H) 8.76 (t, J=5.6 Hz, 1 H) 8.98 (dd, J=2.4, 0.6 Hz, 1 H). ation 26 5-methoxy(5-((3 -methoxypropyl)carbamoyl)pyridinyl)-1H- pyrazolecarboxylic acid [01 87] Combined ethyl 5 —methoxy(5-((3 -methoxypropyl)carbamoyl)pyridinyl)-1H- pyrazolecarboxylate (2.4 g, 6.62 mmol) and dioxane (50 mL) and added 1.0 M aq. lithium hydroxide (29.8 mL, 29.8 mmol) and the mixture was stirred at 20°C for 2 days. The reaction was acidified with 1 N aq. HCl (30 mL) and extracted with chloroform (100 mL then 2x50 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give the title compound (2.195 g, 99 % yield) as an off—white solid. MS m/z 335 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.74 (quin, J=6.6 Hz, 2 H) 3.21 (s, 3 H) 3.30 (q, J=6.7 Hz, 2 H) 3.36 (t, J=6.3 Hz, 2 H) 4.10 (s, 3 H) 7.74 (dd, J=8.5, 0.6 Hz, 1 H) 7.94 (s, 1 H) 8.35 (dd, J=8.5, 2.4 Hz, 1 H) 8.72 (t, J=5.6 Hz, 1 H) 8.94 (dd, J=2.4, 0.6 Hz, 1 H) 12.64 (br. s., 1 Preparation 27 6-(4-bromomethoxy-1H-pyrazolyl)-N-(3- methoxypropyl)nicotinamide [01 89] Combined 5 —methoxy(5-((3 -methoxypropyl)carbamoyl)pyridinyl)-1H-pyrazole- oxylic acid (2.19 g, 6.55 mmol), NBS (1.749 g, 9.83 mmol), and sodium bicarbonate (1.651 g, 19.65 mmol) in DMF (20 mL) and stirred at 20°C for 1 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL, then 2 x 50 mL). The ed organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on a 120 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title compound (2.348 g, 97 % yield) as a white solid. MS m/z 369, 371 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.78 (quin, J=6.6 Hz, 2 H) 3.25 (s, 3 H) 3.30 — 3.37 (m, 2 H) 3.40 (t, J=6.3 Hz, 2 H) 4.05 (s, 3 H) 7.79 (dd, J=8.6, 0.5 Hz, 1 H) 7.85 (s, 1 H) 8.38 (dd, J=8.6, 2.3 Hz, 1 H) 8.74 (t, J=5.6 Hz, 1 H) 8.96 (dd, J=2.4, 0.6 Hz, 1 H).
Preparation 28 6-chloro-N-(4-cyanobenzyl)nicotinamide Combined 6—chloronicotinic acid (1.0 g, 6.35 mmol), 4—(aminomethyl)benzonitrile (1.007 g, 7.62 mmol), and EDC (1.825 g, 9.52 mmol) in methylene chloride (50 mL) then added Hunig’s base (2.328 mL, 13.33 mmol) and the mixture stirred at 20°C for 2 h. More 4— methyl)benzonitrile (250 mg), EDC (750 mg) and Hunig’s base (1 mL) was added and stirring continued for 2 days. The on was concentrated in vacuo to give a residue which was taken up in EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (100 mL) and brine, dried over magnesium e and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 0 to 80% EtOAc in hexanes to give the title compound (1.1 g, 63.8 % yield) as a white solid. MS m/z 272, 274 [M+H]+. 1H NMR (400 MHz, DMSO—dg) 5 ppm 4.58 (d, J=6.1 Hz, 2 H) 7.53 (d, J=8.6 Hz, 2 H) 7.68 (dd, J=8.3, 0.8 Hz, 1 H) 7.77 — 7.85 (m, 2 H) 8.28 (dd, J=8.3, 2.5 Hz, 1 H) 8.89 (dd, J=2.5, 0.5 Hz, 1 H) 9.40 (t, J=5.7 Hz, 1 H).
Preparation 29 N—(4-cyanobenzyl)hydrazinylnicotinamide Combined 6—chloro—N—(4—cyanobenzyl)nicotinamide (500 mg, 1.840 mmol) and hydrazine (0.578 mL, 18.40 mmol) in isopropanol (5 mL) and heated at 90°C for 5 h. The supernatant was decanted and concentrated in vacuo to give a white solid which was stirred usly with water (ca. 10 mL) for 2 hours, then was filtered and the solid dried to give the title compound (batch 1, 101 mg) as a pink solid. The fine solids from the reaction (after supernatant was removed) was stirred vigorously with water (ca. 10 mL) for 2 hours, then filtered and dried in the lyophilizer to give the title compound (batch 2, 179 mg) as a tan solid. Large solids from the reaction (after supernatant was removed) were crushed and stirred usly with water (10 mL) for 1 hour, then filtered and dried in the lizer to give the title (batch 3, 135 mg) as a beige solid. The combined yield was 415 mg (84% yield).
MS m/z 268 [M+H]+. ation 30 6-chloro-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide Combined 6—chloronicotinic acid (2.0 g, 12.69 mmol), (tetrahydro—2H-pyran—4— yl)methanamine (2.193 g, 19.04 mmol) and EDC (4.87 g, 25.4 mmol) in CHzClz (100 mL) then added Hunig’s base (6.65 mL, 38.1 mmol) and the mixture stirred at 20°C for 24 h.
More (tetrahydro-2H-pyranyl)methanamine (1 g, 0.7 , Hunig's base (2.2 mL, 1 equiv.) and DMAP (ca. 10 mg) were added and the reaction was heated at 45°C for 18 h.
More Hunig's base (3 mL) and DMAP (80 mg) was added and heating continued at 50°C for h. The reaction was then concentrated in vacuo to give a residue which was taken up in EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (100 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 0 to 100% EtOAc in hexanes then filtered and dried in the lyophilizer to give the title nd (0.985 g, 30.5 % yield) as a white solid. MS m/z 255, 257 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.12 — 1.28 (m, 2 H) 1.60 (dd, , 1.8 Hz, 2 H) 1.78 (td, J=7.4, 3.7 Hz, 1 H) 3.13 — 3.20 (m, 2 H) 3.26 (td, J=11.7, 2.1 Hz, 2 H) 3.84 (dd, J=11.4, 2.5 Hz, 2 H) 7.64 (dd, J=8.3, 0.5 Hz, 1 H) 8.23 (dd, J=8.3, 2.5 Hz, 1 H) 8.74 (t, J=5.6 Hz, 1 H) 8.82 (dd, J=2.5, 0.8 Hz, 1 H).
Preparation 31 6-hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide Combined 6-chloro-N-((tetrahydro-2H-pyranyl)methyl)nicotinamide (828 mg, 3.25 mmol) and hydrazine (0.510 mL, 16.25 mmol) in isopropanol (10 mL) and heated at 80°C for 22 h. Cool to 20°C and after 2 days a white precipitate formed and was collected by filtration, rinsed with isopropanol, and dried under vacuum to give the title compound as its HCl salt (322 mg) as a white solid. A second crop was collected from the e (500 mg). The combined yield was 822 mg (88%). MS m/z 251 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.09 — 1.26 (m, 2 H) 1.57 (dd, J=12.9, 1.8 Hz, 2 H) 1.75 (dtt, J=14.9, 7.5, 7.5, 3.4, 3.4 Hz, 1 H) 3.11 (t, J=6.3 Hz, 2 H) 3.19 — 3.31 (m, 2 H) 3.83 (dd, J=11.4, 2.5 Hz, 2 H) 4.26 (br. s., 2 H) 6.68 (d, J=8.8 Hz, 1 H) 7.87 (dd, J=8.8, 2.3 Hz, 1 H) 7.97 (s, 1 H) 8.18 (t, J=5.7 Hz, 1 H) 8.49 (d, J=1.8 Hz, 1 H).
Preparation 32 methyl 4-cyanofluorophenyl)methoxy-1H-pyrazol yl)nicotinate Combined methyl 6-(4-bromomethoxy-1H-pyrazolyl)nicotinate (1.0 g, 3.20 mmol), 3-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile (1.583 g, 6.41 mmol), dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(H) (0.209 g, 0.320 mmol) and sodium bicarbonate (1.346 g, 16.02 mmol) in dioxane (10 mL) and water (2.5 mL) and heated at 110°C for 30 min in the microwave. The reaction was diluted with EtOAc, concentrated on Celite® and purified on a 100 g NH column (Moritex) eluted with 10 to 80% EtOAc in hexanes to give the title compound (1.0 g) which was used without further purification. MS m/z 353 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 3.90 (s, 3 H) 3.92 (s, 3 H) 7.81 (dd, J=8.1, 1.8 Hz, 1 H) 7.89 — 7.98 (m, 2 H) 8.00 (dd, J=10.7, 1.6 Hz, 1 H) 8.09 (d, J=3.0 Hz, 1 H) 8.51 (dd, J=8.6, 2.3 Hz, 1 H) 9.08 (dd, J=2.3, 0.5 Hz, 1 H).
Preparation 33 6-(4-(4-cyanofluorophenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid Combined the product of the preparation above, methyl 6-(4-(4-cyano fluorophenyl)methoxy-1H-pyrazolyl)nicotinate (300 mg, 0.638 mmol) and lithium chloride (135 mg, 3.19 mmol) in ous ylpyrrolidinone (5 mL) and heated at 60°C for 16 h. Then 1.0 M aqueous lithium hydroxide (3 mL, 3.00 mmol) was added and stirred at 20°C for 4 h. The reaction mixture was then acidified with 1 N aqueous HCl (5 mL) to form a yellow itate. The precipitate was collected by filtration, rinsed with water and dried under high vacuum (ca. 10 Pa) to give the title compound containing 0.9 equiv. N— methyl—2—pyrrolidinone (230 mg, quantitative yield) as a brown solid. MS m/z 325 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 7.65 (dd, J=8.2, 1.6 Hz, 1 H) 7.80 (dd, J=11.7, 1.6 Hz, 1 H) 8.24 (br. s., 1 H) 8.38 — 8.44 (m, 1 H) 8.52 (br. s., 2 H) 8.87 — 8.94 (m, 1 H) 13.40 (br. s., 1 H). ation 34 tert-butyl 2-(4-cyanofluorophenyl)acetate Combined 4—bromo—3—fluorobenzonitrile (2.0 g, 10.00 mmol), Pd(dba)2 (0.287 g, 0.500 mmol), and 2'—(dicyclohexylphosphino)—N,N—dimethyl-[1,1'-biphenyl]amine (0.394 g, 1.000 mmol) in THF (60 mL) with nitrogen purge. Then (2-(tert-butoxy) oxoethyl)zinc(H) chloride (0.5M, 30 mL, 15.0 mmol) was added via syringe. The reaction mixture was heated in an oil bath at 50°C for 18 hours and then was ed onto silica gel (11 g) and purified by flash chromatography using an eluent of 1:1 heptane/EtOAc on an 80 g silica gel column (Single StepTM) to give a residue. The residue was dissolved in toluene (0.5 mL) and purified by flash chromatography using a gradient eluent of heptane/EtOAc (0-25% EtOAc) on an 80 g silica gel column (Single StepTM) to give the title compound (1.752 g, 74.5 % yield) as a yellow solid. 1H NMR (400 MHz, chloroform—d) 5 ppm 1.45 (s, 9 H) 3.64 (d, J=1.26 Hz, 2 H) 7.36 (dd, J=8.97, 1.39 Hz, 1 H) 7.40 (d, J=7.07 Hz, 1 H) 7.42 — 7.45 (m, 1 H). MS m/z [M+H]+ 236.1.
Preparation 35 ethyl 2-(4-cyanofluorophenyl)acetate Combined tert—butyl 2—(4—cyano—2—fluorophenyl)acetate (227.3 mg, 0.966 mmol) with EtOH (5 mL) and added a 4M hydrogen chloride solution in dioxane (0.121 mL, 0.483 mmol) and stirred in a g block at 60°C for 16 h. Then the reaction mixture was concentrated via rotary evaporation and re-constituted in EtOH (5 mL). An onal portion of a 4M hydrogen chloride solution in e (17.61 mg, 0.483 mmol) was added to the vial and the mixture was stirred at 60°C for an additional 1 h. The reaction mixture was then trated via rotary evaporation and dried in vacuo to give the title compound (198 mg, 99 % yield) as a yellow oil. 1H NMR (400 MHz, chloroform—a0 5 ppm 1.27 (t, J=7.07 Hz, 3 H) 3.72 (d, J=1.26 Hz, 2 H) 4.19 (q, J=7.24 Hz, 2 H) 7.36 — 7.40 (m, 1 H) 7.40 — 7.43 (m, 1 H) 7.43 — 7.46 (m, 1 H). MS m/z [M+H]+ 208.0.
Preparation 36 ethyl 2-(4-cyanofluorophenyl)(dimethylamino)acrylate The title compound was prepared in a manner similar to e Preparation 10 using ethyl yanofluorophenyl)acetate and 1,1-diethoxy-N,N—dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.10 (t, J=7.07 Hz, 3 H) 2.71 (br. s., 6 H) 4.00 (quin, J=6.76 Hz, 2 H) 7.37 (t, J=7.71 Hz, 1 H) 7.60 (dd, J=7.96, 1.64 Hz, 1 H) 7.64 (s, 1 H) 7.75 (dd, J=9.47, 1.64 Hz, 1 H). MS m/z [M+H]+ 236.2, 263.2.
Preparation 37 ethyl 5-hydroxy(5-(((tetrahydro-2H-pyran hyl)carbamoyl)pyridinyl)-1H-pyrazole—4-carboxylate Combined 6-hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide (1.0 g, 4.00 mmol) and potassium carbonate (2.209 g, 15.98 mmol) in water (25 mL) and added diethyl 2-(ethoxymethylene)malonate (0.807 mL, 4.00 mmol) at 23°C. The reaction mixture was stirred at 100°C for 14 hours, then 3N HCl (10 mL, 7.5 eq) was added to give a tan suspension. The solid was filtered, rinsed with water (3 x 5 mL), and dried in vacuo to give the title compound (1.114 g, 74.5 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO—dg) ppm 1.15 — 1.24 (m, 2 H) 1.26 (t, J=7.07 Hz, 3 H) 1.56 — 1.68 (m, 2 H) 1.81 (qdd, J=11.16, 11.16,11.16, 6.95, 3.79 Hz, 1 H) 3.19 (t, J=6.32 Hz, 2 H) 3.27 (td, J=11.75, 2.02 Hz, 2 H) 3.82 — 3.90 (m, 2 H) 4.18 (q, J=7.24 Hz, 2 H) 8.12 (br. s., 1 H) 8.13 — 8.24 (m, 1 H) 8.46 (dd, , 2.27 Hz, 1 H) 8.76 (t, J=5.68 Hz, 1 H) 8.89 (dd, J=2.27, 0.76 Hz, 1 H) 13.73 (br. s., 1 H). MS m/z [M+H]+ 329.3, 375.4.
Preparation 38 ethyl 5-methoxy(5-(((tetrahydro-2H-pyran yl)methyl)carbamoyl)pyridinyl)-1H-pyrazole—4-carboxylate Combined ethyl 5-hydroxy(5-(((tetrahydro-2H-pyran yl)methyl)carbamoyl)pyridinyl)-1H-pyrazole—4-carboxylate (0.6 g, 1.603 mmol), EtOAc (30 mL), and MeOH (10 mL) then added (diazomethyl)trimethylsilane, 2.0 M solution in hexanes (2.60 mL, 5.21 mmol) at 23°C over 20 minutes. The reaction mixture was stirred at 23°C for 1 hour, quenched with acetic acid (0.206 mL, 3.61 mmol), and the mixture was stirred for 2 hours at 23°C. The reaction mixture was concentrated to give an orange-brown oil which was purified by medium pressure chromatography using an eluent of 100% EtOAc on a 25 g silica gel column (Single StepTM) to give the title compound (408 mg, 65.5 % yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.16 - 1.27 (m, 2 H) 1.31 (t, J=7.07 Hz, 3 H) 1.62 (dd, J=12.88, 2.02 Hz, 2 H) 1.81 (ttd, 3, 11.13, 7.31, 7.31, 3.79 Hz, 1 H) 3.20 (t, J=6.44 Hz, 2 H) 3.27 (td, J=11.68, 2.15 Hz, 2 H) 3.85 (dt, J=9.35, 2.27 Hz, 2 H) 4.14 (s, 3 H) 4.27 (q, J=7.07 Hz, 2 H) 7.79 (dd, J=8.34, 0.76 Hz, 1 H) 8.03 (s, 1 H) 8.38 — 8.43 (m, 1 H) 8.78 (t, J=5.81 Hz, 1 H) 8.98 (dd, , 0.76 Hz, 1 H). MS m/z [M+H]+ 389.4.
Preparation 39 oxy(5-(((tetrahydro-2H-pyran yl)methyl)carbamoyl)pyridinyl)-1H-pyrazole—4-carboxylic acid Combined ethyl 5-methoxy(5-(((tetrahydro-2H-pyran yl)methyl)carbamoyl)pyridinyl)-1H-pyrazole—4-carboxylate (401 mg, 1.032 mmol), dioxane (7 mL) and 1M aqueous LiOH (5.16 mL, 5.16 mmol) at 23°C. The reaction mixture was stirred at 23°C for 3 hours, and then quenched with 1N HCl (aq.) (5.16 mL, 5.16 mmol), and concentrated via rotary evaporation to furnish an off—white suspension. The suspension was filtered, rinsed with water (5 x 3 mL), and dried in vacuo to give the title compound (339.8 mg, 91 % yield) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.16 - 1.28 (m, 2 H) 1.58 — 1.67 (m, 2 H) 1.75 — 1.88 (m, 1 H) 3.20 (t, J=6.32 Hz, 2 H) 3.27 (td, 2, 2.02 Hz, 2 H) 3.82 — 3.90 (m, 2 H) 4.14 (s, 3 H) 7.78 (dd, J=8.59, 0.76 Hz, 1 H) 7.98 (s, 1 H) 8.40 (dd, J=8.46, 2.40 Hz, 1 H) 8.78 (t, J=5.81 Hz, 1 H) 8.98 (dd, J=2.40, 0.63 Hz, 1 H) 12.68 (s, 1 H). MS m/z [M+H]+ 361.4.
Preparation 40 6-(4-bromomethoxy-1H-pyrazolyl)-N-((tetrahydro-2H-pyran yl)methyl)nicotinamide Combined 5-methoxy(5-(((tetrahydro-2H-pyranyl)methyl)carbamoyl)pyridin yl)—1H—pyrazole—4—carboxylic acid (329.5 mg, 0.914 mmol) and sodium bicarbonate (307 mg, 3.66 mmol) in DMF (3 mL) then added 1-bromopyrrolidine-2,5-dione (163 mg, 0.914 mmol) at 23°C. The reaction mixture was stirred at 23°C for 30 minutes and then diluted with water (15 mL) to give a suspension. The suspension was filtered, rinsed with water (3 x 5 mL), and dried in vacuo to give the title compound (302 mg, 84 % yield) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.15 — 1.28 (m, 2 H) 1.62 (dd, J=12.88, 1.77 Hz, 2 H) 1.80 (dddt, 8, 11.12, 7.39, 3.44, 3.44 Hz, 1 H) 3.16 — 3.23 (m, 2 H) 3.23 — 3.31 (m, 2 H) 3.81 — 3.89 (m, 2 H) 4.05 (s, 3 H) 7.79 (dd, J=8.59, 0.76 Hz, 1 H) 7.84 (s, 1 H) 8.38 (dd, J=8.46, 2.40 Hz, 1 H) 8.75 (t, J=5.81 Hz, 1 H) 8.96 (dd, J=2.53, 0.76 Hz, 1 H). MS m/z [M+H]+ 395.3, 397.3.
Preparation 41 ethyl ethylamino)(pyridinyl)acrylate Combined ethyl 2-(pyridinyl)acetate (0.927 mL, 6.05 mmol) and 1,1-diethoxy- N,N—dimethylmethanamine (5.19 mL, 30.3 mmol) in DMF (3.03 mL) and heated to 100°C for 6 hours. The reaction mixture was concentrated, diluted with 50 mL dichloromethane, and washed twice with 50 mL water. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to give a residue which was purified on a 60 g NH silica gel column eluted with hexanes and EtOAc to give the title compound (1.333 g, 76%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) 5 ppm 1.13 (t, J=7.1 Hz, 3 H) 2.67 (s, 6 H) 4.06 (q, J=7.1Hz, 2 H) 6.98 — 7.12 (m, 2 H) 7.56 (s, 1 H) 8.29— 8.53 (m, 2 H). ation 42 tert-butyl 2-(4-cyano-2 yphenyl)acetate Combined (2-(tert-butoxy)oxoethyl)zinc(H) chloride (4.24 mL, 2.122 mmol) and 4—bromo-3 -methoxybenzonitrile (0.30g, 1.42 mmol) in THF (4.29 mL), then 2'- (dicyclohexylphosphino)-N,N—dimethyl-[1,1'-biphenyl]amine (0.056 g, 0.141 mmol) and Pd(dba)2 (0.041 g, 0.071 mmol) were added and the on was refluxed at 100°C overnight. The reaction mixture was concentrated down by rotary evaporation and purified on a silica gel column eluting with hexanes and EtOAc to give the title compound as a yellow oil (102 mg, 29%). MS m/z [M+H]+ 248.
Preparation 43 ethyl yanomethoxyphenyl)(dimethylamino)acrylate Combined tert-butyl 2-(4-cyanomethoxyphenyl)acetate (549 mg, 2.218 mmol) and 4N HCl in e (0.277 mL, 1.109 mmol) in ethanol (7.4 mL) and stirred for 16 hours at 60°C. The reaction was concentrated by rotary evaporation and then combined with ethyl 2— nomethoxyphenyl)acetate (0.486 g, 2.217 mmol) and 1,1-diethoxy-N,N— dimethylmethanamine (1.9 mL, 11.08 mmol) in DMF (4.43 mL) and stirred for 16 hours at 100°C. The reaction mixture was diluted with 200 mL EtOAc and washed twice with 200 mL water. Organic layer was dried with sodium sulfate and concentrated to give a residue which was purified on a 60 g NH silica gel column eluting with hexanes and EtOAc to give the title compound (405 mg, 74%).
Preparation 44 tert-butyl 2-(2-chlorocyanophenyl)acetate Combined 4—bromo—3—chlorobenzonitrile (0.600 g, 2.77 mmol) and (2—(tert—butoxy)—2— oxoethyl)zinc(H) chloride (8.32 mL, 4.16 mmol) in THF (5.54 mL), then Pd(dba)2 (0.080 g, 0.139 mmol) and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]amine (0.109 g, 0.277 mmol) were added and the reaction was refluxed overnight at 65°C. The reaction was concentrated by rotary evaporation and purified on a silica gel column g with hexanes and EtOAc to give the title compound (274 mg, 39%) as a yellow oil. MS m/z [M+H]+ 252.
Preparation 45 ethyl 2-(2-chlorocyanophenyl)(dimethylamino)acrylate Combined tert-butyl 2-(2-chlorocyanophenyl)acetate (274 mg, 1.089 mmol) and 4N HCl in dioxane (0.136 mL, 0.544 mmol) in ethanol (2.51 mL). The mixture was stirred for 16 hours at 60°C, then concentrated by rotary evaporation and combined with ethyl 2-(2- chlorocyanophenyl)acetate (0.243 g, 1.086 mmol) and 1,1-diethoxy-N,N- dimethylmethanamine (0.931 mL, 5.43 mmol) in DMF (2.173 mL) and stirred for 16 hours at 100°C. The reaction was concentrated in rotary evaporation and ed on a NH silica gel column eluting with hexanes and EtOAc to give the title compound (164 ) as a yellow oil. 1H NMR (400 MHz, chloroform-d) 5 ppm 1.04 - 1.29 (m, 1 H) 3.96 - 4.31 (m, 1 H) 7.38 (d, J=7.8 Hz, 1 H) 7.49 (dd, J=7.8, 1.8 Hz, 1 H) 7.63— 7.71 (m, 1 H).
Preparation 46 1-(tetrahydro-2H-pyranyl)cyclopropanamine Combined tetrahydro-2H-pyrancarbonitrile (1.000 g, 9.00 mmol) and titanium (IV)isopropoxide (2.90 mL, 9.90 mmol) in ether (45.0 mL), then ethylmagnesium e (6.60 mL, 19.79 mmol) was added and the reaction was d to warm to room temperature for 1 hour. The reaction was stirred for an additional 30 minutes and boron trifluoride etherate (2.280 mL, 18.0 mmol) was added and the reaction was stirred for 2 hours. The reaction was then diluted with 10 mL water and 20 mL 1 N HCl and ted twice with 200 mL EtOAc. The organic layers were ed and concentrated to afford the title nd (850 mg, 53.5%) as a yellow oil.
Preparation 47 6-(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazol yl)nicotinic acid Combined ethyl 2-(4-cyanomethoxyphenyl)(dimethylamino)acrylate (1.427 g, .20 mmol), 6-hydrazinylnicotinic acid (0.664 g, 4.34 mmol), and HCl (4.34 mL, 4.34 mmol) in 2-propanol (21.7 mL) and stirred at room temperature for 8 hours to give a solid. The solid was ted by ion and combined with Hunig’s base (1.50 mL, 8.61 mmol) in 2- propanol (10 mL) and water (1 mL) and stirred for 32 hours at 50°C, then 10 mL of 1 N HCl was added and the reaction was filtered to give a solid. The solid was washed with 30 mL MeOH and 30 mL of ether and dried in vacuo to give the title compound (708 mg, 73.3%) as a beige solid. MS m/z [M+H]+ 337.3.
Preparation 48 N—benzylchloronicotinamide Combined 6-chloronicotinic acid (20 g, 12.74 mmol) and HATU (72.6 g, 19.1 mmol) in DMF (200 mL) and added triethylamine (38.6 g, 38.2 mmol) drop wise, followed by benzylamine (16.36 g, 15.28 mmol) and stirred at room temperature overnight. Then the on mixture was poured into ter and stirred for 20 minutes to give a solid. The solid was collected by filtration, washed with water (30 mLx2), and dried under d pressure to give the title compound (20 g, 64%) as a yellow solid.
Preparation 49 N—benzylhydrazinylnicotinamide ed N—benzyl—6—chloronicotinamide (13 g, 52.8 mmol) and ethanol (60 mL) then added hydrazine hydrate (85%, 30 mL) drop wise at room temperature. After the addition, the solution was heated to reflux overnight. The reaction mixture was then concentrated to remove ethanol and a solid was obtained. The solid was collected by filtration, washed with EtOAc (3x20 mL), and dried under reduced pressure to give the title compound (10 g, 78%) as an off—yellow solid.
Preparation 50 ethyl 2-(4-cyanophenyl)(dimethylamino)acrylate Combined ethyl 2-(4-cyanophenyl)acetate (25 g, 0.132 mol) with A (60 mL) and heated to 70°C for 3 hours. The reaction e was cooled to room temperature and concentrated and then purified by flash chromatography to give the title compound (20 g, 62%) as a solid. 1H NMR (400 MHz, DMSO—dg) 5 ppm 7.71 (d, J=8.4Hz, 2H), 7.59 (s, 1H), 7.29 (d, J=8.4Hz, 2H), 4.03 (q, J=6.8Hz, 2H), 2.67 (s, 6H), 1.13 (t, J=6.8Hz, 3H).
Preparation 51 5-bromohydrazinylmethylpyridine Combined 5—bromo—2—chloro—4—methylpyridine (15.0 g, 72.46 mmol) and EtOH (60 mL) and added hydrazine hydrate (85%, 45 mL) and stirred at 120°C overnight. The reaction mixture was concentrated to give a residue which was extracted with EtOAc (50 mLx2) and water (50 mLx2). Then ed organic layers were extracted with brine, dried over NaZSO4 to and concentrated to give a residue which was purified by flash chromatography (petroleum ether: EtOAc =10:1 tol:5) to give the title compound (7.8 g, 53%).
Preparation 52 4-(1-(5-bromomethylpyridinyl)hydroxy-1H-pyrazol zonitrile Combined 5—bromohydrazinylmethylpyridine (6.0 g, 29.85 mmol) and isopropanol (100 mL) and added ethyl 2-(4-cyanophenyl)-3 -(dimethylamino)acrylate (8.02 g, 32.84 mmol) and HCl on (aqueous, 1.85%, 49.75 mL) and stirred at room temperature for 2h, then DIEA (19.40 g, 149.25 mmol) was added. After about 30 minutes the reaction was ated to give a residue which was ted with EtOAc (50 mLx2) and water (50 mLx2), the EtOAc layers were combined and washed with brine, dried over NaZSO4 to give a residue which was purified by flash chromatography (petroleum ether: EtOAc 5: 1-1 :8) to give the title compound (8.67 g, 82.04%).
Preparation 53 4-(1-(5-bromomethylpyridinyl)((2- (trimethylsilyl)ethoxy)methoxy)-1H-pyrazolyl)benzonitrile ed 4-(1-(5-bromomethylpyridinyl)hydroxy-1H-pyrazol yl)benzonitrile (8.67 g, 24.49 mmol), THF (100 mL), (trimethylsilyl)ethoxy)methyl chloride (8.91 g, 48.98 mmol), and triethylamine (7.42 g, 73.47 mmol) and stir at room temperature for 3h. The reaction e was then evaporated in vacuum to give a residue which was extracted with EtOAc (100 mLx2) and water (100 mLx2), the EtOAc layers were washed with brine, dried over , evaporated to give a residue whish was purified by flash chromatography on silica gel (petroleum ether: EtOAc 10: 1-1 :3) to give the title compound (10.5 g, 88.2%).
Preparation 54 methyl 6-(4-(4-cyanophenyl)((2-(trimethylsilyl)ethoxy)methoxy)- 1 H-pyrazolyl)methylnicotinate Combined 4-(1-(5-bromomethylpyridinyl)((2- (trimethylsilyl)ethoxy)methoxy)-1H-pyrazolyl)benzonitrile (10.0 g, 20.66 mmol), DMF (60 mL) and MeOH(60 mL) then added ylamine (6.26 g, 61.98 mmol) and Pd(dppf)C12 (756.2 mg, 1.033 mmol). The mixture was stirred at 120°C under 1 MPa of CO overnight.
Then the reaction mixture was evaporated in vacuum to give a residue which was combined with water, filtered, and the aqueous was extracted with EtOAc (100 mLx2). The combined EtOAc layers were washed with brine and dried (NaZSO4), and concentrated to give the title compound (8.67 g).
Preparation 55 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)methylnicotinic acid Combined methyl 6-(4-(4-cyanophenyl)((2-(trimethylsilyl)ethoxy)methoxy)-1H- pyrazolyl)methylnicotinate (8.67 g, 25.96 mmol), ol (50 mL), water (50 mL) and LiOH (3.27 g, 77.87 mmol). The reaction mixture was stirred at room temperature for 6h and at 50°C overnight. The reaction mixture was concentrated to remove most of the methanol and then the pH was ed to 3 by addition of 3N HCl to give a solid. The solid was collected by filtration and dried in vacuum to give the title compound (4.3 g, 51.76%).
Preparation 56 ethyl 2-(4-cyanophenyl)acetate Combined ethyl 2-(4-bromophenyl)acetate (30 g, 0.123 mol) and NMP (200 mL).
Then CuCN (33 g, 0.370 mol) was added in ns and then degassed and d with nitrogen three times. Then CuI (4.7 g, 0.0247mol) was added in one portion. The reaction was degassed and refilled with nitrogen three times and then heated to 160°C for 4 hours.
Then the reaction was heated to 180°C for another 3 hours. The solution was then cooled to room ature and diluted with EtOAc (500 mL) and water (500 mL). After stirring for 10 mins, the reaction was d and the aqueous layer was extracted with EtOAc (500 mLx2).
The combined organic layers were washed with brine, dried over NaZSO4 and concentrated to dryness to give the title compound (31 g, 66.5%) as a brown solid. ation 57 N—benzylchloronicotinamide Combined 6—chloronicotinoyl chloride (1.76 g, 10.00 mmol) and DCM (20 mL) and cooled in an ice-bath then triethylamine (2.09 mL, 15.0 mmol) and phenylmethanamine (1.072 g, 10.00 mmol) were added. The reaction was then d at room temperature for 3 hours before being diluted in DCM (30ml), washed with 1N aqueous HCl (50ml), saturated s sodium bicarbonate (50ml), brine (50ml), dried over NaZSO4, and concentrated to give the title compound (2.19g, 89%) as a light beige solid which was used without further purification. MS m/z [M+H]+ 247.1.
Preparation 58 N—benzylhydrazinylnicotinamide Combined hydrazine (1.67 mL, 53.3 mmol) and a on of N—benzyl chloronicotinamide (2.19 g, 8.88 mmol) in ethanol (70 mL) and heated overnight at 100°C.
The reaction mixture was then cooled and evaporated to give a solid. The solid was collected by filtration, washed with 70 mL water, and recrystallized from hot ethanol to give the title compound (1.32g, 61%) as an off—white solid. MS m/z [M+H]+ 243.2.
Preparation 59 methyl 3-(dimethylamino)(pyridinyl)acrylate ed of N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.15 mL, 1.000 mmol), methyl 2-(pyridinyl)acetate (1g, 6.62 mmol), and N,N—dimethylformamide dimethyl acetal (3.9 mL, 29.1 mmol) and heated at 115°C overnight. The reaction mixture was then cooled and partitioned between 12 mL of saturated aqueous ammonium chloride and 12 mL of EtOAc. The organic layer was separated, dried over NazSO4, and concentrated to give the title compound as a dark oil which was used as is in the next step without further ation. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.73 (s, 1 H), 2.64 (brs, 6 H), 3.50 (s, 6H), 7.16 (dd, J=6.95, 5.43 Hz, 1 H), 7.26 (dt, J=7.83, 1.01 Hz, 1 H), 7.54 (s, 1 H), 7.65 (td, J=7.71, 1.77 Hz, 1 H), 8.49 (d, J=4.04 Hz, 1 H). MS m/z [M+H]+ 207.1 Preparation 60 Ethyl 2-(5-cyanopyridinyl)—3-(dimethylamino)acrylate Combined ethyl 2(4-cyanophenyl)acetate (513 mg) and N,N—dimethylformamide yl acetal (323 mg) and heated at 80°C overnight. The reaction mixture was evaporated to give a residue which was dissolved in diethyl ether (20ml) and extracted with water (10ml), brine , the dried with , and evaporated to give the title compound (537mg) as a beige solid. 1H NMR (400 MHz, chloroform-a0 5 ppm 1.20 (t, J=7.07 Hz, 3 H), 2.62 — 2.77 (m, 6 H), 4.13 (q, J=7.07 Hz, 2 H), 7.29 (d, J=8.59 Hz, 2 H), 7.56 (d, J=8.59 Hz, 2 H).
Preparation 61 ethyl 3-(2-(4-(benzylcarbamoyl)phenyl)hydrazinyl)—2-(4- cyanophenyl)acrylate ed N—benzylhydrazinylnicotinamide (126 mg, 0.520 mmol) and ethyl 2-(4- cyanophenyl)(dimethylamino)acrylate (127 mg, 0.520 mmol) in ethanol (10 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to give a residue which was dissolved in DCM (100ml), extracted with saturated s sodium bicarbonate (50ml), dried with NazSO4, and concentrated to a residue which was purified by chromatography (12g SiOz, DCM—MeOH 0 to 10%) to give the title compound (90mg, 39%) as an oil. MS m/z [M+H]+ 442.4.
Preparation 62 methyl 3-(2-(4-(benzylcarbamoyl)phenyl)hydrazinyl)(pyridin yl)acrylate Combined N—benzyl—6-hydrazinylnicotinamide (200mg, 0.826 mmol), methyl 3- (dimethylamino)(pyridinyl)acrylate (170 mg, 0.826 mmol) and TFA (0.127 mL, 1.651 mmol) in ethanol (3 mL) and stirred overnight at room temperature. The reaction mixture was diluted in EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (20ml), brine (20ml), dried with NazSO4 and trated to give the title compound (244mg) as an orange solid, was used t further purification. MS m/z [M+H]+ 404.4.
Preparation 63 tert-butyl 3-(cyclobutyl(methyl)amino)azetidinecarboxylate Combined a solution of utyl 3—oxoazetidine-1—carboxylate (500 mg, 2.92 mmol) and N—methylcyclobutanamine (0.373 mL, 3.50 mmol) in methylene chloride (15 mL) and added sodium triacetoxyborohydride (929 mg, 4.38 mmol) and the solution stirred at 20°C for 3 h. The solution was concentrated in vacuo to give a white solid. The solid was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate, and concentrated in vacuo to give a residue which was purified on a 40 g silica gel column eluted with 0 to 70% ethyl acetate in hexanes to give the title compound (342 mg, 1.423 mmol, 48.7 %) as a clear, colorless oil. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 1.43 (s, 9 H) 1.60 — 1.75 (m, 2 H) 1.85 — 2.04 (m, 4 H) 2.07 (s, 3 H) 2.81 — 2.94 (m, 1 H) 3.27 — 3.30 (m, 1 H) 3.81 — 3.88 (m, 2 H) 3.88 — 3.97 (m, 2 H); MS: 241 (M+H).
Preparation 64 N-cyclobutyl-N—methylazetidinamine Combined a solution of tert—butyl lobutyl(methyl)amino)azetidine—1— carboxylate (285 mg, 1.186 mmol) in methylene chloride (6 mL) and added 4 M HCl in dioxane (1.186 mL, 4.74 mmol) and the solution stirred at 20°C for 30 h. The solution was concentrated in vacuo and concentrated from heptane/methylene chloride to give the title compound as a hydrochloride acid salt (191 mg, 0.896 mmol, 76 %) as a light yellow solid which was used without further purification. ation 65 tert-butyl 3-(cyclopropyl(methyl)amino)azetidinecarboxylate Combined a solution of tert—butyl 3-oxoazetidine—1—carboxylate (175 mg, 1.022 mmol) and N—methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution d at 20°C for 30 min. The solution was trated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with ted sodium bicarbonate (50 mL) and brine, dried with ium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3 %) as a clear, ess oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL—d4) 5 ppm 0.41 — 0.47 (m, 2 H) 0.48 — 0.56 (m, 2 H) 1.43 (s, 9 H) 1.64 (tt, J=6.7, 3.9 Hz, 1 H) 2.28 (s, 3 H) 3.50 (tt, J=7.5, 5.7 Hz, 1 H) 3.84 — 4.01 (m, 4 Preparation 66 N—cyclopropyl-N—methylazetidin-3 -amine Combine a solution of tert—butyl 3—(cyclopropyl(methyl)amino)azetidine-1— carboxylate (73 mg, 0.323 mmol) in methylene chloride (3 mL) and 4 M HCl in dioxane (0.323 mL, 1.290 mmol) and the solution d at 20°C for 4 hours then added 4 M HCl in dioxane (0.323 mL, 1.290 mmol) and stirred at 20°C for 21 h. The solution was then concentrated in vacuo to give the title compound as a hydrochloride salt which was used without further ation.
Preparation 67 tert-butyl 6,6-difiuoromethyl-1,4-diazepanecarboxylate Combined tert—butyl 6,6—difiuoro—1,4—diazepane-1—carboxylate (49 mg, 0.207 mmol) and sodium cyanoborohydride (52 mg, 0.83 mmol) in THF (1.5 mL) and added 37% aqueous formaldehyde (0.077 mL, 1.037 mmol) and acetic acid (0.018 mL, 0.311 mmol) and then stirred at 20°C for 16 h. Then methanol (300 uL) was added and the mixture was trated in vacuo to give a residue which was taken up in ethyl acetate (40 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo to give the title compound (51 mg, 0.204 mmol, 98 %) as a clear, colorless oil. MS: 251 (M+H). 1H NMR (400 MHz, CHLOROFORM—d) 5 ppm 1.46 (s, 9 H) 2.50 (s, 3 H) 2.73 (d, J=4.8 Hz, 2 H) 2.92 (t, J=13.5 Hz, 2 H) 3.55 (d, J=4.8 Hz, 2 H) 3.75 — 3.94 (m, 2 H). ation 68 6,6-difiuoromethyl-1,4-diazepane Combined a solution of tert—butyl 6,6—difluoro—4—methyl—1,4—diazepane—1—carboxylate (50 mg, 0.200 mmol) in dichloromethane (2 mL) and 4 M HCl in dioxane (0.4 mL, 1.6 mmol) and the solution stirred at 20°C for 21 h. The reaction was then trated in vacuo to give the title compound as a hydrochloride acid salt which was used t r purification. MS: 151 (M+H).
Preparation Methyl 2-(4-cyanofiuoromethylphenyl)acetate Combined 4—bromo—2—fiuoro—5—methylbenzonitrile (4 g, 18.69 mmol) and dimethyl malonate (29.9 mL, 262 mmol). While purging the e with nitrogen, added potassium carbonate (3.87 g, 28.0 mmol), ium hydrogencarbonate (2.81 g, 28.0 mmol), tri—tert- butylphosphonium tetrafiuoroborate (0.119 g, 0.411 mmol), and bis(dibenzylidineacetone)palladium (0) (0.118 g, 0.206 mmol). The reaction mixture was heated in an oil bath at 170 °C for 3 hours, then cooled, diluted with ethyl acetate, and filtered through Celite®. The filtrate was concentrated and the residue dissolved in EtOAc, extracted with 1M aqueous sodium ide (2x), twice with 10% aqueous sodium chloride, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo, then purified by flash chromatography to give the title nd (1.67 g, 43%) as a clear ess oil. 1H NMR (400 MHz, CHLOROFORM—aO 5 ppm 2.30 (s, 3 H) 3.67 (s, 2 H) 3.72 (s, 3 H) 7.10 (d, J=9.60 Hz, 1 H) 7.42 (d, J=6.32 Hz, 1 H).
Preparation 69 methyl 2-(4-cyanofluoromethylphenyl)acetate Combine 4—bromo—2—fluoro—3 —methylbenzonitrile (2 g, 9.34 mmol), yl malonate (12.28 mL, 107 mmol), potassium carbonate (1.937 g, 14.02 mmol) and potassium hydrogencarbonate (1.403 g, 14.02 mmol). Nitrogen gas was bubbled through this mixture vigorously for 1 minute and then tri—tert—butylphosphonium tetrafluoroborate (0.030 g, 0.103 mmol), and bis(dibenzylidineacetone)palladium (0) (0.027 g, 0.047 mmol) were added. The on mixture was then heated in an oil bath (170°C) and stirred for 1 hour, then cooled to ambient temperature and diluted with EtOAc (80 mL). The EtOAc layer was decanted and passed through a plug of Celite® (~7 cm wide and 1.5 cm thick). The chunky dark precipitate that was left in the flask was diluted with additional EtOAc portions and sonicated until a fine sion ed. The EtOAc ates were also passed through the Celite® plug. The combined organics from filtration were concentrated in vacuo at ~40°C and then at 90°C for 45 minutes to give a e. The residue was purified using flash column chromatography to give the title compound (1.05 g, 5.07 mmol, 54.2 %) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM—aO 5 ppm 2.17 (d, J=2.27 Hz, 3 H) 3.63 (s, 3 H) 3.91 (s, 2 H) 7.29 (d, J=8.08 Hz, 1 H) 7.71 (t, J=7.33 Hz, 1 H) Preparation 70 methyl 2-(4-cyanofluoromethylphenyl)—3- (dimethylamino)acrylate Combined methyl 2-(4-cyanofluoromethylphenyl)acetate (5.00 g, 24.13 mmol), 1,1-dimethoxy-N,N—dimethylmethanamine (32.2 mL, 241 mmol), and lithium chloride (0.102 g, 2.413 mmol) and heated to 105°C. After 2 hours the reaction mixture was concentrated in vacuo and repeatedly diluted with EtOAc (30 mL) and concentrated to give an oil. The oil was dissolved in EtOAc (50 mL) and washed with water, 10% aqueous sodium chloride, and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford a thick red oil, which was crystallized to give the title compound as a yellow solid (6.1 g, 23.26 mmol, 96 %).1H NMR (400 MHz, DMSO—d6) 5 ppm 2.10 (s, 3 H) 2.34 (s, 1 H) 2.54 — 2.81 (m, 6 H) 3.50 (s, 3 H) 7.20 (d, J=10.11Hz, 1 H) 7.58 (s, 1 H) 7.72 (d, J=7.07 Hz, 1 H).
ESI—MS m/z [M+H]+ 263.2.
Preparation 71 6-(4-(4-cyanofluoromethylphenyl)hydroxy-1H-pyrazol yl)nicotinic acid 2014/031918 Combined 6-hydrazinylnicotinic acid (1.10 g, 7.18 mmol), methyl 2-(4-cyano fluoromethylphenyl)(dimethylamino)acrylate (2.072 g, 7.90 mmol), 2-propanol (18 mL), and 0.5M aqueous hydrochloric acid (17.24 mL, 8.62 mmol). After 2 hours, l—N— isopropylpropanamine (6.26 mL, 35.9 mmol) was added. After another hour the on mixture was diluted with water and washed twice with IPAc. The aqueous phase was acidified to ~pH= 3.5 and stirred for 30 minutes to give a solid which was collected by filtration, washed with water, ethanol, and heptanes, and dried overnight under vacuum to give the title nd (1.60 g, 66%). 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.34 (d, J=2.27 Hz, 3 H) 7.64 (d, J=8.08 Hz, 1 H) 7.69 — 7.80 (m, 1 H) 8.26 (br. s., 1 H) 8.48 (br. s., 2 H) 8.98 (t, J=1.52 Hz, 1 H) 13.45 (br. s., 2 H). EST—MS m/z [M+H]+ 339.2.
Preparation 72 6-(4-(4-cyanofluoromethylphenyl)hydroxy-1H-pyrazol yl)nicotinic acid Combined 6-hydrazinylnicotinic acid (0.73 g, 4.77 mmol), methyl 2-(4-cyano fluoromethylphenyl)(dimethylamino)acrylate (1.375 g, 5.24 mmol), 2-propanol (18 mL), and 0.5M aqueous hydrochloric acid (11.44 mL, 5.72 mmol). After 2 hours, N—ethyl-N— isopropylpropanamine (4.15 mL, 23.83 mmol). After an hour the reaction e was diluted with water and washed with IPAc twice. The aqueous phase was acidified to ~pH= 3.5 and stirred for 30 minutes to give a solid which was collected by filtration, washed with water, ethanol, and heptanes, and dried overnight under vacuum to give the title compound (1.20 g, 74%). 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.41 (s, 3 H) 7.74 (d, J=7.07 Hz, 1 H) 7.91 (d, J=11.62 Hz, 1 H) 8.26 (s, 1 H) 8.37 — 8.47 (m, 1 H) 8.47 — 8.56 (m, 1 H) 8.96 (dd, J=2.15, 0.88 Hz, 1 H). EST—MS m/z [M+H]+ 339.2.
Preparation 73 methyl 2-(4-cyanofluoromethylphenyl)acetate Combined 4—bromo—2—fluoro—5—methylbenzonitrile (4 g, 18.69 mmol) and dimethyl malonate (29.9 mL, 262 mmol) and purged with nitrogen. Potassium carbonate (3.87 g, 28.0 mmol), potassium hydrogencarbonate (2.81 g, 28.0 mmol), tri-tert—butylphosphonium tetrafluoroborate (0.119 g, 0.411 mmol), and benzylidineacetone)palladium(0) (0.118 g, 0.206 mmol) were added. The on mixture was then heated in an oil bath at 170 0C.
After 3 hours, the reaction mixture was cooled, diluted with ethyl acetate, and filtered through Celite®. The filtrate was trated and the residue dissolved in EtOAc. The organic solution was washed with 1N aqueous sodium hydroxide (2x), twice with 10% aqueous sodium chloride, and then brine. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give a e which was purified by flash chromatography to give the title compound (1.67 g, 43%) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM—aO 5 ppm 2.30 (s, 3 H) 3.67 (s, 2 H) 3.72 (s, 3 H) 7.10 (d, J=9.60 Hz, 1 H) 7.42 (d, J=6.32 Hz, 1 H).
Preparation 74 methyl 2-(4-cyanofluoromethylphenyl)acetate Combined o—2—fluoro—3 —methylbenzonitrile (2 g, 9.34 mmol), dimethyl malonate (12.28 mL, 107 mmol), potassium ate (1.937 g, 14.02 mmol) and potassium hydrogencarbonate (1.403 g, 14.02 mmol). Purged with en for 1 min and then tri-tert- butylphosphonium tetrafluoroborate (0.030 g, 0.103 mmol), and bis(dibenzylidineacetone)palladium (0) (0.027 g, 0.047 mmol) were added. The reaction was placed in a pre-heated oil bath (170°C). After 1 hour the mixture was cooled to ambient temperature and d with EtOAc (80 mL). The EtOAc layer was decanted and passed h a plug of Celite® (~7 cm wide and 1.5 cm thick). The chunky dark precipitate that was left in the flask was diluted with additional EtOAc portions and sonicated until a fine suspension resulted. The EtOAc triturates were also passed h the Celite® plug and then concentrated in vacuo at ~40°C and then at 90°C for 45 minutes to give a residue which was purified using flash column chromatography to give the title compound (1.05 g, 5.07 mmol, 54.2 %) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-aO 5 ppm 2.17 (d, J=2.27 Hz, 3 H) 3.63 (s, 3 H) 3.91 (s, 2 H) 7.29 (d, J=8.08 Hz, 1 H) 7.71 (t, J=7.33 Hz, 1 H).
Preparation 75 methyl 2-(4-cyanofluoromethylphenyl)—3- (dimethylamino)acrylate Combined methyl 2-(4-cyanofluoromethylphenyl)acetate (10.0 g, 48.3 mmol), 1,1-dimethoxy-N,N—dimethylmethanamine (17.25 g, 145 mmol), and solid lithium chloride (0.205 g, 4.83 mmol) and heated to 105 °C for 1.5h. The mixture was cooled to 10 °C and water (210 mL) was added slowly. The solid was collected by vacuum filtration, dissolved in DCM and was purified by column chromatography to afford the title compound (7.95 g, 63%) as a pale yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.07 (d, J=2.53 Hz, 3 H) 2.54 — 2.86 (m, 6 H) 3.50 (s, 3 H) 7.10 (d, J=7.83 Hz, 1 H) 7.62 (s, 1 H) 7.63 — 7.66 (m, 1 H).
ESI—MS m/z [M+H]+ 263.2.
Preparation 76 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile In a microwave tube, combined Pd2(dba)3 (0.070 g, 0.077 mmol) and tricyclohexylphosphine (0.103 g, 0.367 mmol). Dioxane (15.32 ml) was added and the resulting e was stirred for 30 minutes at room temperature. Bis(pinacolato)diboron (1.425 g, 5.61 mmol), potassium acetate (0.751 g, 7.65 mmol) and 4—bromo—2— methylbenzonitrile (1 g, 5.10 mmol) were added successively. The tube was flushed with nitrogen. Then the reaction mixture was stirred in microwave at 100°C for 1 hour. The mixture was treated with water (26 mL), and extracted with ether. The c layer was washed with brine, dried over sodium sulfate, and concentrated to give the title compound (1.55 g) which was used in next step without further purification.
Example 1 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)—N—((tetrahydro- anyl)methyl)nicotinamide Combined 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid (30 mg, 0.096 mmol), EDCI (27.6 mg, 0.144 mmol), HOBT (19.47 mg, 0.144 mmol), and DMF (961 [11), then added (tetrahydro-2H-pyranyl)methanamine (17.66 [11, 0.144 mmol) and Hunig’s base (68.3 [11, 0.384 mmol) and stirred at room temperature overnight. The reaction mixture was purified via preparative HPLC to give the title compound (32.1 mg, 82%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) 5 ppm 1.35 (qd, 8, 4.55 Hz, 2 H) 1.71 (d, J=12.88 Hz, 2 H) 1.84 — 1.99 (m, 1 H) 3.42 (td, J=11.68, 1.64 Hz, 2 H) 3.95 (d, J=3.28 Hz, 1 H) 3.98 (s, 3 H) 4.19 (s, 3 H) 7.76 (d, J=6.57 Hz, 1 H) 7.84 (s, 1 H) 8.03 (d, J=6.57 Hz, 1 H) 8.28 — 8.47 (m, 2 H) 8.55 (br. s., 1 H) 8.85 (br. s., 1 H). MS m/z [M+H]+ 410.1.
Example 2 N—benzyl(5-hydroxy(2-methoxypyridinyl)-1H-pyrazol yl)nicotinamide ©/\HN \ I OH / _, N [ii]: \ /N The title compound was prepared in a manner similar to e 1 using phenylmethanamine. 1H NMR (400 MHz, methanol-d4) 5 ppm 4.20 (s, 3 H) 4.59 (s, 2 H) 7.20 — 7.48 (m, 5 H) 7.72 — 7.95 (m, 2 H) 8.04 (d, J=6.32 Hz, 1 H) 8.24 — 8.75 (m, 3 H) 8.90 (br. s., 1 H), MS m/z [M+H]+ 402.1.
Example 3 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- (methoxymethyl)cyclopentyl)nicotinamide 2014/031918 H3C_O\7O HO / N HN I <3me :‘ \ N CH3 The title compound was prepared in a manner similar to Example 1 using 1- (methoxymethyl)cyclopentanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.51 — 1.80 (m, 6 H) 2.00 — 2.11 (m, 2 H) 3.27 (s, 3 H) 3.60 (s, 2 H) 3.91 (s, 3 H) 7.39 — 7.65 (m, 2 H) 8.01 — 8.19 (m, 2 H) 8.43 (br. s., 2 H) 8.68 (br. s., 1 H) 8.86 (t, J=1.52 Hz, 1 H). MS m/z [M+H]+ 424.3.
Example 4 ydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- methylcyclopropyl)nicotinamide )‘Qndj/Q/\N The title compound was prepared in a manner similar to Example 1 using 1- methylcyclopropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.61 — 0.68 (m, 2 H) 0.74 — 0.80 (m, 2 H) 1.39 (s, 3 H) 3.91 (s, 3 H) 7.41 — 7.65 (m, 2 H) 8.09 (d, J=5.81Hz, 1 H) 8.31 — 8.52 (m, 2 H) 8.69 (s, 1 H) 8.82 — 8.97 (m, 2 H). MS m/z [M+H]+ 366.2.
Example 5 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N— isopropy|_1lnicotinamide H3:>—CH3 HO :N / H3 HO)—QNN: The title compound was prepared in a manner similar to Example 1 using amine. MS m/z [M+H]+ 354.2.
Example 6 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N— isobutylnicotinamide NH \ H3O!0W1} I CHso The title compound was prepared in a manner similar to Example 1 using 2- methylpropan-l-amine. MS m/z [M+H]+ 368.3. e 7 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(2- isopropoxyethyl)nicotinamide H3o—<:H_3> O twill; The title compound was prepared in a manner similar to Example 1 using 2- isopropoxyethanamine. MS m/z [M+H]+ 398.3.
Example 8 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N— nicotinamide ”O \ / O,oH3 H3C—/—NH \—N, N: The title compound was ed in a manner similar to Example 1 using propan amine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.92 (t, J=7.45 Hz, 3 H) 1.44 — 1.68 (m, 2 H) 3.14 — 3.34 (m, 2 H) 3.93 (s, 3 H) 7.46 — 7.70 (m, 2 H) 8.10 (d, J=5.81 Hz, 1 H) 8.35 — 8.59 (m, 2 H) 8.61 — 8.80 (m, 2 H) 8.82 — 8.99 (m, 1 H). MS m/z [M+H]+ 354.2.
Example 9 6-(5-hydroxy(2-methoxypyridinyl)—1H-pyrazolyl)-N—((1s,4s)—4- methoxycyclohexyl)nicotinamide O,CH3 H3C\ HO : [‘1 O N N The title compound was prepared in a manner similar to Example 1 using (1s,4s) methoxycyclohexanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.36 — 1.74 (m, 6 H) 1.89 (dd, J=9.09, 4.04 Hz, 2 H) 3.23 (s, 3 H) 3.32 — 3.44 (m, 1 H) 3.72 — 4.09 (m, 4 H) 7.44 — 7.66 (m, 2 H) 8.09 (d, J=5.81 Hz, 1 H) 8.36 — 8.57 (m, 3 H) 8.68 (br. s., 1 H) 8.90 (s, 1 H). MS m/z [M+H]+ 424.2.
Example 10 (S)—N—(sec-butyl)(5-hydroxy(2-methoxypyridinyl)—1H-pyrazol- 1-yl)nicotinamide H30>—/C3H HOW? The title compound was prepared in a manner similar to Example 1 using (S)-butan amine. MS m/z [M+H]+ 368.2.
Example 1 1 6-(5 xy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(2- (tetrahydro-2H-pyranyl)ethyl)nicotinamide OC>_> / N Hm?/ The title compound was prepared in a manner similar to Example 1 using 2- (tetrahydro-2H-pyranyl)ethanamine. MS m/z [M+H]+ 424.3.
Example 12 N—(3-ethoxypropyl)—6-(5-hydroxy(2-methoxypyridinyl)-1H- pyrazolyl)nicotinamide ,CHs H3C 0 \—\¥N)I—I—<f>il_lNON:/ / N The title compound was prepared in a manner similar to Example 1 using 3- propan-l-amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.11 (t, J=6.95 Hz, 3 H) 1.69 — 1.84 (m, 2 H) 3.31 — 3.37 (m, 3 H) 3.40 — 3.45 (m, 3 H) 3.85 (s, 3 H) 7.33 — 7.56 (m, 2 H) 8.05 (d, J=5.56 Hz, 1 H) 8.27 — 8.80 (m, 4 H) 8.84 — 8.98 (m, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 398.3. e 13 N—cyclobutyl(5-hydroxy(2-methoxypyridinyl)—1H-pyrazol yl)nicotinamide ,CH3 HO /\ O \ O \ / Nx / NH N N The title compound was prepared in a manner similar to Example 1 using cyclobutanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.63 - 1.77 (m, 2 H) 2.04 - 2.18 (m, 2 H) 2.19 — 2.30 (m, 2 H) 4.02 (s, 3 H) 4.35 — 4.52 (m, 1 H) 7.63 — 7.85 (m, 2 H) 8.14 (d, J=6.32 Hz, 1 H) 8.32 — 8.68 (m, 2 H) 8.70 — 9.13 (m, 3 H) MS m/z [M+H]+ 366.2.
Example 14 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—((1- (methoxymethyl)cyclopropyl)methyl)nicotinamide WWW/E / HO [I \ / ./ O N N The title compound was prepared in a manner similar to Example 1 using (1- (methoxymethyl)cyclopropyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.31 — 0.48 (m, 2 H) 0.50 — 0.62 (m, 2 H) 3.23 — 3.27 (m, 4 H) 3.35 (d, J=6.06 Hz, 2 H) 3.86 (s, 3 H) 7.34 — 7.58 (m, 2 H) 8.06 (d, J=5.56 Hz, 1 H) 8.35 — 8.72 (m, 4 H) 8.84 — 8.97 (m, 1 H) 8.90 (s, 1H) 13.51 (hrs, 1 H). MS m/z [M+H]+ 410.3.
Example 15 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N— (tetrahydro-2H-pyranyl)nicotinamide /CH3 / \N O N ‘N’ The title compound was prepared in a manner similar to e 1 using ydro- 2H-pyranamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.49 — 1.68 (m, 2 H) 1.80 (dd, J=12.51, 2.40 Hz, 2 H) 3.37 — 3.44 (m, 2 H) 3.82 — 3.95 (m, 5 H) 3.96 — 4.10 (m, 1 H) 7.35 — 7.59 (m, 2 H) 8.06 (d, J=5.56 Hz, 1 H) 8.33 — 8.78 (m, 4 H) 8.86 — 8.97 (m, 1 H) 13.55 (br. s., 1 H). MS m/z [M+H]+ 396.2.
Example 16 (5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- (tetrahydro-2H-pyranyl)ethyl)nicotinamide ,CH3 0 O Ho \N NH \ H3C \ / N O N N The title compound was prepared in a manner similar to Example 1 using (S) (tetrahydro-2H-pyranyl)ethanamine. 1H NMR (400 MHz, 6) 5 ppm 1.14 (s, 3 H) 1.18 — 1.32 (m, 2 H) 1.55 — 1.74 (m, 3 H) 3.19 — 3.30 (m, 2 H) 3.79 — 3.96 (m, 6 H) 7.27 — 7.66 (m, 2 H) 8.06 (d, J=5.30 Hz, 1 H) 8.22 — 8.82 (m, 4 H) 8.84 — 8.97 (m, 1 H) 13.53 (br. s., 1 H).
MS m/z [M+H]+ 424.3.
Example 17 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- methoxymethylpropanyl)nicotinamide /CH3 H39 / N WANWNO HO \ H30 \ 0 N ‘N/ The title compound was prepared in a manner r to Example 1 using 1-methoxy- 2-methylpropanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.30 — 1.41 (m, 6 H) 3.29 (s, 3 H) 3.48 — 3.61 (m, 2 H) 3.78 — 3.93 (m, 3 H) 7.36 — 7.44 (m, 1 H) 7.46 — 7.53 (m, 1 H) 7.95 (s, 1 H) 8.05 (d, J=5.56 Hz, 1 H) 8.30 — 8.68 (m, 3 H) 8.84 (d, J=1.52 Hz, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 398.3.
Example 18 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- (piperidinyl)propyl)nicotinamide \—\_ / H0 \ 0%NH — ‘N/ The title compound was ed in a manner similar to Example 1 using 3- (piperidinyl)propanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.28 - 1.48 (m, 1 H) 1.54 — 1.75 (m, 3 H) 1.75 — 1.88 (m, 2 H) 1.88 — 2.01 (m, 2 H) 2.88 (br. s., 2 H) 3.03 — 3.19 (m, 2 H) 3.32 — 3.50 (m, 4 H) 7.80 (d, J=8.59 Hz, 2 H) 8.15 (d, J=8.08 Hz, 2 H) 8.37 — 8.81 (m, 3 H) 8.82 — 8.98 (m, 2 H) 9.15 (br. s., 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 431.2.
Example 19 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- (pyrrolidinyl)propyl)nicotinamide WO 60810 0 CH3 N\—\> / HO P NH \ O N N The title nd was prepared in a manner similar to Example 1 using 3- (pyrrolidin-l-yl)propanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.71 - 2.21 (m, 6 H) 3.01 (br. s., 2 H) 3.14 — 3.26 (m, 2 H) 3.38 (q, J=6.57 Hz, 2 H) 3.56 (br. s., 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.15 (d, J=8.08 Hz, 2 H) 8.37 — 8.58 (m, 2 H) 8.67 (br. s., 1 H) 8.86 (t, J=5.56 Hz, 1 H) 8.90 — 8.97 (m, 1 H) 9.63 (br. s., 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 417.2.
Example 20 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3-(2- oxopyrrolidinyl)propyl)nicotinamide Q ,CH3 /{\l O N ‘N The title compound was prepared in a manner similar to Example 1 using 1-(3- aminopropyl)pyrrolidinone. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.74 (quin, J=7.07 Hz, 2 H) 1.87 — 1.99 (m, 2 H) 2.17 — 2.28 (m, 2 H) 3.20 — 3.31 (m, 4 H) 3.33 — 3.41 (m, 2 H) 7.80 (d, J=8.34 Hz, 2 H) 8.02 — 8.86 (m, 6 H) 8.87 — 8.99 (m, 1 H) 13.55 (br. s., 1 H). MS m/z [M+H]+ 431.1.
Example 21 N—(3-(1H-imidazolyl)propyl)(5-hydroxy(2-methoxypyridin yl)-1H-pyrazolyl)nicotinamide N/x O/ 3 \—\_ HO /[\‘ NH \ \ / NV O N N The title compound was prepared in a manner similar to Example 1 using 3-(1H- imidazol—l—yl)propan—1—amine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.11 (quin, J=6.76 Hz, 2 H) 3.32 (q, J=6.40 Hz, 2 H) 4.28 (t, J=6.95 Hz, 2 H) 7.69 (t, J=1.52 Hz, 1 H) 7.75 — 7.87 (m, 3 H) 8.15 (d, J=8.59 Hz, 2 H) 8.41 (dd, J=8.84, 2.27 Hz, 1 H) 8.50 (d, J=8.08 Hz, 1 H) 8.68 (s, 1 H) 8.82 (br. s., 1 H) 8.88 — 8.96 (m, 1 H) 9.11 (s, 1 H) 13.95 (br. s., 1 H). MS m/z [M+H]+ 414.1.
Example 22 thylpiperidinyl)(5-hydroxy(2-methoxypyridinyl)—1H- pyrazolyl)nicotinamide H3C\_0w HO \ / N1 O N N The title compound was prepared in a manner r to Example 1 using 1- ethylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.20 (t, J=7.33 Hz, 3 H) 1.69 — 2.08 (m, 4 H) 2.86 — 3.25 (m, 4 H) 3.45 (br. s., 2 H) 3.89 — 4.19 (m, 1 H) 7.73 (d, J=8.34 Hz, 2 H) 8.05 — 8.79 (m, 5 H) 8.84 — 8.99 (m, 1 H) 9.77 — 10.36 (m, 1 H) 13.47 (br. s., 1 H). MS m/z [M+H]+ 417.
Example 23 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(2-(1- methylpyrrolidinyl)ethyl)nicotinamide xCH3 121 / HO ‘N NH \ O N N The title compound was ed in a manner similar to Example 1 using 2-(1- methylpyrrolidinyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.59 — 2.06 (m, 4 H) 2.10 — 2.25 (m, 1 H) 2.28 — 2.42 (m, 1 H) 2.65 — 2.94 (m, 3 H) 3.00 — 3.13 (m, 1 H) 3.22 — 3.46 (m, 3 H) 3.52 — 3.63 (m, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.15 (d, J=7.58 Hz, 2 H) 8.30 — 8.77 (m, 3 H) 8.78 — 9.00 (m, 2 H) 9.63 (br. s., 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 417.
Example 24 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- propylpiperidinyl)nicotinamide MI0:WHNON: The title compound was prepared in a manner similar to Example 1 using 1- propylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.91 (t, J=7.45 Hz, 3 H) 1.23 (br. 5., 1 H) 1.54 — 1.84 (m, 4 H) 1.95 — 2.08 (m, 2 H) 2.75 — 3.03 (m, 3 H) 3.34 — 3.48 (m, 2 H) 4.02 (br. 5., 1 H) 7.53 (d, J=8.59 Hz, 2 H) 7.99 (d, J=8.59 Hz, 3 H) 8.18 (dd, J=8.84, 2.27 Hz, 1 H) 8.43 (br. 5., 1 H) 8.58 (d, J=8.84 Hz, 1 H) 8.81 (d, J=2.02 Hz, 1 H). MS m/z [M+H]+437.
Example 25 6-(5-hydr0xy(2-meth0xypyridinyl)-1H-pyrazolyl)-N—(2- hydroxyethyl)nic0tinamide 0C3,H 0 HO / N HOfNWN /\ I \ \ H N The title compound was ed in a manner similar to Example 1 using 2- amin0ethanol. 1H NMR (400 MHz, DMSO—dg) 5 ppm 3.30 (q, J=5.89 Hz, 2 H) 3.42 — 3.55 (m, 2 H) 3.94 (s, 3 H) 7.52 — 7.73 (m, 2 H) 8.06 (d, J=6.06 Hz, 1 H) 8.35 — 8.52 (m, 2 H) 8.67 — 8.83 (m, 2 H) 8.85 — 8.93 (m, 1 H). MS m/z [M+H]+ 356.1. e 26 6-(5-hydr0xy(2-meth0xypyridinyl)-1H-pyrazolyl)-N—(3- hydroxypropyl)nic0tinamide O,CH3 O HO / \ IN MNWN \H \ The title compound was prepared in a manner similar to Example 1 using 3- amin0pr0panol. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.70 (quin, J=6.63 Hz, 2 H) 3.35 (q, J=6.74 Hz, 2 H) 3.48 (t, J=6.19 Hz, 2 H) 3.92 (s, 3 H) 7.39 — 7.69 (m, 2 H) 8.09 (d, J=5.81 Hz, 1 H) 8.34 — 8.57 (m, 2 H) 8.72 (d, J=7.58 Hz, 2 H) 8.90 (t, J=1.39 Hz, 1 H). MS m/z [M+H]+ 370.2.
Example 27 N—(2-hydr0xy(tetrahydr0furanyl)ethyl)(5-hydr0xy(2- methoxypyridinyl)-1H-pyrazolyl)nicotinamide /CH3 HO HO ’2 O O N N The title compound was prepared in a manner similar to Example 1 using 2-amino (tetrahydrofuranyl)ethanol. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.52 - 1.73 (m, 1 H) 1.85 — 2.06 (m, 1 H) 3.37 — 3.82 (m, 7 H) 3.86 (s, 3 H) 3.93 — 4.03 (m, 1 H) 4.78 (br. s., 1 H) 7.08 — 7.70 (m, 2 H) 8.06 (d, J=5.05 Hz, 1 H) 8.18 — 8.85 (m, 4 H) 8.91 (dt, J=5.56, 1.39 Hz, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+426. e 28 ydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(4- hydroxybutyl)nicotinamide \ O/CH3 NH HO / omN \\ N \ The title compound was prepared in a manner similar to Example 1 using 4- aminobutan-l-ol. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.42 - 1.62 (m, 4 H) 3.24 - 3.34 (m, 2 H) 3.43 (t, J=6.44 Hz, 2 H) 3.85 (s, 3 H) 4.43 (br. s., 1 H) 7.30 — 7.55 (m, 2 H) 8.05 (d, J=5.56 Hz, 1 H) 8.23 — 8.82 (m, 4 H) 8.84 — 8.96 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+3 84.2.
Example 29 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3-(2- methylpiperidinyl)propyl)nicotinamide /CH3 00H. / N Ho \ N\_/—NH \ o N N The title compound was ed in a manner similar to Example 1 using 3-(2- methylpiperidinyl)propanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.16 — 1.36 (m, 3 H) 1.40 — 2.03 (m, 8 H) 2.82 — 3.52 (m, 7 H) 3.83 — 4.03 (m, 3 H) 7.37 — 7.73 (m, 2 H) 8.10 (d, J=4.80 Hz, 1 H) 8.31 — 8.81 (m, 3 H) 8.92 (br. s., 2 H) 9.07 — 9.42 (m, 1 H). MS m/z [M+H]+451.2.
Example 30 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—((1- methylpiperidinyl)methyl)nicotinamide ICH3 N O Q / HO \N NH \ \ / N\ / O N N The title compound was prepared in a manner similar to Example 1 using (1- methylpiperidinyl)methanamine1H NMR (400 MHz, DMSO—dg) 5 ppm 1.38 (d, J=12.88 Hz, 2 H) 1.81 (d, J=3.54 Hz, 1 H) 1.91 (d, J=13.64 Hz, 2 H) 2.76 (d, J=4.55 Hz, 3 H) 2.85 — 2.97 (m, 2 H) 3.23 (t, J=6.32 Hz, 2 H) 3.44 (d, 3 Hz, 2 H) 3.88 (s, 3 H) 7.35 — 7.61 (m, 2 H) 8.07 (d, J=5.81Hz, 1 H) 8.23 — 8.73 (m, 3 H) 8.79 (t, J=5.68 Hz, 1 H) 8.86 — 8.95 (m, 1 H) 9.12 (br. s., 1 H). MS m/z [M+H]+423.2.
Example 31 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(2-(1- methylpyrrolidinyl)ethyl)nicotinamide Ox / N HO \ N NH \ O N ‘N The title compound was prepared in a manner similar to Example 1 using 3-(1- methylpyrrolidinyl)propanamine1H NMR (400 MHz, DMSO-d6) 5 ppm 1.60 — 1.81 (m, 2 H) 1.85 — 2.06 (m, 2 H) 2.11 — 2.23 (m, 1 H) 2.28 — 2.41 (m, 1 H) 2.84 (d, J=4.80 Hz, 3 H) 3.00 — 3.13 (m, 1 H) 3.22 — 3.35 (m, 1 H) 3.40 (q, J=6.32 Hz, 2 H) 3.58 (dd, 9, 7.96 Hz, 1 H) 3.91 (s, 3 H) 7.40 — 7.64 (m, 2 H) 8.09 (d, J=5.81Hz, 1 H) 8.35 — 8.56 (m, 2 H) 8.68 (s, 1 H) 8.78 — 8.99 (m, 2 H) 9.61 (br. s., 1 H). MS m/z 423.2.
Example 32 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- morpholinopropyl)nicotinamide O ,CH \—\_ HO [‘1 NH \ \ / N. / O N N The title compound was prepared in a manner similar to Example 1 using 3- morpholinopropan-l-amine1H NMR (400 MHz, DMSO—dg) 5 ppm 1.89 — 2.00 (m, 2 H) 3.09 (br. s., 2 H) 3.16 — 3.24 (m, 2 H) 3.33 — 3.51 (m, 4 H) 3.65 (t, J=12.00 Hz, 2 H) 3.92 (s, 3 H) 3.99 (d, J=11.62 Hz, 2 H) 7.44 — 7.68 (m, 2 H) 8.10 (d, J=5.81Hz, 1 H) 8.36 — 8.57 (m, 2 H) 8.71 (s, 1 H) 8.80 — 9.01 (m, 2 H) 9.78 (br. s., 1 H). MS m/z [M+H]+439.2.
Example 33 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- methylpiperidinyl)nicotinamide ,CH3 Ho \N H3C—NC>7NH \ O N N The title compound was prepared in a manner similar to Example 1 using 1- methylpiperidinamine1H NMR (400 MHz, 6) 5 ppm 1.68 — 2.00 (m, 2 H) 2.08 (s, 2 H) 2.70 — 2.88 (m, 3 H) 3.01 — 3.24 (m, 2 H) 3.50 (d, J=12.13 Hz, 2 H) 3.95 (s, 3 H) 3.99 — 4.11 (m, 1 H) 7.49 — 7.70 (m, 2 H) 8.11 (d, J=5.81Hz, 1 H) 8.40 — 8.53 (m, 2 H) 8.67 — 8.83 (m, 2 H) 8.84 — 8.98 (m, 1 H) 9.64 (br. s., 1 H). MS m/z [M+H]+409.2.
Example 34 N—ethyl(5-hydroxy(2-methoxypyridinyl)-1H-pyrazol yl)nicotinamide O/ 3 Ho \N /—NH \ H3C WM O N N The title compound was prepared in a manner r to Example 1 using ethanamine hloride 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.16 (t, J=7.20 Hz, 3 H) 3.22 — 3.39 (m, 2 H) 3.90 (s, 3 H) 7.28 — 7.72 (m, 2 H) 8.08 (d, J=5.56 Hz, 1 H) 8.31 — 8.84 (m, 4 H) 8.91 (s, 1 H). MS m/z [M+H]+340.2.
Example 35 N—(3-(1H-imidazolyl)propyl)(5-hydroxy(2-methoxypyridin yl)—1H-pyrazolyl)nicotinamide /CH3 NS / HO [‘1 N \ JWN:NH _ O N N The title compound was prepared in a manner similar to Example 1 using 3-(1H- imidazolyl)propanamine 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.02 - 2.18 (m, 2 H) 3.32 (q, J=6.48 Hz, 2 H) 3.92 (s, 3 H) 4.29 (t, J=6.95 Hz, 2 H) 7.54 (s, 1 H) 7.60 (d, J=5.81 Hz, 1 H) 7.72 (t, J=1.64 Hz, 1 H) 7.85 (t, J=1.64 Hz, 1 H) 8.10 (d, Hz, 1 H) 8.37 — 8.56 (m, 2 H) 8.71 (s, 1 H) 8.84 (t, J=5.68 Hz, 1 H) 8.91 (dd, J=2.27, 0.76 Hz, 1 H) 9.16 (t, J=1.26 Hz, 1 H). MS m/z [M+H]+420.2.
Example 36 6-(5-hydr0xy(2-meth0xypyridinyl)-1H-pyrazolyl)—N—((1- methylpyrrolidin-3 -yl)methyl)nicotinamide /CH3 H3C\N HO \ NH \ \ / N O N N The title compound was prepared in a manner similar to Example 1 using (1- methylpyrrolidinyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.57 — 2.29 (m, 3 H) 2.76 — 3.22 (m, 5 H) 3.32 — 3.73 (m, 4 H) 3.89 — 4.01 (m, 3 H) 7.45 — 7.71 (m, 2 H) 8.11 (d, J=6.06 Hz, 1 H) 8.32 — 8.59 (m, 2 H) 8.72 (s, 1 H) 8.81 — 9.01 (m, 2 H) 9.90 (br. s., 1 H). MS m/z [M+H]+409.2.
Example 37 N—(l-ethylpiperidinyl)(5-hydr0xy(2-meth0xypyridinyl)—1H- pyrazolyl)nicotinamide ,CH3 Ho «N FONH \ H3C WM / o N N The title nd was prepared in a manner similar to Example 1 using 1- ethylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.19 — 1.33 (m, 3 H) 1.69 — 2.15 (m, 4 H) 2.98 — 3.32 (m, 4 H) 3.34 — 3.64 (m, 2 H) 3.93 (s, 3 H) 3.99 — 4.25 (m, 1 H) 7.45 — 7.67 (m, 2 H) 8.10 (d, J=5.81Hz, 1 H) 8.37 — 8.82 (m, 4 H) 8.86 — 8.97 (m, 1 H) 9.29 (br. s., 1 H). MS m/z [M+H]+423.2.
Example 38 6-(5-hydr0xy(2-meth0xypyridinyl)-1H-pyrazolyl)-N—(3- idinyl)pr0pyl)nicotinamide O ,CH3 \—\— / HO ’Z NH \ O N N The title compound was prepared in a manner similar to Example 1 using 3- (piperidin-l-yl)propanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.38 (dd, J=12.25, 3.66 Hz, 1 H) 1.55 — 1.74 (m, 3 H) 1.82 (d, J=14.15 Hz, 2 H) 1.88 — 1.99 (m, 2 H) 2.79 — 2.96 (m, 2 H) 3.11 (dt, J=10.67, 5.15 Hz, 2 H) 3.28 — 3.52 (m, 4 H) 3.93 (s, 3 H) 7.45 — 7.70 (m, 2 H) 8.10 (d, J=5.81 Hz, 1 H) 8.35 — 8.57 (m, 2 H) 8.71 (s, 1 H) 8.82 — 8.99 (m, 2 H) 9.14 (br. s., 1 H). MS m/z [M+H]+437.2.
Example 39 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- (pyrrolidinyl)propyl)nicotinamide O CH3 \—\_ / HO \N NH \ _/ \ N\ / The title compound was ed in a manner r to Example 1 using 3- (pyrrolidin-l-yl)propanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.79 — 2.07 (m, 6 H) 2.93 — 3.07 (m, 2 H) 3.21 (dt, J=10.42, 5.53 Hz, 2 H) 3.32 — 3.43 (m, 2 H) 3.57 (dd, J=10.48, .18 Hz, 2 H) 3.93 (s, 3 H) 7.42 — 7.71 (m, 2 H) 8.10 (d, J=5.81 Hz, 1 H) 8.33 — 8.57 (m, 2 H) 8.72 (s, 1 H) 8.80 — 8.99 (m, 2 H) 9.65 (br. s., 1 H). MS m/z [M+H]+423.2.
Example 40 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N— methylnicotinamide ,CH3 HO \ H3C-NH \ \ / Nx / 0 N N The title compound was prepared in a manner similar to Example 1 using amine hydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.83 (d, J=4.55 Hz, 3 H) 3.95 (s, 3 H) 7.58 (s, 1 H) 7.65 (d, J=5.81 Hz, 1 H) 8.12 (d, J=5.81 Hz, 1 H) 8.38 — 8.52 (m, 2 H) 8.66 — 8.80 (m, 2 H) 8.90 (d, J=1.01 Hz, 1 H). MS m/z [M+H]+326.1.
Example 41 N—(l-cyclopropylpiperidinyl)(5-hydroxy(2-methoxypyridin yl)-1H-pyrazolyl)nicotinamide O/ 3 HO {\1 wow \ \ / N\ / O N N The title compound was prepared in a manner similar to Example 1 using 1- cyclopropylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.74 - 1.02 (m, 3 H) 2.08 (s, 5 H) 2.72 — 2.99 (m, 1 H) 3.58 (br. s., 4 H) 3.92 (s, 3 H) 4.01 — 4.27 (m, 1 H) 7.45 — 7.65 (m, 2 H) 8.10 (d, J=5.56 Hz, 1 H) 8.37 — 8.81 (m, 4 H) 8.90 (s, 2 H). MS m/z 435.2.
Example 42 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- (methylamino)propyl)nicotinamide ,CHs HO «N H3C—NH NH \ O N N The title compound was ed in a manner similar to Example 1 using N1- methylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.75 — 1.93 (m, 2 H) 2.59 (t, J=5.43 Hz, 3 H) 2.90 — 3.01 (m, 2 H) 3.37 (q, J=6.57 Hz, 2 H) 3.88 (s, 3 H) 7.38 — 7.60 (m, 2 H) 8.07 (d, J=5.56 Hz, 1 H) 8.21 — 8.79 (m, 5 H) 8.85 (t, J=5.68 Hz, 1 H) 8.89 — 8.99 (m, 1 H). MS m/z [M+H]+383.2.
Example 43 N—(3-(1H-pyrazolyl)propyl)—6-(5-hydroxy(2-methoxypyridinyl)— azolyl)nicotinamide /CH3 CN / HO \N N \ \_/_NH _ / N. / oniN The title compound was prepared in a manner similar to Example 1 using 3-(1H- pyrazolyl)propanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.97 - 2.12 (m, 2 H) 3.28 (q, J=6.74 Hz, 2 H) 3.93 (s, 3 H) 4.20 (t, J=6.95 Hz, 2 H) 6.17 — 6.31 (m, 1 H) 7.41 — 7.48 (m, 1 H) 7.50 — 7.67 (m, 2 H) 7.74 — 7.81 (m, 1 H) 8.10 (d, J=5.81Hz, 1 H) 8.32 — 8.57 (m, 2 H) 8.63 — 8.85 (m, 2 H) 8.87 — 8.95 (m, 1 H). MS m/z [M+H]+420.2.
Example 44 N—(3-(dimethylamin0)pr0pyl)(5 -hydr0xy(2-meth0xypyridinyl)- 1H-pyrazolyl)nicotinamide /CH3 CH3 HO «N H3C—N’ \ \_/_w“NH _ O N N The title compound was prepared in a manner similar to e 1 using N1,N1- dimethylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.77 — 1.98 (m, 2 H) 2.80 (d, J=4.29 Hz, 6 H) 3.13 (dt, J=10.23, 4.99 Hz, 2 H) 3.37 (q, J=6.32 Hz, 2 H) 3.90 (s, 3 H) 7.40 — 7.66 (m, 2 H) 8.08 (d, J=5.81Hz, 1 H) 8.33 — 8.57 (m, 2 H) 8.68 (s, 1 H) 8.77 — 9.01 (m, 2 H) 9.54 (br. s., 1 H). MS m/z [M+H]+397.3.
Example 45 ydr0xy(2-meth0xypyridinyl)—1H-pyrazolyl)-N—((1R,2S)—2- (methoxymethyl)cycl0pentyl)nic0tinamide ,CH3 HO \ \/N.Z\/ The title compound was prepared in a manner similar to Example 1 using (1R,2S)—2- (methoxymethyl)cyclopentanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.43 - 1.59 (m, 2 H) 1.61 — 1.82 (m, 3 H) 1.87 — 1.99 (m, 1 H) 2.24 — 2.35 (m, 1 H) 3.19 (s, 3 H) 3.20 — 3.24 (m, 1 H) 3.40 (dd, J=9.35, 6.06 Hz, 1 H) 3.92 (s, 3 H) 4.43 (dt, J=14.78, 7.26 Hz, 2 H) 7.52 (s, 1 H) 7.59 (d, J=5.56 Hz, 1 H) 8.10 (d, J=5.81Hz, 1 H) 8.32 (d, J=8.08 Hz, 1 H) 8.38 — 8.55 (m, 2 H) 8.69 (s, 1 H) 8.80 — 8.98 (m, 1 H). MS m/z [M+H]+424.2. e 46 6-(5-hydr0xy(2-meth0xypyridinyl)-1H-pyrazolyl)—N—((4- methylmorpholinyl)methyl)nicotinamide O,CH3 HO \N 0 ”WV/ i \ v O N N The title compound was prepared in a manner r to Example 1 using (4- methylmorpholinyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.76 - 2.92 (m, 4 H) 2.97 — 3.10 (m, 1 H) 3.34 — 3.54 (m, 4 H) 3.68 (t, J=11.87 Hz, 1 H) 3.82 — 3.90 (m, 4 H) 4.07 (dd, J=12.76, 2.65 Hz, 1 H) 7.30 — 7.69 (m, 2 H) 8.07 (d, J=5.56 Hz, 1 H) 8.31 — 8.56 (m, 2 H) 8.65 (s, 1 H) 8.85 — 9.06 (m, 2 H) 10.08 (br. s., 1 H). MS m/z 425.2.
Example 47 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—((1- (methoxymethyl)cyclopentyl)methyl)nicotinamide IO NH \ OWM / [0428] N N The title compound was prepared in a manner similar to Example 1 using (1- (methoxymethyl)cyclopentyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.30 — 1.67 (m, 8 H) 3.19 (s, 2 H) 3.24 — 3.37 (m, 5 H) 3.92 (s, 3 H) 7.41 — 7.66 (m, 2 H) 8.09 (d, J=5.81Hz, 1 H) 8.35 — 8.56 (m, 3 H) 8.69 (s, 1 H) 8.82 — 8.94 (m, 1 H). MS m/z [M+H]+438.2.
Example 48 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide ,CH3 Q HO /\N \N/ \/ O N The title compound was prepared in a manner similar to Example 1 using (tetrahydro- anyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.11 - 1.28 (m, 1 H) 1.37 — 1.54 (m, 3 H) 1.64 (d, J=12.88 Hz, 1 H) 1.72 — 1.86 (m, 1 H) 3.20 — 3.51 (m, 4 H) 3.81 — 4.02 (m, 4 H) 7.57 (s, 1 H) 7.64 (dd, J=5.94, 0.88 Hz, 1 H) 8.11 (d, J=5.81Hz, 1 H) 8.47 (s, 2 H) 8.73 (s, 1 H) 8.82 (t, J=5.81 Hz, 1 H) 8.92 (t, J=1.52 Hz, 1 H). MS m/z [M+H]+410.2.
Example 49 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- methoxymethylpropyl)nicotinamide ,CH3 H3C_O CH3 / N HO \ NH \ \ / N. / 0 N N The title compound was ed in a manner similar to Example 1 using 3-methoxy- 2-methylpropanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.91 (d, J=6.82 Hz, 3 H) 1.94 — 2.08 (m, 1 H) 3.08 — 3.36 (m, 7 H) 3.92 (s, 3 H) 7.53 (s, 1 H) 7.60 (d, J=5.81Hz, 1 H) 8.09 (d, J=5.81Hz, 1 H) 8.36 — 8.52 (m, 2 H) 8.61 — 8.74 (m, 2 H) 8.86 — 8.93 (m, 1 H). MS m/z [M+H]+398.2.
Example 50 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- methoxybutyl)nicotinamide /CH3 HO «N H3C O>_/—NH \ \_/ N\ : H3C o N N The title compound was prepared in a manner similar to Example 1 using 3- methoxybutan-l-amine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.11 (d, J=6.06 Hz, 3 H) 1.55 — 1.80 (m, 2 H) 3.24 (s, 3 H) 3.30 — 3.43 (m, 3 H) 3.92 (s, 3 H) 7.42 — 7.65 (m, 2 H) 8.09 (d, J=5.81Hz, 1 H) 8.35 — 8.53 (m, 2 H) 8.58 — 8.76 (m, 2 H) 8.85 — 8.94 (m, 1 H). MS m/z [M+H]+398.2. e 5 1 N—(1-(dimethylamino)—2-methylpropanyl)(5 xy(2- methoxypyridinyl)-1H-pyrazolyl)nicotinamide ,CH3 H3C CH3 HO \ H3Q fNH \ ,N \ / N. / H3C O N N The title compound was prepared in a manner similar to Example 1 using N1,N1,2- trimethylpropane-1,2-diamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.47 (s, 6 H) 2.86 (s, 6 H) 3.65 (br. s., 2 H) 3.89 (s, 3 H) 7.40 — 7.63 (m, 2 H) 8.07 (d, J=5.56 Hz, 1 H) 8.32 — 8.52 (m, 3 H) 8.66 (s, 1 H) 8.84 — 8.95 (m, 1 H) 9.24 (br. s., 1 H). MS m/z [M+H]+411.2.
Example 52 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—((1s,4s) methylcyclohexyl)nicotinamide O/CHs HO {\1 H3c—<:><NH \ \ / N\ / O N N The title compound was prepared in a manner r to Example 1 using (1s,4s)—4- methylcyclohexanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.89 (d, J=6.57 Hz, 3 H) 0.94 — 1.10 (m, 2 H) 1.36 (qd, J=12.51, 3.16 Hz, 3 H) 1.71 (d, J=11.87 Hz, 2 H) 1.78 — 1.95 (m, 2 H) 3.74 (dtd, J=11.68, 7.74, 7.74, 3.92 Hz, 1 H) 3.92 (s, 3 H) 7.45 — 7.65 (m, 2 H) 8.09 (d, J=5.81Hz, 1 H) 8.35 — 8.54 (m, 3 H) 8.68 (s, 1 H) 8.88 (t, J=1.52 Hz, 1 H). MS m/z [M+H]+408.2.
Example 53 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- cyclopropylethyl)nicotinamide Aflnfi OH Combined HOBT (66.2 mg, 0.490 mmol) and EDCI (94 mg, 0.490 mmol), a solution 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (100 mg, 0.327 mmol, in DMF (1 mL)) and Hunig’s base (169 mg, 1.306 mmol) in DMF (1 mL). Then 2- cyclopropylethanamine (41.7 mg, 0.490 mmol) was added and the reaction was stirred at t temperature for 14h. The reaction mixture was diluted with MeOH (2 mL) and water (3 mL) and ed to pH 4 using 1 N HCl to give a solid which were collected by filtration and recrystallized from MeOH to give the title compound as a solid. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.01 — 0.14 (m, 2 H) 0.35 — 0.49 (m, 2 H) 0.68 — 0.81 (m, 1 H) 1.46 (q, J=7.07 Hz, 2 H) 3.27 — 3.43 (m, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=6.32 Hz, 2 H) 8.34 — 8.79 (m, 4 H) 8.85 — 8.97 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 374.2.
Example 54 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2,2- dimethylcyclopropyl)nicotinamide HBHCANNJhOH The title compound was prepared in a manner similar to Example e 53 using 2,2-dimethylcyclopropanamine. MS m/z [M+H]+ 374.1.
Example 5 5 4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2-methoxy methylpropyl)nicotinamide H3C¥N \ | OH O‘CH3 N/ NWN The title compound was prepared in a manner similar to Example example 53 using 2- methoxymethylpropanamine. MS m/z [M+H]+ 392.1.
Example 56 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—((1- (methoxymethyl)cyclopropyl)methyl)nicotinamide ACHN \ I/ OH <2 N W CH3 N‘ The title compound was prepared in a manner similar to Example e 53 using (1-(methoxymethyl)cyclopropyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.20 — 0.74 (m, 4 H) 3.26 (s, 2 H) 3.32 — 3.38 (m, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=5.31Hz, 2 H) 8.26 — 8.85 (m, 4 H) 8.86 — 8.98 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 404.1.
Example 57 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—((1- methylpiperidinyl)methyl)nicotinamide 0%0N\ \ N ‘ Had N The title compound was prepared in a manner similar to Example example 53 using (1-methylpiperidinyl)methanamine.1H NMR (400 MHz, DMSO-d6) 5 ppm 1.24 - 1.48 (m, 2 H) 1.75 — 1.95 (m, 3 H) 2.70 — 2.98 (m, 5 H) 3.23 (t, J=6.19 Hz, 2 H) 3.44 (d, J=11.62 Hz, 2 H) 7.80 (d, J=8.34 Hz, 2 H) 8.14 (br. s., 2 H) 8.32 — 8.77 (m, 3 H) 8.81 (t, J=5.43 Hz, 1 H) 8.88 — 8.97 (m, 1 H) 9.20 (br. s., 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 417.2. e 58 (R)-N-(sec-butyl)(4-(4-cyanomethylphenyl)—5-hydroxy-1H- pyrazolyl)nicotinamide WO 60810 H3C HO NH _ \ 3 o N N Combined (R)-butanamine (22.8 mg, 0.312 mmol) and a solution consisting of 6- (4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (50 mg, 0.156 mmol), HOBT hydrate (35.9 mg, 0.234 mmol), EDCI (44.9 mg, 0.234 mmol), and Hunig’s base (0.103 mL, 0.624 mmol) in DMA (1 mL) and stirred at 50°C for 4 h. The reaction mixture was then d Via preparative HPLC to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.90 (t, J=7.45 Hz, 3 H) 1.17 (d, J=6.57 Hz, 3 H) 1.44 — 1.63 (m, 2 H) 2.44 (s, 3 H) 3.95 (dt, J=14.02, 7.14Hz, 1 H) 7.57 — 7.90 (m, 3 H) 7.92 — 8.73 (m, 4 H) 8.82 — 8.97 (m, 1 H) 13.20 (br. s., 1 H). MS m/z [M+H]+ 376.
Example 59 4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— (tetrahydro-2H-pyranyl)nicotinamide OGNH HO O%<\:N>7N\N/ CH3 The title compound was prepared in a manner similar to Example 58 using tetrahydro- 2H-pyranamine. 1H NMR (400 MHz, 6) 5 ppm 1.60 (qd, J=11.96, 4.29 Hz, 2 H) 1.80 (dd, J=12.51, 2.40 Hz, 2 H) 2.38 — 2.48 (m, 3 H) 3.41 (td, J=11.62, 1.77 Hz, 2 H) 3.90 (dt, J=9.85, 2.02 Hz, 2 H) 3.98 — 4.10 (m, 1 H) 7.56 — 7.88 (m, 3 H) 8.18 (br. s., 1 H) 8.35 — 8.71 (m, 3 H) 8.82 — 9.02 (m, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 404.2.
Example 60 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— propylnicotinamide H3C—/—NH _ \ / N t / CH3 O N N The title compound was prepared in a manner similar to Example 58 using propan amine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.92 (t, J=7.33 Hz, 3 H) 1.57 (sxt, J=7.33 Hz, 2 H) 2.44 (s, 3 H) 3.19 — 3.33 (m, 2 H) 7.55 — 7.89 (m, 3 H) 7.93 — 8.80 (m, 4 H) 8.81 — 9.09 (m, 1 H) 13.20 (br. s., 1 H) MS m/z [M+H]+ 362.2.
Example 61 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(1- methylcyclopropyl)nicotinamide §—-NH HO H3O WM /\ CH3 O N N The title nd was prepared in a manner similar to Example 58 using 1- methylcyclopropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.53 — 0.62 (m, 2 H) 0.66 — 0.75 (m, 2 H) 1.33 (s, 3 H) 2.36 (s, 3 H) 7.53 — 7.79 (m, 3 H) 8.03 — 8.20 (m, 1 H) 8.32 (d, J=7.33 Hz, 2 H) 8.69 — 9.00 (m, 2 H) 13.13 (br. s., 1 H). MS m/z [M+H]+ 374.2.
Example 62 (S)(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N—(1- methoxymethylbutanyl)nicotinamide 1% HO H3O )f—O—N /\ CH3 H3C O N N The title compound was prepared in a manner similar to Example 58 using (S)—1- ymethylbutanamine. 1H NMR (400 MHz, g) 5 ppm 0.85 — 1.01 (m, 6 H) 1.86 — 1.97 (m, 1 H) 2.38 — 2.48 (m, 3 H) 3.21 — 3.31 (m, 3 H) 3.40 — 3.52 (m, 2 H) 3.93 — 4.07 (m, 1 H) 7.60 — 7.87 (m, 3 H) 7.99 — 8.72 (m, 4 H) 8.83 — 9.03 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 420.2.
Example 63 (R)(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- (tetrahydro-2H-pyranyl)ethyl)nicotinamide O //N HCIIINWN\3 \ / \/ CH3 o N N The title compound was prepared in a manner similar to Example 58 using (R) (tetrahydro-2H-pyranyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.08 — 1.14 (m, 1H) 1.14 — 1.23 (m, 2 H) 1.40 — 1.46 (m, 2 H) 1.56 (d, J=12.88 Hz, 2 H) 2.31 — 2.40 (m, 3 H) 3.14 — 3.33 (m, 4 H) 3.77 (dd, J=11.12, 3.28 Hz, 2 H) 7.55 — 7.79 (m, 3 H) 7.99 — 8.72 (m, 4 H) 8.80 — 8.90 (m, 1 H) 13.14 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Example 64 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- (tetrahydro-2H-pyranyl)ethyl)nicotinamide 2014/031918 \ / Nx / CH3 o N N The title compound was prepared in a manner similar to Example 58 using 2- (tetrahydro-2H-pyranyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.08 — 1.14 (m, 1H) 1.14 — 1.23 (m, 2 H) 1.40 — 1.46 (m, 2 H) 1.56 (d, J=12.88 Hz, 2 H) 2.31 — 2.40 (m, 3 H)3.14 — 3.33 (m, 4 H) 3.77 (dd, J=11.12, 3.28 Hz, 2 H) 7.55 — 7.79 (m, 3 H) 7.99 — 8.72 (m, 4 H) 8.80 — 8.90 (m, 1 H) 13.14 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Example 65 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(1- methoxymethylpropanyl)nicotinamide HngfiNH O)—{>fNHN)j/©/N The title nd was prepared in a manner r to Example 58 using 1- methoxymethylpropanamine. 1H NMR(400 MHz, 6) 5 ppm 1.36 (s, 6 H) 2.44 (s, 3 H) 3.29 (s, 3 H) 3.55 (s, 2 H) 7.62 — 7.81 (m, 3 H) 7.89 — 8.52 (m, 4 H) 8.83 — 8.89 (m,1 H) 13.22 (br. s., 1 H). MS m/z [M+H]+ 406.2.
Example 66 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- (tetrahydrofuranyl)ethyl)nicotinamide Ol:>_\_ HO \ / Nx / CH3 o N N The title compound was prepared in a manner similar to Example 58 using 2- (tetrahydrofuranyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.41 (dq, J=11.94, 7.81 Hz, 1 H) 1.49 — 1.59 (m, 2 H) 1.97 (dtd, J=12.06, 7.48, 7.48, 4.80 Hz, 1 H) 2.13 (dt, J=14.72, 7.42 Hz, 1 H) 2.36 (s, 3 H) 3.15 — 3.30 (m, 3 H) 3.56 (q, J=7.58 Hz, 1 H) 3.66 (td, J=8.21, 4.80 Hz, 1 H) 3.76 (dd, J=7.83, 7.33 Hz, 1 H) 7.55 — 7.80 (m, 3 H) 7.92 — 8.58 (m, 3 H) 8.67 (br. s., 1 H) 8.80 — 8.89 (m, 1H) 13.14(br.s., 1 H). MS m/z [M+H]+ 418.2.
Example 67 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(4- methoxymethylbutanyl)nicotinamide H3C-0W H30 (:ng The title compound was prepared in a manner similar to e 58 using 4- methoxymethylbutanamine in place. MS m/z [M+H]+ 420.2.
Example 68 4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N-((1r,4r)- 4-methoxycyclohexyl)nicotinamide ‘ HO \ / \/ CH3 o N N The title compound was prepared in a manner similar to Example 58 using (1r,4r)—4- methoxycyclohexanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.08 - 1.22 (m, 2 H) 1.25 - 1.41 (m, 2 H) 1.76 — 1.89 (m, 2 H) 1.97 (d, J=10.36 Hz, 2 H) 2.36 (s, 3 H) 2.99 — 3.12 (m, 1 H) 3.13 — 3.22 (m, 3 H) 3.72 (dtd, J=11.27, 7.44, 7.44, 3.92 Hz, 1 H) 7.54 — 7.76 (m, 3 H) 7.85 — 8.61 (m, 4 H) 8.83 (d, J=1.26 Hz, 1 H) 13.12 (br. s., 1 H). MS m/z [M+H]+ 432.2 Example 69 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(4- methoxybutanyl)nicotinamide [049510WNH3OOJN lfi/Q/N The title compound was prepared in a manner similar to Example 58 using 4- methoxybutanamine. 1H NMR (400 MHz, 6) 5 ppm 1.11 (d, J=6.82 Hz, 3 H) 1.58 — 1.80 (m, 2 H) 2.31 — 2.40 (m, 3 H) 3.10 — 3.20 (m, 3 H) 3.31 (t, J=6.44 Hz, 2 H) 3.97 — 4.13 (m, 1 H) 7.52 — 7.78 (m, 3 H) 7.88 — 8.68 (m, 4 H) 8.78 — 8.88 (m, 1 H) 13.13 (br. s., 1 H). MS m/z [M+H]+ 406.2.
Example 70 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(3- (cyclopropylmethoxy)propyl)nicotinamide /_/—NH _ \ / N. / CH3 <(ro o N N The title compound was prepared in a manner similar to Example 58 using 3- (cyclopropylmethoxy)propanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm —0.07 — 0.05 (m, 2 H) 0.24 — 0.35 (m, 2 H) 0.75 — 0.90 (m, 1 H) 1.63 (quin, J=6.63 Hz, 2 H) 2.28 (s, 3 H) 3.07 (d, J=6.82 Hz, 2 H) 3.16 — 3.25 (m, 2 H) 3.30 (t, J=6.32 Hz, 2 H) 7.46 — 7.70 (m, 3 H) 7.81 — 8.64 (m, 4 H) 8.72 — 8.81 (m, 1 H) 13.04 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Example 71 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- hydroxy(tetrahydrofuran-3 -yl)ethyl)nicotinamide NH _ \ / N. : CH3 O N N The title nd was prepared in a manner r to Example 58 using 2-amino (tetrahydrofuranyl)ethanol. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.50 — 1.66 (m, 1 H) 1.81 — 1.97 (m, 1 H) 2.34 — 2.39 (m, 3 H) 3.32 — 3.77 (m, 7 H) 3.86 — 3.96 (m, 1 H) 4.71 (br. s., 1 H) 7.52 — 7.82 (m, 3 H) 7.93 — 8.64 (m, 4 H) 8.86 (ddd, J=5.81, 2.15, 0.88 Hz, 1 H) 13.16 (br. s., 1 H). MS m/z [M+H]+ 434.1.
Example 72 6-(5-hydroxy(2-methoxypyridinyl)—1H-pyrazolyl)-N—(piperidin- 4-yl)nicotinamide HNQNH /N HO / N \ Combined 6—(4—(4—cyanophenyl)—5—hydroxy—1H—pyrazol—1—yl)nicotinic acid (50 mg, 0.163 mmol), EDC (46.9 mg, 0.245 mmol) and HOBT (37.5 mg, 0.245 mmol) and DMA (1 mL), and treated with Hunig's base (0.114 ml, 0.653 mmol) and stirred at ambient temperature for 5 minutes, then added to 4—amino—1—Boc—piperidine (38.5 mg, 0.327 mmol) and stirred at room temperature overnight. The reaction mixture was then diluted to a total volume of about 1.5 mL with methanol and purified via prep HPLC. The t containing fractions were collected and trated in vacuum to give a residue which was treated with TFA (2 mL) in DCM (2 mL). After stirring at ambient temperature overnight the reaction was concentrated in vacuo and dried under vacuum to give the title compound (39.3 mg, 62%) as a yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.65 — 1.82 (m, 2 H) 1.93 — 2.08 (m, 2 H) 2.94 — 3.16 (m, 2 H) 3.35 (d, J=12.63 Hz, 2 H) 3.99 — 4.19 (m, 1 H)7.80 (d, J=8.59 Hz, 2 H) 8.15 (d, J=7.33 Hz, 2 H) 8.29 — 8.78 (m, 6 H) 8.87 — 8.99 (m, 1 H) 13.59 (br. s., 1 H). MS m/z [M+H]+389.2.
Example 73 (S)—6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(pyrrolidin yl)nicotinamide NH //N HN _ \ / Nx / O N N The title compound was prepared in a manner r to e 72 using (S)—tert- butyl opyrrolidinecarboxylate. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.93 — 2.12 (m, 1 H) 2.16 — 2.30 (m, 1 H) 3.11 — 3.53 (m, 4 H) 4.53 (dq, J=11.94, 6.04 Hz, 1 H) 7.80 (d,J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.27 — 9.07 (m, 7 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 375.2.
Example 74 (R)-N—(1-cyanobutanyl)(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazol- 1-yl)nicotinamide ”\l O N \ H I OH Combined 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid (29 mg, 0.095 mmol), EDCI (27.2 mg, 0.142 mmol), HOBT (19.2 mg, 0.142 mmol) in DMF(1 mL) and added N,N—diisopropyl ethylamine (66.0 uL, 0.379 mmol). Then (R)—3— entanenitrile (13.9 mg, 0.142 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (SunFireTM C18, 5 um, ID 30 mm x 75 mm) using a gradient of 40-65% ACN (with 0.035% TFA) in water (with 0.05% TFA) to give the title compound (16.2 mg, 44%). 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.93 (t, J=7.33 Hz, 3 H) 1.67 (quin, J=7.20 Hz, 2 H) 2.70 — 2.95 (m, 2 H) 4.05 — 4.22 (m, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.41 — 8.86 (m, 4 H) 8.94 (s, 1 H). MS m/z [M+H]+ 387.2.
Example 75 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N— cyclohexylnicotinamide (1 O N \ OH H I N NW“ The title compound was prepared in a manner similar to Example 74 using cyclohexanamine.1H NMR (400 MHz, DMSO—dg) 5 ppm 1.06 — 1.23 (m, 1 H) 1.33 (t, J=9.60 Hz, 4 H) 1.52 — 1.66 (m, 1 H) 1.76 (br. s., 2 H) 1.86 (br. s., 2 H) 3.66 — 3.92 (m, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.14 (d, J=5.30 Hz, 2 H) 8.45 (d, J=8.34 Hz, 3 H) 8.53 — 8.76 (m, 1 H) 8.90 (s, 1 H) 13.19 — 13.98 (m, 1 H). MS m/z [M+H]+ 388.2.
Example 76 4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—(1-methylazetidin- 3-yl)nicotinamide ”NA 0 N NW” The title compound was prepared in a manner r to Example 74 using 1- azetidinamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.92 (s, 3 H) 3.98 — 4.27 (m, 4 H) 4.36 — 4.58 (m, 2 H) 4.67 — 4.95 (m, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.03 — 8.29 (m, 2 H) 8.32 — 8.83 (m, 3 H) 8.87 — 9.02 (m, 1 H) 9.17 — 9.41 (m, 1 H). MS m/z [M+H]+ 375.2.
Example 77 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2,2,2- trifluoroethyl)nicotinamide FscAN |\ OH The title compound was prepared in a manner similar to Example 74 using 2,2,2- trifluoroethanamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 4.06 — 4.25 (m, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.15 (d, J=8.34 Hz, 2 H) 8.41 — 8.59 (m, 2 H) 9.35 (t, J=6.32 Hz, 1 H). MS m/z [M+H]+ 388.0.
Example 78 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- fluoroethyl)nicotinamide F\/\N \ OH H | The title compound was prepared in a manner similar to Example 74 using 2- fluoroethanamine. 1H NMR (400 MHz, 6) 5 ppm 3.58 (q, J=5.05 Hz, 1 H) 3.62 — 3.69 (m, 1 H) 4.52 (t, J=5.05 Hz, 1 H) 4.64 (t, J=4.93 Hz, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.15 (d, J=8.08 Hz, 2 H) 8.39 — 8.56 (m, 2 H) 8.67 (br. s., 1 H) 8.89 — 9.02 (m, 2 H). MS m/z [M+H]+ 352.1.
Example 79 N—(6-chloro-2,3-dihydro-1H-indenyl)(4-(4-cyanophenyl)—5- hydroxy-1H-pyrazolyl)nicotinamide N \ N 1W“ The title compound was prepared in a manner similar to e 74 using 6-chloro- 2,3-dihydro-1H-indenamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.92 - 2.13 (m, 1 H) 2.80 — 2.92 (m, 1 H) 2.94 — 3.08 (m, 1 H) 5.57 (q, J=7.83 Hz, 1 H) 7.18 — 7.45 (m, 3 H) 7.79 (d, J=8.34 Hz, 2 H) 8.02 — 8.27 (m, 2 H) 8.35 — 8.58 (m, 2 H) 8.66 (br. s., 1 H) 8.87 — 9.01 (m, 1 H) 9.06 (d, J=7.83 Hz, 1 H) 13.56 (br. s., 1 H). MS m/z [M+H]+ 456.1.
Example 80 N—(sec—butyl)(4—(4—cyanophenyl)—5-hydroxy—1H—pyrazol—1— yl)nicotinamide CH3 O H CdxN The title compound was prepared in a manner similar to Example 74 using butan amine. 1H NMR (400 MHz, DMSO—d6) 5 0.89 (t, J=7.45 Hz, 3 H) 1.17 (d, J=6.57 Hz, 3 H) 1.44 — 1.63 (m, 2 H) 3.95 (dt, J=13.96, 7.04 Hz, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (br. s., 2 H) 8.33 — 8.55 (m, 3 H) 8.66 (br. s., 1 H) 8.85 — 8.98 (m, 1 H). MS m/z [M+H]+ 362.1.
Example 81 4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(tetrahydro-2H- pyranyl)nicotinamide O0 N \ H I OH The title compound was prepared in a manner similar to Example 74 using tetrahydro- an—4—amine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.50 — 1.68 (m, 2 H) 1.80 (dd, J=12.63, 2.27 Hz, 2 H) 3.40 — 3.47 (m, 2 H) 3.84 — 3.96 (m, 2 H) 3.97 — 4.12 (m, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.09 — 8.19 (m, 2 H) 8.33 — 8.48 (m, 2 H) 8.52 — 8.60 (m, 1 H) 8.64 (br. s., 1 H) 8.85 — 8.97 (m, 1 H) 13.31 — 13.80 (m, 1 H). MS m/z [M+H]+ 390.1. e 82 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1-methyl oxopiperidinyl)nicotinamide O N \ H I OH The title compound was prepared in a manner similar to Example 74 using 4-amino- 1-methylpiperidinone. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.76 — 1.94 (m, 1 H) 1.96 — 2.12 (m, 1 H) 2.33 (dd, J=17.05, 8.97 Hz, 1 H) 2.53 — 2.63 (m, 1 H) 2.83 (s, 3 H) 3.31 — 3.35 (m, 2 H) 4.25 (td, J=6.38, 3.41 Hz, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.15 (br. s., 2 H) 8.43 (d, J=7.07 Hz, 2 H) 8.70 (d, J=6.57 Hz, 2 H) 8.91 (s, 1 H) 13.19 — 13.81 (m, 1 H). MS m/z [M+H]+ 456.1.
Example 83 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(6-methoxy-2,3- dihydro- 1 H-indenyl)nicotinamide H3C\ I2 |\ OH N NWN The title compound was prepared in a manner similar to Example 74 using 6- methoxy-2,3-dihydro-1H-indenamine. 1H NMR (400 MHz, g) 5 ppm 1.99 (dd, J=12.63, 8.34 Hz, 1 H) 2.44—2.55 (m, 2H) 2.73 — 2.85 (m, 1 H) 2.92 (dd, J=8.72, 2.91 Hz, 1 H) 3.72 (s, 3 H) 5.55 (d, J=7.83 Hz, 1 H) 6.69 — 6.92 (m, 2 H) 7.19 (d, J=8.08 Hz, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.15 (d, J=7.83 Hz, 2 H) 8.34 - 8.81 (m, 3 H) 8.87 — 9.12 (m, 2 H) 13.24 — 13.87 (m, 1 H). MS m/z [M+H]+ 452.1.
Example 84 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(4,4- difluorocyclohexyl)nicotinamide PO 0 N \ H I OH The title compound was prepared in a manner similar to Example 74 using 4,4- difluorocyclohexanamine. 1H NMR (400 MHz, 6) 5 ppm 1.60 — 1.71 (m, 2 H) 1.85 — 1.98 (m, 3 H) 2.05 — 2.21 (m, 3 H) 3.97—4.10(m, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (br. s., 2 H) 8.33 — 8.55 (m, 3 H) 8.66 (br. s., 1 H) 8.85 — 8.98 (m, 1 H). MS m/z [M+H]+ 424.1.
Example 85 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(1-(2- hydroxyethyl)piperidinyl)nicotinamide HOWU O N \ The title nd was prepared in a manner similar to Example 74 using 2-(4- iperidinyl)ethanol. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.79 — 1.96 (m, 2 H) 1.98 — 2.18 (m, 2 H) 3.07 — 3.25 (m, 4 H) 3.37 (d, J=19.45 Hz, 1 H) 3.59 (d, J=11.87 Hz, 2 H) 3.76 (t, J=4.93 Hz, 2 H) 3.98 — 4.25 (m, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.14 (d, J=6.57 Hz, 2 H) 8.45 (d, J=6.57 Hz, 1 H) 8.52 — 8.71 (m, 1 H) 8.75 (d, J=7.07 Hz, 1 H) 8.93 (s, 1 H). MS m/z [M+H]+ 433.1.
Example 86 (R)—N—(sec—butyl)—6—(4—(4—cyanophenyl)—5-hydroxy—1H-pyrazol—1— yl)nicotinamide H3C\_ o H3C/\N \ | OH N l\\l \ /N The title compound was prepared in a manner similar to Example 74 using (R)-butan- 2—amine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.89 (t, J=7.45 Hz, 3 H) 1.16 (d, J=6.82 Hz, 3 H) 1.42 — 1.65 (m, 2 H) 3.95 (dt, J=13.89, 7.20 Hz, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=5.81Hz, 2 H) 8.41 (dd, J=13.89, 7.58 Hz, 3 H) 8.65 (br. s., 1 H) 8.91 (s, 1 H). MS m/z [M+H]+ 362.1. e 86 (S)(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N- (tetrahydrofuran-3 -yl)nicotinamide o“W1:: H | The title compound was prepared in a manner similar to Example 74 using (S)- tetrahydrofuranamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.83 - 2.01 (m, 1 H) 2.18 (s, 1 H) 3.63 (dd, J=8.97, 4.17 Hz, 1 H) 3.66 — 3.79 (m, 1 H) 3.80 — 3.95 (m, 2 H) 4.41 — 4.59 (m, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (br. s., 2 H) 8.45 (br. s., 2 H) 8.55 — 8.73 (m, 1 H) 8.78 (d, J=6.32 Hz, 1 H) 8.92 (s, 1 H). MS m/z [M+H]+ 376.1.
Example 87 (sec—butyl)—6—(4-(4-cyanophenyl)—5—hydroxy-1H—pyrazol yl)nicotinamide H3C1HOH30 INNgH’Q/N The title compound was prepared in a manner similar to Example 74 using (S)—butan- e. 1H NMR (400 MHz, DMSO—d6) 5 0.90 (t, J=7.45 Hz, 3 H) 1.17 (d, J=6.57 Hz, 3 H) 1.40 — 1.68 (m, 2 H) 3.95 (dt, J=13.89, 7.20 Hz, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 7.99 — 8.25 (m, 2 H) 8.29 — 8.55 (m, 3 H) 8.64 (br. s., 1 H) 8.91 (s, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 362.1.
Example 88 (R)(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1- cyclopropylethyl)nicotinamide CH3 0 V/kEh OH The title compound was prepared in a manner similar to Example 74 using (R) cyclopropylethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.17 — 0.27 (m, 1 H) 0.28 — 0.36 (m, 1 H) 0.36 — 0.44 (m, 1 H) 0.44 — 0.53 (m, 1 H) 0.93 — 1.08 (m, 1 H) 1.25 (d, J=6.82 Hz, 3 H) 3.42 — 3.61 (m, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.13 (br. s., 2 H) 8.44 (d, J=6.82 Hz, 2 H) 8.54 — 8.78 (m, 2 H) 8.91 (s, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 374.1.
Example 89 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- isopropoxyethyl)nicotinamide H I CH / The title compound was prepared in a manner similar to Example 74 using 6-(4-(4- cyanophenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and 2-isopropoxyethanamine. 1H NMR (400 MHz, DMSO—d6) 5 1.10 (d, J=6.06 Hz, 6 H) 3.42 (q, J=5.81 Hz, 2 H) 3.48 — 3.55 (m, 2 H) 3.55 — 3.64 (m, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.42 (d, J=7.58 Hz, 1 H) 8.68 (br. s., 1 H) 8.77 (t, J=5.05 Hz, 1 H) 8.92 (s, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 392.1.
Example 90 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(3-(2- methylpiperidinyl)propyl)nicotinamide CH3 O H | N NW“ The title nd was prepared in a manner similar to Example 74 using 1-(3- aminopropyl)2-methylpiperidine as a TFA salt. 1H NMR (400 MHz, 6) 5 ppm 1.18 — 1.33 (m, 3 H) 1.39 — 1.55 (m, 2 H) 1.56 — 1.73 (m, 2 H) 1.74 — 2.03 (m, 4 H) 2.90 — 3.34 (m, 5 H) 3.42 — 3.86 (m, 2 H) 7.80 (d, J=7.83 Hz, 2 H) 8.06 — 8.29 (m, 2 H) 8.34 — 8.62 (m, 2 H) 8.68 (br. s., 1 H) 8.89 (br. s., 1 H) 8.93 (s, 1 H) 8.98 — 9.33 (m, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 445.3.
Example 91 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(3- morpholinopropyl)nicotinamide N/\/\N \ The title compound was prepared in a manner similar to e 74 using N—(3- aminopropyl)morpholine as a TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.85 — 2.02 (m, 2 H) 3.10 (br. s., 2 H) 3.15 — 3.23 (m, 2 H) 3.34 — 3.43 (m, 3 H) 3.67 (br. s., 3 H) 3.96 (br. s., 2 H) 7.80 (d, J=8.59 Hz, 2 H) 8.15 (d, J=5.31 Hz, 2 H) 8.43 (d, J=7.07 Hz, 1 H) 8.47 — 8.61 (m, 1 H) 8.68 (br. s., 1 H) 8.88 (t, J=5.56 Hz, 1 H) 8.91 — 8.96 (m, 1 H) 9.47 — 10.02 (m, 1 H) 13.21 — 13.71 (m, 1 H)MS m/z [M+H]+ 433.2.
Example 92 6-(4-(4-cyan0phenyl)—5-hydr0xy-1H-pyrazolyl)-N—((1- methylpyrrolidin-3 thyl)nicotinamide ,CH3 C6N 0 N \ The title compound was prepared in a manner similar to Example 74 using (1- methylpyrrolidinyl)methanamine as a TFA salt. 1H NMR (400 MHz, 6) 5 ppm 1.60 — 1.96 (m, 1 H) 1.98 — 2.29 (m, 1 H) 2.45—2.60 (m, 1H) 2.71 — 2.92 (m, 4 H) 2.96 — 3.25 (m, 2 H) 3.30— 3.45 (m, 1H) 3.51 — 3.74 (m, 2 H) 7.80 (d, J=8.59 Hz, 2 H) 8.15 (d, J=7.58 Hz, 2 H) 8.42 (dd, J=8.59, 2.02 Hz, 1 H) 8.51 (br. s., 1 H) 8.67 (br. s., 1 H) 8.88 (br. s., 1 H) 8.90 — 8.98 (m, 1 H) 9.79 (br. s., 1 H) 13.51 (br. s., 1 H). MS m/z [M+H]+ 403.2.
Example 93 6-(4-(4-cyan0phenyl)—5-hydr0xy-1H-pyrazolyl)-N—(1- cyclopropylpiperidinyl)nicotinamide U0 N \ H I OH The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 1-cyclopr0pylpiperidinamine . 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.84 (d, J=6.57 Hz, 2 H) 0.93 — 1.01 (m, 2 H) 1.76 (t, J=6.06 Hz, 2 H) 2.07 — 2.20 (m, 2 H) 2.73 — 2.91 (m, 1 H) 3.25 — 3.41 (m, 2 H) 3.51 — 3.69 (m, 2 H) 4.08 (br. s., 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.45 (br. s., 1 H) 8.50 — 8.81 (m, 3 H) 8.85 — 9.17 (m, 2 H) 13.53 (br. s.,1 H)MS m/z [M+H]+ 429.2.
Example 94 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)-N—((1- methylpiperidinyl)methyl)nicotinamide O/\HN \ I OH /N / H3C N [\‘J \ ’N—— The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (1- methlpiperidinyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.22 - 1.29 (m, 1 H) 1.32 — 1.46 (m, 2 H) 1.80 (d, J=3.54 Hz, 1H) 1.91 (d, J=13.64 Hz, 2 H) 2.44 (s, 3 H) 2.71 — 2.84 (m, 3 H) 2.85 — 3.00 (m, 2 H) 3.23 (t, J=6.19 Hz, 2 H) 3.45 (br. s., 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.71 — 7.90 (m, 2 H) 8.22 (d, J=13.64 Hz, 1 H) 8.43 (br. s., 2 H) 8.82 (br. s., 1 H) 8.93 (dd, J=2.02, 0.76 Hz, 1 H) 9.28 (br. s., 1 H) 13.23 (br. s., 1 H). MS m/z [M+H]+ 431.2.
Example 95 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N—(3- hylamino)propyl)nicotinamide \/\N \ OH (EH3 H I N NW-N The title compound, as a TFA salt, was prepared in a manner similar to e 74 using 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and N1,N1- dimethylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.81 - 2.01 (m, 2 H) 2.44 (s, 3 H) 2.80 (d, J=4.04 Hz, 6 H) 3.13 (dt, J=10.36, 4.93 Hz, 2 H) 3.37 (q, J=6.40 Hz, 2 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.79 (br. s., 1 H) 8.22 (d, J=16.93 Hz, 1 H) 8.43 (br. s., 1 H) 8.86 (br. s., 1 H) 8.93 (dd, J=2.15, 0.88 Hz, 1 H) 9.38 (br. s., 1 H) 13.25 (br. s., 1 H).
MS m/z [M+H]+ 405.2.
Example 96 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—((1- methylpyrrolidin-3 -yl)methyl)nicotinamide H3C—NQ/\IZ \ OH N N \ HZ The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and (1- methylpyrrolidinyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.61 — 1.97 (m, 1 H) 1.98 — 2.29 (m, 1 H) 2.40 — 2.47 (m, 3 H) 2.54 — 2.65 (m, 1 H) 2.73 — 2.91 (m, 4 H) 2.97 — 3.25 (m, 1 H) 3.40 (dt, 1, 6.28 Hz, 2 H) 3.50 — 3.78 (m, 2 H) 7.67 (d, J=7.33 Hz, 1 H) 7.70 — 7.89 (m, 2 H) 8.12 — 8.32 (m, 1 H) 8.33 — 8.74 (m, 2 H) 8.77 — 8.98 (m, 2 H) 9.66 — 9.94 (m, 1 H) 12.62 — 13.68 (m, 1 H). MS m/z [M+H]+ 417.2. e 97 6-(4-(4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)-N—(3-(2- methylpiperidinyl)pr0pyl)nic0tinamide CH3 0 N/\/\N \ OH H | N rx‘1\ ——N The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 3-(2- methylpiperidinyl)pr0panamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.20 - 1.32 (m, 3 H) 1.38 — 1.55 (m, 2 H) 1.56 — 1.74 (m, 2 H) 1.74 — 2.06 (m, 4 H) 2.40 — 2.47 (m, 3 H) 2.91 — 3.16 (m, 2 H) 3.16 — 3.34 (m, 2 H) 3.35 — 3.69 (m, 3 H) 7.63 — 7.70 (m, 1 H) 7.72 — 7.86 (m, 2 H) 8.20 (br. s., 1 H) 8.42 (d, J=7.33 Hz, 2 H) 8.85 — 9.00 (m, 2 H) 9.03 — 9.38 (m, 1 H) 12.63 — 13.81 (m, 1 H). MS m/z [M+H]+ 459.2.
Example 98 6-(4-(4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)-N—(1- ethylpiperidinyl)nic0tinamide The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 1- iperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.13 - 1.31 (m, 3 H) 1.71 — 1.88 (m, 2 H) 1.91 — 2.20 (m, 2 H) 2.44 (s, 3 H) 3.01 — 3.18 (m, 3 H) 3.23 — 3.43 (m, 1 H) 3.55 (d, J=12.13 Hz, 2 H) 3.99 — 4.28 (m, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.70 — 7.86 (m, 2 H) 8.07 — 8.31 (m, 1 H) 8.32 — 8.64 (m, 2 H) 8.73 (d, J=6.32 Hz, 1 H) 8.84 — 8.99 (m, 1 H) 9.24 (br. s., 1 H) 12.78 — 13.45 (m, 1 H). MS m/z [M+H]+ 431.2.
Example 99 6-(4-(4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)-N—(3- (piperidinyl)pr0pyl)nic0tinamide WO 60810 N/\/\N \ OH H | N [\‘1 \ ——N The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3- (piperidinyl)propanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.20 - 1.47 (m, 1 H) 1.52 — 1.75 (m, 3 H) 1.82 (d, J=14.40 Hz, 2 H) 1.88 — 2.02 (m, 2 H) 2.44 (s, 3 H) 2.78 — 2.98 (m, 2 H) 3.11 (dt, J=10.55, 4.96 Hz, 2 H) 3.37 (q, J=6.48 Hz, 2 H) 3.46 (d, J=11.87 Hz, 2 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.20 (br. s., 1 H) 8.42 (d, J=7.58 Hz, 1 H) 8.53 (br. s., 1 H) 8.89 (t, J=5.18 Hz, 1 H) 8.91 — 8.98 (m, 1 H) 9.13 (br. s., 1 H) 13.25 (br. s., 1 H). MS m/z [M+H]+ 445.2.
Example 100 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- methylpiperidinyl)nicotinamide N \ I OH N [\‘1 \ IN The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1- methylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.71 - 1.85 (m, 2 H) 1.92 — 2.14 (m, 2 H) 2.38 — 2.47 (m, 3 H) 2.70 — 2.89 (m, 3 H) 3.06 — 3.18 (m, 2 H) 3.24 — 3.40 (m, 1 H) 3.49 (d, J=11.87 Hz, 1 H) 3.98 — 4.24 (m, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.71 — 7.87 (m, 2 H) 8.21 (d, J=12.13 Hz, 1 H) 8.35 — 8.59 (m, 2 H) 8.72 (d, J=6.32 Hz, 1 H) 8.88 — 8.98 (m, 1 H) 9.46 (br. s., 1 H) 12.72 — 13.42 (m, 1 H). MS m/z [M+H]+ 417.2.
Example 101 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—((4- methylmorpholinyl)methyl)nicotinamide H3C\ NGAHN \ I OH N [\‘j \ :N 2014/031918 The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (4- methylmorpholinyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.44 (s, 3 H) 2.78 — 2.94 (m, 4 H) 2.98 — 3.15 (m, 1 H) 3.31 — 3.58 (m, 4 H) 3.68 (t, J=11.75 Hz, 1 H) 3.78 — 3.95 (m, 1 H) 4.08 (dd, J=12.88, 3.03 Hz, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.21 (d, J=6.32 Hz, 1 H) 8.44 (d, J=7.07 Hz, 2 H) 8.85 — 9.06 (m, 2 H) 9.93 (br. s., 1 H) 12.57 — 13.73 (m, 1 H). MS m/z [M+H]+ 433.2.
Example 102 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(2-(1- methylpyrrolidinyl)ethyl)nicotinamide The title compound, as a TFA salt, was prepared in a manner similar to e 74 using 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2-(1- methylpyrrolidinyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.60 — 1.83 (m, 2 H) 1.83 — 2.08 (m, 2 H) 2.18 (dd, J=12.88, 4.29 Hz, 1 H) 2.27 — 2.41 (m, 1 H) 2.44 (s, 3 H) 2.84 (d, J=3.54 Hz, 3 H) 3.08 (br. s., 1 H) 3.29 (br. s., 1 H) 3.40 (q, J=6.57 Hz, 2 H) 3.58 (d, J=4.29 Hz, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.70 — 7.89 (m, 2 H) 8.20 (br. s., 1 H) 8.42 (br. s., 1 H) 8.50 — 8.71 (m, 1 H) 8.84 (br. s., 1 H) 8.89 — 8.95 (m, 1 H) 9.53 (br. s., 1 H) 12.81 — 13.56 (m, 1 H). MS m/z [M+H]+ 431.2.
Example 103 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— ((1R,2S)—2-(methoxymethyl)cyclopentyl)nicotinamide 0 4N NWN \H N" H3C The title compound was prepared in a manner similar to Example 74 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (1R,2S) (methoxymethyl)cyclopentanamine. 1H NMR (400 MHz, 6) 5 ppm 1.42 - 1.60 (m, 2 H) 1.60 — 1.83 (m, 3 H) 1.84 — 2.01 (m, 1 H) 2.20 — 2.37 (m, 1 H) 2.44 (s, 3 H) 3.19 (s, 3 H) 3.20 — 3.27 (m, 1 H) 3.40 (dd, J=9.35, 6.06 Hz, 2 H) 4.43 (t, J=7.45 Hz, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.74 (br. s., 1 H) 7.81 (d, J=18.69 Hz, 1 H) 8.24 — 8.70 (m, 3 H) 8.88 (d, J=1.77 Hz, 1 H) 13.24 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Example 104 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N—(3- morpholin0pr0py1)nic0tinamide FNMH |\ 0“ O\) N/ N \ :N “3‘3 The title compound was prepared in a manner similar to Example 74 using 6-(4-(4- cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 3-m0rp01in0pr0pan amine TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.17 - 1.31 (m, 2 H) 1.32 - 1.45 (m, 2 H) 1.77 — 1.91 (m, 4 H) 2.40 — 2.46 (m, 3 H) 3.37 — 3.49 (m, 1 H) 3.65 — 3.82 (m, 1 H) 4.58 (br. s., 1 H) 7.65 (dd, , 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.25 — 8.65 (m, 3 H) 8.80 — 9.01 (m, 1 H) 12.36 — 13.83 (m, 1 H). MS m/z [M+H]+ 447.2 Example 105 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N—(3- (pyrrolidinyl)pr0pyl)nic0tinamide N/\/\N \ OH H | N [\l] \ ”N The title compound was prepared in a manner similar to Example 74 using 6-(4-(4- 2-methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 3-(pyrr01idin yl)pr0panamine as a TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.80 — 1.96 (m, 4 H) 1.97 — 2.08 (m, 2 H) 2.44 (s, 3 H) 2.91 — 3.09 (m, 2 H) 3.21 (dt, 6, 5.43 Hz, 2 H) 3.38 (q, J=6.40 Hz, 2 H) 3.49 — 3.64 (m, 2 H) 7.67 (d, J=7.58 Hz, 1 H) 7.74 (s, 2 H) 8.03 — 8.33 (m, 1 H) 8.43 (br. s., 2 H) 8.85 (br. s., 1 H) 8.88 — 8.98 (m, 1 H) 9.50 (br. s., 1 H) 12.61 — 13.62 (m, 1 H). MS m/z [M+H]+ 431.2 Example 106 N—(3-(1H-imidazolyl)pr0pyl)—6-(4-(4-cyan0methylphenyl) hydroxy-1H-pyrazolyl)nic0tinamide {f IZ \_ OH ”‘N \ H The title compound was prepared in a manner similar to Example 74 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3-(1H-imidazol yl)propanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.09 - 2.17 (m, 2 H) 2.44 (s, 3 H) 3.32 (q, J=6.40 Hz, 2 H) 4.28 (t, J=6.95 Hz, 2 H) 7.63 — 7.72 (m, 2 H) 7.74 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 7.83 (t, J=1.64 Hz, 1 H) 8.19 (br. s., 1 H) 8.35 — 8.55 (m, 2 H) 8.82 (t, J=5.68 Hz, 1 H) 8.89 — 8.96 (m, 1 H) 9.11 (s, 1 H) 13.26 — 14.08 (m, 1 H). MS m/z [M+H]+ 428.2 Example 107 4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— methylnicotinamide H3C\N \ OH H | N [\‘l \ «N The title compound was prepared in a manner r to Example 74 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.36 (s, 3 H) 2.76 (d, J=4.55 Hz, 3 H) 7.59 (dd, J=7.96, 1.39 Hz, 1 H) 7.66 (s, 1 H) 7.71 (d, J=7.83 Hz, 1 H) 8.11 (br. s., 1 H) 8.33 (d, J=6.32 Hz, 2 H) 8.61 (d, J=4.55 Hz, 1 H) 8.79 — 8.89 (m, 1 H) 12.66 — 13.53 (m, 1 H). MS m/z [M+H]+ 334.1.
Example 108 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— ethylnicotinamide The title compound was prepared in a manner similar to e 74 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and ethanamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.09 (t, J=7.33 Hz, 3 H) 2.36 (s, 3 H) 3.16 — 3.37 (m, 2 H) 7.59 (d, J=8.08 Hz, 1 H) 7.66 (s, 1 H) 7.71 (br. s., 1 H) 7.99 — 8.22 (m, 1 H) 8.34 (d, J=7.58 Hz, 2 H) 8.65 (t, J=5.05 Hz, 1 H) 8.78 — 8.90 (m, 1 H) 12.84 — 13.41 (m, 1 H). MS m/z [M+H]+ 348.1.
Example 109 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—(1- (dimethylamino)—2-methylpropanyl)nicotinamide H3C\ H3C CH3 0 H | N ”W” The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using N1,N1-trimethylproandiamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.48 (s, 6 H) 2.86 (s, 6 H) 3.66 (s, 2 H) 7.80 (d, J=8.59 Hz, 2 H) 8.15 (br. s., 2 H) 8.29 — 8.85 (m, 4 H) 8.85 — 9.02 (m, 1 H) 9.19 (br. s., 1 H) 13.07 — 13.83 (m, 1 H). MS m/z [M+H]+ 405.2.
Example 110 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—((1R,2S) xymethyl)cyclopentyl)nicotinamide / [I] ;N H \ N \ The title compound was prepared in a manner similar to e 74 using (1R,2S) (methoxymethyl)cyclopentanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.44 - 1.60 (m, 2 H) 1.61 — 1.72 (m, 1 H) 1.72 — 1.82 (m, 2 H) 1.85 — 2.00 (m, 1 H) 2.19 — 2.35 (m, 1 H) 3.16 — 3.26 (m, 4 H) 3.40 (dd, J=9.35, 6.06 Hz, 1 H) 4.36 — 4.51 (m, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.25 — 8.47 (m, 2 H) 8.68 (br. s., 2 H) 8.88 (s, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 418.2.
Example 111 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—((4- methylmorpholinyl)methyl)nicotinamide H3C\ N N \ The title compound, as the TFA salt, was prepared in a manner similar to Example 74 using (4-methylmorpholinyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.79 — 2.94 (m, 4 H) 2.98 — 3.12 (m, 1 H) 3.32 — 3.58 (m, 4 H) 3.69 (t, 5 Hz, 1 H) 3.79 — 3.92 (m, 1 H) 4.07 (dd, J=12.88, 3.03 Hz, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.34 — 8.84 (m, 3 H) 8.84 — 9.14 (m, 2 H) 9.99 (br. s., 1 H) 13.56 (br. s., 1 H). MS m/z [M+H]+ 419.1.
Example 112 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—(2- ethoxyethyl)nicotinamide H3C\/O\/\N \ OH H | N NW“ Combined 6—(4—(4-cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94.0 mg, 0.490 mmol), and HOBT (66.2 mg, 0.490 mmol) in DMF (2.5 mL) and added N,N—diisopropyl ethylamine (227 11L, 1.306 mmol). Then 2- ethoxyethanamine (43.7 mg, 0.490 mmol) was added and the reaction allowed to stir at room temperature for 16 hours. The on mixture was then diluted with water (3.5 mL) and acidified to an approximate pH = 4 to give a solid which was collected by filtration, washed with water, MeOH, and diethyl ether to give the title compound. 1H NMR (400 MHz, DMSO—dg) 5 1.04 (t, J=6.95 Hz, 3 H) 3.33 — 3.41 (m, 4 H) 3.41 — 3.48 (m, 2 H) 7.70 (d, J=8.34 Hz, 2 H) 8.06 (d, J=7.07 Hz, 2 H) 8.26 — 8.49 (m, 2 H) 8.58 (br. s., 1 H) 8.71 (t, J=5.18 Hz, 1 H) 8.77 — 8.93 (m, 1 H) 12.95 — 13.90 (m, 1 H). MS m/z [M+H]+ 378.1.
Example 113 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—(1- (tetrahydrofuranyl)ethyl)nicotinamide CH3 0 d”O N \ | OH N NWN The title compound was prepared in a manner similar to e 112 using 1- (tetrahydrofuranyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 1.11 - 1.23 (m, 3 H) 1.52 — 1.73 (m, 1 H) 1.74 — 1.98 (m, 3 H) 3.66 (dd, J=10.61, 7.07 Hz, 1 H) 3.73 — , 2 H) 3.96 — 4.19 (m, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.14 (br. s., 2 H) 8.33 — 8.79 (m, 4 H) 8.91 (br. s., 1 H) 13.55 (br. s., 1 H). MS m/z [M+H]+ 404.1.
Example 114 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(4- methoxybutanyl)nicotinamide CH3 0 HBC\O/\)\nJK[j H3C / .— 2014/031918 The title compound was prepared in a manner similar to Example 112 using 6-(5- hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and oxybutan amine. 1H NMR (400 MHz, methanol-d4) 5 ppm 1.28 (d, J=6.32 Hz, 3 H) 1.86 (dd, J=6.95, .43 Hz, 2 H) 3.33 (s, 3 H) 3.44 — 3.57 (m, 2 H) 4.18 (s, 3 H) 4.22 — 4.34 (m, 1 H) 7.77 (d, J=5.31 Hz, 1 H) 7.86 (s, 1 H) 8.04 (d, J=6.57 Hz, 1 H) 8.44 (br. s., 3 H) 8.68 — 9.15 (m, 1 H).
MS m/z [M+H]+ 398.2.
Example 115 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(1- isopropylpiperidinyl)nicotinamide HscXU o N \ H I OH N 1W“ The title compound was prepared in a manner similar to Example 112 using 1- isopropyl-piperidinylamine as an HCl salt. 1H NMR (400 MHz, 6) 5 ppm 1.16 - 1.27 (m, 6 H) 1.86 — 2.01 (m, 4 H) 2.96 — 3.11 (m, 2 H) 3.31 — 3.41 (m, 3 H) 3.96 — 4.20 (ml H) 7.73 (d, J=8.34 Hz, 2 H) 8.08 (d, J=6.57 Hz, 2 H) 8.40 (d, J=6.06 Hz, 2 H) 8.60 (br. s., 1 H) 8.77 (d, J=7.07 Hz, 1 H) 8.83 — 8.95 (m, 1 H) 9.96 (br. s., 1 H) 13.07 — 13.88 (m, 1 H). MS m/z [M+H]+ 431.2.
Example 116 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(3 -(thiazol yl)propyl)nicotinamide WWW}N\ N \ 0“ The title compound was prepared in a manner similar to Example 112 using 3- (thiazolyl)propanamine to give the title compound.1H NMR (400 MHz, DMSO—dg) 5 ppm 1.90 — 2.00 (m, 2 H) 3.01 (t, J=7.58 Hz, 2 H) 3.30 — 3.37 (m, 2 H) 7.52 (d, J=3.28 Hz, 1 H) 7.64 (d, J=3.28 Hz, 1 H) 7.72 (d, J=8.59 Hz, 2 H) 8.08 (d, J=7.58 Hz, 2 H) 8.29 — 8.49 (m, 2 H) 8.59 (br. s., 1 H) 8.71 (t, J=5.43 Hz, 1 H) 8.80 — 8.87 (m, 1 H) 13.40 (br. s., 1 H). MS m/z [M+H]+ 431.1.
Example 117 N—(3-(1H-pyrazolyl)propyl)—6-(4-(4-cyanophenyl)hydroxy-1H- pyrazolyl)nicotinamide / / The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid and pyrazolyl)propan amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.00 - 2.10 (m, 2 H) 3.25 — 3.30 (m, 2 H) 4.19 (t, J=6.95 Hz, 2 H) 6.23 (t, J=2.02 Hz, 1 H) 7.45 (d, J=1.77 Hz, 1 H) 7.77 (d, J=1.52 Hz, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=7.33 Hz, 2 H) 8.37 — 8.44 (m, 1 H) 8.45 — 8.58 (m, 1 H) 8.66 (br. s., 1 H) 8.74 (t, J=5.31Hz, 1 H) 8.88 — 8.94 (m, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 414.2.
Example 118 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—(3- (cyclopropylmethoxy)propyl)nicotinamide N NW” The title compound was prepared in a manner similar to Example 112 using 3- (cyclopropylmethoxy)propanamine. 1H NMR (400 MHz, 6) 5 ppm 0.13 — 0.19 (m, 2 H) 0.41 — 0.49 (m, 2 H) 0.99 (tddd, J=9.84, 9.84, 4.96, 3.03, 1.89 Hz, 1 H) 1.78 (quin, J=6.63 Hz, 2 H) 3.22 (d, J=6.82 Hz, 2 H) 3.32 — 3.38 (m, 2 H) 3.45 (t, J=6.32 Hz, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=7.58 Hz, 2 H) 8.38 — 8.43 (m, 1 H) 8.47 (br. s., 1 H) 8.60 — 8.76 (m, 2 H) 8.89 — 8.93 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 418.2.
Example 118A 4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N—(1- (methoxymethyl)cyclopropyl)nicotinamide N r\\1 \ /N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid 1- (methoxymethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.81 (s, 4 H) 2.43 (s, 3 H) 3.29 (s, 3 H) 3.49 (s, 2 H) 7.66 (d, J=7.83 Hz, 1 H) 7.73 (s, 1 H) 7.78 (br. s., 1 H) 8.04 — 8.33 (m, 1 H) 8.42 (d, J=7.07 Hz, 2 H) 8.91 (d, J=1.26 Hz, 1 H) 8.98 (s, 1 H) 12.83 — 13.55 (m, 1 H). MS m/z [M+H]+ 404.1.
Example 119 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)-N—((1s,4s)— 4-meth0xycyc10hexyl)nic0tinamide H | N N\ :N The title compound was prepared in a manner similar to Example 112 using 4- cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (1s,4s) methoxycyclohexanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.35 — 1.48 (m, 2 H) 1.50 — 1.62 (m, 4 H) 1.77 — 1.89 (m, 2 H) 2.36 (s, 3 H) 3.17 (s, 3 H) 3.23 — 3.36 (m, 1 H) 3.80 (dq, J=12.66, 4.87 Hz, 1 H) 7.54 — 7.63 (m, 1 H) 7.66 (s, 1 H) 7.70 (br. s., 1 H) 8.10 (br. s., 1 H) 8.38 (t, J=8.72 Hz, 3 H) 8.74 — 8.92 (m, 1 H) 13.12 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Example 120 (S)(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)-N— (tetrahydrofuran-3 -yl)nic0tinamide fr 0 \v'\ N \ N [‘1 \ ,N The title compound was prepared in a manner r to Example 112 using 4- cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (S)-tetrahydr0furan amine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.84 — 2.02 (m, 1 H) 2.09 — 2.27 (m, 1 H) 2.43 (s, 3 H) 3.63 (dd, J=8.84, 4.04 Hz, 1 H) 3.73 (td, J=8.08, 5.81 Hz, 1 H) 3.83 — 3.95 (m, 2 H) 4.42 — 4.58 (m, 1 H) 7.66 (d, J=7.83 Hz, 1 H) 7.73 (s, 1 H) 7.77 (br. s., 1 H) 8.18 (br. s., 1 H) 8.44 (d, J=6.82 Hz, 2 H) 8.78 (d, J=6.32 Hz, 1 H) 8.92 (s, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 390.1.
Example 121 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N—(3- methoxypropyl)nic0tinamide N N \ ’N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3-methoxypropan amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.79 (quin, J=6.63 Hz, 2 H) 2.44 (s, 3 H) 3.25 (s, 3 H) 3.34 (q, J=6.65 Hz, 2 H) 3.40 (t, J=6.19 Hz, 2 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (d, J=6.82 Hz, 1 H) 8.18 (br. s., 1 H) 8.41 (d, J=6.06 Hz, 2 H) 8.71 (t, J=5.31 Hz, 1 H) 8.83 — 9.01 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 392.2.
Example 122 (S)-N—(sec-butyl)(4-(4-cyanomethylphenyl)hydroxy-1H- pyrazolyl)nicotinamide HC N \ N N\ ——N The title compound was prepared in a manner r to Example 112 using 6-(4-(4- 2-methylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)-butanamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.90 (t, J=7.33 Hz, 3 H) 1.17 (d, J=6.57 Hz, 3 H) 1.46 — 1.63 (m, 2 H) 2.44 (s, 3 H) 3.95 (dt, J=13.83, 7.11 Hz, 1 H) 7.67 (dd, J=8.08, 1.26 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.17 (br. s., 1 H) 8.32 — 8.58 (m, 3 H) 8.87 — 8.95 (m, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 376.2.
Example 123 4-(5-hydroxy(5-(morpholinecarbonyl)pyridinyl)-1H-pyrazol yl)benzonitrile ”W1| 0“ 0Q N/ NWN The title compound was prepared in a manner similar to Example 112 using morpholine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 3.11 — 4.08 (m, 8 H) 7.80 (d, J=8.59 Hz, 2 H) 8.10 (dd, J=8.59, 2.02 Hz, 1 H) 8.15 (d, J=7.83 Hz, 2 H) 8.46 (br. s., 1 H) 8.54 — 8.59 (m, 1 H) 8.65 (br. s., 1 H) 13.51 (br. s., 1 H). MS m/z [M+H]+ 376.1 2014/031918 Example 124 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N— isobutylnicotinamide H3CH? M I : WN N N \ , The title compound was prepared in a manner similar to e 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and isobutylamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.92 (d, J=6.57 Hz, 6 H) 1.87 (dt, J=13.52, 6.63 Hz, 1 H) 2.44 (s, 3 H) 3.13 (t, J=6.32 Hz, 2 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.18 (br. s., 1 H) 8.43 (d, J=6.82 Hz, 2 H) 8.70 (t, J=5.31Hz, 1 H) 8.92 (s, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 376.2.
Example 125 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N—(3- hydroxypropyl)nicotinamide HOMN%\ OH H | N N \ ’N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3-aminopropanol. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.71 (quin, J=6.69 Hz, 2 H) 2.44 (s, 3 H) 3.32 — 3.39 (m, 2 H) 3.49 (br. s., 2 H) 4.51 (br. s., 1 H) 7.66 (dd, , 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=6.82 Hz, 1 H) 8.17 (br. s., 1 H) 8.41 (d, J=6.32 Hz, 2 H) 8.69 (t, J=5.43 Hz, 1 H) 8.88 — 8.95 (m, 1 H) 12.93 — 13.41 (m, 1 H). MS m/z [M+H]+ 378.1.
Example 126 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N—(2- ethoxyethyl)nic0tinamide H3CVO\/\N)h N N \ ’N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2-ethoxyethylamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.12 (t, J=6.95 Hz, 3 H) 2.43 (s, 3 H) 3.42 — 3.49 (m, 4 H) 3.49 — 3.55 (m, 2 H) 7.66 (dd, , 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.75 — 7.85 (m, 1 H) 8.06 — 8.27 (m, 1 H) 8.42 (d, J=6.82 Hz, 2 H) 8.80 (t, J=5.18 Hz, 1 H) 8.88 — 8.96 (m, 1 H) 12.86 — 13.47 (m, 1H). MS m/z [M+H]+ 392.2.
Example 127 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N— cyclopropylnicotinamide *0]:\N\ The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and cyclopropylamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.51 — 0.66 (m, 2 H) 0.66 — 0.82 (m, 2 H) 2.43 (s, 3 H) 2.87 (dt, J=7.39, 3.51 Hz, 1 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.38 (d, J=5.81Hz, 2 H) 8.68 (d, J=4.04 Hz, 1 H) 8.83 — 8.93 (m, 1 H) 12.92 —13.43 (m, 1 H). MS m/z [M+H]+ 360.1 Example 128 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N— isopropylnicotinamide H C N \ H I OH N/ I N. \ ’N The title compound was ed in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and isopropylamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.20 (d, J=6.57 Hz, 6 H) 2.44 (s, 3 H) 4.13 (dd, 5, 6.57 Hz, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.74 (s, 1 H) 7.75 — 7.85 (m, 1 H) 8.07 — 8.28 (m, 1 H) 8.45 (dd, J=19.70, 6.82 Hz, 3 H) 8.84 — 8.98 (m, 1 H) 12.97 — 13.37 (m, 1 H). MS m/z [M+H]+ 362.2.
Example 129 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N—(1- (methoxymethyl)cyclopentyl)nicotinamide ,02 ; H3C N \ OH H | N I)! \ ,N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1- (methoxymethyl)cyclopentanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.45 - 1.74 (m, 6 H) 1.94 — 2.08 (m, 2 H) 2.37 (s, 3 H) 3.20 (s, 3 H) 3.54 (s, 2 H) 7.59 (dd, J=7.96, 1.39 Hz, 1 H) 7.66 (s, 1 H) 7.70 (br. s., 1 H) 8.04 (s, 1 H) 8.06 — 8.18 (m, 1 H) 8.33 (d, J=6.57 Hz, 2 H) 8.75 — 8.86 (m, 1 H) 12.59 — 13.45 (m, 1 H). MS m/z [M+H]+ 432.2 Example 130 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(4- hydroxybutyl)nicotinamide N/ [\\j \ :N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 4-aminobutanol. 1H NMR (400 MHz, DMSO—ds) 5 ppm 1.43 — 1.53 (m, 2 H) 1.53 — 1.64 (m, 2 H) 2.44 (s, 3 H) 3.27 — 3.33 (m, 2 H) 3.44 (br. s., 2 H) 4.43 (br. s., 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.07 — 8.27 (m, 1 H) 8.41 (d, J=6.57 Hz, 2 H) 8.70 (t, J=5.43 Hz, 1 H) 8.85 — 8.97 (m, 1 H) 12.82 — 13.57 (m, 1 H). MS m/z [M+H]+ 392.2 Example 131 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—((1s,4s)— 4-hydroxycyclohexyl)nicotinamide N \ H I OH N "\‘\ /N The title nd was prepared in a manner similar to e 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and ) aminocyclohexanol. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.31 — 1.56 (m, 4 H) 1.55 — 1.80 (m, 4 H) 2.37 (s, 3 H) 3.72 (br. s., 2 H) 4.34 (br. s., 1 H) 7.59 (d, J=8.08 Hz, 1 H) 7.66 (s, 1 WO 60810 H) 7.68 — 7.78 (m, 1 H) 8.01 — 8.18 (m, 1 H) 8.39 (d, J=7.07 Hz, 3 H) 8.81 — 8.87 (m, 1 H) 12.83 — 13.38 (m, 1 H). MS m/z [M+H]+ 418.2 Example 132 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N—((1r,4r)- 4-hydr0xycyclohexyl)nic0tinamide ”’N \ H I OH N 5‘] \ :N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (1r,4r) aminocyclohexanol. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.17 - 1.31 (m, 2 H) 1.32 - 1.45 (m, 2 H) 1.77 — 1.91 (m, 4 H) 2.40 — 2.46 (m, 3 H) 3.37 — 3.49 (m, 1 H) 3.65 — 3.82 (m, 1 H) 4.58 (br. s., 1 H) 7.65 (dd, J=7.83, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.25 — 8.65 (m, 3 H) 8.80 — 9.01 (m, 1 H) 12.36 — 13.83 (m, 1 H). MS m/z [M+H]+ 418.2 Example 133 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N— ((tetrahydrofuranyl)methyl)nic0tinamide Qfll.N\OH N l\\l\ :N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- 2-methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and hydrofuran yl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.49 — 1.67 (m, 1 H) 1.75 — 1.89 (m, 2 H) 1.89 — 2.01 (m, 1 H) 2.44 (s, 3 H) 3.35 — 3.42 (m, 2 H) 3.65 (q, J=7.49 Hz, 1 H) 3.80 (q, J=6.82 Hz, 1 H) 4.00 (t, J=6.32 Hz, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.18 (br. s., 1 H) 8.43 (d, J=6.57 Hz, 2 H) 8.82 (t, J=5.31 Hz, 1 H) 8.93 (s, 1 H) 13.20 (br. s., 1 H). MS m/z [M+H]+ 404.2 Example 134 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N— cyclobutylnicotinamide aONIZ / OI The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and cyclobutylamine. 1H NMR (400 MHz, 6) 5 ppm 1.55 — 1.71 (m, 2 H) 1.95 — 2.09 (m, 2 H) 2.11 — 2.24 (m, 2 H) 2.36 (s, 3 H) 4.28 — 4.48 (m, 1 H) 7.59 (dd, J=8.08, 1.52 Hz, 1 H) 7.66 (s, 1 H) 7.70 (br. s., 1 H) 8.10 (br. s., 1 H) 8.35 (d, J=6.57 Hz, 2 H) 8.78 (d, J=7.33 Hz, 1 H) 8.81 — 8.91 (m, 1 H) 13.12 (br. s., 1 H). MS m/z [M+H]+ 374.2 Example 135 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—((1- (methoxymethyl)cyclopropyl)methyl)nicotinamide The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (1- (methoxymethyl)cyclopropyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.36 — 0.44 (m, 2 H) 0.52 — 0.60 (m, 2 H) 2.43 (s, 3 H) 3.22 — 3.28 (m, 5 H) 3.35 (s, 2 H) 7.66 (d, J=7.83 Hz, 1 H) 7.73 (s, 1 H) 7.77 (br. s., 1 H) 8.08 — 8.26 (m, 1 H) 8.42 (d, J=6.57 Hz, 2 H) 8.64 (t, J=5.56 Hz, 1 H) 8.88 — 8.94 (m, 1 H) 12.96 — 13.46 (m, 1 H). MS m/z [M+H]+ 418.2 Example 136 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- methoxypropanyl)nicotinamide CH3O MNN*00H NN :N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- 2-methylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1-methoxypropan amine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.17 (d, J=6.82 Hz, 3 H) 2.44 (s, 3 H) 3.29 (s, 3 H) 3.30 — 3.33 (m, 1 H) 3.44 (dd, J=9.47, 6.44 Hz, 1 H) 4.15 — 4.32 (m, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (5, 1 H) 7.78 (br. 5., 1 H) 8.19 (br. 5., 1 H) 8.43 (d, J=6.82 Hz, 1 H) 8.50 (d, J=7.83 Hz, 2 H) 8.87 — 8.96 (m, 1 H) 13.19 (br. 5., 1 H). MS m/z [M+H]+ 392.2 e 137 (R)(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)-N— (tetrahydrofuran-3 -yl)nic0tinamide OCL O The title nd was prepared in a manner similar to Example 112 using 6-(4-(4- cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (R)—tetrahydr0furan amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.79 - 1.94 (m, 1 H) 2.03 — 2.19 (m, 1 H) 2.36 (5, 3 H) 3.56 (dd, J=9.09, 4.04 Hz, 1 H) 3.66 (td, J=8.15, 5.94 Hz, 1 H) 3.75 — 3.88 (m, 2 H) 4.42 (dtt, J=8.07, 6.29, 6.29, 4.20, 4.20 Hz, 1 H) 7.54 — 7.63 (m, 1 H) 7.66 (5, 1 H) 7.71 (br. ., 1 H) 8.11 (br. 5., 1 H) 8.20 — 8.62 (m, 2 H) 8.71 (d, J=6.32 Hz, 1 H) 8.80 — 8.90 (m, 1 H) 13.12 (br. 5., 1 H). MS m/z [M+H]+ 390.2 e 138A (R)(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)-N— (1-cyclopropylethyl)nic0tinamide CH3 0 N \ N “1‘ \ »-N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (R) cyclopropylethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.17 — 0.27 (m, 1 H) 0.27 — 0.36 (m, 1 H) 0.36 — 0.44 (m, 1 H) 0.44 — 0.53 (m, 1 H) 0.94 — 1.07 (m, 1 H) 1.25 (d, J=6.82 Hz, 3 H) 2.43 (5, 3 H) 3.42 — 3.57 (m, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.69 — 7.75 (m, 1 H) 7.78 (d, J=7.58 Hz, 1 H) 8.17 (br. 5., 1 H) 8.43 (d, J=6.32 Hz, 2 H) 8.59 (d, J=8.08 Hz, 1 H) 8.85 — 8.95 (m, 1 H) 13.19 (br. 5., 1 H). MS m/z [M+H]+ 388.2.
Example 138B (S)(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N—(1- cyclopropylethyl)nicotinamide 9H3 o wk;N \ OH N '32 :N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)—1- cyclopropylethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.18 — 0.26 (m, 1 H) 0.28 — 0.36 (m, 1 H) 0.36 — 0.44 (m, 1 H) 0.44 — 0.53 (m, 1 H) 0.92 — 1.08 (m, 1 H) 1.25 (d, J=6.82 Hz, 3 H) 2.43 (s, 3 H) 3.39 — 3.60 (m, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=6.57 Hz, 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=6.57 Hz, 2 H) 8.59 (d, J=8.08 Hz, 1 H) 8.79 — 9.05 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 388.2.
Example 139 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—((1r,4r)- 4-hydroxycyclohexyl)nicotinamide HO‘0 ”’N \ H I OH N N \ :N The title compound was prepared in a manner similar to e 112 using 6-(4-(4- 2-methylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid and (Ir, 4r) aminocyclohexanol. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.17 - 1.31 (m, 2 H) 1.32 - 1.45 (m, 2 H) 1.77 — 1.91 (m, 4 H) 2.40 — 2.46 (m, 3 H) 3.37 — 3.49 (m, 1 H) 3.65 — 3.82 (m, 1 H) 4.58 (br. s., 1 H) 7.65 (dd, J=7.83, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.25 — 8.65 (m, 3 H) 8.80 — 9.01 (m, 1 H) 12.36 — 13.83 (m, 1 H). MS m/z [M+H]+ 418.2.
Example 140 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- cyclopropylpiperidinyl)nicotinamide The title compound was prepared in a manner similar to Example 112 using 4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1- cyclopropylpiperidinamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.69 (d, J=6.06 Hz, 2 H) 0.82 (br. s., 2 H) 1.79 (d, J=10.86 Hz, 2 H) 1.97 (d, J=10.86 Hz, 2 H) 2.43 (s, 4 H) 2.88 — 3.14 (m, 2 H) 3.35—3.34 (m, 2 H) 4.00 (d, J=6.57 Hz, 1 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.72 (s, 1 H) 7.79 (d, J=8.08 Hz, 1 H) 8.16 (s, 1 H) 8.35 — 8.50 (m, 2 H) 8.66 (d, J=7.07 Hz, 1 H) 8.92 (t, J=1.52 Hz, 1 H) 11.41 — 12.67 (m, 1 H). MS m/z [M+H]+ 443.2.
Example 141 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—((1r,4r)- 4-hydroxycyclohexyl)nicotinamide <3]an/ OH N N‘WN The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid and (Ir, 4r) aminocyclohexanol. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.06 (quin, J=6.88 Hz, 2 H) 2.44 (s, 3 H) 3.28 (q, J=6.74 Hz, 2 H) 4.20 (t, J=6.82 Hz, 2 H) 6.24 (t, J=2.02 Hz, 1 H) 7.38 — 7.50 (m, 1 H) 7.67 (dd, J=8.21, 1.39 Hz, 1 H) 7.71 — 7.86 (m, 3 H) 8.19 (br. s., 1 H) 8.42 (d, J=7.33 Hz, 2 H) 8.75 (t, J=5.18 Hz, 1 H) 8.87 — 8.95 (m, 1 H) 13.20 (br. s., 1 H). MS m/z [M4HT4282 Example 142 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide CKHN \ I OH O / N rle \ ——N The title compound was ed in a manner similar to Example 112 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and hydro-2H-pyran- 2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.17 - 1.31 (m, 2 H) 1.32 - 1.45 (m, 2 H) 1.77 — 1.91 (m, 4 H) 2.40 — 2.46 (m, 3 H) 3.37 — 3.49 (m, 1 H) 3.65 — 3.82 (m, 1 H) 4.58 (br. s., 1 H) 7.65 (dd, J=7.83, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.25 — 8.65 (m, 3 H) 8.80 — 9.01 (m, 1 H) 12.36 — 13.83 (m, 1 H). MS m/z [M+H]+ 418.2. e 143 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)—N—((1- (methoxymethyl)cyc10pentyl)methyl)nic0tinamide HC\3 o’f‘N OH H |\ N lel\ ’N The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (1- (methoxymethyl)cyclopentyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.26 - 1.38 (m, 2 H) 1.38 — 1.59 (m, 6 H) 2.37 (s, 3 H) 3.13 (s, 2 H) 3.21 (s, 3 H) 3.26 (d, J=6.32 Hz, 2 H) 7.59 (dd, J=7.83, 1.52 Hz, 1 H) 7.66 (s, 1 H) 7.73 (d, J=8.08 Hz, 1 H) 8.09 (s, 1 H) 8.33 (s, 2 H) 8.42 (t, J=6.06 Hz, 1 H) 8.82 (t, J=1.52 Hz, 1 H) 12.56 — 13.49 (m, 1 H). MS m/z [M+H]+ 446.2.
Example 144 6-(4-(4-cyan0phenyl)—5-hydr0xy-1H-pyrazolyl)—N—((1r,4r) methylcyclohexyl)nic0tinamide N \ I OH The title compound was prepared in a manner similar to Example 112 using 6-(4-(4- cyanophenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and )—4- methylcyclohexanamine. 1H NMR (400 MHz, g) 5 ppm 0.82 (d, J=6.57 Hz, 3 H) 0.87 — 1.05 (m, 2 H) 1.29 (qd, J=12.34, 2.91 Hz, 3 H) 1.64 (d, J=11.87 Hz, 2 H) 1.72 — 1.85 (m, 2 H) 3.67 (tdt, J=11.67, 11.67, 7.74, 3.92, 3.92 Hz, 1 H) 7.72 (d, J=8.59 Hz, 2 H) 8.07 (d, J=7.58 Hz, 2 H) 8.23 — 8.48 (m, 3 H) 8.57 (br. s., 1 H) 8.75 — 8.93 (m, 1 H) 13.47 (br. s., 1 H).
MS m/z [M+H]+ 402.2.
Example 145 6-(4-(4-cyan0phenyl)hydr0xy-1H-pyrazolyl)-N—(3- methoxybutyl)nic0tina mide CH3 0 HsC‘o)\/\ The title nd was prepared in a manner r to Example 112 using 6-(4-(4- henyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3-methoxybutanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.05 (d, J=6.32 Hz, 3 H) 1.52 — 1.70 (m, 2 H) 3.17 (s, 3 H) 3.26 — 3.36 (m, 3 H) 7.72 (d, J=8.59 Hz, 2 H) 8.07 (d, J=6.57 Hz, 2 H) 8.27 — 8.50 (m, 2 H) 8.61 (t, J=5.43 Hz, 2 H) 8.76 — 8.96 (m, 1 H) 13.46 (br. s., 1 H). MS m/z [M+H]+ 392.1.
Example 146 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(3-methoxy methylpropyl)nicotinamide H3C\ O/\K\HN \ l OH The title compound was prepared in a manner similar to Example 112 using 3- methoxymethoxypropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.84 (d, J=6.82 Hz, 3 H) 1.85 — 2.02 (m, 1 H) 3.03 — 3.31 (m, 7 H) 7.72 (d, J=8.59 Hz, 2 H) 8.07 (d, J=8.08 Hz, 2 H) 8.26 — 8.50 (m, 2 H) 8.53 — 8.69 (m, 2 H) 8.77 — 8.91 (m, 1 H) 13.47 (br. s., 1 H). MS m/z [M+H]+ 392.1.
Example 147 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1- (methoxymethyl)cyclopentyl)methyl)nicotinamide H3C\O 9 N \ H | OH The title compound was prepared in a manner similar to Example 112 using and (1- (methoxymethyl)cyclopentyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.30 — 1.56 (m, 9 H) 3.13 (s, 2 H) 3.21 (s, 3 H) 3.26 (d, J=6.32 Hz, 2 H) 7.73 (d, J=8.34 Hz, 2 H) 8.08 (br. s., 2 H) 8.34 (d, J=7.83 Hz, 1 H) 8.40 — 8.47 (m, 1 H) 8.63 (br. s., 1 H) 8.76 — 8.93 (m, 1 H) 13.47 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Example 148 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(3- methoxypropyl)nicotinamide Combined 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (4.00 g, 13.06 mmol), EDCI (3.76 g, 19.59 mmol), and HOBT hydrate (3.00 g, 19.59 mmol) in DMF (39.6 mL) and treated with Hunig’s base (6.82 mL, 39.2 mmol). Then 3-methoxypropan amine (2.005 mL, 19.59 mmol) was added and the on mixture was stirred at ambient temperature for 24h. The reaction mixture was then diluted with water (200 mL) and acidified with HCl (aq., 1N) until pH=5 and stirred to give a fine suspension. The solid was collected by filtration, suspended in MeOH (150 mL), and heated to reflux for 8 hours, the slowly cooled to ambient temperature. The solid was collected by filtration and dried in vacuum to give the title compound (4.25 g, 11.26 mmol, 86 % yield) as a light yellow solid. 1H NMR (400 MHz, DMSO—d6) 6 ppm 1.78 (quin, J=6.63 Hz, 2 H) 3.30 — 3.37 (m, 2 H) 3.40 (t, J=6.32 Hz, 2 H) 7.79 (d, J=8.34 Hz, 2 H) 8.14 (d, J=6.57 Hz, 2 H) 8.31 — 8.69 (m, 3 H) 8.71 (t, Hz, 1 H) 8.91 (s, 1 H) 13.54 (br. s., 1 H). MS [M+H] 378. e 149 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1- (methoxymethyl)cyclopentyl)nicotinamide H3C\O 92“ “WH OH N fiN Combine 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid (30 mg, 0.098 mmol), EDCI (28.2 mg, 0.147 mmol), and HOBT hydrate (22.50 mg, 0.147 mmol) in DMF (1 mL) and added Hunig’s base (50.6 mg, 0.392 mmol). Then 1— (methoxymethyl)cyclopentanamine (19.0 mg, 0.147 mmol) was added and the reaction mixture was stirred at ambient temperature for 20h. The reaction mixture was purified using HPLC % ACN in water, TEA-buffered) to give the title compound as a solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.52 — 1.80 (m, 6 H) 2.00 — 2.13 (m, 2 H) 3.27 (s, 3H) 3.60 (s, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 7.96 — 8.78 (m, 6 H) 8.79 — 8.99 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 418.
Example 150 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— methylnicotinamide / ‘N H c3 l‘ ‘M \ N\ \ The title nd was prepared in a manner similar to Example 149 using methylamine. MS m/z [M+H]+ 320 Example 15 1 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— cyclopentylnicotinamide oWWIZ \ \ N\ The title compound was prepared in a manner similar to Example 149 using cyclopentanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.46 — 1.80 (m, 6 H) 1.84 — 2.00 (m, 2 H) 4.25 (dq, 1:13.96, 7.05 Hz, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 7.95 — 8.80 (m, 6 H) 8.83 — 8.97 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 374.
Example 152 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2- methoxyethyl)nicotinamide / N ;N /O\/\H \ \ N \ H3O ‘ The title compound was ed in a manner similar to Example 149 using 2- methoxyethanamine. MS m/z [M+H]+ 364.
Example 153 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— ((tetrahydrofuranyl)methyl)nicotinamide OQ O /']l fiN N \ N.\ The title compound was prepared in a manner r to Example 149 using (tetrahydrofuranyl)methanamine. MS m/z [M+H]+ 390.
Example 154 (R)—6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N— (tetrahydrofuran-3 -yl)nicotinamide ©~ w i“ The title compound was prepared in a manner similar to Example 149 using (R)- tetrahydrofuranamine. MS m/z [M+H]+ 376.
Example 155 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(tetrahydro-2H- pyranyl)nicotinamide O O L) 0” w e“ H \ N.\ WO 60810 The title compound was prepared in a manner similar to Example 149 using tetrahydro-2H-pyran-3 -amine. MS m/z [M+H]+ 390.
Example 156 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1-methoxy methylbutanyl)nicotinamide H3C\ 3C?fi»\Q\N\§/©/O OH / N fiN CH3 N— The title compound was prepared in a manner similar to Example 149 using 1- ymethylbutanamine. MS m/z [M+H]+ 406.
Example 157 N—benzyl(4-cyano-5'-hydroxy-1'H-[1,4'-bipyrazol]-1'- yl)nicotinamide QMNWNE Combined N—benzyl—6—hydrazinylnicotinamide (103 mg, 0.427 mmol) and ethyl 2-(4- cyano-1H-pyrazolyl)(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1.4 mL) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was stirred for 2.5h and then Hunig’s base (297 [11, 1.708 mmol) was added and the resulting red on was stirred at ambient temperature for 2.5h. The reaction mixture was then concentrated in vacuo and purified using HPLC (20-95% ACN in water, TEA-buffered).
Product—containing fractions were concentrated in vacuo to give a solid e ~50 mL).
The solid was filtered and dried in vacuum to give the title compound (65.4 mg, 39.8 % yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 4.53 (d, J=5.81 Hz, 2 H) 7.27 (dq, J=8.46, 4.17 Hz, 1 H) 7.31 — 7.44 (m, 4 H) 8.29 (s, 1 H) 8.33 — 8.58 (m, 3 H) 8.93 (s, 1 H) 8.98 (s, 1 H) 9.30 (t, J=5.81 Hz, 1 H) 12.33 — 14.49 (br s, 1 H). MS m/z [M+H]+ 386. e 158 6-(4-cyano-5'-hydroxy-1'H-[1,4'-bipyrazol]-1'-yl)-N—((tetrahydro-2H- pyranyl)methyl)nicotinamide O@N*0NN§N:{ Combined 6-hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide (107 mg, 0.427 mmol) and ethyl 2-(4-cyano-1H-pyrazolyl)(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1423 pl) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was d overnight (15h) and then Hunig’s base (297 [11, 1.708 mmol) was added and the reaction was d at ambient temperature for 2.5h. The on mixture was then trated in vacuo and purified using HPLC (20-95% ACN in water, TFA—buffered). Product—containing fractions were concentrated in vacuo to give a solid (volume ~20 mL). The solid was filtered and dried in vacuum to give the title compound (57.4 mg, 34.2 % yield) as an ite solid. 1H NMR (400 MHz, 6) 5 ppm 1.22 (qd, J=12.21, 4.29 Hz, 2 H) 1.62 (d, J=12.88 Hz, 2 H) 1.81 (m, J=10.96, 7.29, 3.76, 3.76 Hz, 1 H) 3.20 (t, 2 H) 3.27 (t, J=10.86 Hz, 2 H) 3.86 (dd, J=11.24, 2.65 Hz, 2 H) 8.29 (s, 1 H) 8.42 (br. s., 3 H) 8.74 (t, J=5.68 Hz, 1 H) 8.93 (s, 2 H) 13.41 (br. s., 1 H). MS m/z [M+H]+ 394.
Example 159 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— isopropylnicotinamide H3;NH HaC OwNWOH\ gN Combined 6—(4—(4—cyanophenyl)—5—hydroxy—1H—pyrazol—1—yl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94 mg, 0.490 mmol), HOBT hydrate (75 mg, 0.490 mmol) in DMF (1 mL) and then add Hunig’s base (127 mg, 0.980 mmol). Then propanamine (28.9 mg, 0.490 mmol) was added and the mixture was stirred at ambient temperature for 16h. The mixture was diluted with water (4 mL) and acidified with 1N HCl to pH = 5—6 to give a solid.
The solid was collected by filtration, washed with water (2 mL), and recrystallized from hot MeOH (3—6 mL) to give the title compound (62.0 mg, 54.7 % yield) as an off—white solid. MS m/z [M+H]+ 348.
Example 160 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— isobutylnicotinamide H3C\<::H3 OH /N The title compound was prepared in a manner similar to Example 159 using 2- methylpropanamine. MS m/z [M+H]+ 362 Example 161 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— cyclopropylnicotinamide \ ;N The title compound was ed in a manner similar to e 159 using cyclopropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.55 — 0.66 (m, 2 H) 0.67 — 0.78 (m, 2 H) 2.87 (m, 9, 7.33, 3.98, 3.98 Hz, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.14 (br. s., 2 H) 8.40 (br. s., 1 H) 8.42 — 8.60 (m, 1 H) 8.68 (d, J=3.54 Hz, 2 H) 8.85 — 8.90 (m, 1 H) 13.53 (br. s., 2 H). MS m/z [M+H]+ 346.
Example 162 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(3- ethoxypropyl)nicotinamide H3O O \ / N \ N \ The title compound was prepared in a manner similar to Example 159 using 3- ethoxypropanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.12 (t, J=7.07 Hz, 3 H) 1.78 (quin, 2 H) 3.35 (q, J=6.74 Hz, 2 H) 3.42 (q, J=6.82 Hz, 4 H) 7.79 (d, J=8.34 Hz, 2 H) 8.14 (br. s., 2 H) 8.41 (d, J=7.33 Hz, 2 H) 8.69 (t, J=5.31Hz, 2 H) 8.87 — 8.95 (m, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 392.
Example 163 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(3- isopropoxypropyl)nicotinamide )\ OH \ /N O / 8 Ome N \ The title compound was prepared in a manner similar to Example 159 using 3- isopropoxypropan-l-amine. MS m/z [M+H]+ 406.
Example 164 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1s,4s) hydroxycyclohexyl)nicotinamide H00NH OWWJ‘W/OH\ gN The title compound was prepared in a manner similar to Example 159 using (1s,4s)—4- yclohexanol hydrochloride. MS m/z [M+H]+ 404.
Example 165 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1r,4r)—4- hydroxycyclohexyl)nicotinamide HOI--<:>—NH _ \ / NV O N N The title compound was prepared in a manner similar to e 159 using (1r,4r) aminocyclohexanol hydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.42 — 1.86 (m, 8 H) 3.71 — 3.96 (m, 5 H) 4.41 (br. s., 1 H) 7.21 — 7.68 (m, 2 H) 8.06 (d, J=5.05 Hz, 1 H) 8.13 — 8.79 (m, 4 H) 8.90 (s, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 404.
Example 166 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—((1s,4s)- 4-hydroxycyclohexyl)nicotinamide HO’O‘NWN \HO | O N/ ‘N’ CH3 The title compound was prepared in a manner similar to Example 159 using 6-(5- hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and (1s,4s)—4- aminocyclohexanol hydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.15 - 1.46 (m, 4 H) 1.77 — 1.96 (m, 4 H) 3.38 — 3.48 (m, 1 H) 3.67 — 3.82 (m, 1 H) 4.58 (br. s., 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.14 (d, J=6.82 Hz, 2 H) 8.29 — 8.76 (m, 4 H) 8.89 (s, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 410.
Example 167 ydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—((1r,4r)— 4-hydroxycyclohexyl)nicotinamide \ / ' O N N CH3 WO 60810 The title compound was ed in a manner similar to e 159 using 6-(5- hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and (1r,4r) aminocyclohexanol hydrochloride. MS m/z [M+H]+ 410.
Example 168 6-(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)-N-(1-(2- methoxyethyl)cyclopropyl)nicotinamide The title compound was ed in a manner similar to Example 159 using 6-(4-(4- cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1-(2- methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO—d6) 5 0.58 — 0.74 (m, 4 H) 1.80 (t, J=6.9 Hz, 2 H) 3.14 (s, 4 H) 3.39 (t, J=7.1Hz, 2 H) 3.89 (s, 3 H) 7.32 — 7.44 (m, 2 H) 8.27 — 8.35 (m, 2 H) 8.42 (d, J=8.8 Hz, 1 H) 8.57 (d, J=7.6 Hz, 1 H) 8.76 (s, 1 H) 8.80 (d, J=1.8 Hz, 1 H). MS m/z [M+H]+ 434.5.
Example 169 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N-((1s,2s) methylcyclopropyl)nicotinamide fi' ' I N H OH H3C \ ;N O \ N/ N \ Combine 6—(4—(4—cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94 mg, 0.490 mmol), HOBT hydrate (75 mg, 0.490 mmol) in DMF (1 mL) and added Hunig’s base (127 mg, 0.980 mmol). Then (1s,2s)—2- methylcyclopropanamine (34.8, 0.490 mmol) was added and the mixture was stirred at 60°C for 3h. The reaction mixture was diluted with water (4 mL) and acidified with 1N HCl to pH = 5—6 to give a solid. The solid was collected by filtration, washed with water (2 mL), and recrystallized from hot MeOH (3-6 mL) to give the title compound (79.2 mg, 67.5 % yield) as a white solid. MS m/z [M+H]+ 360.
Example 170 (R)(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N-(1,1,1- trifluoropropanyl)nicotinamide 2014/031918 F78\NH OH \ /N F / F OwNJE/Q/ The title compound was ed in a manner similar to Example 169 using (R)- 1,1,1-trifluoropropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.40 (d, J=7.07 Hz, 3 H) 4.89 (m, J=15.36, 7.44, 7.44, 7.44, 7.44, 7.44 Hz, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.15 (d, J=7.58 Hz, 2 H) 8.35 — 8.77 (m, 3 H) 8.95 (s, 1 H) 9.08 (d, J=8.84 Hz, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 402.
Example 171 (S)—6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1,1,1- trifluoropropanyl)nicotinamide F N” \ /N F / The title nd was prepared in a manner similar to Example 169 using (S)-1,1,1- trifluoropropanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.40 (d, 3 H) 4.89 (m, J=15.47, 7.64, 7.64, 7.64 Hz, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.15 (d, J=5.30 Hz, 2 H) 8.29 — 8.81 (m, 3 H) 8.95 (s, 1 H) 9.09 (d, J=8.59 Hz, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 402.
Example 172 (R)(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N-(1- (tetrahydro-2H-pyranyl)ethyl)nicotinamide x“ NH H3C OH \ ;N The title compound was prepared in a manner similar to Example 169 using (R) (tetrahydro-2H-pyranyl)ethanamine. MS m/z [M+H]+ 418.
Example 173 (S)(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)—N—(1- (tetrahydro-2H-pyranyl)ethyl)nicotinamide H3C O’KQNW/OH\ 3N The title compound was prepared in a manner similar to Example 169 using (S) (tetrahydro-2H-pyranyl)ethanamine. MS m/z [M+H]+ 418.
Example 174 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2-(tetrahydro- 2H-pyranyl)ethyl)nicotinamide The title compound was prepared in a manner similar to Example 169 using 2- (tetrahydro-2H-pyranyl)ethanamine hydrochloride. MS m/z [M+H]+ 418.
Example 175 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(4-methoxy butanyl)nicotinamide N \ / N \ HC\ H 3 O N \_ The title nd was prepared in a manner similar to Example 169 using 4- methoxymethylbutanamine. MS m/z [M+H]+ 406.
Example 176 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(4-methoxybutan- 2-yl)nicotinamide H3C‘O/\)\NH HO //N O \ N/ N \ The title compound was prepared in a manner similar to e 169 using 4- methoxybutanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.18 (d, 3 H) 1.64 — 1.88 (m, 2 H) 3.22 (s, 3 H) 3.38 (t, J=6.57 Hz, 2 H) 4.03 — 4.21 (m, 1 H) 7.79 (d, 2 H) 8.14 (br. s., 2 H) 8.27 — 8.79 (m, 4 H) 8.90 (s, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 392.
Example 177 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2- (tetrahydrofuranyl)ethyl)nicotinamide WNHO “Kg/MWOH\ ;N The title compound was ed in a manner similar to Example 169 using 2- (tetrahydrofuranyl)ethanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.48 (dq, 7, 7.72 Hz, 1 H) 1.62 (qd, J=7.16, 1.52 Hz, 2 H) 2.04 (m, 3, 7.58, 7.58, 4.80 Hz, 1 H) 2.13 — 2.26 (m, 1 H) 3.23 — 3.32 (m, 3 H) 3.58 — 3.67 (m, 1 H) 3.73 (td, J=8.21, 4.80 Hz, 1 H) 3.80 — 3.87 (m, 1 H) 7.79 (d, 2 H) 8.14 (br. s., 2 H) 8.31 — 8.78 (m, 4 H) 8.87 — 8.94 (m, 4 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 404.
Example 178 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2-(tetrahydro- 2H-pyran-3 -yl)ethyl)nicotinamide OwN‘JE/Q/OH\ fiN The title compound was prepared in a manner similar to Example 169 using 2- (tetrahydro-2H-pyranyl)ethanamine. MS m/z [M+H]+ 418.
Example 179 6-(4-(4-cyanomethylphenyl)hydroxy-lH-pyrazolyl)-N—(4- methoxybutyl)nicotinamide /O\/\/\HNmHO \ N/ NQ/Q/\ Combined 6—(4—(4—cyanomethylphenyl)hydroxy- 1H-pyrazolyl)nicotinic acid (50 mg, 0.156 mmol) and 4-methoxybutanamine (29.0 mg, 0.281 mmol) in DMF (1 mL). Then added a solution of 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (50 mg, 0.261 mmol) and triethylamine (0.121 mL, 0.868 mmol) in DMF (0.5 mL), and a solution of HOBT (35 mg, 0.259 mmol) in DMF (0.5 mL). The mixture was then stirred overnight at room temperature. Into the reaction mixture was then poured 20 mL of saturated ammonium chloride solution and was rigorously stirred for 1 hour to give a solid.
The solid was collected on by filtration, washed three times with ted ammonium chloride solution, and then twice with ether, before being dried to give the title compound (49 mg, 77 % yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.50 - 1.61 (m, 4 H) 2.42 (s, 3 H) 3.23 (s, 3 H) 3.25 — 3.45 (m, 8 H) 7.42 — 7.47 (m, 1 H) 7.49 (s, 1 H) 7.80 (s, 1 H) 8.19 (dd, J=8.72, 2.40 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.49 — 8.57 (m, 2 H) 8.83 (d, J=2.02 Hz, 1 H). MS m/z [M+H]+ 406.2.
Example 180 6-(4-(4-cyanomethylphenyl)hydroxy-lH-pyrazolyl)—N— (cyclobutylmethyl)nicotinamide HO é“ The title compound was prepared in a manner similar to e 179 using cyclobutylmethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.64 - 1.90 (m, 4 H) 1.93 — 2.09 (m, 2 H) 2.43 (s, 3 H) 7.61 — 7.84 (m, 3 H) 8.10 — 8.24 (m, 1 H) 8.35 — 8.51 (m, 2 H) 8.62 — 8.76 (m, 1 H) 8.86 — 8.97 (m, 1 H) 12.98 — 13.41 (m, 1 H). MS m/z [M+H]+ 388.2.
Example 181 6-(4-(4-cyanomethylphenyl)hydroxy-lH-pyrazolyl)—N—(3- methoxybutyl)nicotinamide HO / N H3C\O)\/\HN / \ N N.N_ The title compound was prepared in a manner similar to Example 179 using 3- methoxybutan-l-amine, HCl . 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.11 (d, J=6.06 Hz, 3 H) 1.54 — 1.80 (m, 2 H) 2.41 (s, 3 H) 3.24 (s, 3 H) 7.23 (br. s., 3 H) 7.36 — 7.50 (m, 2 H) 7.72 (s, 1 H) 8.14 (dd, J=8.84, 2.27 Hz, 1 H) 8.34 — 8.40 (m, 1 H) 8.46 (d, J=10.61 Hz, 1 H) 8.58 (s, 1 H) 8.80 (d, J=2.02 Hz, 1 H). MS m/z [M+H]+ 406.2.
Example 182 6-(4-(4-cyanomethylphenyl)hydroxy-lH-pyrazolyl)—N—(3- methoxymethylpropyl)nicotinamide mHO //N H30‘0/\(\HN \ / \ CH3 N‘N_ The title compound was prepared in a manner similar to Example 179 using 3- ymethylpropanamine, HCl. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.90 (d, J=6.82 Hz, 3 H) 2.01 (dd, 4, 6.57 Hz, 1 H) 2.41 (s, 3 H) 3.07 — 3.17 (m, 1 H) 3.17 — 3.23 (m, 1 H) 3.26 (s, 3 H) 7.24 (br. s., 4 H) 7.40 (dd, J=8.21, 1.64 Hz, 1 H) 7.43 (s, 1 H) 7.71 (s, 1 H) 8.15 (dd, J=8.84, 2.53 Hz, 1 H) 8.39 (d, J=8.34 Hz, 1 H) 8.46 (t, J=5.68 Hz, 1 H) 8.56 (d, J=8.84 Hz, 1 H) 8.81 (d, J=2.02 Hz, 1 H). MS m/z [M+H]+ 406.2.
Example 183 6-(4-(4-cyanomethylphenyl)hydroxy-lH-pyrazolyl)—N—((1r,4r)- 4-methylcyclohexyl)nicotinamide H3C0 mHO ;N .,,N \ H N/ N\ \ The title compound was prepared in a manner similar to e 179 using (1r,4r)methylcyclohexanamine — 0.92 (m, 3 . 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.84 H) 0.95 — 1.11 (m, 2 H) 1.26 — 1.44 (m, 3 H) 1.65 — 1.94 (m, 4 H) 2.41 (s, 3 H) 3.66 — 3.82 (m, 1 H) 7.27 (br. s., 2 H) 7.43 (d, J=8.34 Hz, 1 H) 7.46 — 7.50 (m, 1 H) 7.77 (s, 1 H) 8.14 — 8.34 (m, 3 H) 8.54 (d, J=8.84 Hz, 1 H) 8.81 (d, J=2.02 Hz, 1 H). MS m/z [M+H]+ 416.2.
Example 184 4-(5-hydroxy(5-(3 -methoxyazetidinecarbonyl)pyridinyl)— 1H- pyrazolyl)methylbenzonitrile N \ / The title compound was prepared in a manner similar to Example 179 using 3- methoxyazetidine, HCl. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.41 (s, 3 H) 3.24 (s, 3 H) 3.86 (br. s., 1 H) 4.26 (br. s., 3 H) 4.53 (br. s., 1 H) 7.21 (br. s., 3 H) 7.38 — 7.49 (m, 2 H) 7.71 — 7.78 (m, 1 H) 7.99 (dd, , 2.40 Hz, 1 H) 8.35 (d, J=8.34 Hz, 1 H) 8.57 (d, J=8.84 Hz, 1 H) 8.63 (d, J=2.02 Hz, 1 H); MS m/z [M+H]+ 390.2. e 185 4-(1-(5-(2-oxaazaspiro[3.3]heptanecarbonyl)pyridinyl) hydroxy- 1H-pyrazolyl)-3 -methylbenzonitrile Combined 6—(4—(4—Cyanomethylphenyl)hydroxy- 1H-pyrazolyl)nicotinic acid (27 mg, 0.084 mmol) and 2-oxaazaspiro[3.3]heptane (12.53 mg, 0.126 mmol) in acetonitrile (1 mL) and DMF (0.5 mL). Then triethylamine (0.035 mL, 0.253 mmol) and 1- (3-dimethylaminopropyl)—3—ethylcarbodiimide hydrochloride (19.39 mg, 0.101 mmol) were added and the reaction was d at room temperature overnight. Afew drops of 1N NaOH solution were added to give a clear solution, and then the mixture was diluted in ACN and d by HPLC (Waters SunFire C18, 5 um, ID 30x75mm, 35—65 % ACN/water + 0.05% TFA) to give the title compound (3.6 mg, 10.64 % yield) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.43 (s, 3 H) 4.23 - 4.30 (m, 2 H) 4.53 - 4.60 (m, 2 H) 4.65 - 4.74 (m, 3 H) 7.61 - 7.88 (m, 4 H) 8.24 (br. s., 2 H) 8.49 - 8.78 (m, 2 H) 13.27 (br. s., 2 H). MS m/z [M+H]+ 402.1.
Example 186 6-(4-(4-cyanomethylphenyl)hydroxy-1H—pyrazolyl)-N-(1- methylazetidin-3 -yl)nicotinamide H c—3 N©NNHW~N\ N \N/ CH3 Combined 4—cyanomethylphenyl)hydroxy- 1H-pyrazolyl)nicotinic acid (27 mg, 0.084 mmol), 1-methylazetidinamine, 2HCl (16.09 mg, 0.101 mmol) and 1- hydroxybenzotriazole (13.67 mg, 0.101 mmol) in acetonitrile (1 mL) and DMF (0.5 mL).
Then triethylamine (0.047 mL, 0.337 mmol) and 1-(3 -dimethylaminopropyl) ethylcarbodiimide hydrochloride (19.39 mg, 0.101 mmol) were added and the reaction was stirred at room temperature overnight. The reaction mixture was then diluted with acetonitrile and purified by preparatory HPLC (Waters e C18, 5 um, ID 30x75mm, 20—50 % ACN/water + 0.05% TFA) to give the title compound as the TFA salt (12 mg, 28.3 % yield) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.43 (s, 3 H) 2.88 — 2.97 (m, 3 H) 3.99 — 4.60 (m, 5 H) 4.76 (br. s., 1 H) 7.57 — 7.87 (m, 3 H) 8.22 (br. s., 1 H) 8.36 — 8.72 (m, 2 H) 8.94 (s, 1 H) 9.32 (d, Hz, 1 H) 9.83 (br. s., 1 H) 13.25 (br. s., 1 H). MS m/z [M+H]+ 389.1.
Example 187 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N-(1- (dimethylamino)methylpropanyl)nicotinamide HO éN H30 01'st 8L“N \ N/ \ ,N~ N CH3 H 03 The title compound was prepared in a manner similar to Example 185 using N1 ,N1,2-trimethylpropane-1,2-diamine, 2HCl to give the title nd as a TFA salt (36 mg, 40.1 % yield) as a white solid. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.35 — 1.64 (m, 6 H) 2.44 (s, 3 H) 2.74 — 2.94 (m, 6 H) 3.59 — 3.73 (m, 3 H) 7.59 — 7.91 (m, 3 H) 8.04 — 8.73 (m, 4 H) 8.82 — 8.99 (m, 1 H) 9.14 (br. s., 1 H) 13.21 (br. s., 1 H). MS m/z [M+H]+ 419.2.
Example 188 N—benzyl(4-(4-cyanofluorophenyl)—5-hydroxy-1H-pyrazol yl)nicotinamide NH _ F \ / N o N N Combined N—benzyl—6-hydrazinylnicotinamide (30 mg, 0.124 mmol), methyl 2-(4- cyanofluorophenyl)-3 thylamino)acrylate (40.0 mg, 0.161 mmol) and acetic acid (0.021 mL, 0.371 mmol) in 2-propanol (1.0 mL) and stirred at 20°C for 28 h. Then Hunig’s base (0.130 mL, 0.743 mmol) was added and the reaction mixture was heated at 50°C for 15 h. The reaction mixture was diluted with DMSO (0.1 mL) and d by prep HPLC to give the title compound (22 mg, 43.0 % yield) as a peach solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 4.53 (d, J=5.8 Hz, 2 H) 7.21 — 7.30 (m, 1 H) 7.31 — 7.39 (m, 4 H) 7.85 (t, J=7.7 Hz, 1 H) 7.99 (d, J=8.3 Hz, 1 H) 8.10 (d, J=11.9 Hz, 1 H) 8.42 — 8.58 (m, 2 H) 8.74 (br. s., 1 H) 8.97 (d, J=1.5 Hz, 1 H) 9.27 (t, J=5.9 Hz, 1H) 13.81 (hrs, 1 H). MS m/z 414 [M+H]+. e 189 6—(4-(4-cyanofluorophenyl)—5-hydroxy-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide QO N NH _ F \ / N\ , O N N The title compound was prepared in a manner similar to Example 188 using 6- hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide, HCl. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.13 — 1.30 (m, 2 H) 1.62 (d, J=12.9 Hz, 2 H) 1.81 (ddd, J=11.1, 7.3, 4.0 Hz, 1 H) 3.20 (t, J=6.3 Hz, 2 H) 3.27 (td, J=11.6, 1.8 Hz, 2 H) 3.86 (dd, J=11.2, 2.7 Hz, 2 H) 7.80 — 7.90 (m, 1 H) 7.99 (d, J=8.1Hz, 1 H) 8.10 (d, J=12.1Hz, 1 H) 8.37 — 8.45 (m, 1 H) 8.48 (br. s., 1 H) 8.66 — 8.81 (m, 2 H) 8.91 (s, 1 H) 13.82 (br. s., 1 H). MS m/z 422 [M+H]+.
Example 190 6-(5-hydroxy(4-oxopyridin-1(4H)-yl)-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide 1 16 2014/031918 Q:W:50 Combined 6-hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide, 1.0 HCl (30 mg, 0.105 mmol), ethyl 3-(dimethylamino)(4-oxopyridin-1(4H)-yl)acrylate (37.1 mg, 0.157 mmol) and acetic acid (0.018 mL, 0.314 mmol) in 2—propanol (0.8 mL) and stirred at °C for 1 hour and then at 50°C for 16 hours and then 80°C for 24 h. The reaction mixture was then diluted with 200 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (11 mg, 26.6 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.11 — 1.32 (m, 2 H) 1.62 (d, J=13.4 Hz, 2 H) 1.73 — 1.90 (m, 1 H) 3.20 (t, J=6.2 Hz, 2 H) 3.25 (s, 2 H) 3.86 (dd, J=11.4, 2.8 Hz, 2 H) 6.56 (br. s., 2 H) 8.19 (br. s., 2 H) 8.40 (t, J=7.7 Hz, 3 H) 8.71 (t, J=5.3 Hz, 1 H) 8.91 (s, 1 H). MS m/z 396 [M+H]+.
Example 191 N—benzyl(5-hydroxy(4-oxopyridin-1(4H)-yl)-1H-pyrazol yl)nicotinamide NWNHN>jN// The title nd was prepared in a manner similar to Example 188 using N- hydrazinylnicotinamide and ethyl 3 -(dimethylamino)(4-oxopyridin-1(4H)- yl)acrylate. MS m/z 388 [M+H]+. 1H NMR (400 MHz, DMSO—d6) 5 ppm 4.53 (d, J=5.6 Hz, 2 H) 6.68 (br. s., 2 H) 7.27 (dq, J=8.5, 4.2 Hz, 1 H) 7.30 — 7.41 (m, 4 H) 8.29 (br. s., 2 H) 8.37 — 8.54 (m, 3 H) 8.97 (s, 1 H) 9.27 (t, J=5.8 Hz, 1 H).
Example 192 6-(5-hydroxy(2-oxopyridin-1(2H)-yl)-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide Og—C>fN2:1th The title compound was prepared in a manner similar to Example 188 using 6- hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide and ethyl 3-(dimethylamino)- 2-(2-oxopyridin-1(2H)-yl)acrylate. 1H NMR (400 MHz, 6) 5 ppm 1.10 - 1.32 (m, 2 H) 1.62 (d, J=12.9 Hz, 2 H) 1.81 (ddd, J=11.1, 7.3, 4.0 Hz, 1 H) 3.20 (t, J=6.3 Hz, 2 H) 3.24 — 3.31 (m, 2 H) 3.86 (dd, J=11.2, 2.7 Hz, 2 H) 6.31 (t, J=6.6 Hz, 1 H) 6.44 — 6.59 (m, 1 H) 7.48 (t, J=7.8 Hz, 1 H) 7.80 (br. s., 1 H) 8.27 — 8.61 (m, 2 H) 8.73 (br. s., 1 H) 8.92 (s, 1 H) 13.12 (br. s., 1 H). MS m/z 396 [M+H]+.
Example 193 N—benzyl(5-hydroxy(2-oxopyridin-1(2H)-yl)—1H-pyrazol yl)nicotinamide Og—C>fl\JHIRE/IQ The title compound was prepared in a manner similar to Example 188 using ethyl 3- (dimethylamino)(2-oxopyridin-1(2H)-yl)acrylate. 1H NMR (400 MHz, DMSO-d6) 5 ppm 4.52 (d, J=5.8 Hz, 2 H) 6.31 (td, J=6.8, 1.1 Hz, 1 H) 6.49 (d, J=9.1 Hz, 1 H) 7.19 — 7.40 (m, 6 H) 7.47 (ddd, J=9.2, 6.8, 2.0 Hz, 1 H) 7.80 (d, J=6.1 Hz, 1 H) 8.28 (br. s., 1 H) 8.36 — 8.56 (m, 1 H) 8.93 — 9.02 (m, 1 H) 9.27 (t, J=5.8 Hz, 1 H) 13.05 (br. s., 1 H). MS m/z388 [M+H]+.
Example 194 6-(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)—N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide The title nd was prepared in a manner similar to e 188 using ethyl 2- (4-cyanomethoxyphenyl)(dimethylamino)acrylate and 6-hydrazinyl-N—((tetrahydro-2H- 4-yl)methyl)nicotinamide to afford the title compound. 1H NMR (400 MHz, DMSO— d6) 5 ppm 1.09 (t, J=7.1Hz, 11 H) 1.22 (d, J=9.6 Hz, 3 H) 1.62 (d, J=12.1Hz, 2 H) 3.19 (dd, J=11.6, 5.6 Hz, 4 H) 3.86 (d, J=9.6 Hz, 2 H) 3.97 (s, 3 H) 7.38 — 7.57 (m, 2 H) 8.43 (br. s., 2 H) 8.72 (br. s., 1 H) 8.92 (s, 1 H). MS m/z [M+H]+ 434.4.
Example 195 N—benzyl(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazol yl)nicotinamide The title compound was prepared in a manner similar to Example 188 using ethyl 2- (4-cyanomethoxyphenyl)(dimethylamino)acrylate and N—benzyl hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO—d6) 5 ppm 3.97 (s, 3 H) 4.53 (d, J:56 Hz, 2 H) 7.27 (d, J=3.8 Hz, 1 H) 7.36 (d, J=4.0 Hz, 5 H) 7.42 — 7.59 (m, 2 H) 8.47 (d, J=6.6 Hz, 1 H) 8.98 (s, 1 H) 9.28 (br. s., 1 H). MS m/z [M+H]+ 426.4.
Example 196 N—benzyl(4-(2-chlorocyanophenyl)hydroxy-1H-pyrazol yl)nicotinamide @HN \ | OH N r\\1 \ /N The title nd was prepared in a manner similar to Example 188 using ethyl 2- (2-chlorocyanophenyl)(dimethylamino)acrylate and N—benzyl hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO-d6) 5 ppm 4.44 (d, J=5.8 Hz, 2 H) 7.13 — 7.22 (m, 2 H) 7.27 (d, J=4.3 Hz, 5 H) 7.75 (d, J=8.3 Hz, 1 H) 8.00 (s, 1 H) 8.30 — 8.47 (m, 2 H) 8.90 (s, 1 H) 9.20 (t, J=5.3 Hz, 1 H). MS m/z [M+H]+ 430.3.
Example 197 2-chlorocyanophenyl)hydroxy-1H-pyrazolyl)—N— ahydro-2H-pyranyl)methyl)nicotinamide (OmN \ I. O“ N[\\]\ :N The title compound was prepared in a manner similar to Example 188 using 6- hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide and ethyl 2-(2-chloro cyanophenyl)(dimethylamino)acrylate. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.13 — 1.39 (m, 4 H) 1.68 (d, J=12.9 Hz, 2 H) 3.20 — 3.37 (m, 6 H) 3.63 (s, 1 H) 3.92 (dd, J=11.2, 2.7 Hz, 2H) 7.90 (d, J=8.1Hz, 1 H) 8.15 (s, 1 H) 8.49 (d, J=3.8 Hz, 2 H) 8.73 — 8.87 (m, 1 H) 8.98 (s, 1 H). MS m/z [M+H]+ 438.4.
Example 198 give 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(1- methylcyclopropyl)nicotinamide CH3 HO VLNH — \ / N\ / O N N Combined EDC (56.3 mg, 0.294 mmol), HOBT (39.7 mg, 0.294 mmol) and 6—(4—(4— cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid (45 mg, 0.147 mmol) in DMF (0.8 mL) then added 1-methylcyclopropanamine hydrochloride (47.4 mg, 0.441 mmol) and s base (0.180 mL, 1.028 mmol) and stirred at 20°C for 16 h. The reaction mixture was diluted with 100 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (27 mg, 51.1 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.60 — 0.68 (m, 2 H) 0.73 — 0.81 (m, 2 H) 1.40 (s, 3 H) 7.75 (d, J=8.6 Hz, 2 H) 8.06 — 8.16 (m, 2 H) 8.35 (dd, J=8.6, 2.3 Hz, 1 H) 8.46 (d, J=8.8 Hz, 1 H) 8.54 (s, 1 H) 8.82 — 8.90 (m, 2 H) 13.53 (br. s., 1 H). MS m/z 360 [M+H]+.
Example 199 4-cyanophenyl)hydroxy-1H-pyrazolyl)-N-(1- (methoxymethyl)cyclobutyl)nicotinamide O/CHg //N NH _ \ / N~ / O N N Combined 6—(4—(4—cyanophenyl)—5—hydroxy—1H—pyrazol—1—yl)nicotinic acid (48 mg, 0.157 mmol), HATU (119 mg, 0.313 mmol) and 1-(methoxymethyl)cyclobutanamine hloride (47.5 mg, 0.313 mmol) in DMF (0.9 mL) then added Hunig’s base (0.137 mL, 0.784 mmol) and the reaction mixture was stirred at 20°C for 1 h. Water (100 uL) was then added and the mixture was heated at 70°C for 16 h, then diluted with 100 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (25 mg, 39.5 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.72 - 1.95 (m, 2 H) 2.10 — 2.21 (m, 2 H) 2.21 — 2.35 (m, 2 H) 3.31 (s, 3 H) 3.65 (s, 2 H) 7.79 (d, J=8.6 Hz, 2 H) 8.14 (d, J=6.1 Hz, 2 H) 8.44 (d, J=6.6 Hz, 2 H) 8.65 (s, 2 H) 8.87 — 8.95 (m, 1 H) 13.55 (br. s., 1 H). MS m/z 404 [M+H]+.
Example 200 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N-(1-methoxy methylpropanyl)nicotinamide HsgiNHO HO H3C \ / N‘ / O N N The title compound was prepared in a manner similar to Example 199 using 1- methoxymethylpropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.35 (s, 6 H) 3.29 (s, 3 H) 3.49 — 3.59 (m, 2 H) 7.80 (d, J=8.6 Hz, 2 H) 7.96 (s, 1 H) 8.15 (d, J=4.5 Hz, 2 H) 8.40 (d, J=7.1Hz, 2 H) 8.66 (br. s., 1 H) 8.82 — 8.89 (m, 1 H) 13.57 (br. s., 1 H). MS m/z 392 [M+H]+.
Example 201 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1- xymethyl)cyclopropyl)nicotinamide H30\ OQ~NH HO \ / Nx / o N N The title compound was prepared in a manner similar to Example 199 using 1- (methoxymethyl)cyclopropanamine hloride. 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.80 (s, 4 H) 3.29 (s, 3 H) 3.49 (s, 2 H) 7.79 (d, J=8.6 Hz, 2 H) 8.15 (d, J=7.6 Hz, 2 H) 8.38 — 8.55 (m, 2 H) 8.66 (br. s., 1 H) 8.89 — 8.95 (m, 1 H) 8.97 (s, 1 H) 13.52 (s, 1 H). MS m/z 390 [M+H]+.
Example 202 N—(tert-butyl)(4-(4-cyanophenyl)hydroxy-1H-pyrazol otinamide H3C HO H3C+NH _ O N N Combined EDC (45.1 mg, 0.235 mmol), HOBT (21.18 mg, 0.157 mmol) and 6-(4-(4- cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid (48 mg, 0.157 mmol) in DMF (1 mL) then added tert—butylamine (0.050 mL, 0.470 mmol) and Hunig’s base (0.082 mL, 0.470 mmol) and then stirred at 20°C for 21 h. Addition EDC (45 mg) and tert-butyl amine (100 uL) were then added and stirring continued at 20°C for 4 h. Then additional HATU (119 mg, 0.313 mmol) was added and stirring continued at 20°C for 2 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with ted aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate, and concentrated in vacuo to give a residue which was ved in DMSO (1 mL) and purified by prep HPLC (ACN/water with formic acid) to give the title compound (9.5 mg, 16.77 % yield) as a tan solid. 1H NMR (400 MHz, DMSO- d6) 5 ppm 1.34 (s, 9 H) 7.72 (d, J=8.3 Hz, 2 H) 7.98 (s, 1 H) 8.07 (br. s., 2 H) 8.33 (d, J=7.3 Hz, 2 H) 8.58 (br. s., 1 H) 8.79 (s, 1 H) 13.48 (br. s., 1 H). MS m/z 362 [M+H]+.
Example 203 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(3- methoxypropyl)nicotinamide /CH3 H30_O \—\—NH HO «N O N N The title compound was prepared in a manner similar to Example 198 using 6-(5- y(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.77 (quin, J=6.6 Hz, 2 H) 3.24 (s, 3 H) 3.28 — 3.36 (m, 2 H) 3.38 (t, J=6.3 Hz, 2 H) 3.88 (s, 3 H) 7.46 (br. s., 1 H) 7.53 (d, J=5.3 Hz, 1 H) 8.06 (d, J=5.6 Hz, 1 H) 8.36 — 8.53 (m, 2 H) 8.65 (br. s., 1 H) 8.70 (t, J=5.6 Hz, 1 H) 8.85 — 8.92 (m, 1 H). MS m/z 384 [M+H]+.
Example 204 N—cyclopropyl(5-hydroxy(2-methoxypyridinyl)-1H-pyrazol yl)nicotinamide HO «N D—NH \ \ / Nt / O N N The title compound was prepared in a manner r to Example 198 using 6-(5- hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and cyclopropanamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.49 — 0.57 (m, 2 H) 0.63 — 0.71 (m, 2 H) 2.80 (td, J=7.3, 3.8 Hz, 1 H) 3.82 (s, 3 H) 7.41 (br. s., 1 H) 7.48 (d, J=5.6 Hz, 1 H) 8.01 (d, J=5.8 Hz, 1 H) 8.27 — 8.35 (m, 1 H) 8.38 (br. s., 1 H) 8.51 — 8.68 (m, 2 H) 8.76 — 8.85 (m, 1 H). MS m/z 352 [M+H]+.
Example 205 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- (methoxymethyl)cyclopropyl)nicotinamide WO 60810 O/CH3 IJ'sc‘o / HO \N Q‘NH \ WN /_ \ O N N The title compound was prepared in a manner similar to Example 198 using 6-(5- hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and 1- (methoxymethyl)cyclopropanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.80 (s, 4 H) 3.28 (s, 3 H) 3.48 (s, 2 H) 3.90 (s, 3 H) 7.49 (br. s., 1 H) 7.57 (d, J=5.3 Hz, 1 H) 8.08 (d, J=5.6 Hz, 1 H) 8.35 — 8.50 (m, 2 H) 8.68 (br. s., 1 H) 8.90 (t, J=1.4 Hz, 1 H) 8.98 (s, 1 H). MS m/z 396 [M+H]+.
Example 206 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N-(2- (tetrahydro-2H-pyranyl)ethyl)nicotinamide 0xO H3C NH _ \ / N\ / O N N The title compound was prepared in a manner similar to Example 198 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2-(tetrahydro-2H- pyranyl)ethanamine hloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.13 — 1.27 (m, 1 H) 1.38 — 1.50 (m, 3 H) 1.60 (d, J=12.9 Hz, 1 H) 1.62 — 1.70 (m, 2 H) 1.71 — 1.82 (m, 1 H) 2.44 (s, 3 H) 3.26 — 3.33 (m, 2 H) 3.35 — 3.45 (m, 2 H) 3.87 (dd, J=11.0, 1.9 Hz, 1 H) 7.66 (dd, J=8.0, 1.4 Hz, 1 H) 7.72 (s, 1 H) 7.80 (d, J=8.1 Hz, 1 H) 8.16 (s, 1 H) 8.40 (br. s., 2 H) 8.67 (t, J=5.6 Hz, 1 H) 8.90 (t, J=1.5 Hz, 1 H) 13.18 (br. s., 1 H). MS m/z 432 [M+H]+.
Example 207 ydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(2- (tetrahydro-2H-pyranyl)ethyl)nicotinamide mo Ho «N NH \ \ / Nt / O N N The title compound was prepared in a manner similar to Example 198 using 6-(5- hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and 2-(tetrahydro-2H- pyranyl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.06 — 1.19 (m, 1 H) 1.31 — 1.43 (m, 3 H) 1.52 (d, J=12.9 Hz, 1 H) 1.58 (q, J=7.1Hz, 2 H) 1.65 — 1.75 (ml H) 3.18 — 3.25 (m, 2 H) 3.29 — 3.38 (m, 2 H) 3.81 (m, J=2.0 Hz, 4 H) 7.34 (br. 5., 1 H) 7.42 (d, J=5.1Hz, 1 H) 7.98 (d, J=5.6 Hz, 1 H) 8.26 — 8.34 (m, 1 H) 8.37 (br. 5., 1 H) 8.52 (br. 5., 1 H) 8.59 (t, J=5.4 Hz, 1 H) 8.82 (5, 1 H) 13.45 (br. 5., 1 H). MS m/z 424 [M+H]+.
Example 208 6-(4-(4-cyan0phenyl)hydr0xy-1H-pyrazolyl)-N—(1-(2- methoxyethyl)cyc10pr0py1)nic0tinamide H3C\O //N NH _ \ / N. / o N N The title compound was ed in a manner similar to Example 198 using 6-(4-(4- cyanophenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 1-(2- methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.58 — 0.73 (m, 4 H) 1.79 (t, J=6.9 Hz, 2 H) 3.14 (s, 3 H) 3.39 (t, J=6.9 Hz, 2 H) 7.72 (d, J=8.6 Hz, 2 H) 8.07 (d, J=7.8 Hz, 2 H) 8.27 — 8.34 (m, 1 H) 8.37 (br. 5., 1 H) 8.57 (br. 5., 1 H) 8.77 (s, 1 H) 8.79 — 8.83 (m, 1 H) 13.46 (br. s., 1 H). MS m/z 404 [M+H]+.
Example 209 6-(5-hydr0xy(2-meth0xypyridinyl)-1H-pyrazolyl)-N—(1-(2- methoxyethyl)cyc10pr0py1)nic0tinamide H3C_O / N HO \ NH \ O N N The title nd was prepared in a manner similar to Example 198 using 6-(5- hydroxy(2-meth0xypyridinyl)-1H-pyrazolyl)nic0tinic acid and 1-(2- methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.57 — 0.73 (m, 4 H) 1.79 (t, J=7.1Hz, 2 H) 3.14 (s, 3 H) 3.39 (t, J=7.1Hz, 2 H) 3.79 (s, 3 H) 7.37 (br. 5., 1 H) 7.44 (br. 5., 1 H) 7.99 (d, J=5.6 Hz, 1 H) 8.31 (d, J=7.8 Hz, 2 H) 8.57 (br. 5., 1 H) 8.77 (s, 1 H) 8.79 — 8.84 (m, 1 H) 13.52 (br. 5., 1 H). MS m/z 410 [M+H]+.
Example 210 6-(4-(4-cyan0flu0r0phenyl)—5-hydr0xy-1H-pyrazolyl)—N—(1-(2- methoxyethyl)cyc10pr0py1)nic0tinamide Hac‘o 0” NH _ \ / Nx / o N N The title compound was prepared in a manner similar to Example 198 using 6-(4-(4- cyanofluorophenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid and 1-(2- methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, g) 5 ppm 0.58 — 0.66 (m, 2 H) 0.66 — 0.73 (m, 2 H) 1.80 (t, J=6.9 Hz, 2 H) 3.14 (s, 3 H) 3.39 (t, J=7.1Hz, 2 H) 7.61 (dd, J=8.2, 1.6 Hz, 1 H) 7.75 (dd, J=11.9, 1.5 Hz, 1 H) 8.14 (d, J=3.0 Hz, 1 H) 8.30 (dd, J=8.7, 2.1 Hz, 1 H) 8.40 (d, J=8.6 Hz, 1 H) 8.56 (t, J=8.0 Hz, 1 H) 8.76 (s, 1 H) 8.80 (d, J=1.5 Hz, 1 H) 13.69 (br. s., 1 H). MS m/z 422 [M+H]+.
Example 211 6-(5-hydroxy(1-methyloxo-1,2-dihydropyridinyl)-1H-pyrazolyl)-N-((tetrahydro-2H-pyranyl)methyl)nicotinamide O O Q CH / 3 Ho w” NH _ \ / N. / O N N ed 6—(4—bromo—5—methoxy—1H—pyrazol—1—yl)-N—((tetrahydro-2H—pyran—4— yl)methyl)nicotinamide (25 mg, 0.063 mmol), 1-methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)pyridin-2(1H)-one (29.7 mg, 0.127 mmol), PdClz(dppf)— CHzClz adduct (4.13 mg, 5.06 umol) and sodium bicarbonate (26.6 mg, 0.316 mmol) in dioxane (0.2 mL) and water (0.05 mL) and heated at 110°C for 1 h in the ave. More dppf)— CHzClz adduct (ca. 3 mg), sodium bicarbonate (10 mg) and water (100 uL) was added and the mixture was heated at 110°C for 1 h in the microwave. The on was concentrated onto Celite® purified on 12 g NH silica gel column eluted with 0 to 5% MeOH in methylene chloride to give 6-(5-methoxy(1-methyloxo-1,2-dihydropyridinyl)-1H-pyrazolyl)- N—((tetrahydro-2H-pyranyl)methyl)nicotinamide as a brown oil (24 mg). MS m/z 424 [M+H]+.
Combined 6—(5—methoxy(1-methyloxo-1,2-dihydropyridinyl)-1H-pyrazol yl)-N-((tetrahydro-2H-pyranyl)methyl)nicotinamide (24 mg, 0.057 mmol) and lithium chloride (12.01 mg, 0.283 mmol) in DMA (0.5 mL) and heated at 50°C for 26 h. The reaction mixture was diluted with 0.5 mL DMSO and purified by prep HPLC using acetonitrile/water with ammonium hydroxide to give the title compound (4 mg, 17.24 % yield) as a yellow solid. MS m/z 410 [M+H]+.
Example 212 6-(4-(2-(dimethylamino)pyridinyl)hydroxy-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide H30\N,CH3 QO \N .0 D \N/ \/ O N Combined 6—(4—bromo—5—methoxy—1H—pyrazol—1—yl)—N-((tetrahydro—2H-pyran—4— yl)methyl)nicotinamide (80 mg, 0.202 mmol), N,N—dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)pyridinamine hydrochloride (173 mg, 0.607 mmol), PdClz(dppf)— CHzClz adduct (16.53 mg, 0.020 mmol) and sodium bicarbonate (136 mg, 1.619 mmol) in dioxane (0.6 mL) and water (0.15 mL) was let stir for 15 min. The mixture was then capped and heated at 110°C for 1 h in the microwave. Additional dppf)— CH2Cl2 adduct (17 mg) was then added and the heating continued at 110°C for 1 h in the microwave. The reaction mixture was d with EtOAc, concentrated onto Celite® and purified on a 10 g NH silica gel column eluted with 10 to 100% EtOAc in hexanes to give 6-(4-(2- hylamino)pyridinyl)-5 -methoxy-1H-pyrazolyl)-N-((tetrahydro-2H-pyran yl)methyl)nicotinamide as a brown oil. MS m/z 437 [M+H]+.
Combined 6—(4—(2-(dimethylamino)pyridinyl)methoxy-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide from the above reaction and lithium chloride (42.7 mg, 1.008 mmol) and DMA (1 mL) and heated at 60°C for 20 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (ammonium hydroxide conditions) to give the title compound (42 mg, 49.3 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO—616)?) ppm 1.12 — 1.28 (m, 2 H) 1.56 — 1.67 (m, 2 H) 1.81 (ddt, J=14.9, 7.5, 3.8, 3.8 Hz, 1 H) 3.05 (s, 6 H) 3.17 (t, J=6.4 Hz, 2 H) 3.28 (td, J=11.6, 1.8 Hz, 2 H) 3.86 (dd, , 2.5 Hz, 2 H) 7.07 (d, J=4.5 Hz, 1 H) 7.35 (br. s., 1 H) 7.67 (d, J=6.1 Hz, 1 H) 7.90 (s, 1 H) 8.10 — 8.19 (m, 1 H) 8.47 — 8.59 (m, 2 H) 8.80 (d, J=2.0 Hz, 1 H). MS m/z 423 [M+H]+.
Example 213 6-(4-(4-cyanofluorophenyl)hydroxy-1H-pyrazolyl)-N-(3- methoxypropyl)nicotinamide H3C-O F NH _ \ / Nx , O N N ed 6—(4—bromo—5—methoxy— 1H—pyrazol—1—yl)-N—(3— methoxypropyl)nicotinamide (60 mg, 0.163 mmol), 3-fluoro(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)benzonitrile (120 mg, 0.488 mmol), PdClz(dppf)— CHzClz adduct (19.91 mg, 0.024 mmol) and sodium bicarbonate (68.3 mg, 0.813 mmol) in dioxane (0.6 mL) and water (0.15 mL) and heated at 110°C for 1 h in the microwave. The reaction mixture was diluted with EtOAc, concentrated onto Celite®, and purified on a 10 g NH silica gel column eluted with 0 to 80% EtOAc in hexanes to give 6-(4-(4-cyanofluorophenyl)methoxy- 1H-pyrazolyl)-N—(3 -methoxypropyl)nicotinamide as a white solid. MS m/z 410 [M+H]+.
Combined 6—(4—(4—cyanofluorophenyl)methoxy-1H-pyrazolyl)—N—(3- methoxypropyl)nicotinamide and lithium chloride (34.7 mg, 0.818 mmol) and DMA (1 mL) and heated at 50°C for 15 h. The reaction was diluted with 0.2 mL DMSO and purified by prep HPLC (TFA conditions) to give the title compound as a TFA salt (27 mg, 41.7 % yield) as a light green solid. 1H NMR (400 MHz, g) 5 ppm 1.72 — 1.85 (m, 2 H) 3.25 (s, 3 H) 3.31 — 3.37 (m, 2 H) 3.40 (t, J=6.3 Hz, 2 H) 7.72 (dd, J=8.2, 1.6 Hz, 1 H) 7.87 (dd, J=11.6, 1.5 Hz, 1 H) 8.29 (br. s., 1 H) 8.39 — 8.46 (m, 1 H) 8.48 (br. s., 1 H) 8.60 (br. s., 1 H) 8.73 (t, J=5.4 Hz, 1 H) 8.89 — 8.96 (m, 1 H) 13.77 (br. s., 1 H). MS m/z 396 [M+H]+.
Example 214 6-(5-hydroxy(2-methoxymethylpyridinyl)—1H-pyrazolyl)- ethoxypropyl)nicotinamide /CH3 HO \ NHWM /_ \ CH3 O N N The title compound was prepared in a manner similar to Example 212 using 6-(4- bromomethoxy-1H-pyrazolyl)-N-(3-methoxypropyl)nicotinamide and (2-methoxy methylpyridinyl)boronic acid. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.71 (quin, J=6.6 Hz, 2 H) 2.30 (s, 3 H) 3.18 (s, 3 H) 3.22 — 3.30 (m, 2 H) 3.32 (t, J=6.3 Hz, 2 H) 3.79 (s, 3 H) 7.16 (br. s., 1 H) 7.31 (br. s., 1 H) 8.31 (br. s., 1 H) 8.33 — 8.53 (m, 2 H) 8.61 (br. s., 1 H) 8.82 (s, 1 H) 13.35 (br. s., 1 H). MS m/z 398 .
Example 215 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1-(2- methoxyethyl)cyclopropyl)nicotinamide H301)? H3C gig—QB]; The title nd was prepared in a manner r to Example 200 using 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1-(2- methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.65 — 0.73 (m, 2 H) 0.72 — 0.80 (m, 2 H) 1.86 (t, J=7.1 Hz, 2 H) 2.43 (s, 3 H) 3.21 (s, 3 H) 3.46 (t, J=6.9 Hz, 2 H) 7.64 (dd, J=8.1, 1.5 Hz, 1 H) 7.71 (s, 1 H) 7.80 (d, J=8.1Hz, 1 H) 8.14 (s, 1 H) 8.38 (br. s., 2 H) 8.83 (s, 1 H) 8.87 (t, J=1.5 Hz, 1 H) 13.17 (br. s., 1 H). MS m/z 418 [M+H]+.
Example 216 6-(5-hydroxy(1-methyloxo-1,6-dihydropyridinyl)—1H-pyrazol- 1-yl)-N—(3 -methoxypropyl)nicotinamide H3C-O N O WNWHO\\ / N. / O N N The title compound was prepared in a manner similar to Example 212 using 6-(4- bromomethoxy-1H-pyrazolyl)-N-(3-methoxypropyl)nicotinamide and 1-methyl-5 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridin-2(1H)-one. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.70 (quin, J=6.7 Hz, 2 H) 3.18 (s, 3 H) 3.21 — 3.29 (m, 2 H) 3.32 (t, J=6.3 Hz, 2 H) 3.38 (s, 3 H) 6.34 (d, J=9.3 Hz, 1 H) 7.81 (dd, J=9.5, 2.4 Hz, 1 H) 8.03 (s, 1 H) 8.20 (d, J=1.8 Hz, 1 H) 8.24 (dd, J=8.8, 2.3 Hz, 1 H) 8.39 (d, J=8.6 Hz, 1 H) 8.56 (t, J=5.4 Hz, 1 H) 8.78 (d, J=1.8 Hz, 1 H) 12.62 (br. s., 1 H). MS m/z 384 [M+H]+. e 217 6-(4-(4-(cyanomethyl)phenyl)hydroxy-1H-pyrazolyl)-N—(3- methoxypropyl)nicotinamide H3C-O \ NH _ O N N The title compound was ed in a manner similar to Example 212 using 6-(4- bromomethoxy-1H-pyrazolyl)-N-(3-methoxypropyl)nicotinamide and (4- (cyanomethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.71 (quin, J=6.7 Hz, 2 H) 3.18 (s, 3 H) 3.21 — 3.30 (m, 2 H) 3.33 (t, J=6.2 Hz, 2 H) 3.94 (s, 2 H) 7.25 (d, J=8.3 Hz, 2 H) 7.86 (d, J=8.1Hz, 2 H) 8.25 — 8.34 (m, 2 H) 8.36 (br. s., 1 H) 8.62 (t, J=5.6 Hz, 1 H) 8.79 — 8.86 (m, 1 H) 12.97 (br. s., 1 H). MS m/z 392 [M+H]+.
Example 218 6-(4-(2-ethoxypyridinyl)—5-hydroxy-1H-pyrazolyl)-N—(3- ypropyl)nicotinamide H3C‘O\_\— / HO [\1 Of<\:N>7N\N/NH _ )j/©\Q/\CH3 The title compound was prepared in a manner similar to Example 213 using 6-(4- bromomethoxy-1H-pyrazolyl)-N-(3-methoxypropyl)nicotinamide and (2- ethoxypyridinyl)boronic acid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.25 (t, J=7.1 Hz, 3 H) 1.71 (quin, J=6.7 Hz, 2 H) 3.18 (s, 3 H) 3.21 — 3.29 (m, 2 H) 3.32 (t, J=6.3 Hz, 2 H) 4.22 (q, J=7.1 Hz, 2 H) 7.31 (s, 1 H) 7.40 (d, J=5.3 Hz, 1 H) 7.94 (d, J=5.6 Hz, 1 H) 8.26 — 8.34 (m, 1 H) 8.34 — 8.42 (m, 1 H) 8.47 (br. s., 1 H) 8.61 (t, J=5.6 Hz, 1 H) 8.82 (d, J=1.5 Hz, 1 H) 13.42 (br. s., 1 H). MS m/z 398 [M+H]+.
Example 219 6-(4-(4-(cyanomethyl)fluorophenyl)—5-hydroxy-1H-pyrazolyl)—N— (3 xypropyl)nicotinamide H30-O \ \—\_ \N \ / \/ O N N Combined romo—5—methoxy— 1H—pyrazol—1—y1)-N—(3— methoxypropyl)nicotinamide (50 mg, 0.135 mmol), 2-(2-fluoro(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl)acetonitrile (70.7 mg, 0.271 mmol), dichloro[1,1'-bis(di-tbutylphosphino )ferrocene]palladium(H) (8.83 mg, 0.014 mmol) and sodium bicarbonate (56.9 mg, 0.677 mmol) in dioxane (0.60 mL) and water (0.150 mL) was heated at 110°C in the microwave for 40 min. Additional dichloro[1,1'-bis(di-t- butylphosphino)ferrocene]palladium(H) was added (10 mg) and the reaction heated at 110°C in the microwave for 1 h. The reaction mixture was diluted with EtOAc, concentrated onto Celite®, and purified on a 10 g NH silica gel column eluted with 0 to 100% EtOAc in hexanes to 4-(cyanomethyl)-3 -fluorophenyl)—5 -methoxy-1H-pyrazolyl)—N—(3 - methoxypropyl)nicotinamide (27 mg, 47.1 % yield). MS m/z 424 [M+H]+.
Combined 4—(cyanomethy1)—3—fluoropheny1)—5—methoxy-1H—pyrazoly1)—N—(3 - methoxypropyl)nicotinamide (27 mg, 0.064 mmol) and lithium chloride (27.0 mg, 0.638 mmol) in DMA (1.0 mL) and heated at 60°C for 24 h. The reaction mixture was diluted with 0.2 mL DMSO and d by prep HPLC (formic acid conditions) to give the title compound (15 mg, 57.5 % yield) as an off—white solid. 1H NMR (400 MHz, 6) 5 ppm 1.79 (quin, J=6.7 Hz, 2 H) 3.25 (s, 3 H) 3.30 — 3.37 (m, 2 H) 3.40 (t, J=6.3 Hz, 2 H) 4.03 (s, 2 H) 7.42 (br. s., 1 H) 7.52 — 8.06 (m, 2 H) 8.41 (br. s., 1 H) 8.50 — 8.82 (m, 3 H) 8.91 (d, J=1.5 Hz, 1 H) 13.28 (br. s., 1 H). MS m/z 410 [M+H]+.
Example 220 N—benzyl(4-(4-cyanofluorophenyl)—5-hydroxy-1H-pyrazol yl)nicotinamide @HN \ | O“ F N N \ /N Combined N—benzyl—6—hydrazinylnicotinamide (53.3 mg, 0.220 mmol) and ethyl 2-(4- cyanofiuorophenyl)—3-(dimethylamino)acrylate (75 mg, 0.286 mmol) in 2-propanol (1 mL) and added acetic acid (0.038 mL, 0.660 mmol) at 23°C. The reaction mixture was stirred at 23°C for 18.5 hours, Hunig’s base (0.230 mL, 1.320 mmol) was added, and the reaction mixture was stirred at 60°C for 6 hours. The reaction mixture was cooled to 23°C and concentrated via rotary evaporation to furnish a brown oil which was dissolved in DMSO (1 mL), filtered through a Hydrophilic PTFE 0.45 pm filter (Millipore MillexTM-LCR), rinsed with DMSO (2 x 0.5 mL), and d via ative HPLC (SunFireTM C18, 5 um, ID mm x 75 mm) using a gradient of 50—80% ACN (with 0.035% TFA) in water (with 0.05% TFA). Product ning fractions were combined and trated via rotary evaporation to furnish an off-white solid which was collected by filtration, rinsed with water (5 x 2 mL), and dried in vacuo to give the title compound (9.1 mg, 10.01 % yield) as a tan solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 4.53 (d, J=5.81 Hz, 2 H) 7.21 — 7.40 (m, 5 H) 7.72 (dd, J=8.34, 1.52 Hz, 1 H) 7.87 (dd, 5, 1.39 Hz, 1 H) 8.29 (br. s., 1 H) 8.42 — 8.54 (m, 2 H) 8.60 (br. s., 1 H) 8.95 — 9.03 (m, 1 H) 9.29 (t, J=5.94 Hz, 1 H) 13.78 (br. s., 1 H). MS m/z [M+H]+ 414.3.
Example 221 6-(4-(4-cyanofiuorophenyl)—5-hydroxy-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide N \ I OH F O / N N \ :N The title compound was prepared in a manner similar to Example 220 using 6- hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide. 1H NMR (400 MHz, DMSO- 516)?) ppm 1.22 (qd, J=12.25, 4.42 Hz, 2 H) 1.55 — 1.70 (m, 2 H) 1.81 (tdd, J=15.03, 15.03, 6.82, 3.79 Hz, 1 H) 3.20 (t, J=6.19 Hz, 2 H) 3.24 — 3.32 (m, 2 H) 3.86 (dd, J=11.24, 2.91 Hz, 2 H) 7.66 — 7.77 (m, 1 H) 7.87 (dd, J=11.87, 0.76 Hz, 1 H) 8.28 (br. s., 1 H) 8.35 — 8.54 (m, 2 H) 8.60 (br. s., 1 H) 8.73 (t, J=5.81 Hz, 1 H) 8.92 (s, 1 H) 13.76 (br. s., 1 H). MS m/z [M+H]+ 422.4.
Example 222 4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)-N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide H I O / Combined 6—(4—bromo—5—methoxy—1H—pyrazol—1—yl)—N-((tetrahydro—2H-pyran—4— yl)methyl)nicotinamide (25 mg, 0.063 mmol), (4—cyano-2—methylphenyl)boronic acid (30.5 mg, 0.190 mmol), sodium carbonate (26.6 mg, 0.316 mmol), and PdC12(dppf)—CH2C12 adduct (2.58 mg, 3.16 umol) in dioxane (0.2 mL) and water (0.05 mL) and purged with nitrogen.
The reaction mixture was heated in a microwave on high absorbance for 1 hour at 110°C, cooled to 23°C and diluted with water (1 mL) to give a residue. The residuewas extracted with EtOAc (2 x 1 mL), the organic layers were combined, washed with brine (0.5 mL), dried over NaZSO4, filtered through a Hydrophilic PTFE 0.45 um filter pore MillexTM—LCR), rinsed with EtOAc, and dried in vacuo to provide 6-(4—(4—cyano-2—methylphenyl)—5—methoxy- 1H-pyrazolyl)-N-((tetrahydro-2H-pyranyl)methyl)nicotinamide (27.3 mg, 100 % yield) as a brown oil. MS m/z [M+H]+ 432.5.
Combined 6—(4—(4—cyanomethylphenyl)methoxy-1H-pyrazolyl)-N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide (27.3 mg, 0.063 mmol) and lithium chloride (13.41 mg, 0.316 mmol) in DMA (0.5 mL) then heated at 50°C using a heating block for 24 hours. Additional portion of lithium chloride (8.05 mg, 0.190 mmol) was added and the reaction mixture was stirred at 50°C for an additional 14 hours. The reaction mixture was cooled to 23°C, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore MillexTM— LCR), rinsed with DMSO (2 x 0.5 mL), and purified via preparative HPLC (SunFireTM C18, um, ID 30 mm x 75 mm) using a nt of 30-60% ACN (with 0.035%TFA) in water (with 0.05% TFA). The product containing fractions were ed and concentrated via rotary evaporation to furnish an ite solid which was collected by ion, rinsed with water (5 x 2 mL), and dried in vacuo to give the title compound (8.2 mg, 31.0 % yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.15 - 1.28 (m, 2 H) 1.58 - 1.67 (m, 2 H) 1.75 — 1.86 (m, 1 H) 2.43 (s, 3 H) 3.20 (t, J=6.32 Hz, 2 H) 3.27 (td, J=11.75, 2.02 Hz, 2 H) 3.81 — 3.90 (m, 2 H) 7.60 — 7.69 (m, 1 H) 7.73 (s, 1 H) 7.78 (br. s., 1 H) 8.05 — 8.25 (m, 1 H) 8.35 — 8.45 (m, 1 H) 8.69 — 8.80 (m, 1 H) 8.89 — 8.95 (m, 1H) 13.21 (br.s., 1 H). MS m/z [M+H]+ 418.5.
Example 223 6-(5 -hydroxy(2-methylpyridinyl)-1H-pyrazolyl)-N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide N \ H I OH O N/N\ ’N N \/ Combined 6—(4—bromo—5—methoxy—1H—pyrazol—1—yl)—N-((tetrahydro—2H-pyran—4— yl)methyl)nicotinamide (25 mg, 0.063 mmol), (2-methylpyridinyl)boronic acid (26.0 mg, 0.190 mmol), sodium bicarbonate (26.6 mg, 0.316 mmol), and PdClz(dppf)—CH2C12 adduct (2.58 mg, 3.16 umol) in dioxane (0.2 mL) and water (0.05 mL) and purged with nitrogen.
The mixture was heated in a microwave reactor on high absorbance for 1 hour at 110°C.
Additional portions of hylpyridinyl)boronic acid (26.0 mg, 0.190 mmol), sodium bicarbonate (26.6 mg, 0.316 mmol), PdClz(dppf)— CHzClz Adduct (2.58 mg, 3.16 umol), dioxane (0.1 mL), and water (0.025 mL) were added and the reaction e was heated again in a ave reactor on high absorbance for 1 hour at 110°C, then cooled to 23°C and diluted with water (1 mL) to give a residue which was ted with EtOAc (2 x 1 mL), the organic layers were combined, washed with brine (0.5 mL), dried over NaZSO4, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore MillexTM-LCR), rinsed with EtOAc, and dried in vacuo to provide crude 6—(5-methoxy—4—(2-methylpyridinyl)—1H—pyrazol—1— yl)—N—((tetrahydro-2H-pyranyl)methyl)nicotinamide (25.8 mg, 100 % yield) as a brown oil. MS m/z [M+H]+ 408.5.
Combined 6—(5—methoxy(2-methylpyridinyl)-1H-pyrazolyl)-N—((tetrahydro- 2H-pyranyl)methyl)nicotinamide (25.8 mg, 0.063 mmol) and lithium de (13.42 mg, 0.317 mmol) in DMA (0.5 mL) and then heated at 50°C using a heating block for 2 days.
Additional portion of lithium chloride (13.42 mg, 0.317 mmol) was added and the reaction mixture was stirred at 100°C for 17 hours. The reaction mixture was cooled to 23°C, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore MillexTM—LCR), rinsed with DMSO (2 x 0.5 mL), and purified via preparative HPLC (SunFireTM C18, 5 um, ID 30 mm x 75 mm) using a nt of 10-40% ACN (with 0.035%TFA) in water (with 0.05% TFA) to give a residue. The residue was ved in DMSO, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore MillexTM-LCR), rinsed with DMSO, and d again via preparative HPLC (SunFireTM C18, 5 um, ID 30 mm x 75 mm) using an isocratic method of 17% ACN (with 0.05% TFA) in water (with 0.05%TFA) to give the title compound, as a TFA salt, (6.2 mg, 19.30 % yield) as a green oil. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.16 - 1.26 (m, 2 H) 1.55 — 1.67 (m, 2 H) 1.77 — 1.84 (m, 1 H) 2.51 (br. s., 3 H) 3.17 — 3.24 (m, 2 H) 3.24 — 3.32 (m, 2 H) 3.83 — 3.88 (m, 2 H) 7.77 — 8.07 (m, 2 H) 8.07 — 8.22 (m, 1 H) 8.22 — 8.30 (m, 1 H) 8.36 — 8.44 (m, 1 H) 8.58 — 8.67 (m, 1 H) 8.67 — 8.81 (m, 1 H) 8.81 — 8.92 (m, 1 H) 13.58 (br. s.,1 H). MS m/z [M+H]+ 394.5. e 224 6-(4-(2,6-dimethylpyridinyl)hydroxy-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide o / ’ N 1:1\\ \ /N The title compound, as a TFA salt, was prepared in a manner similar to Example 222 using 6—(4-bromomethoxy-1H-pyrazolyl)-N-((tetrahydro-2H-pyran yl)methyl)nicotinamide and (2,6-dimethylpyridinyl)boronic acid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.15 — 1.27 (m, 2 H) 1.57 — 1.67 (m, 2 H) 1.77 — 1.86 (m, 1 H) 2.57 (br. s., 6 H) 3.17 — 3.24 (m, 2 H) 3.24 — 3.32 (m, 2 H) 3.79 — 3.92 (m, 2 H) 8.06 (br. s., 2 H) 8.42 — 8.60 (m, 2 H) 8.72 — 8.86 (m, 2 H) 8.86 — 8.97 (m, 1 H) 14.03 (br. s., 1 H). MS m/z [M+H]+ 408.5.
Example 225 N—benzyl(5-hydroxy(pyridinyl)-1H-pyrazolyl)nicotinamide @HN \ I OH \ \ / Combined ethyl 3-(dimethylamino)(pyridinyl)acrylate (40.0 mg, 0.182 mmol) and N—benzylhydrazinylnicotinamide (33.8 mg, 0.140 mmol) in 2—propanol (0.698 mL) and stirred for 18 hours at room temperature. s base (0.219 mL, 1.257 mmol) was then added and the reaction was d for 24 hours at 50°C. The reaction mixture was then purified by preparative HPLC (SunFireTM C18, 5 um, ID 30 mm x 75 mm) eluting with ACN (with 0.035% TFA) in water (with 0.05% TFA) to give the title compound (18.5 mg, 35.7%) as a yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 4.58 (d, J=5.8 Hz, 2 H) 7.33 (dq, J=8.5, 4.3 Hz, 1 H) 7.37 — 7.45 (m, 4 H) 8.28 (d, J=6.3 Hz, 2 H) 8.45 (d, J=7.1Hz, 2 H) 8.49 — 8.58 (m, 2 H) 8.63 (s, 1 H) 8.99 (s, 1 H) 9.33 (t, J=5.9 Hz, 1 H). MS m/z [M+H]+ 372.4.
Example 226 6-(5-hydroxy(pyridinyl)-1H-pyrazolyl)-N-((tetrahydro-2H- pyranyl)methyl)nicotinamide N \ H I OH O N/N\ #N \ \/ The title nd was prepared in a manner similar to Example 225 using 6- hydrazinyl-N—((tetrahydro-2H-pyranyl)methyl)nicotinamide. 1H NMR (400 MHz, DMSO- d6) 5 ppm 1.04 — 1.36 (m, 3 H) 1.62 (d, J=12.4 Hz, 2 H) 1.73 — 1.90 (m, 1 H) 3.19 (t, J=6.2 Hz, 2 H) 3.86 (dd, J=11.0, 2.4 Hz, 2 H) 8.23 (d, J=6.3 Hz, 2 H) 8.40 — 8.53 (m, 4 H) 8.62 (s, 1 H) 8.74 (t, J=5.7 Hz, 1 H) 8.88 (s, 1 H). MS m/z [M+H]+ 380.4.
Example 227 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1s,4s) methoxycyclohexyl)nicotinamide N \ H I OH ed 6—(4—(4—cyanophenyl)—5—hydroxy—1H-pyrazol—1—yl)nicotinic acid (100 mg, 0.327 mmol), (1s,4s)methoxycyclohexanamine, HCl (81 mg, 0.490 mmol), and N1- ((ethylimino)methylene)-N3,N3 -dimethylpropane-1,3-diamine, HCl (94 mg, 0.490 mmol) in DMF (1.555 mL). Then added 1H-benzo[d][1,2,3]triazoloL, water (75 mg, 0.490 mmol) and Hunig’s base (0.171 mL, 0.980 mmol) and stirred for 4 hours at room temperature. The reaction mixture was acidified to a pH of 5 to give a solid. The solid was washed with 50 mL MeOH and 50 mL s, and then dried to afford the title compound (95.3 mg, 66.4%) as light yellow solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.24 (br. s., 2 H) 1.39 (d, J=14.7 Hz, 2 H) 1.89 (br. s., 2 H) 2.05 (d, J=10.9 Hz, 2 H) 3.25 (s, 3 H) 3.35 (hrs, 2 H) 7.80 (d, J=8.3 Hz, 2 H) 8.82 — 8.96 (m, 1 H). MS m/z [M+H]+ 418.4.
Example 228 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1r,4r)—4- methoxycyclohexyl)nicotinamide H3C’OI"Q o N \ N W "N The title compound was prepared in a manner similar to Example 227 using 1- (tetrahydro-2H-pyranyl)cyclopropanamine to afford the title compound. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.59 — 0.83 (m, 4 H) 1.18 — 1.45 (m, 2 H) 1.54 — 1.78 (m, 3 H) 3.23 (t, J=11.2 Hz, 2 H) 3.86 (dd, , 3.7 Hz, 2 H) 7.79 (d, J=8.6 Hz, 3 H) 8.14 (d, J=6.1Hz, 2 H) 8.41 (d, J=6.8 Hz, 1 H) 8.83 (s, 1 H) 8.89 (s, 1 H). MS m/z [M+H]+ 430.5.
Example 229 6-(4-(4-cyan0phenyl)hydr0xy-1H-pyrazolyl)-N—((1r,4r)—4- methoxycyclohexyl)nicotinamide 'I’N \ H I OH The title compound was prepared in a manner similar to Example 227 using (1r,4r)meth0xycyclohexanamine, HCl. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.24 (br. s., 2 H) 1.39 (d, J=14.7 Hz, 2 H) 1.89 (br. s., 2 H) 2.05 (d, J=10.9 Hz, 2 H) 3.25 (s, 3 H) 3.35 (hrs, 2 H) 7.80 (d, J=8.3 Hz, 2 H) 8.82 — 8.96 (m, 1 H). MS m/z [M+H]+ 418.4.
Example 230 6-(4-(4-cyan0meth0xyphenyl)hydr0xy-1H-pyrazolyl)—N— ((1s,4s)meth0xycyclohexyl)nicotinamide H3O U 0 N \ H I OH N N\ ——N The title compound was prepared in a manner similar to Example 227 using 6-(4- n0meth0xyphenyl)hydr0xy-1H-pyrazolyl)nicotinic acid and (1s,4s) methoxycyclohexanamine, HCl. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.42 - 1.54 (m, 2 H) 1.55 — 1.69 (m, 4 H) 1.90 (s, 1 H) 1.88 (s, 1 H) 3.23 (s, 3 H) 3.38 (br. s., 1 H) 3.87 (hrs, 1 H) 3.96 (s, 3 H) 7.33 — 7.59 (m, 2 H) 8.44 (t, J=7.1Hz, 3 H) 8.68 (br. s., 1 H) 8.91 (s, 1 H) 13.40 (br. s., 1 H). MS m/z [M+H]+ 448.5.
Example 231 6-(4-(4-cyan0meth0xyphenyl)—5-hydr0xy-1H-pyrazolyl)-N—(3- methoxypropyl)nicotinamide H3C\O/\/\N \ OH H | N NWN The title compound was prepared in a manner r to Example 227 using 6-(4- (4-cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3- methoxypropanamine — 1.88 (m, 3 H) 3.25 . 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.66 (s, 5 H) 3.96 (s, 5 H) 7.33 — 7.56 (m, 3 H) 8.31 — 8.56 (m, 1 H) 8.70 (br. s., 1 H) 8.91 (s, 1 H).
MS m/z [M+H]+ 408.4.
Example 232 6-(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)—N— ropylnicotinamide N \ H I OH N [\ll \ ——N The title compound was ed in a manner similar to Example 227 using 6- (4-(4-cyanomethoxyphenyl)—5-hydroxy- 1 H-pyrazol- 1 cotinic acid and cyclopropanamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.61 (br. s., 2 H) 0.67 — 0.80 (m, 2 H) 2.78 — 2.93 (m, 1 H) 3.96 (s, 3 H) 7.37 — 7.55 (m, 2 H) 8.38 (d, J=7.6 Hz, 1 H) 8.46 (br. s., 1 H) 8.59 (br. s., 1 H) 8.68 (br. s., 1 H) 8.75 (br. s., 1 H) 8.89 (s, 1 H) 13.40 (br. s., 1 H). MS m/z [M+H]+ 376.4.
Example 233 6-(5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)-N—(1- (tetrahydro-2H-pyranyl)cyclopropyl)nicotinamide H3C\ N \ O O / "’ N [\‘l \ \ /N The title compound was prepared in a manner similar to Example 227 using 6- (5-hydroxy(2-methoxypyridinyl)—1H-pyrazolyl)nicotinic acid and 1-(tetrahydro-2H- pyranyl)cyclopropanamine — 1.03 (m, 5 H) . 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.82 1.25 (s, 1 H) 1.45 — 1.67 (m, 3 H) 1.74 (d, J=12.4 Hz, 2 H) 3.37 (t, J=11.6 Hz, 2 H) 4.03 (dd, J=11.4, 3.5 Hz, 2 H) 4.09 (s, 3 H) 7.22 (s, 1 H) 7.31 (d, J=6.1Hz, 1 H) 7.41 (s, 1 H) 7.83 (d, J8.6 Hz, 1 H) 7.90 (s, 1 H) 8.13 (d, J=6.1Hz, 1 H) 8.37 (dd, J=8.7, 2.1 Hz, 1 H) 8.83 (d, J=1.8 Hz, 1 H). MS m/z [M+H]+ 436.4.
Example 234 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(3- methoxypropyl)—N—methylnicotinamide 2014/031918 H3C\O/\/\N)K[j OH ] The title compound was prepared in a manner similar to Example 227 using 3- methoxy-N-methylpropanamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.66 — 1.94 (m, 3 H) 2.98 (s, 4 H) 3.11 (br. s., 2 H) 3.22 (br. s., 1 H) 3.27 (br. s., 2 H) 3.51 (br. s., 1 H) 7.80(d, J=8.3 Hz, 2 H) 8.02 — 8.23 (m, 4 H) 8.54 (d, J=9.3 Hz, 2 H) 8.68 (br. s., 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 392.4.
Example 235 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(4- methoxybutyl)nicotinamide H3C/ H | N NWN ] The title compound was prepared in a manner similar to Example 227 using 4- methoxybutan-l-amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.51 — 1.65 (m, 4 H) 3.23 (s, 3 H) 3.28 — 3.40 (m, 8 H) 7.80 (d, J=8.3 Hz, 2 H) 8.14 (br. s., 2 H) 8.42 (d, J=6.8 Hz, 1 H) 8.70 (t, J=5.4 Hz, 2 H) 8.86 — 8.97 (m, 1 H). MS m/z [M+H]+ 392.4.
Example 236 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2- (trifluoromethoxy)ethyl)nicotinamide /O\/\ F3C N \ | OH [0101 1] N \ The title compound was prepared in a manner similar to Example 227 using 2- (trifluoromethoxy)ethanamine, HCl. 1H NMR (400 MHz, 6) 5 ppm 3.62 (q, J:53 Hz, 2 H) 4.24 (t, J=5.3 Hz, 2 H) 7.80 (d, J=8.6 Hz, 2 H) 8.15 (br. s., 2 H) 8.43 (d, J=7.6 Hz, 1H) 8.69 (br. s., 1 H) 8.91 — 8.96 (m, 1 H) 9.00 (t, J=5.3 Hz, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 418.3.
Example 237 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2- oxaspiro [3 .3 ]heptanyl)nicotinamide (Ego N \ H I OH The title compound was ed in a manner similar to Example 227 using 2- oxaspiro[3.3]heptanamine, HCl. 1HNMR (400 MHz, DMSO-d6) 5 ppm 2.13 - 2.25 (m, 2 H) 2.49 — 2.59 (m, 2 H) 4.08 — 4.27 (m, 1 H) 4.46 (s, 2 H) 4.57 (s, 2 H) 7.69 (d, J=8.6 Hz, 2H) 8.06 (d, J=8.3 Hz, 2 H) 8.30 (dd, J=8.7, 2.1 Hz, 1 H) 8.40 (d, J=8.8 Hz, 1 H) 8.51 (s, 1 H) 8.71 (d, z, 1 H) 8.81 (d, J=1.8 Hz, 1 H) 13.46 (br. s., 1 H). MS m/z [M+H]+ 402.4.
Example 238 6-(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)-N—(4- ybutyl)nicotinamide H3C,O\/\/\H \ l OH The title compound was prepared in a manner similar to Example 227 using 4- methoxybutan-l-amine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.50 — 1.63 (m, 4 H) 3.23 (s, 3 H) 3.27 — 3.41 (m, 8 H) 3.91 (br. s., 3 H) 7.28 (br. s., 2 H) 8.14 (s, 1 H) 8.20 (br. s., 1 H) 8.26 (d, J=2.3 Hz, 1 H) 8.56 (t, J=5.4 Hz, 2 H) 8.80 (d, J=6.3 Hz, 1 H) 8.86 (br. s., 1 H) 12.97 (br. s., 1 H). MS m/z [M+H]+ 422.4.
Example 239 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—cyclopropyl- N—methylnicotinamide [)1 \ I OH The title compound was prepared in a manner similar to Example 227 using N—methylcyclopropanamine, HCl. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.47 (br. s., 2 H) 0.54 — 0.74 (m, 2 H) 3.02 (s, 4 H) 7.80 (d, J=8.6 Hz, 2 H) 8.15 (br. s., 2 H) 8.21 (d, J=7.1Hz, 1 H) 8.48 (br. s., 1 H) 8.65 (br. s., 2 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 360.3.
Example 240 6-(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)-N—(3- methoxypropyl)—N—methylnicotinamide H3C\O/\/\'il \ I OH CH3 N/ ”W“! HsC‘O The title compound was prepared in a manner similar to Example 227 using 6- (4-(4-cyanomethoxyphenyl)—5-hydroxy-1H-pyrazol-l-yl)nicotinic acid and 3-methoxy-N— methylpropan-l-amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.76 — 2.04 (m, 2 H) 3.09 (d, J=7.3 Hz, 3 H) 3.21 (s, 2 H) 3.36 (s, 2 H) 3.43 — 3.56 (m, 2 H) 3.65 (t, J=6.9 Hz, 1 H) 3.98 (s, 3 H) 7.31 — 7.36 (m, 2 H) 8.05 (br. s., 1 H) 8.28 — 8.64 (m, 3 H). MS m/z [M+H]+ 422.4.
] Example 241 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- (tetrahydrofuranyl)ethyl)nicotinamide om0 O N \ H I OH N NW“ The title compound was prepared in a manner similar to Example 227 using 2- (tetrahydrofuranyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.33 — 1.51 (m, 1 H) 1.65 — 1.91 (m, 4 H) 1.99 (dddd, J=11.8, 8.2, 6.6, 5.2 Hz, 1 H) 3.23 — 3.47 (m, 3 H) 3.52 — 3.68 (m, 1 H) 3.71 — 3.89 (m, 2 H) 7.79 (d, J=8.6 Hz, 2 H) 8.10 — 8.18 (m, 2 H) 8.41 (d, J=7.1 Hz, 1 H) 8.60 — 8.75 (m, 2 H) 8.86 — 8.95 (m, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 404.4.
Example 242 6-(4-(4-cyanomethoxyphenyl)hydroxy-1H-pyrazolyl)-N—(2- (tetrahydrofuranyl)ethyl)nicotinamide owe0 N \ OH H | N [\‘j \ :N HsC'O The title nd was ed in a manner similar to Example 227 using 6- (5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and 2- (tetrahydrofuranyl)ethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.26 - 1.46 (m, 1 H) 1.66 (q, J=6.9 Hz, 2 H) 1.70 — 1.82 (m, 2 H) 1.85 — 2.03 (m, 1 H) 3.29 — 3.39 (m, 2 H) 3.47 — 3.60 (m, 1 H) 3.65 — 3.77 (m, 2 H) 3.79 (s, 3 H) 7.35 (br. s., 1 H) 7.42 (d, J=4.8 Hz, 1 H) 7.98 (d, J=5.6 Hz, 1 H) 8.28 — 8.35 (m, 1 H) 8.37 (br. s., 1 H) 8.53 (br. s., 1 H) 8.63 (t, J=5.4 Hz, 1 H) 8.77 — 8.87 (m, 1 H) 13.47 (br. s., 1 H). MS m/z [M+H]+ 410.3.
Example 243 N—cyclopropyl(5-hydroxy(2-methoxypyridinyl)—1H- pyrazolyl)-N-methylnicotinamide CH3 N/ NW [{1\ \ / O—CHs The title compound was prepared in a manner similar to Example 227 using 6- (5-hydroxy(2-methoxypyridinyl)-1H-pyrazolyl)nicotinic acid and N- methylcyclopropanamine, HCl. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.40 (br. s., 2 H) 0.47 — 0.60 (m, 2 H) 2.95 (s, 5 H) 3.81 (s, 3 H) 7.39 (br. s., 1 H) 7.47 (d, J=4.5 Hz, 1 H) 8.01 (d, J=5.6 Hz, 1 H) 8.13 (d, J=8.3 Hz, 1 H) 8.34 (br. s., 1 H) 8.57 (br. s., 2 H). MS m/z [M+H]+ 366.3.
Example 244 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(2- oxaspiro [3 .3 ]heptanyl)nicotinamide (Ugo N \ H I OH N [\‘l \ ——N The title nd was prepared in a manner r to Example 227 using 6- (4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2- oxaspiro[3.3]heptanamine, HCl. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.13 - 2.26 (m, 2 H) 2.36 (s, 3 H) 2.48 — 2.60 (m, 2 H) 4.18 (sxt, J=8.0 Hz, 1 H) 4.46 (s, 2 H) 4.57 (s, 2 H) 7.55 — 7.62 (m, 1 H) 7.65 (s, 1 H) 7.72 (d, J=8.1Hz, 1 H) 8.09 (s, 1 H) 8.33 (br. s., 2 H) 8.73 (d, J=7.3 Hz, 1 H) 8.82 (t, J=1.5 Hz, 1 H) 13.10 (br. s.,1 H). MS m/z [M+H]+ 416.3. e 245 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(2- (tetrahydrofuranyl)ethyl)nicotinamide oweO N \ OH H | N [\‘j\ :N ] The title compound was prepared in a manner similar to Example 227 using 2- (tetrahydrofuranyl)ethanamine and 6-(4-(4-cyanomethylphenyl)hydroxy-1H- pyrazol-l-yl)nicotinic acid. 1H NMR (400 MHz, DMSO-d6) 5 1.21 - 1.29 (m, 1 H) 1.37 — 1.51 (m, 1 H) 1.68 — 1.89 (m, 4 H) 1.99 (dddd, J=11.8, 8.2, 6.6, 5.2 Hz, 1 H) 2.44 (s, 3 H) 3.26 — 3.47 (m, 3 H) 3.61 (td, J=7.9, 6.4 Hz, 1 H) 3.70 — 3.88 (m, 2 H) 7.63 — 7.68 (m, 1 H) 7.71 — 7.81 (m, 2 H) 8.18 (br. s., 1 H) 8.41 (d, J=6.3 Hz, 1 H) 8.72 (t, J=5.4 Hz, 1 H) 8.88 — 8.95 (m, 1 H). MS m/z [M+H]+ 418.4.
Example 246 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— cyclopropyl—N—methylnicotinamide The title compound was prepared in a manner r to e 227 using 6- (4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and N- methylcyclopropanamine, HCl. 1H NMR (400 MHz, DMSO—d6) 5 0.40 (br. s., 2 H) 0.47 — 0.63 (m, 2 H) 2.36 (s, 3 H) 2.95 (s, 4 H) 7.58 (d, J=8.1Hz, 1 H) 7.65 (s, 1 H) 7.73 (d, J=7.8 Hz, 1 H) 8.06 (s, 1 H) 8.12 (d, J=8.1Hz, 1 H) 8.30 (d, J=8.3 Hz, 1 H) 8.58 (br. s., 1 H). MS m/z [M+H]+ 374.3. ] e 247 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— ((4,4-difluorocyclohexyl)methyl)nicotinamide FfiHN \ I OH N ”WN The title compound was prepared in a manner similar to Example 227 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (4,4- difluorocyclohexyl)methanamine hydrochloride. 1H NMR (400 MHz, DMSO—d6) 5 1.09 — 1.25 (m, 2 H) 1.60 — 1.82 (m, 5 H) 1.95 (d, J=8.1Hz, 2 H) 2.37 (s, 3 H) 3.15 (t, J=6.3 Hz, 2 H) 7.59 (d, J=7.6 Hz, 1 H) 7.67 (s, 1 H) 8.36 (br. s., 1 H) 8.70 (br. s., 1 H) 8.82 — 8.88 (m, 1 H) 13.16 (br. s., 1 H). MS m/z [M+H]+ 452.5.
Example 248 4-(5-hydroxy(5-(4-(methoxymethyl)piperidine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile N \ l OH o / H30’ , N [\‘l \ ——N ] The title compound was prepared in a manner similar to Example 227 using 6- (4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 4- (methoxymethyl)piperidine hydrochloride . 1H NMR (400 MHz, DMSO—d6) 5 1.10 (qd, J=12.3, 4.0 Hz, 2 H) 1.59 (br. s., 1 H) 1.67 (br. s., 1 H) 1.70 — 1.85 (m, 1 H) 2.36 (s, 3 H) 2.74 (br. s., 1 H) 3.14 (d, J=6.3 Hz, 2 H) 3.17 (s, 3 H) 3.57 (br. s., 1 H) 4.41 (br. s., 1 H) 7.57 (dd, J=8.0, 1.4 Hz, 1 H) 7.64 (s, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 7.96 (dd, J=8.6, 2.3 Hz, 1 H) 8.03 — 8.09 (m, 1 H) 8.31 (d, J=8.3 Hz, 1 H) 8.42 — 8.47 (m, 1 H) 13.03 (br. s., 1 H). MS m/z [M+H]+ 432.5.
Example 249 4-(5-hydroxy(5-(4-methoxypiperidinecarbonyl)pyridinyl)— 1H-pyrazolyl)—3-methylbenzonitrile \ OH H3C\OO N/ [\‘l \ :N The title compound was prepared in a manner similar to Example 227 using 6- (4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 4- ypiperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 1.14 - 1.32 (m, 3 H) 1.63 — 1.93 (m, 5 H) 1.96 — 2.10 (m, 2 H) 2.44 (s, 3 H) 3.22 (t, J=6.3 Hz, 2 H) 7.67 (d, J=7.6 Hz, 1 H) 7.74 (s, 1 H) 7.81 (br. s., 1 H) 8.25 (br. s., 1 H) 8.43 (br. s., 1 H) 8.57 (br. s., 1 H) 8.78 (br. s., 1 H) 8.91 — 8.94 (m, 1 H) 13.25 (br. s., 1 H). MS m/z [M+H]+ 418.4. e 250 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(2- (trifluoromethoxy)ethyl)nicotinamide FO\/\T H*0N \ H N [\‘j \ :N The title compound was prepared in a manner similar to Example 227 using 6- (4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2- (trifluoromethoxy)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO—d6) 5 2.36 (s, 3 H) 3.55 (q, J=5.3 Hz, 2 H) 4.16 (t, J=5.3 Hz, 2 H) 7.59 (d, J=7.8 Hz, 1 H) 7.66 (s, 1 H) 7.71 (br. s., 1 H) 8.14 (br. s., 1 H) 8.36 (d, J=7.3 Hz, 1 H) 8.84 — 8.88 (m, 1 H) 8.93 (t, J=4.4 Hz, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 432.4.
Example 251 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(3- methoxypropyl)-N-methylnicotinamide HSC\O/\/\N \ | OH The title compound was prepared in a manner similar to Example 227 using 6- (4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid and 3-methoxy-N— methylpropan-l-amine. 1H NMR (400 MHz, 6) 5 1.62 — 1.84 (m, 2 H) 2.36 (s, 3 H) 2.91 (s, 3 H) 3.04 (br. s., 1 H) 3.14 — 3.21 (m, 3 H) 7.59 (dd, J=8.1, 1.5 Hz, 1 H) 7.65 (s, 1 H) 7.72 (d, J=8.1 Hz, 1 H) 7.95 — 8.04 (m, 1 H) 8.05 — 8.09 (m, 1 H) 8.30 (d, J=8.3 Hz, 1 H) 8.46 (d, J=9.9 Hz, 1 H). MS m/z [M+H]+ 406.4.
Example 252 4-(5-hydroxy(5-(3-(methoxymethyl)pyrrolidine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile #0“ \ I 0“ H3C‘O N/ l\|l \ :N The title compound was ed in a manner r to Example 227 using 6- (4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3- (methoxymethyl)pyrrolidine. 1H NMR (400 MHz, DMSO—d6) 5 1.51 — 1.66 (m, 1 H) 1.83 — 1.99 (m, 1 H) 2.36 (s, 3 H) 3.14 (s, 1 H) 3.22 (s, 2 H) 3.37 — 3.62 (m, 4 H) 7.56 — 7.61 (m, 1 H) 7.65 (s, 1 H) 7.74 (d, J=8.1Hz, 1 H) 8.03 — 8.15 (m, 2 H) 8.31 (d, J=8.3 Hz, 1 H) 8.55 — 8.62 (m, 1 H) 13.07 (br. s., 1 H). MS m/z [M+H]+ 418.4.
Example 253 6-(4-(4-cyano-3 xyphenyl)hydroxy-1H-pyrazolyl)—N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide The title compound was prepared in a manner similar to Example 213 using 6-(4- bromomethoxy-1H-pyrazolyl)-N-((tetrahydro-2H-pyranyl)methyl)nicotinamide (50 mg, 0.127 mmol), (4-cyanomethoxyphenyl)boronic acid. 1H NMR (400 MHz, 6) 1.14 (d, J=10.6 Hz, 2 H) 1.55 (d, J=11.9 Hz, 3 H) 3.11 (br. s., 2 H) 3.72 — 3.90 (m, 7 H) 6.47 (s, 1 H) 7.41 (d, J=15.4 Hz, 3 H) 7.77 (br. s., 1 H) 8.03 — 8.23 (m, 3 H) 8.41 — 8.60 (m, 2 H) 877(bns,1rryhASnyz[nnrfl+4344. e 254 6-(4-(5-fluoromethoxypyridinyl)—5-hydroxy-1H-pyrazol yl)-N-((tetrahydro-2H-pyranyl)methyl)nicotinamide N \ O O / —" N [E]\\ \ /N ] The title compound was prepared in a manner similar to Example 213 using 6-(4- bromomethoxy-1H-pyrazolyl)-N-((tetrahydro-2H-pyranyl)methyl)nicotinamide (60.0 mg, 0.152 mmol), (5—fluoromethoxypyridinyl)boronic acid. 1H NMR (400 MHz, DMSO—d6)51.15(qd, J=12.3, 4.4 Hz, 2 H) 1.55 (d, J=12.9 Hz, 2 H) 1.74 (ddt, J=11.1, 7.4, 3.9, 3.9 Hz, 1 H) 3.13 (t, J=6.3 Hz, 2 H) 3.74 — 3.82 (m, 5 H) 7.74 (d, J=4.8 Hz, 1 H) 8.03 (d, J=3.0 Hz, 1 H) 8.16 (d, J=2.5 Hz, 1 H 8.30 — 8.45 (m, 2 H) 8.66 (t, J=5.7 Hz, 1 H) 8.84 (d, J=1.3 Hz, 1 H). MS m/z [M+H]+ 428.5.
Example 255 6-(4-(2,3-dimethoxypyridinyl)—5-hydroxy-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide (QAHN \ | OH / , N IEI\\ N O‘CHs [01 070] Combined 6—(4—bromomethoxy—1H—pyrazol—1—yl)—N-((tetrahydro—2H-pyran— 4-yl)methyl)nicotinamide (60.0 mg, 0.152 mmol), (2,3-dimethoxypyridinyl)boronic acid 2014/031918 (41.7 mg, 0.228 mmol), PdClz(dppf)— CHzClz Adduct (6.20 mg, 7.59 umol), and sodium bicarbonate (63.8 mg, 0.759 mmol) in dioxane (1139 [11) and water (3 80 [11) and heated in a microwave reactor for 60 minutes at 110°C. The reaction mixture was diluted with 150 mL EtOAc and washed with 1 N HCl. Organic layers were ted, dried with sodium sulfate, and concentrated to a residue which was purified on a 60 g silica gel column and eluted with hexanes and EtOAc to give 6-(4-(2,3-dimethoxypyridinyl)methoxy-1H-pyrazolyl)— trahydro-2H-pyranyl)methyl)nicotinamide (29.4 mg, 42.7%) as a yellow oil. MS m/z [M+H]+ 454.4.
Combined 6-(4-(2,3 -dimethoxypyridinyl)methoxy-1H-pyrazolyl)—N— ((tetrahydro-2H-pyranyl)methyl)nicotinamide (0.029 g, 0.064 mmol) and lithium chloride (0.014 g, 0.320 mmol) in DMA (0.639 mL) and heated at 50°C for 16 hours. The reaction mixture was purified by ative HPLC (SunFireTM C18, 5 um, ID 30 mm x 75 mm) eluting with ACN (with 0.1% ammonium hydroxide) in water (with 0.1% ammonium hydroxide) to give the title compound (7.3 mg, 26.0%). 1H NMR (400 MHz, DMSO—d6) 5 1.05 — 1.23 (m, 2 H) 1.49 — 1.58 (m, 2 H) 1.74 (ttt, J=11.1,11.1, 7.3, 7.3, 3.7, 3.7 Hz, 1H) 2.01 (s, 1 H) 3.08 — 3.13 (m, 3 H) 3.63 (s, 3 H) 3.77 (d, J=2.8 Hz, 1 H) 3.80 (s, 4 H) 7.07 (br. s., 1 H) 7.63 (d, J=5.3 Hz, 1 H) 8.04 — 8.09 (m, 2 H) 8.19 (dd, J=8.8, 2.3 Hz, 1 H) 8.45 (d, J=8.8 Hz, 1 H) 8.53 (t, J=5.8 Hz, 1 H) 8.78 (d, J=2.0 Hz, 1 H). MS m/z [M+H]+ 440.5.
Combined 6—(4—(3 —cyanofiuorophenyl)—5-methoxy-1H-pyrazolyl)-N- ((tetrahydro-2H-pyranyl)methyl)nicotinamide (32 mg, 0.073 mmol) and lithium chloride (15.58 mg, 0.367 mmol) in DMA (0.735 mL) and heated at 50°C for 16 hours. The reaction mixture was purified by preparative HPLC reTM C18, 5 um, ID 30 mm x 75 mm) eluting with ACN (with 0.1% ammonium hydroxide) in water (with 0.1% um hydroxide) to give the title compound (14.6 mg, 47.1%) as a white solid. 1H NMR (400 MHz, DMSO—d6) 51.14(qd, J=12.3, 4.3 Hz, 2 H) 1.57 (s, 1 H) 1.53 (s, 1H) 1.74(ddd, J=11.1, 7.3, 3.9 Hz, 1 H) 3.09 — 3.14 (m, 3 H) 3.79 (dd, J=11.2, 2.7 Hz, 2 H) 7.05 (br. s., 1 H) 7.37 (t, J=9.1Hz, 1 H) 8.15 — 8.28 (m, 3 H) 8.33 (dd, J=6.3, 2.3 Hz, 1 H) 8.45 (d, J=8.8 Hz, 1 H) 8.57 (t, J=5.7 Hz, 1 H) 8.80 (d, J=1.8 Hz, 1 H). MS m/z [M+H]+ 422.4.
Example 256 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— (cyclobutylmethyl)nicotinamide DAHN \ | OH N NWN 2014/031918 Combined 6—(4—(4—cyanophenyl)hydroxy-lH-pyrazolyl)nicotinic acid (200 mg, 0.654 mmol) and HATU (372 mg, 0.98 mmol) in DMF (3mL) was added triethylamine (198 mg, 1.961 mmol). Then cyclobutylmethanamine (0.784 mmol) was added and the on was stirred at room temperature for 4h. The reaction mixture was purified by preparative HPLC to give the title compound as a solid. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.90 (s, 1H), 8.70—8.65 (m, 2H), 8.45—8.40 (m, 2H), 8.13 (d, J=7.6Hz, 2H), 7.78 (d, J=7.6Hz, 2H), 3.31 (m, 2H), 2.56—2.53 (m, 1H), 2.05—2.00 (m, 2H), 1.85—1.82 (m, 2H), 1.75— 1.72 (m, 2H). MS m/Z [M+H]+ 374.1.
Example 257 4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((3- methylcyclobutyl)methyl)nicotinamide fin fl“ OH H3C \ NWN The title compound was ed in a manner similar to Example 256 using (3- methylcyclobutyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.90 (s, 1H), 8.67— 8.61 (m, 2H), 8.44—8.39 (m, 2H), 8.12 (d, J=8.0Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 3.39—3.36 (m, 2H), 2.37—2.33 (m, 1H), 2.16—2.14 (m, 2H), 1.90—1.89 (m, 1H), 1.66—1.65(m, 1H), 1.33— 1.29(m, 1H), 1.09—0.99 (m, 3H). MS m/Z [M+H]+ 388.1.
Example 258 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1s,3r) hydroxycyclopentyl)nicotinamide HON-O o ’/N OH ] The title compound was prepared in a manner similar to Example 256 using (1r,3s)aminocyclopentanol. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.89 (s, 1H), 8.63—8.57 (m, 2H), 8.41 (d, J=6.8Hz, 2H), 8.11 (d, J=7.6Hz, 2H), 7.77 (d, J=7.6Hz, 2H), 4.24—4.18 (m, 1H), 4.14—4.10 (m, 1H), 2.22—2.18 (m, 1H), 1.93—1.88 (m, 1H), 1.76—1.71 (m, 2H), 1.63—1.61 (m, 1H), 1.53—1.50 (m, 1H). MS m/Z [M+H]+ 390.1.
Example 259 4-cyanophenyl)hydroxy-lH-pyrazolyl)-N—((1s,3s) hydroxycyclopentyl)nicotinamide \ NW!“ The title compound was prepared in a manner similar to Example 256 using (1s,3s)-3 cyclopentanol. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.89 (s, 1H), 8.65 (s, 1H), 8.54—8.40 (m, 3H), 8.13 (d, J=8.4Hz, 2H), 7.78 (d, J=8.4Hz, 2H), 4.51—4.44 (m, 1H), 4.24—4.22 (m, 1H), 2.10—2.07 (m, 1H), 2.00—1.93 (m, 2H), 1.74—1.70 (m, 1H), 1.52—1.48 (m, 2H). MS m/Z [M+H]+ 390.2.
Example 260 (S)(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1- cyclopropylethyl)nicotinamide CH3 0 V/kHN / N OH \ ”W” The title compound was prepared in a manner similar to Example 256 using (R)- 1-cyclopropylethanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.90 (s, 1H), 8.65 (s, 1H), 8.61—8.43 (m, 3H), 8.13 (d, J=8.0Hz, 2H), 7.79 (d, z, 2H), 3.52—3.46 (m, 1H), 1.24 (d, J=6.8Hz, 3H), 1.01—0.99 (m, 1H), 0.54—0.45 (m, 1H), .36 (m, 1H), 0.32—0.30 (m, 1H), 0.24—0.21 (m, 1H). MS m/Z [M+H]+ 374.1.
Example 261 6-(4-(4-cyanophenyl)hydroxy-lH-pyrazolyl)-N—((3- methyloxetanyl)methyl)nicotinamide.
Hfl fl“ OH 0 \ ”WI“ The title compound was prepared in a manner similar to e 256 using (3- oxetanyl)methanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 8.92 (s, 1H), 8.84 (s, 1H), 8.65 (s, 1H), 8.50—8.42 (m, 2H), 8.13 (d, J=8.0Hz, 2H), 7.78 (d, J=8.0Hz, 2H), 4.49 (d, J=6.0Hz, 2H), 4.22 (d, J=6.0Hz, 2H), 3.51 (d, J=6.0Hz, 2H), 1.28 (s, 3H). MS m/Z [M+H]+ 390.1. e 262 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2- methylcyclopropyl)nicotinamide NHJK©\/ N OH \ “[1qu The title compound was ed in a manner similar to Example 256 using 2- methylcyclopropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.90 (s, 1H), 8.64—8.61 (m, 2H), 8.45—8.35 (m, 2H), 8.12 (d, J=8.0Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 2.58—2.54 (m, 1H), 1.07 (d, J=6.0Hz, 3H), .95 (m, 1H), 0.78—0.76 (m, 1H), 0.53—0.51 (m, 1H). MS m/Z [M+H]+ 360.1.
Example 263 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1- fluorocyclohexyl)methyl)nicotinamide (jfiN / N OH \ ”W” The title compound was prepared in a manner similar to Example 256 using (1- yclohexyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.95 (s, 1H), 8.83 (t, 1H), 8.67 (s, 1H), 8.53—8.40 (m, 2H), 8.13 (d, J=8.4Hz, 2H), 7.78 (d, J=8.4Hz, 2H), 3.55—3.49 (m, 2H), 1.77—1.74 (m, 2H), .46 (m, 7H), 1.29—1.21 (m, 1H). MS m/Z [M+H]+ 420.1.
Example 264 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((3,3- difluorocyclobutyl)methyl)nicotinamide 3mm fl“ 0“ \ ”WM The title compound was prepared in a manner similar to Example 256 using (3,3- difluorocyclobutyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.91 (s, 1H), 8.84— 8.81 (m, 1H), 8.64 (s, 1H), 8.46—8.39 (m, 2H), 8.13 (d, J=8.0Hz, 2H), 7.78 (d, J=8.0Hz, 2H), 3.44—3.41 (m, 2H), .67 (m, 2H), 2.44—2.38 (m, 3H). MS m/Z [M+H]+ 410.1.
Example 265 4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(3,3- difluorocyclobutyl)nicotinamide H l \ NW“! The title compound was prepared in a manner r to Example 256 using 3,3- difluorocyclobutanamine. 1H NMR (400 MHZ, DMSO—dg) 5 ppm 9.06 (d, J=6.4Hz, 1H), 8.91 (s, 1H), 8.67 (s, 1H), 8.50—8.40 (m, 2H), 8.14 (d, J=8.0Hz, 2H), 7.79 (d, J=8.0Hz, 2H), 4.33— 4.26 (m, 1H), 3.01—2.97 (m, 2H), 2.81—2.76 (m, 2H). MS m/Z [M+H]+ 396.1.
Example 266 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— ethylnicotinamide HscAN / N OH H | \ “[1qu The title compound was prepared in a manner similar to Example 256 using mine. 1H NMR (400 MHz, 6) 5 ppm 8.90 (s, 1H), 8.70—8.78 (m, 2H), 8.50— 8.40 (m, 2H), 8.13 (d, J=8.4Hz, 2H), 7.78 (d, J=8.4Hz, 2H), 3.34—3.31 (m, 2H), 1.15 (t, J=7.2Hz, 3H). MS m/Z [M+H]+ 334.1.
Example 267 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N— propylnicotinamide NJI\<1Nk OH \ ”W” The title compound was prepared in a manner similar to Example 256 using propan-l-amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.91 (s, 1H), 8.69—8.62 (m, 2H), 8.42—8.40 (m, 2H), 8.12 (d, J=8.4Hz, 2H), 7.77 (d, J=8.4Hz, 2H), 3.25—3.23 (m, 2H), 1.61— 1.51 (m, 2H), 0.91 (t, 3H). MS m/Z [M+H]+ 348.1.
] Example 268 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(2- (dimethylamino)ethyl)nicotinamide WO 60810 C|H3 o \ NW“! The title nd was prepared in a manner similar to Example 256 using N1,N1-dimethylethane-1,2-diamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.87 (s, 1H), 8.87—8.79 (m, 1H), 8.57—8.55(d, J=8.4Hz, 1H), 8.32—8.28 (m, 2H), 8.05 (d, J=8.4Hz, 2H), 7.65 (d, J=8.4Hz, 2H), 3.64—3.60(m, 2H), 3.27—3.24(m, 2H), 2.84(s, 6H). MS m/Z [M+H]+ 377.1.
Example 269 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(3- (dimethylamino)propyl)nicotinamide H3O‘N/\/\N / N OH 'l \ ’ ] The title compound was prepared in a manner similar to Example 256 using N1,Nl-dimethylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.91 (s, 1H), 8.83 (t, 1H), 8.62 (s, 1H), 8.49—8.38 8.62 (m, 2H), 8.13 (d, J=8.4Hz, 2H), 7.77 (d, J=8.4Hz, 2H), 3.36—3.34 (m, 2H), 3.14—3.10(m, 2H), 2.79 (s, 6H), 1.93—1.86 (m, 2H). MS m/Z [M+H]+ 391.2.
Example 270 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(1- piperidinyl)nicotinamide N / N H I \ [$qu ] The title compound was prepared in a manner similar to Example 256 .The product was purified by preparative HPLC to afford the title compound as an off-white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 13.53(brs, 1H), 10.15(br, 1H), 8.97 (s, 1H), .94 (m, 1H), 8.67—8.66(m, 1H), 8.50—8.46(m, 1H), 8.13 (d, J=7.6Hz, 1H), 7.78 (d, J=7.6Hz, 2H), 4.18—4.04(m, 1H), 3.46—3.43(m, 2H), 3.12—3.07(m, 2H), 2.77(s, 3H), 2.04—2.02(m, 2H), 1.92— 1.86(m, 2H). MS m/Z [M+H]+ 403.1. [01 118] Example 271 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1- methylpiperidinyl)methyl)nicotinamide cm a~ 0H H3C/N \ “‘1qu The title compound was prepared in a manner similar to Example 256 using (1- methylpiperidinyl)methanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.89 (s, 1H), 8.74 (s, 1H), 8.52—8.49 (m, 2H), 8.37—8.34 (m, 1H), 8.11 (d, J=8.0Hz, 2H), 7.73 (d, J=8.0Hz, 2H), 3.45—3.40 (m, 2H), 3.23—3.21 (m, 2H), 2.91—2.89 (m, 2H), 2.76 (s, 3H), 1.91—1.81 (m, 3H), 1.39—1.37 (m, 2H). MS m/Z [M+H]+ 417.1.
] Example 272 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(3- (methylamino)propyl)nicotinamide hydrochloride H30\ MM” / IN OH [\|] \ :N [01 122] N\ [01 123] Combined 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (200 mg, 0.65 mmol) HATU (372 mg, 0.98 mmol), and Et3N (198 mg, 1.96 mmol) in DMF (3.0 mL) . The mixture was stirred at room temperature for 0.5 hour, then tert-butyl (3- aminopropyl)(methyl)carbamate (147.39 mg, 0.79 mmol) was added. The mixture was stirred ght at room temperature. The reaction mixture was purified by preparative HPLC to give tert—butyl (3 -(6-(4-(4-cyanophenyl)—5-hydroxy- 1H-pyrazol yl)nicotinamido)propyl)(methyl)carbamate (150 mg, 48%). [01 124] Combined tert-butyl (3-(6-(4-(4-cyanophenyl)—5-hydroxy- 1H-pyrazol otinamido)propyl)(methyl)carbamate and EtOAc (5mL) and added HCl-EtOAc (5 mL) and stir at room ature for 5h. The reaction mixture was ated in vacuo to give the title compound as a yellow green solid. 1H NMR (400 MHz, 6) 5 ppm 9.09 — 9.04 (m, 1H), 9.00 (s, 1H), 8.89 (br. s., 2H), 8.67 (s, 1H), 8.48 (br. s., 2H), 8.15 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 3.38 (d, J=6.0 Hz, 2H), 2.95 (br. s., 2H), 2.54 (t, J=5.3 Hz, 3H), 1.96 — 1.85 (m, 2H). MS m/Z [M+H]+ 377.1.
Example 273 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N,4- dimethylnicotinamide N/ NWN Combined 6-(4-(4-cyanophenyl)hydroxy-lH-pyrazolyl)methylnicotinic acid (200 mg, 0.625 mmol), HATU (356.25 mg, 0.938 mmol) and triethylamine (315.63 mg, 3.125 mmol) and stirred at room temperature for 0.5 h. Then methanamine (108.75 mg, 1.25 mmol) was added and the on was stirred at room temperature overnight. The reaction mixture was d by ative HPLC to afford the title compound as a light yellow solid (88.38mg, 42.46%). 1H NMR (400 MHz, DMSO—d6) 5 ppm 8.59 (brs, 1H), 8.49—8.48 (m, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.11 (m, 2H), 7.77 (d, J=8.0 Hz, 2H), 2.79 (d, J=4.4 Hz, 3H), 2.48 (s, 3H). MS m/Z [M+H]+ 334.1. [01 128] e 274 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—ethyl methylnicotinamide N/ NW!“ The title compound was prepared in a manner similar to Example 273 using ethanamine. 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.57 - 8.52 (m, 2H), 8.41 (s, 1H), 8.31— 8.26 (m, 1H), 8.10 (m., 2H), 7.79 (d, J=8.4 Hz, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.47 (s, 3H), 1.14 (t, J=7.2 Hz, 3H). MS m/Z [M+H]+ 348.1.
Example 275 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—cyclopropyl- 4-methylnicotinamide H | N NW!“ The title compound was prepared in a manner similar to Example 273 using cyclopropanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.58 (m, 2H), 8.38 (s, 1H), 8.24 (s, 1H), 8.10 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 2.86—2.83 (m, 1H), 2.46 (s, 3H), .70 (m, 2H), 0.58—0.54 (m, 2H). MS m/Z [M+H]+ 360.1.
Example 276 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(2- methoxyethyl)methylnicotinamide 1 5 2 0 CH3 N NW!“ The title compound was prepared in a manner similar to Example 273 using 2- methoxyethanamine. 1H NMR (400 MHz, g) 5 ppm .54 (m, 2H), 8.53 (s, 1H), 8.41—8.40 (brs, 1H), 8.11—8.10(m, 2H), 7.79 (d, J=8.0 Hz, 2H), 3.42—3.39 (m, 2H), 3.30—3.26 (m, 2H), 3.25 (s, 3H), 2.47 (s, 3H)), 1.79—1.73 (m, 2H). MS m/Z [M+H]+ 392.1.
Example 277 (S)(4-(4-cyanophenyl)hydroxy-lH-pyrazol-l-yl)—4-methyl-N- hydrofuranyl)nicotinamide {lo CH3 N \ I OH N NW“ ] The title compound was prepared in a manner r to Example 273 using (S)- tetrahydrofuranamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.76 (d, J=6.4 Hz, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.26 (brs., 1H), 8.09 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 4.45 (s, 1H), 3.88—3.82 (m, 2H), 3.73—3.70 (m, 1H), 3.63—3.62 (m, 1H), 2.46 (s, 3H), 2.21—2.11 (m, 1H), 1.88—1.87 (m, 1H). MS m/Z [M+H]+ 390.1.
Example 278 6-(4-(4-cyanophenyl)hydroxy-lH-pyrazolyl)-N—((1s,4s) hydroxycyclohexyl)—4-methylnicotinamide HO],O 0 CH3 "’N \ | OH N ”W” The title compound was prepared in a manner similar to Example 273 using (1s,4s)aminocyclohexanol. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.57 (brs, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.10 (m, 2H), 7.79 (d, J=8.4 Hz, 2H), 4.40 (brs, 1H), 3.80—3.73 (m, 2H), 2.46 (s, 3 H), 1.73—1.51(m, 8H). MS m/Z [M+H]+ 418.2.
Example 279 6-(4-(4-cyanophenyl)hydroxy-lH-pyrazol-l-yl)methyl-N—(2- (tetrahydro-2H-pyranyl)ethyl)nicotinamide N \ H | N [\‘1 \ :N The title compound was prepared in a manner similar to e 273 using 2- (tetrahydro-2H-pyran-3 -yl)ethanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 8.57—8.54 (m, 2H), 8.40 (s, 1H), 8.25 (s, 1H), 8.11 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 3.80—3.74 (m, 2H), 3.30—3.25 (m, 3H), 3.01 (t, J=10.4 Hz, 1H), 2.47 (s, 3H), 1.85—1.84 (m, 1H), 1.58—1.35 (m, 5H), 1.16—1.11 (m, 1H). MS m/Z [M+H]+ 432.2 ] Example 280 N—benzyl(5-hydroxy(pyridinyl)-1H-pyrazolyl)benzamide 0 HO MN \ N/I \ ©f ‘N’ [01 148] Combined methyl 3 -(2-(5-(benzylcarbamoyl)pyridinyl)hydrazinyl)(pyridin- 2-yl)acrylate (110 mg, 0.273 mmol) and potassium carbonate (56.5 mg, 0.409 mmol) in ethanol (10 mL) and heated at 60°C for 1 hour. The precipitate was filtered and washed with ethanol to give an off-white solid. This solid was then dissolved in ethyl acetate. The organic layer was washed with water, dried and concentrated to give the title compound as a yellow solid. (60 mg, 59%). 1H NMR (400 MHz, DMSO-d6) 5 ppm 4.50 (d, J=6.06 Hz, 2 H), 6.69 (ddd, J=7.07, 4.80, 1.26 Hz, 1 H), 7.19 — 7.30 (m, 1 H), 7.34 (d, J=4.55 Hz, 4 H), 7.44 (ddd, J=8.21, 7.20, 2.02 Hz, 1 H), 7.85 (s, 1 H), 8.10 — 8.19 (m, 2 H), 8.19 — 8.25 (m, 1 H), 8.64 (dd, J=8.84, 0.76 Hz, 1 H), 8.84 (dd, J=2.53, 0.76 Hz, 1 H), 9.04 (t, J=5.81 Hz, 1 H). MS m/z [M+H]+ 372.4 ] Example of 281 N—benzyl(4-(4-cyanophenyl)hydroxy-1H-pyrazol otinamide / OH M \ Combined ethyl 3-(2-(5-(benzylcarbamoyl)pyridinyl)hydrazono)(4- cyanophenyl)propanoate (90mg, 0.204 mmol) and ium carbonate (42.3 mg, 0.306 mmol) in ethanol (2 mL) and heated for 1hour at 60°C. The reaction mixture was evaporated to give a residue which was purified by HPLC (ZQ9, Prep-TFA—50—55, Rt 4.54min) to give the title compound (5mg, 6%) as an off— white solid. 1H NMR (400 MHz, chloroform-d) 5 ppm 4.69 (d, J=5.56 Hz, 2 H), 6.37 (br. s., 1 H), 7.30 — 7.42 (m, 5 H), 7.62 — 7.69 (m, 2 H), 7.77 — 7.83 (m, 2 H), 7.91 (s, 1 H), 8.02 (d, J=8.08 Hz, 1 H), 8.32 (dd, J=8.84, 2.27 Hz, 1 H), 8.80 (d, J=1.77 Hz, 1 H). MS m/z [M+H]+ 396.3.
Example 282 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)—5-hydroxy-1H- pyrazolyl)methylbenzonitrile OWN \\ OH H30VN N [01 154] Combined 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (0.524 g, 1.636 mmol) in THF (3 mL) and added DMSO (1 mL) and DMAP (3.00 mg, 0.025 mmol) followed by a dropwise addition of a solution of CD1 (0.292 g, 1.80 mmol) in DMSO (1 mL). The resulting clear solution was stirred at ambient ature for 45 minutes and an additional portion of CD1 (73.0 mg, 0.450 mmol) was added. The mixture was d for a total of 2 hours and 1-ethylpiperazine (0.270 mL, 2.127 mmol) was added. The resulting mixture was stirred for 4.5 hours and then diluted with water (6 mL, dropwise), acidified to pH =7 with 6N aqueous hydrochloric acid, and then further d with water (4 mL) to give a solid. The solid was filtered and dried in vacuum to give the title nd (0.613 g, 90%). 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.06 (t, J=7.07 Hz, 3 H) 2.43 (s, 3 H) 2.53 — 2.63 (m, 4 H) 3.57 (br. s., 6 H) 7.61 (d, J=8.08 Hz, 1 H) 7.67 (s, 1 H) 7.90 (d, J=8.08 Hz, 1 H) 8.02 (dd, , 2.27 Hz, 1 H) 8.06 (s, 1 H) 8.42 (d, J=8.59 Hz, 1 H) 8.52 (d, J=1.77 Hz, 1 H); MS (M+H)+ 417.
Example 283 4-(5-hydroxy(5-(4-propylpiperazinecarbonyl)pyridinyl)— 1H-pyrazolyl)—3-methylbenzonitrile ]/\N \ l OH HsCNNd N/ :N [01 157] Combined 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (0.5 g, 1.561 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.449 g, 2.342 mmol), HOBT (0.359 g, 2.342 mmol) and 1-propylpiperazine dihydrobromide (0.543 g, 1.873 mmol) in DMF (1.56 mL) and added DIPEA (1.09 mL, 6.24 mmol) to give an orange solution. After stirring for 20 minutes the reaction mixture was 2014/031918 heated to 60°C for 3 hours, then was diluted with water (5 mL) and ed with 6N aqueous hydrochloric acid to pH 6 and stirred at ambient temperature for 30 minutes to give a solid. The solid was ted by filtration, washed with water (3 mL) and suspended in ACN (10 mL). The suspension was treated with 1N aqueous hydrochloric acid (2 mL) and heated to 40°C. Ethyl ether was then added until the mixture became slightly cloudy (~8 mL) and then allowed to cool to ambient temperature to give a solid, and then cooled in an ice bath for s. The solid was collected by filtration and dried in vacuum at 80°C for 1.5 hour to give the title compound as a hydrochloride salt (81.3 mg, 0.174 mmol, 11.15 %). 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.92 (t, J=7.45 Hz, 3 H) 1.64 — 1.79 (m, 2 H) 2.43 (s, 3 H) 2.81 — 3.20 (m, 4 H) 3.21 — 4.90 (m, 6 H) 7.67 (d, J=7.58 Hz, 1 H) 7.71 — 7.91 (m, 2 H) 7.93 — 8.74 (m, 4 H) 10.75 (br. s., 1 H) 13.23 (br. s., 1 H); [M+H]+ 431.
Example 284 6-(4-(4-cyanofiuorophenyl)hydroxy-1H-pyrazolyl)-N- ((1s,4s)methoxycyclohexyl)nicotinamide H3C\o><:><NH HO \ / Nx / 0 N N Combined EDC (115 mg, 0.601 mmol), HOBT (27.1 mg, 0.200 mmol), (cis) methoxycyclohexanamine hloride (66.4 mg, 0.401 mmol) and 6-(4-(4-cyano fiuorophenyl)hydroxy-1H-pyrazolyl)nicotinic acid (65 mg, 0.200 mmol) in DMF (0.8 mL) and then added DIPEA (0.175 mL, 1.002 mmol). After 24 hours, the reaction mixture was purified by preparative HPLC (ACN/water with formic acid) to give the title compound (23 mg, 0.053 mmol, 26.3 %) as a tan solid. MS: 436 (M+H). 1H NMR (400 MHz, DMSO— d6) 5 ppm 1.34 — 1.48 (m, 2 H) 1.49 — 1.65 (m, 4 H) 1.76 — 1.88 (m, 2 H) 3.17 (s, 3 H) 3.31 (br. s., 1 H) 3.73 — 3.87 (m, 1 H) 7.62 (dd, J=8.2, 1.6 Hz, 1 H) 7.77 (dd, J=11.7, 1.6 Hz, 1 H) 8.16 (d, J=3.0 Hz, 1 H) 8.31 — 8.44 (m, 3 H) 8.55 (t, J=8.0 Hz, 1 H) 8.84 (dd, J=2.0, 1.0 Hz, 1 H) 13.71 (br.s., 1H).
Example 285 6-(4-(4-cyanofiuorophenyl)hydroxy-1H-pyrazolyl)-N-(4- methoxybutyl)nicotinamide H3C\ / N flu] \/\ \ / O N N 2014/031918 ] The title compound was prepared in a manner similar to Example 284 using 4- methoxybutan-l-amine. MS: 410 (M+H). 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.42 - 1.57 (m, 4 H) 3.16 (s, 3 H) 3.19 — 3.32 (m, 4 H) 7.61 (d, J=8.1 Hz, 1 H) 7.75 (d, J=11.6 Hz,1 H) 8.16 (d, J=2.5 Hz, 1 H) 8.28 — 8.36 (m, 1 H) 8.37 — 8.46 (m, 1 H) 8.56 (t, J=8.0 Hz, 1 H) 8.61 (t, J=5.6 Hz, 1 H) 8.83 (s, 1 H) 13.72 (br. s., 1 H).
Example 286 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(2- (dimethylamino)ethyl)—N—methylnicotinamide H3C H3C :N CH3 HO H30 —\—N'WM_ \ \ / . / O N N The title compound was prepared in a manner r to Example 284 using N 1 ,N 1 ,N2-trimethylethane- 1 ,2-diamine and 6-(4-(4-cyanomethylphenyl)hydroxy-1H- pyrazol-l-yl)nicotinic acid to give a formic acid salt (61 mg, 0.135 mmol, 72.3 %) as an off— white solid. MS: 405 (M+H). 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.42 (s, 3 H) 2.53 — 2.70 (m, 4 H) 3.02 (s, 3 H) 3.11 — 3.80 (m, 6 H) 7.53 (d, J=8.3 Hz, 1 H) 7.58 (s, 1 H) 7.89 — 7.99 (m, 2 H) 8.10 (br. s., 1 H) 8.50 (m, 2 H). [01 167] Example 287 4-(5-hydroxy(5-(4-methyl-1,4-diazepanecarbonyl)pyridin yl)-1H-pyrazolyl)—3 -methylbenzonitrile HBC / N \ / N H3C K‘— HO N — \ / Nt / O N N The title compound was prepared in a manner similar to Example 284 using 1- methyl-1,4-diazepane and 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazol yl)nicotinic acid to give a formic acid salt (67 mg, 0.145 mmol, 77 %) as an off—white solid.
MS: 417 (M+H). 1H NMR (400 MHz, 6) 5 ppm 1.88 (br. s., 2 H) 2.35 (s, 3 H) 2.54 (br. s., 2 H) 2.86 (d, J=17.7 Hz, 3 H) 3.01 (br. s., 1 H) 3.39 — 3.76 (m, 5 H) 7.45 (d, J=8.1Hz, 1 H) 7.50 (s, 1 H) 7.78 — 7.91 (m, 2 H) 8.04 (d, J=7.6 Hz, 1 H) 8.42 (br. s., 2 H) 11.65 (br. s., 1 H) Example 288 (+/-)(5-hydroxy(5-(octahydropyrrolo[1,2-a]pyrazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile 2014/031918 {WHO\N/ H3C O\—N The title compound was prepared in a manner similar to Example 284 using octahydropyrrolo[1,2-a]pyrazine and 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazol- 1—yl)nicotinic acid to give a formic acid salt (47 mg, 0.099 mmol, 79 %) as a white solid.
MS: 429 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.15 — 1.52 (m, 1 H) 1.72 (br. s., 3 H) 2.09 (br. s., 1 H) 2.21 (d, J=8.8 Hz, 2 H) 2.43 (s, 3 H) 2.54 — 2.61 (m, 1 H) 2.87 — 3.15 (m, 3 H) 3.50 — 3.88 (m, 1 H) 4.30 — 4.68 (m, 1 H) 7.63 (d, J=8.1Hz, 1 H) 7.69 (s, 1 H) 7.88 (d, J=8.1 Hz, 1 H) 8.03 (dd, J=8.6, 2.0 Hz, 1 H) 8.09 (s, 1 H) 8.42 (d, J=8.3 Hz, 1 H) 8.52 (d, J=2.0 Hz, 1 H) 12.77 (br. s., 1 H).
] Example 289 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— methyl-N-(1-methylpiperidinyl)nicotinamide WC}[CH3 Ho mw /_ \ 0 N N The title compound was prepared in a manner similar to Example 284 using N,1- dimethylpiperidinamine and 6-(4-(4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazol yl)nicotinic acid to give a formic acid salt (42 mg, 0.088 mmol, 70.6 %) as a white solid.
MS: 431 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.71 (d, J=11.6 Hz, 2 H) 1.78 — 1.95 (m, 2 H) 2.35 (s, 3 H) 2.78 (s, 3 H) 2.92 — 3.83 (m, 7 H) 4.34 (br. s., 1 H) 7.43 (d, J=8.3 Hz, 1 H) 7.48 (s, 1 H) 7.76 — 7.88 (m, 2 H) 8.06 — 8.11 (m, 1 H) 8.38 (br. s., 1 H) 8.43 (d, J=8.8 Hz, 1 H).
Example 290 4-(5-hydroxy(5-(4-methylpiperazinecarbonyl)pyridinyl)- 1H-pyrazolyl)—3-methylbenzonitrile H3C\ / N 0N H30 N — \ / Nx / O N N The title nd was prepared in a manner r to Example 284 using 1- methylpiperazine and 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid to give a formic acid salt (22 mg, 0.055 mmol, 43.8 %) as a white solid. MS: 403 2014/031918 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.32 (s, 3 H) 2.43 (s, 3 H) 3.28 — 3.70 (m, 8 H) 7.62 (d, J=8.1 Hz, 1 H) 7.68 (s, 1 H) 7.90 (d, J=8.1 Hz, 1 H) 8.02 (dd, J=8.6, 2.3 Hz, 1 H) 8.08 (s, 1 H) 8.43 (d, J=8.6 Hz, 1 H) 8.52 (d, J=2.0 Hz, 1 H) 12.74 (br. s., 1 H).
Example 291 4-(1-(5-(4-(tert-butyl)piperazinecarbonyl)pyridinyl) y-1H-pyrazolyl)—3 -methylbenzonitrile H3C CH3 0N H30 / \ \ O _N N The title compound was prepared in a manner similar to Example 284 using 1-t- butyl piperazine and 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid to give a formic acid salt (53 mg, 0.119 mmol, 76 %) as a white solid. MS: 445 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.10 (s, 9 H) 2.43 (s, 3 H) 2.71 (br. s., 4 H) 3.57 (br. s., 4 H) 7.56 — 7.62 (m, 1 H) 7.65 (s, 1 H) 7.94 (d, J=8.1Hz, 1 H) 7.98 — 8.07 (m, 2 H) 8.42 (d, J=8.6 Hz, 1 H) 8.52 (d, J=1.5 Hz, 1 H) 12.42 (br. s., 1 H).
Example 292 4-(5-hydroxy(5-((3aR,6aS)methyloctahydropyrrolo[3,4— c]pyrrolecarbonyl)pyridinyl)-1H-pyrazolyl)-3 -methylbenzonitrile H3C\ / N _\\H / H\" HO / \ N\ O ‘N N [01 184] Combined 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (50 mg, 0.156 mmol), thylimino)methylene)-N3,N3 -dimethylpropane-1,3-diamine hydrochloride (90 mg, 0.468 mmol) and HOBT (21.09 mg, 0.156 mmol) in DMF (0.8 mL) and added N—ethyl—N—isopropylpropan—2—amine (0.056 mL, 0.468 mmol) and (3 aR,6aS)-2— methyloctahydropyrrolo[3,4-c]pyrrole (79 mg, 0.624 mmol). After 17 hours, the reaction mixture was diluted with DMSO (100 uL) and purified by preparative HPLC (ACN/water with formic acid) to give the title nd as a 0.63 formic acid salt (60 mg, 0.131 mmol, 84 %) as a tan solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.35 (s, 3 H) 2.48 (s, 3 H) 2.77 (br. s., 2 H) 2.91 (br. s., 4 H) 3.43 (br. s., 2 H) 3.67 (dd, J=11.5, 6.4 Hz, 2 H) 7.43 — 7.49 (m, 1 H) 7.51 (s, 1 H) 7.87 (s, 1 H) 7.94 (dd, J=8.7, 2.4 Hz, 1 H) 8.02 (d, J=8.1 Hz, 1 H) 8.41 (d, J=8.6 Hz, 1 H) 8.49 (d, J=1.8 Hz, 1 H) 11.91 (br. s., 1 H). [01 185] Example 293 4-(5-hydroxy(5 -(2-methyl-2,6-diazaspiro[3 .4] octane carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile 8 //N / \ N\ O ‘N N The title compound was ed in a manner similar to Example 292 using 2- methyl-2,6-diazaspiro[3.4]octane to a 0.56 formic acid salt (48 mg, 0.106 mmol, 67.7 %) as a tan solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.08 (d, J=4.3 Hz, 2 H) 2.35 (s, 3 H) 2.54 — 2.72 (m, 3 H) 3.45 (t, J=6.8 Hz, 1 H) 3.50 (d, J=6.6 Hz, 1 H) 3.60 — 3.71 (m, 2 H) 3.71 — 3.81 (m, 2 H) 3.81 — 3.93 (m, 2 H) 7.38 (d, J=8.1 Hz, 1 H) 7.42 (s, 1 H) 7.74 (s, 1 H) 7.88 (d, J=8.1Hz, 1 H) 8.22 (dd, J=13.9, 8.3 Hz, 1 H) 8.48 (d, J=8.6 Hz, 2 H) 10.87 — 12.25 (m, 1 H).
Example 294 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— methyl-N-(1-propylpiperidinyl)nicotinamide H3CMQN[CH3 HO / \ \ 0 ‘N N The title nd was prepared in a manner similar to Example 292 using N- propylpiperidinamine and purified by ative HPLC (ACN/water with TFA) to give a TFA salt (129 mg, 0.225 mmol, 72.2 %) as a white solid. MS: 459 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.90 (br. s., 3 H) 1.65 (br. s., 2 H) 1.93 (d, J=11.9 Hz, 2 H) 2.07 (q, J=11.8 Hz, 2 H) 2.43 (s, 3 H) 2.87 (s, 3 H) 2.98 — 3.27 (m, 2 H) 3.42 — 3.85 (m, 5 H) 7.67 (d, J=7.3 Hz, 1 H) 7.74 (br. s., 1 H) 7.80 (br. s., 1 H) 8.09 (br. s., 1 H) 8.24 (br. s., 1 H) 8.56 (br. s., 1 H) 9.15 (br. s., 1 H) 13.23 (br. s., 1 H).
Example 295 (+/-)(1-(5-(3-((ethyl(methyl)amino)methyl)pyrrolidine carbonyl)pyridinyl)-5 -hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile HBC\N/\CH3 / N KO / 0 N N The title compound was prepared in a manner similar to Example 292 using N- methyl-N-(pyrrolidin-3 -ylmethyl)ethanamine and purified by preparative HPLC (ACN/water with TFA) to give a TFA salt (73 mg, 0.131 mmol, 84 %) as a white solid. MS: 445 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.11 — 1.30 (m, 3 H) 1.69 (t, J=9.2 Hz, 1 H) 2.13 (br. s., 1 H) 2.43 (s, 3 H) 2.56 — 2.70 (m, 1 H) 2.70 — 2.85 (m, 3 H) 3.24 — 3.36 (m, 2 H) 3.46 — 3.69 (m, 5 H) 3.69 — 3.88 (m, 1 H) 7.67 (d, J=7.6 Hz, 1 H) 7.74 (s, 1 H) 7.81 (br. s., 1 H) 8.11 — 8.62 (m, 2 H) 8.66 (s, 1 H) 8.90 — 9.27 (m, 1 H) 13.22 (br. s., 1 H).
] Example 296 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- cyclopropylpiperidinyl)-N-methylnicotinamide OH30 OWHNN: ] The title compound was prepared in a manner r to Example 292 using 1- cyclopropyl-N—methylpiperidinamine (62.6 mg, 0.406 mmol) and purified by preparative HPLC (ACN/water with TFA) to give a TFA salt (53 mg, 0.093 mmol, 59.5 %) as a white solid. MS: 457 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.71 — 1.00 (m, 4 H) 1.85 — 2.09 (m, 4 H) 2.43 (s, 3 H) 2.86 (s, 3 H) 3.14 (br. s., 1 H) 3.50 — 3.78 (m, 4 H) 4.57 (br. s., 1 H) 7.67 (d, J=7.3 Hz, 1 H) 7.74 (s, 1 H) 7.80 (br. s., 1 H) 8.10 (br. s., 1 H) 8.24 (br. s., 1 H) 8.57 (br. s., 1 H) 8.93 (br. s., 1 H) 13.24 (br. s., 1 H).
Example 297 4-(1-(5-(3-(cyclobutyl(methyl)amino)azetidinecarbonyl)pyridin- 2-yl)hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile H3C-N //N b H3C NWM. / O ‘N N The title compound was prepared in a manner similar to Example 292 using N- cyclobutyl-N—methylazetidinamine dihydrochloride and purified by preparative HPLC (ACN/water with trifluoroacetic acid) to give a TFA salt (48 mg, 0.086 mmol, 69.1 %) as a white solid. MS: 443 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.55 — 1.82 (m, 2 H) 2.00 — 2.27 (m, 4 H) 2.43 (s, 3 H) 2.68 (br. s., 3 H) 3.71 (d, J=8.1Hz, 1 H) 4.19 (d, J=5.3 Hz, 1 H) 4.31 (br. s., 2 H) 4.62 (br. s., 2 H) 7.67 (d, J=7.8 Hz, 1 H) 7.74 (s, 2 H) 8.26 (d, J=8.3 Hz, 2 H) 8.53 (br. s., 1 H) 8.74 (d, J=1.5 Hz, 1 H) 13.23 (br. s., 1 H). 2014/031918 e 29 8 4-(1-(5-(3 -(cyclopropyl(methyl)amino)azetidinecarbonyl)pyridin- 2-yl)hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile H3C-N 4N b H3C O ‘N N The title compound was prepared in a manner similar to Example 292 using N- cyclopropyl-N-methylazetidinamine dihydrochloride and purified by preparative HPLC (ACN/water with trifluoroacetic acid) to give a TFA salt (35 mg, 0.065 mmol, 51.7 %) as a white solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.42 — 1.05 (m, 4 H) 2.43 (s, 3 H) 2.66 (br. s, 3 H) 4.28 (br. s., 4 H) 4.58 (br. s., 2 H) 7.67 (d, J=7.6 Hz, 1 H) 7.74 (s, 1 H) 7.76 — 7.89 (m, 1 H) 8.28 (br. s., 2 H) 8.60 (br. s., 1 H) 8.75 (s, 1 H) 13.23 (br. s., 1 Example 299 4-(1-(5-(6,6-difluoromethyl-1,4-diazepanecarbonyl)pyridin yl)—5-hydroxy-1H-pyrazolyl)methylbenzonitrile H30 4” ‘N F K‘ HO O ‘N N The title compound was prepared in a manner similar to Example 292 using 6,6- difluoro-l-methyl-1,4-diazepane hydrochloride and purified by preparative HPLC (ACN/water with trifluoroacetic acid) to give a TFA salt (40 mg, 0.071 mmol, 45.2 %) as a white solid. MS: 453 (M+H). 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.43 (s, 3 H) 2.54 — 2.78 (m, 2 H) 2.85 — 3.26 (m, 2 H) 3.27 — 3.70 (m, 3 H) 3.71 — 4.30 (m, 4 H) 7.67 (d, J=8.1Hz, 1 H) 7.74 (s, 1 H) 7.77 (br. s., 1 H) 8.12 (br. s., 2 H) 8.29 — 8.53 (m, 1 H) 8.58 (br. s., 1 H) 13.22 (br. s., 1 H).
Example 300 4-cyanocyclopropylphenyl)hydroxy-1H-pyrazolyl)- N—(3—methoxypropyl)nicotinamide WM‘ \ MNH N N/ Me‘0 Combined 6—(4—bromomethoxy-1H-pyrazolyl)-N-(3- methoxypropyl)nicotinamide (150 mg, 0.406 mmol), 3-cyclopropyl(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)benzonitrile (219 mg, 0.813 mmol), and THF (3047 [11) water (1016 [11) in a microwave vial. The reaction mixture was degassed by bubbling nitrogen through the mixture. After a few minutes of degassing, Pd(PPh3)4 (23.47 mg, 0.020 mmol) and sodium ate (172 mg, 1.625 mmol) were added. The reaction was degassed 2 minutes more, then capped, and subjected to microwave irradiation to 110 0C for 1 hour. The reaction e was then diluted with ethyl acetate (20 mL) and washed with water (2 x 10 mL) followed by brine (20 mL). The organic layer was collected, dried with sodium sulfate, and concentrated to residue which was purified by column (30 g, 60 mesh silica, 10% to 100% EtOAc in heptane gradient) to give 6-(4-(4-cyano-3 -cyclopropylphenyl)methoxy-1H- pyrazolyl)-N-(3-methoxypropyl)nicotinamide (134 mg, 76%) as a white solid.
Combined 4—cyanocyclopropylphenyl)methoxy-1H-pyrazolyl)—N— (3-methoxypropyl)nicotinamide (134 mg, 0.311 mmol) and lithium chloride (132 mg, 3.11 mmol) in DMA (3.1 mL) and heated at 70 0C for 2 days. The reaction mixture was cooled to ambient temperature, d with DMSO (0.3 mL), and purified via preparative HPLC to give the title compound (44.6 mg, 0.107 mmol, 26 %) as a white solid. 1H NMR (400 MHz, DMSO—616)?) ppm 0.60 — 0.75 (m, 2 H) 0.83 — 0.95 (m, 2 H) 1.72 (quin, J=6.69 Hz, 2 H) 2.10 (d, J=5.05 Hz, 1 H) 3.18 (s, 3 H) 3.22 — 3.36 (m, 4 H) 7.41 (d, J=1.26 Hz, 1 H) 7.57 (dd, J=8.08, 1.77 Hz, 1 H) 7.63 — 8.55 (m, 4 H) 8.64 (br. s., 1 H) 8.77 — 8.90 (m, 1 H); EST—MS m/z [M+H]+418.4. e 301 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N,N— ylnicotinamide CH3 HO Wm \\ / Nx / CH3 ] 0 N N Combined 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid (107 mg, 0.334 mmol), HOBT hydrate (77 mg, 0.501 mmol), N1- ((ethylimino)methylene)—N3,N3 —dimethylpropane-1,3—diamine hydrochloride (96 mg, 0.501 mmol) in DMF (2 mL), and added triethylamine (0.188 mL, 1.336 mmol), stirred at ambient temperature for 5 minutes and ylamine hydrochloride (54.5 mg, 0.668 mmol) was added. The reaction was stirred at 50°C for 3 hours, then cooled to ambient temperature and diluted with MeOH (5mL), water (5mL), and acidified to pH 5 using 1N aqueous hydrochloric acid, to give a solid which was filtered, washed with water, and dried under vacuum to give the title compound (76.2 mg, 0.219 mmol, 66 %) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.43 (s, 3 H) 3.01 (br. s., 6 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.70 — 7.82 (m, 2 H) 8.02 — 8.20 (m, 2 H) 8.37 (br. s., 1 H) 8.56 (dd, J=2.27, 0.76 Hz, 1 H) 13.11 (br. s., 1 H). ESI—MS m/z [M+H]+ 348.3.
Example 302 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- -trifluoroethyl)piperidinyl)nicotinamide F F N //N \ / \ / Me O N N The title compound was prepared in a manner similar to Example example 301 using 1-(2,2,2-trifluoroethyl)piperidinamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.60 (qd, 2, 3.66 Hz, 2 H) 1.81 (d, J=9.60 Hz, 2 H) 2.35 — 2.48 (m, 5 H) 2.87 — 3.00 (m, 2 H) 3.18 (q, J=10.11Hz, 2 H) 3.71 — 3.89 (m, 1 H) 7.59 — 7.81 (m, 3 H) 8.15 (br. s., 1 H) 8.23 — 8.53 (m, 3 H) 8.82 — 8.96 (m, 1 H) 13.14 (br. s., 1 H). EST—MS m/z [M+H]+ 485.2. e 303 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— methyl-N-(3 -(piperidinyl)propyl)nicotinamide NIB—Nfl \\ / N. / Me O N N Combined 4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid (70 mg, 0.219 mmol), HOBT hydrate (50.2 mg, 0.328 mmol), N1- ((ethylimino)methylene)—N3,N3 —dimethylpropane-1,3—diamine hydrochloride (62.8 mg, 0.328 mmol) in DMF (1 mL), and added triethylamine (0.092 mL, 0.656 mmol), then stirred at ambient temperature for 5 minutes and N—methyl(piperidinyl)propanamine (0.085 mL, 0.437 mmol) was added. The reaction was stirred at 50°C for 3 hours. The crude on was then cooled to ambient temperature and diluted with DMSO (1 mL) and purified via preparative HPLC (25-45% acetonitrile in water, with trifluoroacetic acid) to give the title compound (61.5 mg, 0.134 mmol, 61.4%) as a tan solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.30 — 1.49 (m, 1 H) 1.68 (br. s., 3 H) 1.82 (br. s., 2 H) 1.93 — 2.07 (m, 2 H) 2.43 (s, 3 H) 2.88 — 3.15 (m, 7 H) 3.31 — 3.43 (m, 1 H) 3.45 — 3.58 (m, 3 H) 7.65 — 7.87 (m, 3 H) 8.04 — 8.67 (m, 4 H) 9.35 (br. s., 1 H). ESl—MS m/z [M+H]+ 459.3.
Example 304 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—methyl-N—(3- (piperidinyl)propyl)nicotinamide Me—N _ 0flu /N N The title compound was prepared in a manner similar to Example 303 using 6-(4- nophenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid and yl(piperidin yl)propyl amine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.39 (d, J=9.60 Hz, 1 H) 1.66 (d, J=13.89 Hz, 3 H) 1.82 (br. s., 2 H) 2.01 (br. s., 2 H) 2.83 — 3.13 (m, 7 H) 3.32 — 3.58 (m, 4 H) 7.79 (d, J=8.34 Hz, 2 H) 8.13 (br. s., 3 H) 8.58 (br. s., 3 H) 9.05 — 9.50 (m, 1 H) 12.43 — 14.49 (m, 1 H). ESI—MS m/z [M+H]+ 445.2.
] Example 305 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)—5-hydroxy-1H- pyrazolyl)—2-fluoromethylbenzonitrile KN \ | OH l/Nd N/ b.1\ :N CH3 N\ “30 F Combined 6-(4-bromomethoxy-1H-pyrazolyl)nicotinic acid (500 mg, 1.677 mmol), o-3 -methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile (876 mg, 3.35 mmol), THF (10.500 mL), and water (3.50 mL) in a microwave vial. Degassed with nitrogen then added [1,1’-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(H) (1093 mg, 1.677 mmol) and sodium carbonate (711 mg, 6.71 mmol). The on was degassed 2 minutes more, then capped and subjected to microwave irradiation at 110 0C for 1 hour. The reaction mixture was then diluted with EA (20 mL) and washed with water (20 mL). A precipitate was observed in the aqueous layer which was filtered and the solids collected to give 6-(4-(4-cyano-3 -fluoromethylphenyl)-5 -methoxy-1H-pyrazolyl)nicotinic acid (275 mg, 0.781 mmol, 46.5%) which was dried under vacuum and used in the next stepwithout further ation. ESI—MS m/z [M+H]+ 353.2.
Combined 6-(4-(4-cyanofluoromethylphenyl)methoxy- 1H-pyrazol yl)nicotinic acid (106 mg, 0.300 mmol), HOBT hydrate (68.9 mg, 0.450 mmol), N1— ((ethylimino)methylene)—N3,N3 —dimethylpropane-1,3—diamine hydrochloride (86 mg, 0.450 mmol), and N—ethyl-N—isopropylpropanamine (0.157mL) in DMF (1 mL) and stirred for 5 min. The mixture was then added to 1-ethylpiperazine (68.5, 0.600 mmol). After 18 hours the reaction mixture was d via preparative HPLC (20-40% acetonitrile in water, with TFA) to give 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)methoxy-1H-pyrazol yl)—2-fluoromethylbenzonitrile (70 mg, 0.156 mmol, 52%). ESI-MS m/z [M+H]+ 449.3.
Combined 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)methoxy-1H- pyrazolyl)—2-fluoromethylbenzonitrile (70 mg, 0.156 mmol) and DMA (1561 [11) then added lithium chloride (66.2 mg, 1.561 mmol) and heated at 70°C overnight. The crude reaction was then diluted with DMSO (500 uL) and purified via preparative HPLC nitrile—water, with TFA) to give the title compound (24.6 mg, 0.057 mmol, 36.3 %) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.23 (t, J=7.33 Hz, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 3.16 (t, J=7.20 Hz, 2 H) 3.24 — 4.06 (m, 8 H) 7.49 — 7.84 (m, 2 H) 8.04 — 8.30 (m, 2 H) 8.43 (br. s., 1 H) 8.60 (dd, J=2.15, 0.63 Hz, 1 H). ESI—MS m/z [M+H]+ 435.3.
Example 306 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)—5-hydroxy-1H- lyl)—2-fluoromethylbenzonitrile 6W1 F l 0“ (Nd N/ N \ :N CH3 N\ The title nd was prepared in a manner similar to Example 305 using 2- fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.24 (t, J=7.33 Hz, 3 H) 2.42 (s, 3 H) 3.17 (q, J=7.24 Hz, 2 H) 3.26 — 4.82 (m, 8 H) 7.79 (d, J=7.07 Hz, 1 H) 7.88 (d, J=11.37 Hz, 1 H) 8.13 (dd, J=8.72, 2.15 Hz, 1 H) 8.29 (br. s., 1 H) 8.47 (br. s., 1 H) 8.60 (d, J=2.27 Hz, 1 H). EST—MS m/z [M+H]+ 435.3.
Example 307 4-(1-(5-(4-cyclopropylpiperazinecarbonyl)pyridinyl)—5- hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile 2014/031918 “30 F The title compound was prepared in a manner similar to Example 305 using 1- ropylpiperazine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.68 (br. s., 4 H) 2.33 (d, J=2.27 Hz, 3 H) 3.06 (br. s., 4 H) 3.55 (br. s., 4 H) 7.63 (d, J=8.08 Hz, 1 H) 7.70 — 7.85 (m, 1 H) 8.11 (dd, J=8.59, 2.02 Hz, 1 H) 8.23 (br. s., 1 H) 8.42 (br. s., 1 H) 8.58 (d, J=1.52 Hz, 1 H). ESI—MS m/z [M+H]+ 447.3.
Example 308 4-(1-(5-(4-cyclopropylpiperazinecarbonyl)pyridinyl)—5- hydroxy-1H-pyrazolyl)—2-fluoromethylbenzonitrile “a .
WW I o.
N/ NWN The title compound was prepared in a manner similar to Example 305 using 1- cyclopropylpiperazine and 2-fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.64 - 1.07 (m, 4 H) 2.42 (s, 3 H) 2.60 — 2.85 (m, 1 H) 3.30 (br. s., 4 H) 3.47 — 4.15 (m, 4 H) 7.79 (d, J=7.07Hz, 1 H) 7.88 (d, J=10.86 Hz, 1 H) 8.13 (dd, J=8.72, 2.15 Hz, 1 H) 8.29 (br. s., 1 H) 8.47 (br. s., 1 H) 8.60 (dd, J=2.27, 0.51 Hz, 1 H). EST—MS m/z [M+H]+ 447.3.
Example 309 5-(4-ethylpiperazinecarbonyl)pyridinyl)—5-hydroxy-1H- pyrazolyl)—2,3-dimethylbenzonitrile 6W1| OH (Nd N/ N \ :N CH3 N\ “30 CH3 The title compound was prepared in a manner similar to Example 305 using 2,3- dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.23 (t, J=7.20 Hz, 3 H) 2.30 (s, 3 H) 2.49 — 2.49 (m, 2 H) 3.16 (d, J=7.33 Hz, 3 H) 3.41 (br. s., 8 H) 7.44 (d, J=7.83 Hz, 1 H) 7.60 (s, 1 H) 7.78 — 7.80 (m, 1 H) 8.12 (d, J=7.33 Hz, 2 H) 8.47 — 8.63 (m, 1 H). EST—MS m/z [M+H]+ 431.3.
Example 3 10 4-(1-(5 -(4-cyclopropylpiperazinecarbonyl)pyridinyl)—5 - hydroxy-1H-pyrazolyl)—2,3 hylbenzonitrile V/ N [El\ :N The title compound was prepared in a manner r to Example 305 using 1- cyclopropylpiperazine and 2,3-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.80 (br. s., 4 H) 2.30 (s, 3 H) 2.49 (br. s., 3 H) 3.32 — 5.12 (m, 8 H) 7.44 (d, J=7.58 Hz, 1 H) 7.61 (d, J=8.08 Hz, 1 H) 7.76 — 8.73 (m, 4 H). ESI—MS m/z [M+H]+ 443.3. e 311 4-(1-(5-(4-(2,2-difluoroethyl)piperazinecarbonyl)pyridinyl)—5- hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile 2~F N ON HO \ / N\ / CH3 0 N N The title compound was prepared in a manner r to Example 301 using 1- (2,2-difluoroethyl)piperazine hydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.42 (s, 3 H) 2.58 (br. s., 4 H) 2.79 (td, J=15.66, 4.29 Hz, 2 H) 3.39 — 3.68 (m, 4 H) 5.95 — 6.35 (m, 1 H) 7.67 (d, J=8.26 Hz, 1 H) 7.71 — 7.80 (m, 2 H) 8.03 — 8.21 (m, 2 H) 8.53 (m, J=2.10, 0.90 Hz, 2 H) 13.13 (br. s., 1 H). ESI—MS m/z [M+H]+ 453.3minutes.
Example 312 4-(5-hydroxy(5-(4-(2,2,2-trifluoroethyl)piperazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile F / N ON HO ”@ \/\ N. / CH3 O N N The title compound was prepared in a manner similar to Example 301 using 1- (2,2,2-trifluoroethyl)piperazine ochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.42 (s, 3 H) 2.59 — 2.74 (m, 4 H) 3.25 (q, J=10.11Hz, 2 H) 3.39 — 3.71 (m, 4 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.72 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 8.06 (dd, J=8.72, 2.15 Hz, 1 H) 8.15 (s, 1 H) 8.39 (d, J=8.34 Hz, 1 H) 8.53 (dd, J=2.27, 0.76 Hz, 1 H) 12.45 — 13.65 (m, 1 H). ESI—MS m/z [M+H]+ 471.2.
] Example 313 4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)-N—(3- (dimethylamin0)pr0pyl)-N-methylnic0tinamide H3C_N)—® \\ / Nx / CH3 O N N ] The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)nic0tinic acid and N1,N1,N3 -trimethylpr0pane-1,3-diamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.98 (br. s., 2 H) 2.43 (s, 3 H) 2.68 — 2.95 (m, 7 H) 3.00 (s, 3 H) 3.13 (br. s., 1 H) 3.23 — 3.61 (m, 2 H) 7.60 — 7.89 (m, 3 H) 7.99 — 8.82 (m, 4 H) 9.53 (br. s., 1 H) 12.69 — 13.62 (m, 1 H). ESI—MS m/z [M+H]+ 419.3.
Example 314 4-(1-(5-([1,3'-bipiperidine]-1'-carb0nyl)pyridinyl)hydr0xy-1H- pyrazolyl)methylbenzonitrile O HO ”EN \/\ v CH3 0 N N The title compound was prepared in a manner similar to Example 303 using 4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)nic0tinic acid and 1,3'- bipiperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.54 (d, J=12.88 Hz, 2 H) 1.62 — 1.89 (m, 7 H) 2.17 (d, J=10.86 Hz, 1 H) 2.43 (s, 3 H) 2.97 — 3.51 (m, 6 H) 3.56 — 4.15 (m, 1 H) 4.32 — 4.88 (m, 1 H) 7.62 — 7.85 (m, 3 H) 7.82 — 7.83 (m, 1 H) 7.95 — 8.64 (m, 4 H) 9.40 (br. s., 1 H) 12.56 — 13.62 (m, 1 H). ESI—MS m/z [M+H]+ 471.3.
Example 315 (R)(1-(5-(3-(dimethylamin0)piperidinecarb0nyl)pyridinyl)hydr0xy-1H-pyrazolyl)—3 -methylbenzonitrile WO 60810 H3C\ [NI - -O Ho H3C — 0%QN‘N/N CH3 The title compound was prepared in a manner similar to Example 301 using (R)- N,N—dimethylpiperidinamine dihydrochloride. 1H NMR (500 MHz, DMSO—d6) 5 ppm 1.32 — 1.97 (m, 3 H) 2.15 (br. s., 1 H) 2.39 — 2.46 (m, 3 H) 2.54 — 3.71 (m, 10 H) 3.87 — 4.56 (m, 1 H) 7.65(dd, , 1.71 Hz, 1 H) 7.68 — 7.74 (m, 1 H) 7.80 (d, J=7.81 Hz, 1 H) 8.04 — 8.18 (m, 2 H) 8.40 (d, J=8.79 Hz, 1 H) 8.59 (br. s., 1 H) 12.04 (br. s.,1 H). ESI—MS m/z [M+H]+ 431.3.
Example 316 2-fluoro(5-hydroxy(5-(4-methoxypiperidine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile O //N C) H0 N _ F O N N The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 4-methoxypiperidine. 1H NMR (500 MHz, DMSO—dg) 5 ppm 1.49 (br. s., 2 H) 1.75 — 1.97 (m, 2 H) 2.33 (d, J=1.95 Hz, 3 H) 3.11 — 3.68 (m, 7 H) 3.92 (br. s., 1 H) 7.64 (br. s., 1 H) 7.70 — 7.79 (m, 1 H) 8.07 (d, J=7.81 Hz, 1 H) 8.12 — 8.65 (m, 3 H). EST—MS m/z [M+H]+ 436.3.
Example 317 (R)(1-(5-(3 -(dimethylamino)pyrrolidinecarbonyl)pyridin yl)hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H3C //N ,N,..
H3C O HO ”WV F \ / \/ CH3 0 N N The title compound was prepared in a manner similar to Example 301 using 6-(4- nofluoromethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid and (R)-N,N— dimethylpyrrolidin-3 -amine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.07 - 2.22 (m, 1 H) 2.33 (s, 4 H) 2.70 — 2.95 (m, 6 H) 3.71 (d, J=5.05 Hz, 3 H) 3.83 — 4.01 (m, 2 H) 7.64 (br. s., 1 H) 7.68 — 7.80 (m, 1 H) 8.05 — 8.61 (m, 3 H) 8.67 (s, 1 H). EST—MS m/z [M+H]+ 435.3.
Example 3 18 (S)(1-(5-(3-(dimethylamino)pyrrolidinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H30 //N H3O ‘0 HO “12—0” \ F \ / ~ / CH3 0 N N The title compound was prepared in a manner similar to Example 301 using 6-(4- nofluoromethylphenyl)hydroxy-lH-pyrazolyl)nicotinic acid and (S)-N,N— dimethylpyrrolidin-3 . 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.09 — 2.30 (m, 1 H) 2.33 (d, J=2.27 Hz, 4 H) 2.76 — 2.93 (m, 6 H) 3.52 — 3.78 (m, 3 H) 3.83 — 4.00 (m, 2 H) 7.63 (d, J=7.83 Hz, 1 H) 7.74 (t, J=7.58 Hz, 1 H) 8.21 (d, J=7.58 Hz, 3 H) 8.67 (s, 1 H). ). ESI—MS m/z [M+H]+ 435.3.
Example 319 (R)(1-(5-(3-(dimethylamino)piperidinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H3C\ [NI-K > HO H3C Nfl \ F \ / N\ / CH3 0 N N ] The title compound was prepared in a manner similar to Example 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-lH-pyrazolyl)nicotinic acid and (R)-N,N— dimethylpiperidinamine. 1H NMR (500 MHz, DMSO-d6) 5 ppm 1.53 (d, J=13.18 Hz, 1 H) 1.77 (m, J=16.10 Hz, 2 H) 2.10 (br. s., 1 H) 2.33 (s, 3 H) 2.57 — 2.89 (m, 6 H) 2.90 — 4.77 (m, H) 7.63 (br. s., 1 H) 7.74 (t, J=7.54 Hz, 1 H) 8.09 (d, J=7.81 Hz, 1 H) 8.24 (br. s., 1 H) 8.35 — 8.66 (m, 2 H) 9.86 (br. s., 1 H). ESI—MS m/z [M+H]+ 449.3.
Example 320 (1-(5-(3-(dimethylamino)piperidinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H3C\ H3C 0%QN‘N’N _ F The title compound was prepared in a manner similar to Example 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-lH-pyrazolyl)nicotinic acid and (S)-N,N— ylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.54 (d, J=11.12 Hz, 1 H) 1.78 (m, J=16.20 Hz, 2 H) 2.12 (d, J=10.86 Hz, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.67 — 2.94 (m, WO 60810 6 H) 3.13 — 4.79 (m, 5 H) 7.48 — 7.70 (m, 1 H) 7.70 — 7.80 (m, 1 H) 7.98 — 8.34 (m, 2 H) 8.57 (m, J=1.50 Hz, 2 H) 9.44 — 10.31 (m, 1 H). ESI—MS m/z [M+H]+ 449.3.
] Example 321 4-(1-(5-(3-(dimethylamino)azetidinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile [CH3 H3C-N 0N ”@V F \ / ./ CH3 0 N N The title compound was prepared in a manner similar to Example 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and N,N— dimethylazetidinamine. 1H NMR (500 MHz, DMSO—dg) 5 ppm 2.33 (d, J=1.95 Hz, 3 H) 2.81 (s, 6 H) 4.07 — 4.21 (m, 1 H) 4.29 (br. s., 2 H) 4.47 — 4.59 (m, 1 H) 4.66 (m, J=7.80 Hz, 1 H) 7.63 (br. s., 1 H) 7.71 — 7.78 (m, 1 H) 7.91 — 8.81 (m, 4 H). ESI—MS m/z [M+H]+ 421.3.
Example 322 2-fluoro(5-hydroxy(5-(4-methylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 lbenzonitrile H3C\N N L—) HO NMNN/_ F The title compound was prepared in a manner r to Example 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1- methylpiperazine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 2.33 (d, J=2.53 Hz, 3 H) 2.84 (s, 3 H) 3.17 (s, 8 H) 7.63 (d, J=7.58 Hz, 1 H) 7.70 — 7.79 (m, 1 H) 8.04 — 8.57 (m, 3 H) 8.59 (d, J=1.52 Hz, 1 H). ESI—MS m/z [M+H]+ 421.3.
Example 323 4-(1-(5-(4-cyclopropyl-1,4-diazepanecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile \NO / \ / \ / CH3 0 N N The title compound was prepared in a manner similar to Example 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1- cyclopropyl-1,4-diazepane. 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.66 — 1.06 (m, 4 H) 1.94 — 2.23 (m, 2 H) 2.33 (d, J=2.02 Hz, 3 H) 2.81 — 3.07 (m, 1 H) 3.41 — 4.30 (m, 8 H) 7.54 — 7.70 (m, 1 H) 7.75 (t, J=7.45 Hz, 1 H) 7.98 — 8.65 (m, 4 H). ESI—MS m/z [M+H]+ 461.3.
Example 324 2-fluoro(5-hydroxy(5-(4-methyl-4,7-diazaspiro[2.5]octane-7— carbonyl)pyridinyl)-1H-pyrazolyl)-3 -methylbenzonitrile H3C\ / N D6— > HO Nflw\ F O N/ ‘N/ CH3 The title compound was prepared in a manner similar to e 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and yl- 4,7-diazaspiro[2.5]octane. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.58 — 1.34 (m, 4 H) 2.33 (d, J=2.27 Hz, 3 H) 2.91 (s, 3 H) 3.31 — 3.85 (m, 6 H) 7.62 (d, J=7.83 Hz, 1 H) 7.70 — 7.78 (m, 1 H) 7.82 — 8.75 (m, 4 H). ESI—MS m/z [M+H]+ 447.3.
Example 325 2-fluoro(5-hydroxy(5-(pyrrolidinecarbonyl)pyridinyl)— 1H-pyrazolyl)—3-methylbenzonitrile O HO ”@ 7 F \ / N. / CH3 O N N The title compound was prepared in a manner similar to Example 301 using 6-(4- (4-cyano-3 -fluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and pyrrolidine. 1H NMR (500 MHz, DMSO—d6) 5 ppm 1.79 — 1.95 (m, 4 H) 2.33 (d, J=2.44 Hz, 3 H) 3.49 (t, J=5.61 Hz, 4 H) 7.42 — 7.82 (m, 2 H) 7.84 — 8.76 (m, 4 H). ESI—MS m/z [M+H]+ 392.3.
Example 326 6-(4-(4-cyanofluoromethylphenyl)hydroxy-1H-pyrazol (3 -methoxypropyl)-N-methylnicotinamide H3C-O [CH3 HO \ / N. / CH3 0 N N The title nd was prepared in a manner similar to Example 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 3- methoxy-N-methylpropanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.66 — 1.93 (m, 2 H) 2.34 (d, J=2.27 Hz, 3 H) 2.98 (s, 3 H) 3.07 — 3.67 (m, 7 H) 7.64 (br. s., 1 H) 7.70 — 7.81 (m, 1 H) 7.84 — 8.64 (m, 4 H). ESI—MS m/z [M+H]F 424.3.
Example 327 o(5-hydroxy(5-(morpholinecarbonyl)pyridinyl)- 1H-pyrazolyl)—3-methylbenzonitrile OO HO ”@ \ F \ / N. / CH3 O N N The title compound was prepared in a manner similar to Example 301 using 6-(4- (4-cyano-3 -fluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and morpholine. 1H NMR (500 MHz, DMSO—d6) 5 ppm 2.33 (d, J=1.95 Hz, 3 H) 3.34 (br. s., 2 H) 3.64 (br. s., 6 H) 7.64 (br. s., 1 H) 7.74 (t, J=7.32 Hz, 1 H) 7.90 — 8.63 (m, 4 H). ESI—MS m/z [M+H]F 408.3.
Example 328 (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H3C—\ N HschN HO ”7—CH \ F \ / \ / CH3 0 N N ] The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S) ethylmethylpiperazine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.22 (t, J=7.20 Hz, 6 H) 2.33 (d, J=2.27 Hz, 3 H) 3.08 — 3.36 (m, 4 H) 3.42 (br. s., 2 H) 4.11 — 4.93 (m, 3 H) 7.64 (br. s., 1 H) 7.71 — 7.80 (m, 1 H) 7.87 — 8.79 (m, 4 H) 9.53 — 10.44 (m, 1 H) 12.23 — 14.36 (m, 1 H). ESI—MS m/z [M+H]F 449.3.
Example 329 (S)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H3C\ N HschN HO ”fir F \ / \ / CH3 ] 0 N N The title compound was prepared in a manner r to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)—1,2- dimethylpiperazine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.28 (br. s., 3 H) 2.33 (d, J=2.27 WO 60810 Hz, 3 H) 2.84 (s, 3 H) 3.13 — 3.74 (m, 7 H) 7.63 (d, J=6.82 Hz, 1 H) 7.71 — 7.78 (m, 1 H) 7.90 — 8.67 (m, 4 H). ESI—MS m/z [M+H]+ 435.3.
] Example 330 (R)(1-(5-(4-ethylmethylpiperazinecarb0nyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-flu0r0-3 -methylbenzonitrile ch—\ N Q‘CH3N HO \ / \ / CH3 0#CH \N N The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyan0flu0r0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (R) ethyl-3 -methylpiperazine and 6-(4-(4-cyan0methylphenyl)hydr0xy-1H-pyrazol yl)nic0tinic acid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.24 (t, J=7.33 Hz, 3 H) 1.38 (d, J=7.07 Hz, 3 H) 2.33 (d, J=2.53 Hz, 3 H) 2.95 — 3.26 (m, 4 H) 3.34 — 3.55 (m, 2 H) 3.73 — 4.28 (m, 3 H) 7.64 (br. s., 1 H) 7.71 — 7.78 (m, 1 H) 7.93 — 8.68 (m, 4 H). ESI—MS m/z [M+H]+ 449.3.
Example 331 (R)(1-(5-(3-(cyclopropyl(methyl)amin0)piperidine carbonyl)pyridinyl)hydr0xy-1H-pyrazolyl)flu0r0-3 -methylbenzonitrile H3C\ N"-< > HO <1 ”W \ F \ / N. / OH3 0 N N The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyan0flu0r0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (R)—1- ethylmethylpiperazine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.61 — 1.18 (m, 4 H) 1.50 — 1.66 (m, 1H) 1.71 — 2.01 (m, 2 H) 2.16 — 2.28 (m, 1 H) 2.33 (d, J=2.53 Hz, 3 H) 2.77 — 3.04 (m, 4 H) 3.09 — 3.23 (m, 1 H) 3.70 — 4.02 (m, 4 H) 7.64 (br. s., 1 H) 7.70 — 7.79 (m, 1 H) 7.86 — 8.78 (m, 4 H) 8.91 — 9.92 (m, 1 H). ESI—MS m/z [M+H]+ 475.3.
Example 332 (S)flu0r0(5-hydr0xy(5-(3-(methyl(2,2,2- roethyl)amin0)piperidinecarb0nyl)pyridinyl)-1H-pyrazolyl)-3 - methylbenzonitrile H3C\ F N—O HO F—]—/ N _ F O N N The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)- N- methyl-N-(2,2,2-trifluoroethyl)piperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.34 — 1.92 (m, 4 H) 2.26 — 2.41 (m, 4 H) 2.59 — 2.80 (m, 2 H) 2.93 — 3.36 (m, 3 H) 3.55 (br. s., 1 H) 3.75 — 4.19 (m, 2 H) 4.36 — 4.54 (m, 1 H) 7.55 — 7.68 (m, 1 H) 7.71 — 7.78 (m, 1 H) 8.53 (s, 4 H). ESI—MS m/z [M+H]+ 517.3.
Example 333 (S)(1-(5-(3-((2,2-difluoroethyl)(methyl)amino)piperidine carbonyl)pyridinyl)hydroxy-1H-pyrazolyl)fluoro-3 -methylbenzonitrile F IN><:> HO H3C Nfl, \ F \ / N. / CH3 0 N N The title compound was prepared in a manner similar to Example 303 using 6-(4- nofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)-N— (2,2-difluoroethyl)-N—methylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.41 - 1.93 (m, 3 H) 1.98 — 2.06 (m, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.52 — 3.90 (m, 9 H) 4.26 — 4.73 (m, 1 H) 5.99 — 6.62 (m, 1 H) 7.63 (d, J=7.33 Hz, 1 H) 7.74 (t, J=7.58 Hz, 1 H) 8.08 (d, J=8.34 Hz, 1 H) 8.13 — 8.51 (m, 2 H) 8.54 (d, J=1.77 Hz, 1 H). EST—MS m/z [M+H]+ 499.3. e 334 (R)fluoro(5-hydroxy(5-(octahydropyrrolo[1,2-a]pyrazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile MW\— F N/ / CH3 ] O N The title compound was prepared in a manner r to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)- octahydropyrrolo[1,2-a]pyrazine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.08 (s, 4 H) 2.33 (d, J=2.53 Hz, 3 H) 2.81 — 4.24 (m, 9 H) 7.64 (br. s., 1 H) 7.75 (t, J=7.45 Hz, 1 H) 7.95 — 8.83 (m, 4 H). ESI—MS m/z [M+H]+ 447.3.
Example 335 2-fluoro(5-hydroxy(5-(3-(piperidinyl)azetidine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile Q a HO \ / \ / CH3 O N N The title compound was prepared in a manner r to e 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1- (azetidinyl)piperidine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.22 — 2.00 (m, 6 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (br. s., 2 H) 3.23 — 3.70 (m, 2 H) 4.06 — 4.19 (m, 1 H) 4.33 (br. s., 2 H) 4.61 (br. s., 1 H) 4.66 — 4.77 (m, 1 H) 7.63 (d, J=7.07 Hz, 1 H) 7.75 (t, J=7.45 Hz, 1 H) 7.98 — 8.89 (m, 4 H). ESI—MS m/z [M+H]+ 461.3. [0131 7] Example 3 3 6 (R)(1-(5-(3 -((2,2-difluoroethyl)(methyl)amino)piperidine carbonyl)pyridinyl)hydroxy-1H-pyrazolyl)fluoro-3 -methylbenzonitrile F /N : / F [NI-K > HO H3C Nfl \ \ / N\ / CH3 O N N The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and (R)—N— (2,2-difluoroethyl)-N—methylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.41 - 1.58 (m, 1 H) 1.61 — 1.94 (m, 2 H) 1.97 — 2.07 (m, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.54 — 2.87 (m, 3 H) 3.11 (br. s., 3 H) 3.40 — 3.97 (m, 2 H) 4.20 — 4.76 (m, 1 H) 6.03 — 6.58 (m, 1 H) 7.64 (br. s., 1 H) 7.68 — 7.80 (m, 1 H) 7.94 — 8.62 (m, 4 H). ESI—MS m/z [M+H]+ 499.3.
Example 3 3 7 (R)fluoro(5 -hydroxy(5-(4-isopropyl-3 -methylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile H3C—< /N H3C““80—) H0 \ / N. / CH3 O N N The title compound was prepared in a manner similar to Example 303 using 6-(4- nofluoromethylphenyl)hydroxy-lH-pyrazol-l-yl)nicotinic acid and (R)—1- pylmethylpiperazine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.18 (d, J=5.81 Hz, 4 H) 1.30 (d, J=6.32 Hz, 5 H) 2.33 (d, J=2.27 Hz, 3 H) 2.85 — 3.65 (m, 5 H) 3.89 (br. s., 2 H) 4.20 — 4.83 (m, 1 H) 7.64 (br. s., 1 H) 7.70 — 7.79 (m, 1 H) 7.93 — 8.77 (m, 4 H) 9.36 — 10.10 (m, 1 H). ESI—MS m/z [M+H]+ 463.3.
Example 338 (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile MeiNflN—) HO \ / \ / CH3 O N N The title nd was prepared in a manner r to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)—1- ethylmethylpiperazine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.22 (m, J=7.20, 7.20 Hz, 6 H) 2.33 (d, J=2.27 Hz, 3 H) 2.91 — 4.72 (m, 9 H) 7.63 (br. s., 1 H) 7.71 — 7.79 (m, 1 H) 7.94 — 8.81 (m, 4 H) 9.52 — 10.21 (m, 1 H). ESI—MS m/z [M+H]+ 449.3. e 339 fluoro(5-hydroxy(5-(4-isopropylmethylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile H3C—< , N men-ON HO ”xCH \ F \ / . / CH3 O N N The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S) isopropylmethylpiperazine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.02 — 1.50 (m, 9 H) 2.33 (d, J=2.53 Hz, 3 H) 2.88 — 3.64 (m, 5 H) 3.89 (br. s., 2 H) 4.22 — 4.92 (m, 1 H) 7.53 — 7.69 (m, 1 H) 7.70 — 7.79 (m, 1 H) 7.84 — 8.79 (m, 4 H) 9.49 — 10.25 (m, 1 H). ESI—MS m/z [M+H]+ 463.3.
Example 340 (R)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H3C\ N H301.—) HO WM\_ .
/ . / CH3 0 N N The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyano-3 -fluoromethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and (R)—1,2- WO 60810 dimethylpiperazine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.01 — 1.53 (m, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (br. s., 3 H) 2.93 — 4.70 (m, 7 H) 7.63 (d, J=7.07 Hz, 1 H) 7.71 — 7.80 (m, 1 H) 7.88 - 8.77 (m, 4 H). ESI—MS m/z [M+H]+ 435.3.
Example 341 (1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoro-3 -methylbenzonitrile H3C—\ / N The title compound was prepared in a manner similar to Example 303 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S) ethylmethylpiperazine. 1H NMR (400 MHz, 6) 5 ppm 1.24 (t, J=7.20 Hz, 3 H) 1.38 (d, J=7.07 Hz, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.68 — 5.32 (m, 9 H) 7.63 (d, J=7.33 Hz, 1 H) 7.70 — 7.80 (m, 1 H) 7.94 — 8.73 (m, 4 H) 8.97 — 10.49 (m, 1 H). ESI—MS m/z [M+H]+ 449.3.
Example 342 2-fluoro(5-hydroxy(5-(6-methyl-2,6-diazaspiro[3.3]heptane carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile N N % // 0%QNN/N _ F The title compound was prepared in a manner similar to Example 301 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2-methyl- 2,6-diazaspiro[3.3]heptane dihydrochloride. 1H NMR (400 MHz, g) 5 ppm 2.33 (d, J=2.27 Hz, 3 H) 2.80 (d, J=4.55 Hz, 3 H) 3.94 — 4.67 (m, 8 H) 7.61 (d, J=8.08 Hz, 1 H) 7.69 — 7.78 (m, 1 H) 8.16 — 8.29 (m, 2 H) 8.42 (d, J=8.59 Hz, 1 H) 8.69 (br. s., 1 H). ESI—MS m/z [M+H]+ 433.3.
Example 343 2-fluoro(5-hydroxy(5-(6-methyl-2,6-diazaspiro[3.3]heptane carbonyl)pyridinyl)-1H-pyrazolyl)—5 -methylbenzonitrile N N N _ \ / N \/ CH3 0 N N 2014/031918 The title compound was prepared in a manner similar to Example 303 using 6-(4- nofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2-methyl- 2,6-diazaspiro[3.3]heptane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.42 (s, 3 H) 2.80 (br. s., 3 H) 4.05 — 4.44 (m, 6 H) 4.50 — 4.64 (m, 2 H) 7.79 (d, J=7.07 Hz, 1 H) 7.87 (d, J=8.59 Hz, 1 H) 8.13 — 8.79 (m, 4 H) 9.63 — 10.00 (m, 1 H). EST—MS m/z [M+H]+ 433.3.
Example 344 4-(5-hydroxy(5-(3 -(piperidinyl)azetidinecarbonyl)pyridin- 2-yl)-1H-pyrazolyl)-3 -methylbenzonitrile The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and 1-(azetidinyl)piperidine dihydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.36 (d, J=4.80 Hz, 2 H) 1.41 — 1.54 (m, 4 H) 2.23 — 2.34 (m, 3 H) 2.36 (s, 3 H) 3.13 — 3.21 (m, 1 H) 3.86 (dd, J=9.47, 4.67 Hz, 1 H) 4.05 (t, J=8.46 Hz, 1 H) 4.20 (d, J=4.80 Hz, 1 H) 4.28 — 4.43 (m, 1 H) 7.55 (dd, J=8.08, 1.52 Hz, 1 H) 7.62 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 8.03 (s, 1 H) 8.15 (dd, J=8.72, 2.40 Hz, 1 H) 8.35 (d, J=8.84 Hz, 1 H) 8.65 (dd, J=2.27, 0.76 Hz, 1 H) 12.19 — 13.21 (m, 1 H); EST—MS m/z [M+H]+ 443.3 Example 345 4-(1-(5-(3-(dimethylamino)azetidinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile L*0N \ OH H“ , N N \ «N CH3 [5 Combined 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (105 mg, 0.328 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3- diamine hloride (94.0 mg, 0.490 mmol), HOBT (66.4 mg, 0.492 mmol) in DMF (1.0 mL) and added N,N—diisopropylethylamine (0.285 mL, 1.639 mmol). Then added N,N— dimethylazetidinamine hydrochloride (67.2 mg, 0.492 mmol) and the reaction was allowed to stir at room ature for 16 hours. The reaction e was diluted with water (3.5 1 80 mL) and acidified to pH 4 with 10% citric acid to give a solid, which was collected by filtration, washed with water, methanol, and diethyl ether and dried to give the title compound as a citrate salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.17 (s, 6 H) 2.36 (s, 3 H) 2.52 — 2.58 (m, 1 H) 2.61 — 2.68 (m, 1 H) 3.24 (ddd, J=12.25, 7.07, 5.18 Hz, 1 H) 3.87 (d, J=5.05 Hz, 1 H) 4.07 (t, J=8.34 Hz, 1 H) 4.20 (br. s., 1 H) 4.37 (t, J=7.83 Hz, 1 H) 7.57 (dd, J=7.96, 1.39 Hz, 1 H) 7.63 (s, 1 H) 7.75 (d, J=8.08 Hz, 1 H) 8.06 (s, 1 H) 8.17 (dd, J=8.59, 2.27 Hz, 1 H) 8.34 (d, J=8.84 Hz, 1 H) 8.66 (dd, J=2.27, 0.76 Hz, 1 H); ESI—MS m/z [M+H]+ 403.1.
Example 346 4-(5-hydroxy(5-(7-methyl-2,7-diazaspiro[4.4]nonane carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile N \ I OH H C’N / 3 N [\‘1 \ "N.— ] ”30 ] The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and 2-methyl-2,7- diazaspiro[4.4]nonane to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO- d6) 5 ppm 1.81 — 1.98 (m, 1 H) 2.07 (d, J=7.83 Hz, 3 H) 2.43 (s, 3 H) 2.77 — 2.86 (m, 2 H) 2.89 (br. s., 1 H) 2.97 — 3.14 (m, 1 H) 3.14 — 3.29 (m, 1 H) 3.49 (d, J=11.62 Hz, 1 H) 3.60 (d, J=7.83 Hz, 4 H) 3.67 (d, J=8.34 Hz, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.04 — 8.28 (m, 2 H) 8.43 (br. s., 1 H) 8.67 (d, J=8.34 Hz, 1 H) 9.73 — 10.22 (m, 1 H); ESI— MS m/z [M+H]+ 443.2.
Example 347 ydroxy(5-(3-morpholinopyrrolidinecarbonyl)pyridin yl)—1H-pyrazolyl)—3 -methylbenzonitrile N/ N \ "N C“) 'N‘ The title nd was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 4-(pyrrolidin yl)morpholine to give the title compound. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.68 — 1.84 (m, 1 H) 2.04 — 2.20 (m, 1 H) 2.29 — 2.39 (m, 1 H) 2.39 — 2.48 (m, 5 H) 2.77 — 2.97 (m, 1 H) 3.24 — 3.35 (m, 1 H) 3.37 — 3.84 (m, 8 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.72 (s, 1 H) 7.78 (d, J=7.83 Hz, 1 H) 8.13 (s, 1 H) 8.19 (td, J=5.49, 2.40 Hz, 1 H) 8.36 (br. s., 1 H) 8.65 (s, 1 H) 13.03 (br. s., 1 H); ESI—MS m/z [M+H]+ 459.2.
Example 348 (S)(5-hydroxy(5-(2-(pyrrolidinylmethyl)pyrrolidine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile O — CNwwN‘N/ CH3 The title compound was ed in a manner similar to e 74 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)—1-(pyrrolidin ylmethyl)pyrrolidine to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO- d6) 5ppm 1.71 — 1.88 (m, 2 H) 1.88 — 1.99 (m, 3 H) 1.99 — 2.10 (m, 3 H) 2.11 — 2.22 (m, 1 H) 2.44 (s, 3 H) 3.12 (br. s., 1 H) 3.21 (br. s., 1 H) 3.26 — 3.36 (m, 1 H) 3.45 — 3.56 (m, 2 H) 3.59 — 3.75 (m, 2 H) 3.83 (br. s., 1 H) 4.44 — 4.63 (m, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.18 (d, J=5.81Hz, 1 H) 8.19 — 8.27 (m, 1 H) 8.42 (br. s., 1 H) 8.63 — 8.75 (m, 1 H) 9.46 (br. s., 1 H); ESI—MS m/z [M+H]+ 457.2.
Example 349 4-(1-(5-(3-((dimethylamino)methyl)pyrrolidinecarbonyl)pyridin- 2-yl)hydroxy-1H-pyrazolyl)—3-methylbenzonitrile $1NJKO OH N/ ”WM N—CH3 The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and N,N—dimethyl (pyrrolidinyl)methanamine to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.63 — 1.76 (m, 1 H) 2.05 — 2.20 (m, 1 H) 2.43 (s, 3 H) 2.57 — 2.73 (m, 1 H) 2.77 (s, 3 H) 2.85 (s, 3 H) 3.08 — 3.21(m,1H)3.21— 3.37 (m, 2 H) 3.47 — 3.69 (m, 2 H) 3.69 — 3.86 (m, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.77 (br. s., 1 H) 8.19 (d, Hz, 2 H) 8.43 (br. s., 1 H) 8.66 (s, 1 H) 9.35 — 9.67 (m, 1 H); ESI—MS m/z [M+H]+ 431.2.
Example 350 ydroxy(5-(7-methyl-2,7-diazaspiro[4.4]nonane carbonyl)pyridinyl)-1H-pyrazolyl)benzonitrile DC“ \ I 0“ H30” N/ NWN The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 2-methyl-2,7- diazaspiro[4.4]nonane to give a TFA salt. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.81 — 2.01 (m, 2 H) 2.07 (d, J=8.08 Hz, 2 H) 2.81 (br. s., 2 H) 2.89 (br. s., 1 H) 2.98 — 3.14 (m, 1 H) 3.18 (dd, J=13.01, 7.45 Hz, 1 H) 3.44 — 3.76 (m, 6 H) 7.80 (d, J=8.34 Hz, 2 H) 8.06 — 8.28 (m, 3 H) 8.54 (d, J=17.68 Hz, 1 H) 8.67 (d, J=7.07 Hz, 2 H); ESI—MS m/z [M+H]+ 429.2.
Example 351 4-(5-hydroxy(5-(3-morpholinopyrrolidinecarbonyl)pyridin yl)-1H-pyrazolyl)benzonitrile {JN [01363] ] The title compound was ed in a manner r to Example 74 using 6-(4- (4-cyanophenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 4-(pyrrolidin yl)morpholine to give a TFA salt. 1H NMR (400 MHz, DMSO-dg) 5 ppm 2.09 - 2.22 (m, 1 H) 2.28 — 2.44 (m, 1 H) 3.32 (br. s., 4 H) 3.49 — 3.70 (m, 2 H) 3.75 (d, J=4.29 Hz, 3 H) 3.87 (br. s., 2 H) 3.97 (br. s., 2 H) 7.80 (d, J=8.59 Hz, 2 H) 8.15 (d, J=6.82 Hz, 2 H) 8.21 (br. s., 1 H) 8.37 — 8.58 (m, 1 H) 8.67 (br. 5., 2 H); ESI—MS m/z [M+H]+ 445.2.
Example 352 (S)(5-hydroxy(5-(2-(pyrrolidinylmethyl)pyrrolidine carbonyl)pyridinyl)-1H-pyrazolyl)benzonitrile < :N 0 The title compound was prepared in a manner similar to Example 74 using (S) (pyrrolidinylmethyl)pyrrolidine to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.71 — 1.87 (m, 2 H) 1.87 — 1.99 (m, 3 H) 1.99 — 2.11 (m, 2 H) 2.11 — 2.23 (m, 1 H) 3.03 — 3.17 (m, 1 H) 3.21 (br. s., 1 H) 3.26 — 3.36 (m, 1 H) 3.44 — 3.57 (m, 2 H) 3.65 (dt, J=10.04, 6.98 Hz, 2 H) 3.82 (br. s., 1 H) 4.48 — 4.61 (m, 1 H) 7.80 (d, J=8.34 Hz, 2 H) 8.06 — 8.20 (m, 2 H) 8.20 — 8.31 (m, 1 H) 8.40 — 8.59 (m, 1 H) 8.59 — 8.79 (m, 2 H) 9.33 (br. s., 1 H); ESI—MS m/z [M+H]+ 443.2.
Example 353 4-(1-(5-(3-((dimethylamino)methyl)pyrr01idinecarb0nyl)pyridin- 2-yl)hydr0xy-1H-pyrazolyl)benzonitrile l—NCH3 The title nd was prepared in a manner similar to Example 74 using N,N- dimethyl(pyrr01idinyl)methanamine to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) ppm 1.62 — 1.77 (m, 1 H) 2.05 — 2.19 (m, 1 H) 2.58 — 2.73 (m, 1 H) 2.77 (s, 3 H) 2.85 (s, 3 H) 3.11 — 3.21 (m, 1 H) 3.25 (d, J=6.82 Hz, 1 H) 3.27 — 3.37 (m, 1 H) 3.46 — 3.69 (m, 2 H) 3.69 — 3.86 (m, 1 H) 7.80 (d, J=8.59 Hz, 2 H) 8.06 — 8.26 (m, 3 H) 8.36 — 8.61 (m, 1 H) 8.61 — 8.79 (m, 2 H) 9.37 — 9.67 (m, 1 H) 13.49 (br. s., 1 H); ESI—MS m/z [M+H]+ 417.2. e 354 6-(4-(4-cyan0phenyl)—5-hydr0xy-1H-pyrazolyl)-N-(1-(2- methoxyethyl)cyclopentyl)nicotinamide H3C\ A >—< O N \ N’ N.
N \W” The title compound was ed in a manner similar to Example 112 using 1-(2- methoxyethyl)cyclopentanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.55 — 1.75 (m, 6 H) 2.07 — 2.16 (m, 2 H) 2.16 — 2.27 (m, 2 H) 3.16 — 3.22 (m, 3 H) 3.38 (t, J=6.95 Hz, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 7.99 (s, 1 H) 8.13 (d, J=7.07 Hz, 2 H) 8.37 (d, J=6.57 Hz, 2 H) 8.62 (br. s., 1 H) 8.79 — 8.88 (m, 1 H) 13.50 (br. s., 1 H); ESI—MS m/z [M+H]+ 432.2.
Example 355 6-(4-(4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)-N-((1- ethylpyrrolidinyl)methyl)-N-methylnicotinamide Cf] \ | 0“ H3C N\ 2014/031918 ] The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1-(1- ethylpyrrolidinyl)-N—methylmethanamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.92 — 1.36 (m, 3 H) 1.60 — 1.96 (m, 2 H) 2.11 (br. s., 1 H) 2.43 (s, 3 H) 2.60 — 2.95 (m, 2 H) 3.06 (br. s., 3 H) 3.12 — 3.58 (m, 5 H) 3.58 — 3.84 (m, 1 H) 7.54 (d, J=8.08 Hz, 1 H) 7.59 (s, 1 H) 7.93 (s, 1 H) 7.98 (dd, J=8.72, 2.15 Hz, 1 H) 8.07 (br. s., 1 H) 8.48 (d, J=8.08 Hz, 1 H) 8.50 — 8.54 (m, 1 H); ESI—MS m/z [M+H]+ 445.2.
Example 356 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- cyclopropylpiperidinyl)nicotinamide —< O N |\ OH N [\‘J\ ——N The title compound was prepared in a manner similar to Example 112 using 6-(4- nomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1-(2- methoxyethyl)cyclopentanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.54 — 1.75 (m, 6 H) 2.12 (t, J=6.95 Hz, 2 H) 2.15 — 2.25 (m, 2 H) 2.43 (s, 3 H) 3.19 (s, 3 H) 3.38 (t, J=6.95 Hz, 2 H) 7.66 (dd, J=7.96, 1.39 Hz, 1 H) 7.73 (s, 1 H) 7.76 (br. s., 1 H) 8.00 (s, 1 H) 8.14 (br. s., 1 H) 8.37 (d, J=6.57 Hz, 2 H) 8.81 — 8.88 (m, 1 H) 13.14 (br. s., 1 H); ESI—MS m/z [M+H]+ 446.3 Example 357 (R)(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N—(4- methoxybutanyl)nicotinamide CH3 0 H | N "3 The title compound was prepared in a manner similar to Example 112 using (R)- 4-methoxybutanamine to give the title compound. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.11(d, J=6.82 Hz, 3 H) 1.59 — 1.70 (m, 1 H) 1.70 — 1.81 (m, 1 H) 3.16 (s, 3 H) 3.31 (t, J=6.57 Hz, 2 H) 3.99 — 4.11 (m, 1 H) 7.72 (d, J=8.59 Hz, 2 H) 8.07 (d, J=6.82 Hz, 2 H) 8.35 (d, J=8.08 Hz, 3 H) 8.56 (br. s., 1 H) 8.74 — 8.93 (m, 1 H) 13.42 (br. s., 1 H); ESI—MS m/z [M+H]+ 392.2.
WO 60810 Example 3 5 8 (S)(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—(4- methoxybutanyl)nicotinamide 9H3 O H3C\O/\/\N*0 O“ N NWN The title compound was prepared in a manner similar to Example 112 using (S) methoxybutanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.19 (d, J=6.82 Hz, 3 H) 1.68 — 1.77 (m, 1 H) 1.77 — 1.87 (m, 1 H) 3.23 (s, 3 H) 3.39 (t, J=6.57 Hz, 2 H) 4.08 — 4.18 (m, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=6.57 Hz, 2 H) 8.42 (d, J=7.83 Hz, 3 H) 8.64 (br. s., 1 H) 8.87 - 8.93 (m, 1 H); ESI—MS m/z [M+H]+ 392.2.
Example 359 (R)(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— (4-methoxybutanyl)nicotinamide CH3 0 H30\O/\/'\N \ OH H | N N\ HN The title compound was ed in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R) methoxybutanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.19 (d, J=6.82 Hz, 3 H) 1.67 — 1.77 (m, 1 H) 1.77 — 1.89 (m, 1 H) 2.44 (s, 3 H) 3.39 (t, J=6.57 Hz, 2 H) 4.05 — 4.20 (m, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=7.07 Hz, 3 H) 8.87 — 8.95 (m, 1 H) 12.98 — 13.34 (m, 1 H); ESI—MS m/z [M+H]+ 406.2.
Example 360 (S)(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)—N— (4-methoxybutanyl)nicotinamide QHso H ‘ “3‘3 The title compound was prepared in a manner similar to e 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S) methoxybutanamine. 1H NMR (400 MHz, 6) 5 ppm 1.19 (d, J=6.82 Hz, 3 H) 1.67 —1.77(m, 1 H) 1.77 — 1.88 (m, 1 H) 2.44 (s, 3 H) 3.23 (s, 3 H) 3.39 (t, J=6.57 Hz, 2 H) 4.06 — 4.20 (m, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.73 (s, 1 H) 7.78 (br. s., 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=7.33 Hz, 3 H) 8.89 — 8.95 (m, 1 H) 13.16 (br. s., 1 H); ESI—MS m/z [M+H]+ 406.2.
Example 361 6-(4-(4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)-N— methyl-N—((1-methylpiperidin-3 -yl)methyl)nic0tinamide OAN \ I OH I}! N/ I)! \ :N CH3 N‘ The title compound was prepared in a manner similar to e 112 using 6-(4- (4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and yl-l-(lmethylpiperidinyl )methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.09 - 1.27 (m, 1 H) 1.45 — 1.92 (m, 3 H) 2.15 (br. s., 2 H) 2.37 — 2.47 (m, 4 H) 2.57 — 2.75 (m, 3 H) 2.96 (s, 4 H) 3.28 (dd, J=12.88, 5.81 Hz, 3 H) 3.49 (d, J=15.41 Hz, 1 H) 7.47 (d, J=8.53 Hz, 1 H) 7.52 (s, 1 H) 7.84 (s, 1 H) 7.89 (br. s., 1 H) 8.20 (d, J=8.34 Hz, 1 H) 8.49 (br. s., 1 H) 8.52 (d, J=8.84 Hz, 1 H); ESI—MS m/z [M+H]+ 445.2.
Example 362 6-(4-(4-cyan0methylphenyl)—5-hydr0xy-1H-pyrazolyl)-N—((1- isopropylpyrrolidinyl)methyl)—N—methylnic0tinamide 0”” \ | 0H H C3 The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 1-(1- isopropylpyrrolidin-3 -yl)—N—methylmethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.21 (br. s., 5 H) 2.09 (br. s., 1 H) 2.42 (s, 3 H) 2.60 — 2.78 (m, 1 H) 2.90 — 3.09 (m, 4 H) 3.09 — 3.44 (m, 5 H) 7.44 (d, J=8.49 Hz, 1 H) 7.47 (s, 1 H) 7.76 — 7.80 (m, 1 H) 7.85 (d, J=7.33 Hz, 1 H) 8.30 (d, J=8.34 Hz, 1 H) 8.45 (br. s., 1 H) 8.55 (d, J=8.59 Hz, 1 H); ESI—MS m/z [M+H]+ 459.2.
Example 363 6-(4-(4-cyan0phenyl)hydr0xy-1H-pyrazolyl)-N—((1- ethylpyrrolidinyl)methyl)-N-methylnic0tinamide WO 60810 vakm OH Nj CH3 N/ NWN CH3 N‘ The title compound was prepared in a manner similar to Example 74 using 1-(1- yrrolidinyl)-N—methylmethanamine to give a TFA salt. 1H NMR (400 MHz, DMSO- d6) 5 ppm 1.14 — 1.40 (m, 3 H) 1.76 — 1.91 (m, 1 H) 1.99 (d, J=5.56 Hz, 2 H) 2.21 — 2.36 (ml H) 3.04 (s, 3 H) 3.19 (br. s, 2 H) 3.43 (br. s., 1 H) 3.64 (br. s., 1 H) 3.76 (br. s., 1 H) 3.85 (br. s., 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (br. s., 3 H) 8.33 — 8.63 (m, 2 H) 8.63 — 8.79 (m, 1 H) 9.39 (br. s., 1 H); ESI—MS m/z [M+H]+ 431.2.
Example 364 (R)—4-(5-hydroxy(5-(2-(pyrrolidinylmethyl)pyrrolidine carbonyl)pyridinyl)-1H-pyrazolyl)benzonitrile i :N\. 0 The title compound was prepared in a manner similar to Example 74 using (R) (pyrrolidinylmethyl)pyrrolidine to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.68 — 1.87 (m, 2 H) 1.87 —1.99(m, 3 H) 2.06 (d, 6 Hz, 2 H) 2.11 — 2.23 (m, 1 H) 3.01 — 3.26 (m, 2 H) 3.26 — 3.37 (m, 1 H) 3.44 — 3.57 (m, 2 H) 3.59 — 3.73 (m, 2 H) 3.82 (br. s., 1 H) 4.48 — 4.62 (m, 1 H) 7.79 (d, J=8.59 Hz, 2 H) 8.15 (d, J=7.33 Hz, 2 H) 8.22 (dd, J=8.59, 2.02 Hz, 1 H) 8.49 (br. s., 1 H) 8.68 (d, J=1.52 Hz, 2 H) 9.43 (br. s., 1 H); ESI—MS m/z [M+H]+ 443.3.
Example 365 (R)—4-(5-hydroxy(5-(2-(pyrrolidinylmethyl)pyrrolidine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile [:NE 0 N/ [\‘1 \ :N The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)(pyrrolidin ylmethyl)pyrrolidine to give a TFA salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.69 — 1.87 (m, 2 H) 1.87 — 1.99 (m, 3 H) 2.06 (d, J=10.61Hz, 2 H) 2.11 — 2.24 (m, 1 H) 2.44 (s, 3 H) 3.12 (br. 5., 1 H) 3.21 (br. 5., 1 H) 3.26 — 3.37 (m, 1 H) 3.44 — 3.57 (m, 2 H) 3.60 — 3.73 (m, 2 H) 3.83 (br. 5., 1 H) 4.47 — 4.61 (m, 1 H) 7.62 — 7.70 (m, 1 H) 7.74 (5, 1 H) 7.76 (br. 5., 1 H) 8.18 (br. 5., 1 H) 8.22 (dd, J=8.59, 1.52 Hz, 1 H) 8.45 (br. 5., 1 H) 8.64 — 8.73 (m, 1 H) 9.37 (br. 5., 1 H); ESI—MS m/z [M+H]+ 457.3.
Example 366 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—((1- ethylpyrrolidinyl)methyl)-N-methylnicotinamide Cf] \ | 0“ <“ rW The title compound was prepared in a manner similar to Example 74 using 1-(1- ethylpyrrolidinyl)—N—methylmethanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.23 (br. ., 3 H) 1.61 — 1.94 (m, 1 H) 2.02 — 2.32 (m, 1 H) 2.64 — 2.96 (m, 2 H) 3.02 (5, 4 H) 3.19 (br. ., 3 H) 3.33 — 3.86 (m, 5 H) 7.80 (d, J=8.34 Hz, 2 H) 8.14 (br. 5., 3 H) 8.35 — 8.76 (m, 3 H) 9.72 (br. 5., 1 H); ESI—MS m/z [M+H]+ 445.3.
] Example 367 6-(4-(4-cyanophenyl)hydroxy-1H-pyrazolyl)-N—methyl-N—((1- methylpiperidinyl)methyl)nicotinamide (9%] \ | OH I}! N/ NWN CH3 N‘ The title compound was prepared in a manner similar to Example 112 using N- methyl(1-methylpiperidinyl)methanamine to give a hydrochloride salt. 1H NMR (400 MHz, 6) 5 ppm 1.42 (d, J=12.38 Hz, 1 H) 1.55 — 2.02 (m, 4 H) 2.67 — 2.87 (m, 2 H) 3.00 (5, 3 H) 3.06 — 3.20 (m, 1 H) 3.36 (br. 5., 1 H) 3.46 — 4.14 (m, 5 H) 7.72 (d, J=8.34 Hz, 2 H) 8.08 (br. 5., 3 H) 8.58 (br. 5., 3 H) 10.42 — 11.10 (m, 1 H); ESI—MS m/z [M+H]+ 431.3.
] Example 368 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— methyl-N-( 1 -methylpyrrolidin-3 -yl)nicotinamide H3C—N [)1 \ I OH The title compound was prepared in a manner r to Example 74 using 6-(4- (4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and N,1- dimethylpyrrolidin-3 -amine to give a TFA salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.09 — 2.32 (m, 2 H) 2.43 (s, 3 H) 2.76 — 2.94 (m, 3 H) 2.98 (s, 3 H) 3.13 — 3.45 (m, 2 H) 3.72 (br. s., 2 H) 4.94 (br. s., 1 H) 7.61 — 7.84 (m, 3 H) 8.01 — 8.26 (m, 2 H) 8.42 (br. s., 1 H) 8.58 (br. s., 1 H); ESI—MS m/z [M+H]+ 417.2.
Example 369 4-(5-hydroxy(5-(4-(pentan-3 -yl)piperazinecarbonyl)pyridin yl)-1H-pyrazolyl)—3 -methylbenzonitrile N\J H3C/j/ / N [\‘j \ _,N ] The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1-(pentan yl)piperazine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.88 (t, J=7.33 Hz, 6 H) 1.29 (dt, J=14.08, 6.98 Hz, 2 H) 1.47 (dt, J=14.08, 6.98 Hz, 2 H) 2.26 (t, J=6.57 Hz, 1 H) 2.43 (s, 3 H) 2.56 (br. s., 4 H) 3.37 — 3.48 (m, 2 H) 3.62 (br. s., 2 H) 7.64 (dd, J=8.08, 1.52 Hz, 1 H) 7.71 (s, 1 H) 7.82 (d, J=8.08 Hz, 1 H) 8.05 (dd, J=8.59, 2.27 Hz, 1 H) 8.12 (s, 1 H) 8.39 (d, J=8.59 Hz, 1 H) 8.53 (d, J=2.27 Hz, 1 H) 12.82 (br. s., 1 H); ESI—MS m/z [M+H]+ 459.3.
] Example 370 (1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile N \ 3 \/ N N \ :N 6H3 [{1\ The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)ethyl methylpiperazine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.87 — 1.19 (m, 6 H) 2.42 (s, 3 H) 2.47 (br. s., 1 H) 2.52 — 2.59 (m, 1 H) 2.62 — 2.76 (m, 1 H) 2.77 — 2.98 (m, 2 H) 3.06 (d, J=10.61Hz, 1 H) 3.35 (br. s., 1 H) 3.46 — 3.75 (m, 1 H) 4.05 (br. s., 1 H) 7.60 (dd, J=7.96, 1.64 Hz, 1 H) 7.66 (d, J=1.26 Hz, 1 H) 7.90 (d, J=8.34 Hz, 1 H) 8.01 (dd, J=8.72, 2.15 Hz, 1 H) 8.06 (s, 1 H) 8.43 (d, J=8.59 Hz, 1 H) 8.51 (d, J=1.77 Hz, 1 H) 11.83 — 12.92 (m, 1 H); ESI—MS m/z [M+H]+ 431.3.
Example 3 71 (R)(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N— (3 -methoxybutyl)nicotinamide 9H3 O H3C\O/\/\N \ OH H | N [\‘j \ :N The title nd was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R) methoxybutan-l-amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.11 (d, J=6.32 Hz, 3 H) 1.58 — 1.79 (m, 2 H) 2.43 (s, 3 H) 3.24 (s, 3 H) 3.30 — 3.42 (m, 3 H) 7.66 (dd, J=7.83, 1.26 Hz, 1 H) 7.73 (s, 1 H) 7.77 (br. s., 1 H) 8.18 (br. s., 1 H) 8.29 — 8.59 (m, 2 H) 8.68 (t, J=5.31 Hz, 1 H) 8.87 — 8.94 (m, 1 H) 13.17 (br. s., 1 H); ESI—MS m/z [M+H]+ 406.2.
Example 372 (S)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile ”W1| OH ;) N/ [\‘l \ :N CH3 N\ ] H30 The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)-1,2- dimethylpiperazine dihydrochloride. 1H NMR (400 MHz, 6) 5 ppm 1.16 (br. s., 3 H) 2.36 (s, 3 H) 2.60 (s, 3 H) 2.90 (br. s., 1 H) 3.04 (br. s., 1 H) 3.26 (br. s., 2 H) 3.41 — 3.57 (m, 1 H) 3.73 (d, J=17.68 Hz, 1 H) 4.29 (br. s., 1 H) 7.59 (dd, J=8.08, 1.52 Hz, 1 H) 7.66 (s, 1 H) 7.72 (d, J=8.08 Hz, 1 H) 8.03 (dd, J=8.59, 2.02 Hz, 1 H) 8.10 (s, 1 H) 8.35 (d, J=7.83 Hz, 1 H) 8.51 (d, J=1.52 Hz, 1 H) 12.09 (br. s., 1 H); ESI—MS m/z [M+H]+ 417.3.
Example 373 4-(1-(5-(4-cyclobutylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile 2014/031918 The title nd was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1- cyclobutylpiperazine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.58 — 1.71 (m, 2 H) 1.76 — 1.90 (m, 2 H) 1.90 — 2.07 (m, 2 H) 2.37 (br. s., 4 H) 2.42 (s, 3 H) 2.83 (quin, Hz, 1 H) 3.44 (d, J=7.07 Hz, 2 H) 3.64 (br. s., 2 H) 7.63 (dd, J=7.96, 1.64 Hz, 1 H) 7.69 (s, 1 H) 7.84 (d, J=8.08 Hz, 1 H) 8.03 (dd, J=8.59, 2.27 Hz, 1 H) 8.11 (s, 1 H) 8.40 (d, J=8.59 Hz, 1 H) 8.52 (dd, J=2.27, 0.76 Hz, 1 H); ESI—MS m/z [M+H]+ 443.3.
] Example 374 (5-hydroxy(5-(3 -methylpropylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile IV N/WN\ H C3 The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)methyl propylpiperazine dihydrochloride. 1H NMR (500 MHz, DMSO—dg) 5 ppm 0.86 (t, J=7.32 Hz, 3 H) 0.90 — 1.15 (m, 3 H) 1.35 — 1.56 (m, 2 H) 2.31 — 2.41 (m, 2 H) 2.43 (s, 3 H) 2.58 — 2.73 (m, 2 H) 2.81 — 3.01 (m, 1 H) 3.02 — 3.17 (m, 2 H) 3.44 — 3.65 (m, 1 H) 4.02 (br. s., 1 H) 7.62 (dd, J=8.05, 1.71 Hz, 1 H) 7.69 (d, J=0.98 Hz, 1 H) 7.86 (d, J=7.81 Hz, 1 H) 8.03 (dd, J=8.54, 2.20 Hz, 1 H) 8.08 (s, 1 H) 8.41 (d, J=8.30 Hz, 1 H) 8.52 (d, J=1.95 Hz, 1 H); ESI— MS m/z [M+H]+ 445.3.
Example 375 (R)—4-(1-(5-(4-cyclopropylmethylpiperazinecarbonyl)pyridin- 2-yl)hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile H3C"'(\N \ | OH V/ N/ N \ :N The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)—1-cyclopropyl- 2-methylpiperazine dihydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.26 (br. s., 1 H) 0.36 — 0.51 (m, 2 H) 0.61 (d, J=5.56 Hz, 1 H) 0.93 — 1.29 (m, 3 H) 1.65 (br. s., 1 H) 2.16 — 2.40 (m, 1 H) 2.43 (s, 3 H) 2.58 (br. s., 1 H) 2.75 — 3.03 (m, 2 H) 3.15 (br. s., 1 H) 3.43 — 3.59 (m, 1 H) 4.09 (br. s., 1 H) 7.66 (d, J=8.32 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 8.06 (dd, J=8.59, 2.02 Hz, 1 H) 8.15 (s, 1 H) 8.38 (br. s., 1 H) 8.53 (d, J=1.77 Hz, 1 H); ESI— MS m/z [M+H]+ 443.3.
Example 376 (S)(1-(5-(3-(dimethylamin0)piperidinecarb0nyl)pyridinyl)hydr0xy-1H-pyrazolyl)—3 lbenzonitrile N/ (WM ,N\ N‘ H3O CH3 ] The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (S)-N,N— dimethylpiperidinamine dihydrochloride. 1H NMR (400 MHz, g) 5 ppm 1.53 (d, J=13.39 Hz, 1 H) 1.83 (br. s., 2 H) 2.06 — 2.23 (m, 1 H) 2.43 (s, 3 H) 2.81 (br. s., 7 H) 3.04 — 3.25 (m, 1 H) 3.35 — 3.42 (m, 1 H) 3.54 (br. s., 1 H) 4.02 (br. s., 1 H) 4.44 (br. s., 1 H) 7.67 (d, J=8.22 Hz, 1 H) 7.74 (s, 1 H) 7.78 (d, J=7.83 Hz, 1 H) 8.11 (dd, J=8.59, 1.77 Hz, 1 H) 8.17 (br. s., 1 H) 8.42 (br. s., 1 H) 8.58 (d, J=1.52 Hz, 1 H); ESI—MS m/z [M+H]+ 431.3.
Example 377 4-(5-hydr0xy(5-(3,3,4-trimethylpiperazinecarb0nyl)pyridin yl)—1H-pyrazolyl)—3 -methylbenzonitrile ,N _.
H3C N [\‘l \ ——N The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 1,2,2- trimethylpiperazine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.95 (br. s., 6 H) 2.20 (s, 3 H) 2.35 (s, 3 H) 2.60 (t, J=5.05 Hz, 2 H) 2.97 — 3.72 (m, 4 H) 7.53 (dd, J=8.08, 1.52 Hz, 1 H) 7.59 (d, J=1.01Hz, 1 H) 7.85 (d, J=8.08 Hz, 1 H) 7.93 (d, J=7.33 Hz, 1 H) 7.98 (s, 1 H) 8.36 (d, J=8.59 Hz, 1 H) 8.43 (br. s., 1 H); ESI—MS m/z [M+H]+ 431.3.
Example 378 5-(4-ethyl-3,3-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile H3cfl/\N \ | OH H3C\/N\) N/ NWN The title nd was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 1-ethyl,2,2- dimethylpiperazine. 1H NMR (400 MHz, ACETONITRILE-d3) 5 ppm 0.79 — 1.20 (m, 9 H) 2.36 — 2.48 (m, 5 H) 2.59 (d, J=6.06 Hz, 2 H) 3.15 (br. s., 1 H) 3.44 (br. s., 2 H) 3.69 (br. s., 1 H) 7.53 — 7.59 (m, 1 H) 7.60 — 7.63 (m, 1 H) 7.63 — 7.66 (m, 1 H) 7.75 (s, 1 H) 8.01 (br. s., 2 H) 8.42 (br. s., 1 H); ESI—MS m/z [M+H]+ 445.3.
Example 379 (R)(5-hydroxy(5-(4-isopropylmethylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile H3C/,,(\N \ I OH CH3 N\ The title compound was prepared in a manner r to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)isopropyl methylpiperazine. 1H NMR (500 MHz, CHLOROFORM—aO 5 ppm 0.93 (br. s., 3 H) 1.01 (br. s., 2 H) 1.16 (br. s., 5 H) 2.43 (s, 1 H) 2.47 (s, 3 H) 2.61 (d, J=12.20 Hz, 1 H) 2.75 — 2.98 (m, 1 H) 3.07 (br. s., 1 H) 3.29 (br. s., 2 H) 4.39 (br. s., 1 H) 7.47 — 7.62 (m, 3 H) 7.68 (s, 1 H) 7.95 — 8.11 (m, 2 H) 8.44 (s, 1 H); ESI—MS m/z [M+H]+ 445.3.
Example 380 5-(3-(diethylamino)piperidinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile N [\‘l \ ——N H3CVNVCH3 N\ The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and N,N— diethylpiperidinamine ochloride. 1H NMR (500 MHz, CHLOROFORM-aO 5 ppm 1.26 (br. s., 6 H) 1.57 (br. s., 2 H) 1.76 — 2.17 (m, 2 H) 2.36 — 2.90 (m, 9 H) 3.02 (br. s., 1 H) 3.70 (br. s., 1 H) 4.52 — 4.92 (m, 1 H) 7.48 — 7.60 (m, 3 H) 7.63 — 7.73 (m, 1 H) 7.95 — 8.10 (m, 2 H) 8.43 (s, 1 H); ESI—MS m/z [M+H]+ 459.3.
Example 381 (S)(5-hydr0xy(5-(3-(pyrr01idinyl)piperidine yl)pyridinyl)-1H-pyrazolyl)—3 lbenzonitrile L7 H30 The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyan0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (S)—3-(pyrr01idin yl)piperidine dihydrochloride. 1H NMR (500 MHz, DMSO-d6) 5 ppm 1.42 - 1.55 (m, 1 H) 1.61 (d, J=9.76 Hz, 1 H) 1.77 (br. s., 5 H) 2.06 (d, J=8.79 Hz, 1 H) 2.42 (s, 3 H) 2.77 (br. s., 2 H) 2.87 — 3.09 (m, 2 H) 3.12 — 3.24 (m, 2 H) 3.33 (br. s., 1 H) 3.47 — 3.92 (m, 1 H) 3.93 — 4.48 (m, 1 H) 7.53 (dd, J=8.30, 1.95 Hz, 1 H) 7.58 (s, 1 H) 7.90 — 7.95 (m, 2 H) 8.08 (d, J=7.81 Hz, 1 H) 8.46 — 8.51 (m, 2 H); ESI—MS m/z [M+H]+ 457.3.
Example 382 (R)(1-(5-(3 -(ethyl(methyl)amin0)piperidinecarb0nyl)pyridin- 2-yl)hydr0xy-1H-pyrazolyl)-3 lbenzonitrile | OH N/ h] \ :N H3CVN\ N\ The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyan0methylphenyl)-5 -hydr0xy-1H-pyrazolyl)nic0tinic acid and (R)-N—ethyl-N— methylpiperidinamine dihydrochloride to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) ppm 1.15 — 1.33 (m, 3 H) 1.57 (d, J=12.63 Hz, 1 H) 1.77 (d, 2 Hz, 2 H) 2.11 (d, J=10.36 Hz, 1 H) 2.43 (s, 3 H) 2.80 (br. s., 3 H) 3.08 — 3.36 (m, 3 H) 3.38 — 3.52 (m, 2 H) 3.52 — 3.69 (m, 1 H) 4.60 (br. s., 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.71 — 7.81 (m, 2 H) 8.10 (d, J=7.07 Hz, 2 H) 8.40 — 8.64 (m, 2 H) 9.66 (br. s., 1 H); ESI—MS m/z [M+H]+ 445.3.
Example 383 (R)(1-(5-(3-(cyclopropyl(methyl)amin0)piperidine carbonyl)pyridinyl)-5 -hydr0xy-1H-pyrazolyl)-3 -methylbenzonitrile 0“ \ I OH N/ “1qu N N\ ‘CH3 \7 “30 The title nd was ed in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-lH-pyrazolyl)nicotinic acid and (R)—N—cyclopropyl- N—methylpiperidinamine dihydrochloride. 1H NMR (400 MHZ, DMSO—dg) 5 ppm 0.13 — 0.61 (m, 4 H) 1.38 — 1.64 (m, 2 H) 1.64 — 2.09 (m, 3 H) 2.15 — 2.41 (m, 3 H) 2.43 (s, 3 H) 2.55 — 2.86 (m, 2 H) 3.04 (br. s., 1 H) 3.49 — 3.87 (m, 1 H) 4.33 — 4.77 (m, 1 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.72 (s, 1 H) 7.81 (d, J=8.08 Hz, 1 H) 8.05 (dd, J=8.59, 2.02 Hz, 1 H) 8.13 (s, 1 H) 8.40 (d, J=7.33 Hz, 1 H) 8.53 (d, J=1.77 Hz, 1 H); ESI—MS m/z [M+H]+ 457.3.
Example 384 (S)(1-(5-(3 l(methyl)amino)piperidinecarbonyl)pyridin- 2-yl)hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile N \ I OH N “W” HBC\/N\C|'|3 N\ The title compound was ed in a manner similar to Example 74 using 6-(4- (4-cyanomethylphenyl)-5 -hydroxy-lH-pyrazol-l-yl)nicotinic acid and (S)-N—ethyl-N— methylpiperidinamine dihydrochloride to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) ppm 1.09 — 1.34 (m, 3 H) 1.57 (d, J=12.13 Hz, 1 H) 1.77 (d, J=10.86 Hz, 2 H) 2.11 (d, J=11.12 Hz, 1 H) 2.43 (s, 3 H) 2.64 — 2.90 (m, 3 H) 3.23 (br. s., 3 H) 3.39 — 3.69 (m, 2 H) 3.80 — 4.77 (m, 2 H) 7.63 — 7.71 (m, 1 H) 7.74 (s, 1 H) 7.77 (br. s., 1 H) 7.99 — 8.28 (m, 2 H) 8.34 — 8.68 (m, 2 H) 9.67 (br. s., 1 H); ESI—MS m/z [M+H]+ 445.3. e 385 (R)(1-(5-(2,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile CH3 0 H\N|\ OH H3C’N\) N/ :N The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyanomethylphenyl)hydroxy- lH-pyrazolyl)nicotinic acid and (R)-1,3 - dimethylpiperazine dihydrochloride to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.37 (d, J=7.07 Hz, 3 H) 2.43 (s, 3 H) 3.09 (br. s., 1 H) 3.23 (d, J=9.09 Hz, 1 H) 3.41 (br. s., 3 H) 3.67 — 4.42 (m, 1 H) 4.42 — 5.15 (m, 1 H) 7.67 (d, J=8.30 Hz, 1 H) 7.72 — 7.81 (m, 2 H) 8.10 (d, J=8.08 Hz, 1 H) 8.19 (br. s., 1 H) 8.33 — 8.62 (m, 2 H) 9.98 (br. s., 1 H) 13.20 (br. 5., 1 H); ESI—MS m/z [M+H]+ 417.3.
Example 386 (1-(5-(3 -(cyclopropyl(methyl)amino)piperidine carbonyl)pyridinyl)-5 -hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile 0“ \ I OH [11‘ N\ The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)-N—cyclopropyl— N—methylpiperidinamine dihydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.68 — 1.16 (m, 4 H) 1.49 — 1.68 (m, 1 H) 1.71 — 2.00 (m, 2 H) 2.17 — 2.30 (m, 1 H) 2.43 (s, 3 H) 2.91 (d, J=12.38 Hz, 4 H) 3.18 (br. s., 1 H) 3.56 (br. s., 2 H) 3.91 — 4.58 (m, 1 H) 4.79 (br. s., 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.71 — 7.86 (m, 2 H) 8.00 — 8.28 (m, 2 H) 8.57 (s, 2 H) 9.53 (br. s., 1 H); ESI—MS m/z [M+H]+ 457.3.
Example 387 (R)(5-hydroxy(5-(3-(pyrrolidinyl)piperidine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile N/ :N ; I] \ N N\ The title compound was prepared in a manner similar to e 74 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)(pyrrolidin yl)piperidine ochloride. 1H NMR (400 MHz, g) 5 ppm 1.54 (d, J=9.09 Hz, 1 H) 1.72 — 1.96 (m, 4 H) 1.96 — 2.11 (m, 2 H) 2.16 (br. s., 1 H) 2.43 (s, 3 H) 2.82 — 3.35 (m, 3 H) 3.35 — 3.87 (m, 5 H) 4.26 (br. s., 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 2 H) 8.11 (d, J=8.08 Hz, 2 H) 8.57 (d, J=2.02 Hz, 2 H) 9.83 (br. s., 1 H); ESI—MS m/z [M+H]+ 457.3.
Example 388 (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile H3C"'(\N \ | OH “30W N/W The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and (R)ethyl methylpiperazine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.96 (m, J=7.20, 7.20 Hz, 6 H) 2.36 (s, 3 H) 2.39 (br. s., 1 H) 2.45 — 2.52 (m, 1 H) 2.53 — 2.68 (m, 1 H) 2.71 — 2.90 (m, 2 H) 2.99 (br. s., 1 H) 3.41 — 3.66 (m, 1 H) 3.97 (br. s., 1 H) 7.53 (d, J=7.83 Hz, 1 H) 7.60 (s, 1 H) 7.84 (d, J=8.08 Hz, 1 H) 7.94 (d, J=7.79 Hz, 1 H) 7.99 (s, 1 H) 8.36 (d, J=8.59 Hz, 1 H) 8.44 (d, J=1.77 Hz, 1 H); ESI—MS m/z [M+H]+ 431.3.
Example 389 (S)(1-(5-(4-cyclopropyl-3 -methylpiperazinecarbonyl)pyridin- 2-yl)hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile E \ \\Z The title compound was prepared in a manner r to Example 112 using 6-(4- nomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)—1-cyclopropyl- 2-methylpiperazine dihydrochloride. 1H NMR (400 MHZ, DMSO—dg) 5 ppm 0.09 — 0.71 (m, 4 H) 0.87 — 1.23 (m, 3 H) 3.43 (br. s., 1 H) 2.36 (s, 3 H) 2.48 — 2.65 (m, 1 H) 2.72 — 3.14 (m, 3 H) 3.43 (br. s., 2 H) 4.05 (br. s., 1 H) 7.59 (d, J=7.64 Hz, 1 H) 7.66 (s, 1 H) 7.70 (br. s., 1 H) 8.00 (d, J=8.08 Hz, 1 H) 8.09 (br. s., 1 H) 8.34 (br. s., 1 H) 8.44 — 8.50 (m, 1 H); EST—MS m/z [M+H]+ 443.3.
] Example 390 4-(5-hydroxy(5-(4-methyl-4,7-diazaspiro[2.5]octane carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile (\N|\ OH ,NZ 6 .— H3C N/ NWN The title compound was ed in a manner similar to Example 112 using 6-(4- (4-cyanomethylphenyl)-5 -hydroxy-1H-pyrazolyl)nicotinic acid and 4-methyl-4,7- piro[2.5]octane dihydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.32 (br. s., 1 H) 0.50 — 0.78 (m, 3 H) 2.39 (s, 3 H) 2.42 (s, 3 H) 2.86 (br. s., 2 H) 3.31 (br. s., 1 H) 3.41 — 3.62 (m, 2 H) 3.73 (br. s., 1 H) 7.63 — 7.68 (m, 1 H) 7.72 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.04 (br. s., 1 H) 8.14 (s, 1 H) 8.38 (d, J=8.08 Hz, 1 H) 8.50 (br. s., 1 H) 12.85 (br. s., 1 H); ESI—MS m/z [M+H]+ 429.3.
Example 391 (S)(1-(5-(2,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile 9H3 o FW1 0“ ch/Nd | N/ [\‘l \ :N The title nd was ed in a manner similar to Example 74 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)-1,3- dimethylpiperazine to give a TFA salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.36 (d, J=7.33 Hz, 3 H) 2.43 (s, 3 H) 2.84 (s, 3 H) 3.09 (br. s., 1 H) 3.22 (d, J=9.85 Hz, 1 H) 3.28 — 3.93 (m, 3 H) 3.93 — 5.17 (m, 2 H) 7.67 (d, J=8.08 Hz, 1 H) 7.71 — 7.86 (m, 2 H) 8.02 — 8.30 (m, 2 H) 8.57 (d, J=2.02 Hz, 2 H) 9.78 (br. s., 1 H); ESI—MS m/z [M+H]+ 417.3.
Example 392 (R)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile HBO/"(\N \ | OH ,N / The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)-1,2- ylpiperazine dihydrochloride to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.28 (br. s., 3 H) 2.43 (s, 3 H) 2.85 (br. s., 3 H) 2.91 — 3.11 (m, 1 H) 3.12 — 3.63 (m, 4 H) 3.63 — 4.81 (m, 2 H) 7.67 (dd, J=8.08, 1.26 Hz, 1 H) 7.71 — 7.87 (m, 2 H) 8.02 — 8.30 (m, 2 H) 8.32 — 8.64 (m, 2 H) 9.92 — 10.48 (m, 1 H); ESI—MS m/z [M+H]+ 417.3.
Example 393 (S)(5-hydroxy(5-(4-isopropylmethylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile H3C"'(\N \ | OH “WV N’ ”NW CH3 N\ The title compound was prepared in a manner similar to Example 112 using 6-(4- nomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)isopropyl methylpiperazine to give a TFA salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.98 — 1.51 (m, 9 H) 2.43 (s, 3 H) 2.88 — 3.28 (m, 2 H) 3.28 — 3.66 (m, 2 H) 3.90 (br. s., 2 H) 4.61 (br. s., 1 H) 7.64 — 7.71 (m, 1 H) 7.71 — 7.82 (m, 2 H) 8.08 — 8.39 (m, 2 H) 8.63 (s, 2 H) 9.80 (br. s., 1 H); ESI—MS m/z [M+H]+ 445.3.
Example 394 4-(1-(5-(3-(dimethylamino)azetidinecarbonyl)pyridinyl) y-1H-pyrazolyl)—2-fluoromethylbenzonitrile I-I3C\N/C/ AmN \ F . N N \ ’N CH3 [5 The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and N,N— dimethylazetidinamine dihydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.37 (s, 3 H) 2.77 (br. s., 6 H) 4.07 — 4.18 (m, 1 H) 4.26 (br. s., 2 H) 4.52 (br. s., 1 H) 4.63 (br. s., 1 H) 7.70 (d, J=6.82 Hz, 1 H) 7.79 (d, J=11.37 Hz, 1 H) 8.19 — 8.26 (m, 2 H) 8.43 (d, J=8.84 Hz, 1 H) 8.69 (d, J=2.27 Hz, 1 H); ESI—MS m/z [M+H]+ 421.3.
Example 395 (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoromethylbenzonitrile [[301],pr F H3CVN\) N/ N \ :N The title nd was prepared in a manner similar to Example 112 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)—1- 2-methylpiperazine . 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.03 (t, J=7.20 Hz, 6 H) 2.33 (s, 3 H) 2.65 — 2.79 (m, 2 H) 2.88 — 3.02 (m, 2 H) 3.06 (d, J=10.86 Hz, 1 H) 3.10 — 3.21 2014/031918 (m, 1 H) 3.39 (br. s., 1 H) 3.57 — 4.21 (m, 2 H) 7.52 (d, J=7.07 Hz, 1 H) 7.84 — 7.92 (m, 1 H) 7.95 (s, 1 H) 8.23 (d, J=13.14 Hz, 1 H) 8.37 — 8.50 (m, 2 H); ESI—MS m/z [M+H]+ 449.3.
Example 396 2-flu0r0(5-hydr0xy(5-(4-methylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)—5 -methylbenzonitrile 6W1 F | 0“ H3C/N\) N/ [\‘l \ :N “3‘3 The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyan0flu0r0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and 1- methylpiperazine to give a TFA salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.26 (d, J=17.18 Hz, 3 H) 2.42 (s, 3 H) 2.85 (br. s., 3 H) 3.21 (br. s., 1 H) 3.34 (br. s., 1 H) 3.40 — 3.74 (m, 2 H) 7.80 (d, J=7.07 Hz, 1 H) 7.87 (br. s., 1 H) 8.13 (d, J=8.59 Hz, 1 H) 8.30 (br. s., 1 H) 8.49 (br. s., 1 H) 8.56 — 8.65 (m, 1 H) 9.85 — 10.51 (m, 1 H); ESI—MS m/z [M+H]+ 421.3.
Example 397 (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-flu0r0methylbenzonitrile H3CV®H3C NJKEE F I OH N '1‘\ "N—— The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyan0flu0r0methylphenyl)hydr0xy-1H-pyrazolyl)nic0tinic acid and (S) ethylmethylpiperazine. 1H NMR (400 MHz, 6) 5 ppm 0.95 — 1.30 (m, 6 H) 2.41 (s, 3 H) 2.79 (dt, J=12.95, 6.54 Hz, 2 H) 2.94 — 3.10 (m, 2 H) 3.13 (d, J=11.37 Hz, 1 H) 3.23 (dd, 4, 8.34 Hz, 1 H) 3.46 (br. s., 1 H) 3.61 — 4.25 (m, 2 H) 7.59 (d, J=7.33 Hz, 1 H) 7.91 — 8.00 (m, 1 H) 8.03 (s, 1 H) 8.30 (d, J=13.14 Hz, 1 H) 8.45 — 8.57 (m, 2 H); ESI—MS m/z [M+H]+ 449.3.
Example 398 2—flu0r0(5-hydr0xy(5-(morpholinecarb0nyl)pyridinyl)- 1H-pyrazolyl)—5-methylbenzonitrile “*0 F O\) N/ N \ :N The title compound was ed in a manner similar to Example 112 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and morpholine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.42 (s, 3 H) 3.40 — 3.87 (m, 8 H) 7.79 (d, J=7.07 Hz, 1 H) 7.88 (d, J=10.86 Hz, 1 H) 8.10 (dd, J=8.59, 2.02 Hz, 1 H) 8.27 (br. s., 1 H) 8.44 (br. s., 1 H) 8.57 (dd, J=2.27, 0.76 Hz, 1 H) 13.47 (br. s., 1 H); ESI—MS m/z [M+H]+ 408.3.
Example 399 2-fluoro(5-hydroxy(5-(4-methyl-4,7-diazaspiro[2.5]octane yl)pyridinyl)-1H-pyrazolyl)—5 -methylbenzonitrile MN \ F /N\) AYE/L H30 N N \ _.N—— The title compound was prepared in a manner similar to Example 112 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and 4-methyl- 4,7-diazaspiro[2.5]octane ochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.26 — 0.83 (m, 4 H) 2.41 (d, J=3.79 Hz, 6 H) 2.89 (br. s., 2 H) 3.40 — 3.91 (m, 4 H) 7.73 (d, J=7.07 Hz, 1 H) 7.98 (d, J=11.87 Hz, 2 H) 8.20 (s, 1 H) 8.35 — 8.63 (m, 2 H); ESI—MS m/z [M+H]+ 447.3. e 400 (S)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoromethylbenzonitrile H3CY\N \ H3C’N\) | OH N N \ ——N The title compound was prepared in a manner similar to Example 74 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (S)-1, 2- methylpiperazine to give a TFA salt. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.07 — 1.47 (m, 3 H) 2.42 (s, 3 H) 2.85 (br. s., 3 H) 3.07 — 3.71 (m, 5 H) 3.74 — 4.10 (m, 1 H) 4.57 (br. s., 1 H) 7.80 (d, J=7.07 Hz, 1 H) 7.87 (br. s., 1 H) 8.13 (d, J=8.34 Hz, 1 H) 8.30 (br. s., 1 H) 8.49 (br. s., 1 H) 8.60 (d, J=1.52 Hz, 1 H) 9.87 — 10.44 (m, 1 H); ESI—MS m/z [M+H]+ 435.3.
Example 401 (R)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—2-fluoromethylbenzonitrile ch’NdH3CI,IK\N)J\ON/ NWN “3‘3 The title compound was ed in a manner r to Example 74 using 6-(4- (4-cyanofluoromethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid and (R)—1, 2- methylpiperazine to give a TFA salt. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.05 — 1.53 (m, 3 H) 2.42 (s, 3 H) 2.85 (br. s., 3 H) 3.09 — 3.41 (m, 3 H) 3.42 — 3.73 (m, 2 H) 3.75 — 4.09 (m, 1 H) 4.55 (br. s., 1 H) 7.80 (d, J=7.07 Hz, 1 H) 7.87 (br. s., 1 H) 8.13 (d, J=8.08 Hz, 1 H) 8.30 (br. s., 1 H) 8.49 (br. s., 1 H) 8.60 (d, J=1.52 Hz, 1 H) 9.83 — 10.45 (m, 1 H); ESI—MS m/z [M+H]+ 435.3.
Example 402 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(3- methoxypropyl)nicotinamide H3C-O \—\¥ HO NH _ \ CH3 O N N Combined 6—(4—bromomethoxy-1H-pyrazolyl)-N—(3 - methoxypropyl)nicotinamide (50 mg, 0.135 mmol), 2-methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)benzonitrile (65.8 mg, 0.271 mmol), [1,1’-bis(di-tert—butylphosphino) ferrocene]dichloropalladium(II) (13.86 mg, 0.021 mmol) and sodium bicarbonate (56.9 mg, 0.677 mmol) in dioxane (599 [11) and water (150 [11) was heated at 110°C in the microwave for 40 minutes. The reaction mixture was filtered through Celite® and concentrated in vacuo to give 6-(4-(4-cyanomethylphenyl)methoxy-1H-pyrazolyl)—N—(3- methoxypropyl)nicotinamide which was used in next step without further purification. ed 4-cyanomethylphenyl)methoxy-1H-pyrazolyl)-N—(3- methoxypropyl)nicotinamide (54.7 mg, 0.135 mmol) and lithium de (57.2 mg, 1.350 mmol) in DMA (2109 [11) and heated at 60°C for 24 hours. The reaction mixture was then diluted with 0.6 mL DMSO and purified by preparative HPLC (35-60% acetonitrile in water under TFA conditions) and then again (15-40% acetonitrile in water under basic conditions) to give the title compound (14 mg, 0.036 mmol, 26.5 %) as an ite solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.77 (quin, J=6.63 Hz, 2 H) 2.43 (s, 3 H) 3.25 (s, 3 H) 3.38 — 3.41 (m, 4 H) 7.08 (br. s., 2 H) 7.58 (d, J=8.08 Hz, 1 H) 7.88 (d, J=9.35 Hz, 1 H) 7.97 (s, 1 H) 8.29 (dd, J=8.46, 2.40 Hz, 1 H) 8.50 (d, J=8.34 Hz, 1 H) 8.61 (t, J=6.06 Hz, 1 H) 8.85 (d, J=1.77 Hz, 1 H); MS (M+H)+ 392.
Example 403 6-(4-(4-cyano-2,5-dimethylphenyl)—5-hydroxy-1H-pyrazol-l-yl)-N— (3 -methoxypropyl)nicotinamide ch—o CN \—\~NH HO \ CH3 ] o N N ] The title compound was prepared in a manner similar to Example 402 using 2,5- dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.77 (quin, J=6.63 Hz, 2 H) 2.36 (s, 3 H) 2.39 (s, 3 H) 3.25 (s, 3 H) 3.38 — 3.41 (m, 4 H) 7.15 (br. s., 1 H) 7.45 (s, 1 H) 7.84 (s, 1 H) 8.06 (s, 1 H) 8.22 (dd, J=8.72, 2.40 Hz, 1 H) 8.50 — 8.61 (m, 2 H) 8.83 (d, J=1.77 Hz, 1 H); EST—MS m/z (M+H)+ calc’d for C22H23N503, ; found 406.4.
Example 404 6-(4-(4-cyanofluoromethylphenyl)hydroxy-1H-pyrazol yl)—N—(3-methoxypropyl)nicotinamide H3C-O H3C NH _ OwN‘N/ The title compound was prepared in a manner similar to Example 402 using 3- fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. ESI-MS m/z (M+H)+ calc’d for C21H20FN503, 410.16; found 410.4.
Example 405 6-(4-(4-cyanofluoromethylphenyl)hydroxy-1H-pyrazol yl)—N—(3 xypropyl)nicotinamide H3C-O CN \_\_ H0 NHWI“ /_ F O N N The title compound was prepared in a manner similar to Example 402 using 2- fluoromethyl(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.74 — 1.82 (m, 2 H) 2.42 (s, 3 H) 3.25 (s, 3 H) 3.38 — 3.44 (m, 4 H) 6.54 (br. s., 1 H) 7.79 (d, J=7.07 Hz, 1 H) 7.89 (br. s., 1 H) 8.28 (br. s., 1 H) 8.41 (d, J=6.32 Hz, 1 H) 8.71 (t, J=5.68 Hz, 1 H) 8.91 (s, 1 H) 13.61 (br. s., 1 H); ESI—MS m/z (M+H)+ calc’d for C21H20FN503, 410.16; found 410.5.
Example 406 6-(4-(4-cyanofiuoromethylphenyl)hydroxy-1H-pyrazol yl)—N—(3-methoxypropyl)nicotinamide H3C-O H3C \—\— HO NHW” /— O N N The title nd was prepared in a manner similar to Example 402 using 2- fiuoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.70 — 1.82 (m, 2 H) 2.33 (d, J=2.27 Hz, 3 H) 3.25 (s, 3 H) 3.38 — 3.43 (m, 4 H) 6.54 (br. s., 1 H) 7.64 (br. s., 1 H) 7.72 — 7.80 (m, 1 H) 8.25 (br. s., 1 H) 8.41 (d, J=6.57 Hz, 1 H) 8.71 (t, J=5.56 Hz, 1 H) 8.91 (d, J=1.01Hz, 1 H) 13.48 (br. s., 1 H); ESI—MS m/z (M+H)+ calc’d for C21H20FN503, 410.16; found 410.4.
Example 407 4-(5-hydroxy(5-(octahydropyrrolo[1,2-a]pyrazine yl)pyridinyl)-1H-pyrazolyl)—3 -methylbenzonitrile N H3C <— HO N — \ / N / 0 N N [01 533] Combined 6—(4—(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (500 mg, 1.561 mmol), EDC (449 mg, 2.342 mmol) and HOBT (316 mg, 2.342 mmol) in DMF (3122 [11) and treated with DIPEA (818 [11, 4.68 mmol). Octahydropyrrolo[1,2— a]pyrazine (296 mg, 2.342 mmol) was then added. The on was d to stir for 8 hours and filtered and the filtrate was purified by preparative HPLC (15 -40% ACN/water under basic conditions) to give a solid which was recrystallized from MeOH, filtered, and dried in vacuum to give the title compound (286 mg, 0.603 mmol, 38.6 %) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.34 (br. s., 1 H) 1.72 (br. s., 3 H) 2.12 (br. s., 1 H) 2.23 (d, J=7.07 Hz, 2 H) 2.42 (s, 3 H) 2.51 — 2.53 (m, 1 H) 3.06 (t, J=8.08 Hz, 3 H) 3.72 (br. s., 1 H) 4.44 — 4.56 (m, 1 H) 7.63 (dd, J=8.08, 1.77 Hz, 1 H) 7.69 (d, J=1.26 Hz, 1 H) 7.84 (d, J=8.08 Hz, 1 H) 8.04 (dd, J=8.59, 2.27 Hz, 1 H) 8.09 (s, 1 H) 8.40 (d, J=7.58 Hz, 1 H) 8.52 (d, J=2.27 Hz, 1 H); EST—MS m/z (M+H)+ calc’d for C24H24N602, 429.20; found 429.3. e 408 4-(5-hydroxy(5-(4-methylpiperazinecarbonyl)pyridinyl)- 1H-pyrazolyl)methylbenzonitrile H3C\ //N ON H C3 N — O N N Combined EDC (599 mg, 3.12 mmol), HOBT (211 mg, 1.561 mmol) and 6-(4-(4- cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid (500 mg, 1.561 mmol) in DMF (10 ml) and added 1-methylpiperazine (519 111, 4.68 mmol) and DIPEA (818 111, 4.68 mmol) and the solution was stirred at 20°C overnight. The reaction mixture was then purified by preparative HPLC (15—40% ACN in water under basic conditions) to give the free base, which was suspended in acetonitrile (28 mL) and treated with 1N aqueous hydrochloric acid (2.341 mL, 2.341 mmol). The ing cloudy mixture was heated until cleared and allowed to cool to ambient temperature. The mixture was filtered and the filtrate was cooled to 0°C and filtered again. The filtrate was diluted with ethyl ether (10 mL) to give a solid and the mixture was heated until all solids ved, and then cooled to ambient temperature to give a solid. The mixture was cooled to 0°C and filtered, and the solid was dried in vacuum at 80°C for 1 hour to give the title compound as a hydrochloride salt (94 mg, 13.7%) as a light pink solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.43 (s, 3 H) 2.79 (s, 3 H) 3.16 (br. s., 4 H) 3.64 — 4.57 (m, 4 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.12 (d, J=7.33 Hz, 1 H) 8.21 (br. s., 1 H) 8.51 (br. s., 1 H) 8.57 — 8.61 (m, 1 H); EST—MS m/z (M+H)+ calc’d for C22H22N602, 403.18; found 403.2.
Example 409 4-cyano-2,3-dimethylphenyl)hydroxy-1H-pyrazol-l-yl)-N- (3 -methoxypropyl)nicotinamide H3C-O CN NH _ \ / N. / O N N The title compound was prepared in a manner similar to Example 402 using 2,3- yl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.78 (quin, J=6.69 Hz, 2 H) 2.32 (s, 3 H) 2.44 (s, 3 H) 3.25 (s, 3 H) 3.33 — 3.43 (m, 4 H) 7.13 (br. s., 1 H) 7.43 (d, J=8.34 Hz, 1 H) 7.69 — 7.76 (m, 2 H) 8.21 (dd, J=8.84, 2014/031918 2.27 Hz, 1 H) 8.48 — 8.56 (m, 2 H) 8.83 (d, J=1.77 Hz, 1 H); ESI—MS m/z (M+H)+ calc’d for C22H23N503, ; found 406.4.
Example 410 6-(4-(4-cyano(methoxymethyl)phenyl)hydroxy-1H-pyrazol yl)—N—(3 -methoxypropyl)nicotinamide H3C_O H3C-O CN NHWM. /— O N N The title compound was prepared in a manner similar to Example 402 using 3- (methoxymethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.73 — 1.83 (m, 2 H) 3.25 (s, 3 H) 3.34 — 3.43 (m, 4 H) 4.52 (s, 2 H) 7.75 (dd, J=8.21, 1.39 Hz, 1 H) 7.83 (d, J=1.77 Hz, 1 H) 7.96 — 8.10 (m, 2 H) 8.37 (dd, J=8.59, 2.78 Hz, 1 H) 8.45 (br. s., 1 H) 8.66 (t, J=5.43 Hz, 1 H) 8.89 (d, J=3.03 Hz, 1 H); ESI-MS m/z (M+H)+ calc’d for C22H23N504, 422.18; found 422.5.
] Example 411 6-(4-(4-cyanomethoxymethylphenyl)—5-hydroxy-1H-pyrazol- 1-yl)-N—(3 xypropyl)nicotinamide H3C-O CN \ / \ / CH3 0 N N The title compound was prepared in a manner similar to Example 402 using 2- methoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.73 — 1.83 (m, 2 H) 2.31 (s, 3 H) 3.25 (s, 3 H) 3.33 — 3.44 (m, 4 H) 3.89 (s, 3 H) 7.52 — 7.61 (m, 2 H) 8.06 (br. s., 1 H) 8.33 — 8.47 (m, 2 H) 8.65 (t, J=5.31Hz, 1 H) 8.86 — 8.92 (m, 1 H); ESI-MS m/z (M+H)+ calc’d for C22H23N504, 422.18; found 422.5.
Example 412 (S)—4-(1-(5-(3-(dimethylamino)pyrrolidinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile N N \ :N H3C—N\ [L]\ [01 548] Combined 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)nicotinic acid (50.0 mg, 0.156 mmol), (S)—N,N—dimethylpyrrolidinamine (26.7 mg, 0.234 mmol), and N 1 -((ethylimino)methylene)-N3 ,N3 -dimethylpropane-1,3 -diamine hydrochloride (44.9 WO 60810 mg, 0.234 mmol) in DMF (1561 [11). HOBT (35.9 mg, 0.234 mmol) and DIPEA (136 [11, 0.781 mmol) were added. The reaction was allowed to stir overnight. Then 1N aqueous hydrochloric acid (21 ML) was added and reaction e was then purified using preparative HPLC eluting with 0.1% formic acid in water and 5-30% acetonitrile to give the title compound (30 mg, 0.072 mmol, 46.1 %) as an off—white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.78 — 1.88 (m, 1 H) 2.24 (br. s., 3 H) 2.36 (br. s., 3 H) 2.42 (s, 3 H) 2.88 — 3.05 (m, 2 H) 3.59 — 3.81 (m, 4 H) 7.58 (d, J=7.83 Hz, 1 H) 7.64 (s, 1 H) 7.95 (d, J=7.83 Hz, 1 H) 8.01 (s, 1 H) 8.11 (d, J=9.09 Hz, 1 H) 8.43 (d, J=8.84 Hz, 1 H) 8.62 (s, 1 H); ESI—MS m/z (M+H)+ calc’d for C23H24N602, 417.20; found 417.5.
Example 413 (R)(1-(5-(3-(dimethylamino)pyrrolidinecarbonyl)pyridin yl)—5-hydroxy-1H-pyrazolyl)methylbenzonitrile OIJKO OH / The title compound was prepared in a manner similar to Example 412 using (R)- methylpyrrolidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.80 - 1.91 (m, 1 H) 2.27 (br. s., 3 H) 2.40 (br. s., 3 H) 2.42 (s, 3 H) 2.90 — 3.16 (m, 2 H) 3.38 — 3.51 (m, 2 H) 3.69 — 3.81 (m, 2 H) 7.58 (d, J=8.08 Hz, 1 H) 7.64 (s, 1 H) 7.94 (d, J=8.08 Hz, 1 H) 8.02 (s, 1 H) 8.11 (dd, J=8.84, 2.02 Hz, 1 H) 8.42 (d, J=8.84 Hz, 1 H) 8.62 (s, 1 H); ESI—MS m/z (M+H)+ calc’d for C23H24N602, 417.20; found 417.5.
Example 414 4-(1-(5-(4-cyclopropylpiperazinecarbonyl)pyridinyl)—5- hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile The title compound was prepared in a manner similar to e 412 using 1- cyclopropylpiperazine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.30 — 0.38 (m, 2 H) 0.39 — 0.48 (m, 2 H) 1.64 — 1.72 (m, 1 H) 2.43 (s, 3 H) 2.52 — 2.69 (m, 4 H) 3.58 (br. s., 4 H) 7.61 — 7.68 (m, 1 H) 7.70 (s, 1 H) 7.82 (d, J=8.08 Hz, 1 H) 8.04 (dd, J=8.59, 2.27 Hz, 1 H) 8.11 (s, 1 H) 8.39 (d, J=8.34 Hz, 1 H) 8.52 (d, J=2.27 Hz, 1 H); ESI—MS m/z (M+H)+ calc’d for C24H24N602, 429.20, found 429.5 Example 415 4-(5-hydroxy(5-(4-propylpiperazinecarbonyl)pyridinyl)— azolyl)—3-methylbenzonitrile H3C/\/©N \ I OH N/ h“ \ :N The title compound was prepared in a manner similar to Example 412 using 1- propylpiperazine dihydrobromide. 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.87 (t, J=7.33 Hz, 3 H) 1.53 (dq, J=15.09, 7.43 Hz, 2 H) 2.42 (s, 3 H) 2.53 — 2.60 (m, 2 H) 2.74 (br. s., 4 H) 3.63 (br. s., 4 H) 7.60 — 7.65 (m, 1 H) 7.68 (s, 1 H) 7.83 (d, J=8.08 Hz, 1 H) 8.05 (dd, J=8.59, 2.27 Hz, 1 H) 8.09 (s, 1 H) 8.14 (s, 1 H) 8.39 (d, J=8.59 Hz, 1 H) 8.54 (d, J=1.52 Hz, 1 H); ESI— MS m/z (M+H)+ calc’d for C24H26N602, 431.21; found 431.5.
Example 416 5-(4-(dimethylamino)piperidinecarbonyl)pyridinyl) hydroxy-1H-pyrazolyl)—3 -methylbenzonitrile O \ I OH CH3 N\ ] H30 The title compound was prepared in a manner similar to Example 412 using N,N— dimethylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.55 - 1.72 (m, 2 H) 2.01 (br. s., 2 H) 2.42 (s, 3 H) 2.68 (s, 6 H) 3.33 (t, J=11.49 Hz, 1 H) 4.21 (br. s., 4 H) 7.52 (d, J=8.08 Hz, 1 H) 7.56 (s, 1 H) 7.88 — 7.96 (m, 2 H) 8.09 (d, J=8.08 Hz, 1 H) 8.45 — 8.56 (m, 2 H); ESI-MS m/z (M+H)+ calc’d for C24H26N602, 431.21; found 431.5.
Example 417 4-(5-hydroxy(5-((3aR,7aS)methyloctahydro-1H-pyrrolo[3,4- c]pyridine-5 -carbonyl)pyridinyl)-1H-pyrazolyl)-3 -methylbenzonitrile ”30 ”30 The title compound was prepared in a manner similar to Example 412 using 2- methyloctahydro-1H-pyrrolo[3,4-c]pyridine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.61 — 1.86 (m, 2 H) 2.43 (s, 3 H) 2.55 (br. s., 2 H) 2.72 (br. s., 3 H) 3.08 (br. s., 1 H) 3.15 (d, J=9.60 2014/031918 Hz, 1 H) 3.24 — 3.30 (m, 2 H) 3.59 (d, J=11.37 Hz, 2 H) 3.80 (br. s., 2 H) 7.44 — 7.50 (m, 1 H) 7.51 (s, 1 H) 7.80 — 7.88 (m, 2 H) 8.16 (s, 1 H) 8.20 (d, J=8.08 Hz, 1 H) 8.41 (br. s., 1 H) 8.57 (br. s., 1 H); ESI—MS m/z (M+H)+ calc’d for C25H26N602, 443.21; found 443.5.
Example 418 4-(1-(5-(4-(cyclopropylmethyl)piperazinecarbonyl)pyridinyl)- xy-1H-pyrazolyl)—3 -methylbenzonitrile ”‘N \ The title compound was prepared in a manner similar to Example 412 using 1- propylmethyl)piperazine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.09 — 0.15 (m, 2 H) 0.46 — 0.53 (m, 2 H) 0.84 — 0.91 (m, 1 H) 2.32 — 2.37 (m, 2 H) 2.42 (s, 3 H) 2.60 (br. s., 4 H) 3.58 (br. s., 4 H) 7.60 (d, J=8.34 Hz, 1 H) 7.67 (s, 1 H) 7.90 (d, J=8.08 Hz, 1 H) 8.01 (dd, J=8.72, 2.15 Hz, 1 H) 8.05 (s, 1 H) 8.41 (d, J=8.59 Hz, 1 H) 8.51 (d, J=1.77 Hz, 1 H); ESI— MS m/z (M+H)+ calc’d for C25H26N602, 443.21; found 443.5. e 419 4-(1-(5-(4-((dimethylamino)methyl)piperidinecarbonyl)pyridin- 2-yl)hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile The title compound was prepared in a manner similar to Example 412 using N,N— dimethyl-l-(piperidinyl)methanamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.07 - 1.22 (m, 2 H) 1.75 (d, J=9.60 Hz, 2 H) 1.93 — 2.02 (m, 1 H) 2.42 (s, 3 H) 2.55 (s, 6 H) 2.68 (d, J=6.82 Hz, 2 H) 2.85 — 3.14 (m, 2 H) 4.40 (br. s., 2 H) 7.46 — 7.51 (m, 1 H) 7.54 (s, 1 H) 7.82 — 7.90 (m, 2 H) 8.14 — 8.16 (m, 1 H) 8.43 (d, J=1.77 Hz, 1 H) 8.50 (d, J=8.59 Hz, 1 H); ESI— MS m/z (M+H)+ calc’d for C25H28N602, 445.23; found 445.5.
Example 420 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— cyclopropyl-N-(1-methylpiperidinyl)nicotinamide H3C\U NJKEE OH A N/ ”WM The title compound was prepared in a manner similar to Example 412 using N- cyclopropylmethylpiperidinamine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.40 — 0.46 (m, 2 H) 0.59 — 0.65 (m, 2 H) 1.98 (d, J=12.38 Hz, 2 H) 2.22 (td, J=12.69, 9.22 Hz, 2 H) 2.42 (s, 3 H) 2.56 (s, 3 H) 2.67 — 2.75 (m, 2 H) 2.88 (dt, J=6.88, 3.25 Hz, 1 H) 3.26 — 3.28 (m, 2 H) 4.05 (ddd, J=12.00, 8.08, 3.92 Hz, 1 H) 7.47 — 7.52 (m, 1 H) 7.54 (s, 1 H) 7.87 (s, 1 H) 8.00 (dd, J=8.72, 2.40 Hz, 1 H) 8.12 — 8.16 (m, 1 H) 8.48 (d, J=8.59 Hz, 1 H) 8.55 (d, J=1.52 Hz, 1 H); EST—MS m/z (M+H)+ calc’d for N602, 457.23; found 457.5.
Example 421 4-(5-hydroxy(5-(4-morpholinopiperidinecarbonyl)pyridin -pyrazolyl)—3 -methylbenzonitrile 0N N/ N\Q’Q’:N The title compound was prepared in a manner similar to Example 412 using 4- (piperidinyl)morpholine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.44 (qd, J=11.87, 4.04 Hz, 2 H) 1.86 (br. s., 2 H) 2.43 (s, 3 H) 2.58 (br. s., 4 H) 2.86 (br. s., 2 H) 3.52 — 3.76 (m, 6 H) 4.46 (br. s., 1 H) 7.63 (dd, J=8.08, 1.52 Hz, 1 H) 7.70 (s, 1 H) 7.82 (d, J=8.08 Hz, 1 H) 8.04 (dd, J=8.59, 2.27 Hz, 1 H) 8.10 (s, 1 H) 8.38 (d, J=8.59 Hz, 1 H) 8.52 (d, J=1.52 Hz, 1 H); EST—MS m/z (M+H)+ calc’d for C26H28N6O3, 473.22; found 473.5.
Example 422 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(2- yethyl)—N—(1-methylpiperidinyl)nicotinamide H3C\I\O\ O H N/ “1qu H30“0 N\ ] The title compound was prepared in a manner similar to Example 412 using N—(2- methoxyethyl)methylpiperidinamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.85 (d, WO 60810 J=12.13 Hz, 2 H) 2.11 (br. 5., 2 H) 2.42 (5, 3 H) 2.57 (br. 5., 2 H) 2.74 (br. 5., 2 H) 3.25 (br. 5., 3 H) 3.45 (br. 5., 3 H) 3.70 (br. 5., 5 H) 7.55 (dd, J=8.08, 1.77 Hz, 1 H) 7.60 (5, 1 H) 7.92 (dd, J=8.59, 2.53 Hz, 1 H) 7.96 (s, 1 H) 8.02 (d, J=8.08 Hz, 1 H) 8.41 — 8.52 (m, 2 H); ESI—MS m/z (M+H)+ calc’d for C26H30N603, 475.24; found 475.6.
Example 423 5-(4-(2-(dimethylamino)ethyl)piperazinecarbonyl)pyridin- -hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile (\N \ I OH CH3 N\ The title compound was prepared in a manner similar to Example 412 using N,N— dimethyl(piperazinyl)ethanamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 2.41 (s, 3 H) 2.60 (s, 2 H) 2.61 — 2.70 (m, 6 H) 3.02 (t, J=6.44 Hz, 2 H) 3.54 (br. 5., 8 H) 7.42 — 7.47 (m, 1 H) 7.48 (s, 1 H) 7.79 (s, 1 H) 7.83 (dd, J=8.46, 2.40 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.43 (d, J=1.77 Hz, 1 H) 8.55 (d, J=8.59 Hz, 1 H); ESI—MS m/z (M+H)+ calc’d for C25H29N702, 460.24; found 460.5.
Example 424 4-(5-hydroxy(5-(4-propyl-1,4-diazepanecarbonyl)pyridin yl)—1H-pyrazolyl)—3 -methylbenzonitrile The title compound was prepared in a manner similar to Example 412 using 1- propyl-1,4-diazepane. 1H NMR (400 MHz, DMSO—d6) 5 ppm 0.77 — 0.94 (m, 3 H) 1.42 — 1.59 (m, 2 H) 1.89 (br. 5., 2 H) 2.42 (s, 3 H) 2.56 (br. 5., 1 H) 2.72 (br. 5., 1 H) 2.78 — 2.97 (m, 3 H) 3.04 (br. 5., 1 H) 3.50 (br. 5., 2 H) 3.65 (br. 5., 1 H) 3.73 (br. 5., 1 H) 7.52 — 7.59 (m, 1 H) 7.61 (s, 1 H) 7.89 — 8.06 (m, 3 H) 8.45 (d, J=8.08 Hz, 1 H) 8.49 (d, J=1.01 Hz, 1 H); ESI—MS m/z (M+H)+ calc’d for N602, 445.23; found 445.5.
Example 425 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- ethylpiperidinyl)—N—methylnicotinamide The title compound was prepared in a manner similar to e 412 using 1- ethyl-N—methylpiperidinamine. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.11 (br. s., 3 H) 1.82 (d, J=12.13 Hz, 2 H) 1.91 — 2.01 (m, 2 H) 2.07 (s, 2 H) 2.42 (s, 3 H) 2.87 (s, 3 H) 7.51 (dd, , 1.77 Hz, 1 H) 7.56 (d, J=1.26 Hz, 1 H) 7.87 — 7.97 (m, 2 H) 8.11 (d, J=8.08 Hz, 1 H) 8.42 — 8.54 (m, 2 H); EST—MS m/z (M+H)+ calc’d for C25H28N602, 445.23; found 445.5.
Example 426 6-(4-(4-cyanomethoxymethylphenyl)—5-hydroxy-1H-pyrazol- 1-yl)-N—(3 -methoxypropyl)nicotinamide H3C-O CN [CH3 NHWN /_ o 0 N N The title compound was prepared in a manner similar to Example 402 using 2- methoxymethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzonitrile. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.78 (dt, J=13.20, 6.41 Hz, 2 H) 2.34 (br. s., 3 H) 3.25 (s, 3 H) 3.36 — 3.44 (m, 4 H) 3.89 (s, 3 H) 7.56 (br. s., 2 H) 8.15 (br. s., 1 H) 8.39 (d, J=7.33 Hz, 1 H) 8.68 (br. s., 1 H) 8.90 (br. s., 1 H); ESI—MS m/z (M+H)+ calc’d for C22H23N504, 422.18; found 422.5.
Example 427 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)-N—(1- (2-methoxyethyl)piperidinyl)-N—methylnicotinamide H3C’O\/\I\O\ o [*0 o.
] The title compound was prepared in a manner similar to Example 412 using 1-(2- methoxyethyl)-N-methylpiperidinamine. 1H NMR (400 MHz, DMSO—dg) 5 ppm 1.69 (d, J=11.37 Hz, 2 H) 1.84 — 1.96 (m, 2 H) 2.42 (s, 3 H) 2.69 (br. s., 2 H) 2.86 (s, 3 H) 3.10 (br. s., 2 H) 3.24 (br. s., 3 H) 3.46 (br. s., 4 H) 4.34 (br. s., 1 H) 6.51 (br. s., 1 H) 7.52 (d, J=8.08 Hz, 1 H) 7.57 (s, 1 H) 7.91 (s, 2 H) 8.09 (d, J=8.08 Hz, 1 H) 8.40 — 8.51 (m, 2 H); ESI—MS m/z (Md—Hyr calc’d fOI' C26H30N603, 475.24; found 475.6 ] Example 428 (S)(1-(5-(1,4-diazabicyclo[3.2.2]nonanecarbonyl)pyridin yl)—5-hydroxy-1H-pyrazolyl)-3 -methylbenzonitrile ON |\ OH N1 / N W:N The title compound was prepared in a manner similar to Example 412 using 1,4- diazabicyclo[3.2.2]nonane dihydrochloride. 1H NMR (400 MHZ, DMSO—dg) 5 ppm 1.97 (br. s., 2 H) 2.16 (br. s., 2 H) 2.43 (s, 3 H) 3.24 (d, J=5.31Hz, 6 H) 3.71 (br. s., 2 H) 4.75 (br. s., 1 H) 6.50 (br. s., 1 H) 7.51 (d, J=8.08 Hz, 1 H) 7.56 (s, 1 H) 7.88 — 7.99 (m, 2 H) 8.12 — 8.14 (m, 1 H) 8.56 (br. s., 2 H); ESI—MS m/z (M+H)+ calc’d for C24H24N602, 429.20; found 429.5. e 429 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— ethyl-N—(l -methylpiperidinyl)nicotinamide N \ OH k I CH3 N N \ :N The title compound was prepared in a manner similar to Example 412 using N- ethylmethylpiperidinamine. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.11 (br. s., 3 H) 1.81 (d, J=11.12 Hz, 2 H) 2.01 (br. s., 2 H) 2.42 (s, 3 H) 2.45 (br. s., 2 H) 3.14 (br. s., 3 H) 3.64 — 4.56 (m, 5 H) 7.47 — 7.52 (m, 1 H) 7.54 (s, 1 H) 7.83 — 7.89 (m, 2 H) 8.14 (d, J=8.08 Hz, 1 H) 8.41 (d, J=2.02 Hz, 1 H) 8.49 (d, J=8.59 Hz, 1 H); ESI—MS m/z (M+H)+ calc’d for C25H28N602, 445.23; found 445.5.
Example 430 4-(5-hydroxy(4-methyl(4-methylpiperazine carbonyl)pyridinyl)-1H-pyrazolyl)benzonitrile 0 CH3 ”W1| N/ “11qu The title nd was prepared in a manner similar to Example 412 using 6-(4- (4-cyanophenyl)hydroxy-1H-pyrazolyl)methylnicotinic acid and 1-methylpiperazine. 1H NMR (400 MHz, DMSO—d6) 5 ppm 2.39 (s, 3 H) 2.82 (s, 3 H) 4.02 (br. s., 4 H) 4.56 (br. s., 4 H) 7.79 (d, J=8.59 Hz, 2 H) 8.12 (br. s., 2 H) 8.37 (s, 1 H) 8.59 (br. s., 2 H); ESI—MS m/z (M+H)+ calc’d for C22H22N602, 403.18; found 403.3.
Example 431 6-(4-(4-cyanophenyl)—5-hydroxy-1H-pyrazolyl)-N,4-dimethyl-N— (1-methylpiperidinyl)nicotinamide ©\ 0 CH3 [)1 \ I OH The title compound was ed in a manner similar to Example 412 using 6-(4- (4-cyanophenyl)hydroxy-1H-pyrazolyl)—4-methylnicotinic acid and N, 1 - dimethylpiperidinamine. ESI-MS m/z (M+H)+ calc’d for C24H26N602, 431.21; found 43 1.5.
Example 432 6-(4-(4-cyanomethylphenyl)—5-hydroxy-1H-pyrazolyl)-N— methyl-N-(1-methylazetidin-3 -yl)nicotinamide HC-NyN3 [CH3 / \ \ O ‘N N The title compound was ed in a manner similar to Example 412 using N, 1- dimethylazetidinamine hydrochloride. 1H NMR (400 MHz, DMSO—dg) 5 ppm 2.43 (s, 3 H) 2.90 (br. s., 3 H) 3.06 (br. s., 3 H) 3.99 — 5.12 (m, 5 H) 7.67 (d, J=7.83 Hz, 1 H) 7.69 — 7.89 (m, 2 H) 8.10 (br. s., 1 H) 8.22 (br. s., 1 H) 8.58 (br. s., 2 H) 9.80 (br. s., 1 H); ESI—MS m/z (M+H)+ calc’d for C22H22N602, 403.18; found 403.3.
Example 433 (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) hydroxy- 1H-pyrazolyl)—2-f1uoromethylbenzonitrile < F /N H3N HO \ / N\/ CH3 O”@N N Combined 6-(4-(4-cyanof1uoromethylphenyl)hydroxy-1H-pyrazol yl)nicotinic acid (100 mg, 0.296 mmol), 1H-benzo[d][1,2,3]triazol—1—ol (47.9 mg, 0.355 mmol), N 1 -((ethylimino)methylene)-N3,N3 -dimethylpropane-1,3 -diamine hloride (68.0 mg, 0.355 mmol), DMF (Volume: 591 [11), and N—ethyl—N—isopropylpropan—2—amine (258 pl, 1.478 mmol). The orange solution was stirred at t temperature for 5 minutes then (S)—1—ethyl—3—methylpiperazine dihydrochloride (65.4 mg, 0.325 mmol) was added and the reaction was stirred at ambient temperature for 12h. The reaction mixture was d with a pre-made solution of water:ethanol (1 : 1, 5 mL). The reaction was acidified to pH 5 using 1N HCl. The solution was left to stir slowly at ambient temperature overnight. The precipitate was filtered and the solids were washed with water:ethanol (1: 1, 2 mL), then dried on the filter paper. The white solids were collected and dried further under . The dried solids were taken up in 10 volumes of water:ethanol (1:1) and stirred at reflux until the solution was almost completely translucent. The hot solution was filtered and then slowly cooled to ambient temperature and stirred slowly at ambient temperature overnight to give solids. The solids were d and washed with water:ethanol (1 : 1, 2 mL), partially dried on filter paper, then dried under vacuum to give the title compound (57.9 mg, 0.129 mmol, 43.7 % yield) as a white solid.1H NMR (400 MHz, DMSO—d6) 5 ppm 1.06 (t, J=7.20 Hz, 3 H) 1.30 (d, J=6.82 Hz, 3 H) 2.14 — 2.28 (m, 1 H) 2.31 — 2.45 (m, 4 H) 2.53 — 2.60 (m, 2 H) 2.81 — 3.06 (m, 2 H) 3.13 — 3.43 (m, 2 H) 4.08 — 4.62 (m, 1 H) 7.64 (d, J=7.33 Hz, 1 H) 7.96 (dd, J=8.84, 2.27 Hz, 1 H) 8.08 (s, 1 H) 8.19 (d, 3 Hz, 1 H) 8.43 — 8.52 (m, 2 H). EST—MS m/z [M+H]+ 449.3, ret time: 0.79 minutes.
Example 434 (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl) y-1H-pyrazolyl)—3 -methylbenzonitrile < / N O‘CH3N HO \ / N\ / CH3 O”flN N Combined 6-(4-(4-cyanomethylphenyl)hydroxy-1H-pyrazolyl)nicotinic acid (100 mg, 0.312 mmol), 1H-benzo[d][1,2,3]triazol-1—ol (50.6 mg, 0.375 mmol), N1— ((ethylimino)methylene)—N3,N3 —dimethylpropane-1,3—diamine hydrochloride (71.8 mg, 0.375 mmol), DMF (Volume: 624 pl), and l-N—isopropylpropanamine (273 pl, 1.561 mmol). The solution was stirred at ambient temperature for 5 minutes then (R)—1-ethyl methylpiperazine dihydrochloride (69.1 mg, 0.343 mmol) was added. The on was stirred at ambient temperature for 12h. The reaction was diluted with a pre-made solution of water:ethanol (1:1, 10 mL). The reaction was acidified to pH 5 using 1N HCl and left to stir slowly at ambient ature overnight. The precipitate was filtered and the solids were washed with water:ethanol (1 : 1, 2 mL), then dried on the filter paper. The white solids were collected and dried further under vacuum. The dried solids were taken up in 10 volumes of water:ethanol (1: 1) and stirred at reflux until the solution was almost completely translucent.
The hot solution was filtered and then slowly cooled to ambient temperature and stirred slowly at ambient temperature overnight to give solids. The solids were d and washed with water:ethanol (1: 1, 2 mL), partially dried on filter paper, then collected and dried under vacuum to give the title compound (67.7 mg, 0.157 mmol, 50.4 % yield) as a white solid. 1H NMR (400 MHz, DMSO—d6) 5 ppm 1.01 (s, 3 H) 1.21 — 1.37 (m, 3 H) 1.92 — 2.06 (m, 1 H) 2.09 — 2.21 (m, 1 H) 2.42 (s, 5 H) 2.67 — 2.99 (m, 2 H)3.05 — 4.61 (m, 3 H) 7.61 (dd, , 1.52 Hz, 1 H) 7.68 (s, 1 H) 7.86 (d, J=8.08 Hz, 1 H) 8.00 (dd, J=8.59, 2.27 Hz, 1 H) 8.08 (s, 1 H) 8.40 (d, J=8.59 Hz, 1 H) 8.49 (d, J=2.27 Hz, 1 H). ESI—MS m/z [M+H]+ 431.3, ret time: 0.80 s.
] Example R1 N—tert—butyl—6—(5—oxo—4—pyridin—3—yl—2,5—dihydro—lH—pyrazol—l— idinecarboxamide HsC HO \ H30+NH \ H3C WN\: O ‘N N The free base of compound ofUS 2010/0093803 Example 18 was prepared. 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.42 (s, 9 H) 1.40 — 1.44 (m, 1 H) 7.40 (dd, J=7.83, 4.80 Hz, 1 H) 8.06 (s, 1 H) 8.30 (d, J=6.82 Hz, 1 H) 8.35— 8.44 (m, 2 H) 8.55 (br. s., 1 H) 8.78 — 8.93 (m, 1 H) 9.13 (br. s., 1 H) 13.29 (br. s., 1 H), ESI—MS m/z [M+H]+ 337.4.
The compounds of the invention can be stered alone or in the form of a pharmaceutical composition. In practice, the compounds of the ion are usually administered in the form of pharmaceutical compositions, that is, in admixture with at least one pharmaceutically acceptable excipient. The proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard ceutical practice.
In another embodiment, the present invention provides pharmaceutical compositions comprising: a compound of ion and at least one pharmaceutically acceptable excipient.
In effecting treatment of a patient in need of such ent, a compound of the invention can be administered in any form and route which makes the compound bioavailable. The compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules. The nds of the invention can be administered parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, ermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
One skilled in the art can readily select the proper form and route of administration depending upon the ular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the invention may be administered to the patient, for example, in the form of tablets, es, cachets, papers, es, wafers, s, ointments, transdermal patches, ls, inhalants, suppositories, solutions, and suspensions.
The pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient. The amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1% to about 50% of the weight of the unit dose form. The term “pharmaceutically acceptable excipient” refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient. Some es of pharmaceutically acceptable excipients are found in ton’s Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, ts, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and .
The present ceutical compositions are preferably formulated in a unit dose form, each dose typically containing from about 0.5 mg to about 100 mg of a compounds of the invention. The term “unit dose form” refers to a physically te unit containing a predetermined quantity of active ingredient, in ation with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regimen to produce the desired therapeutic . One or more “unit dose form” may be taken to affect the treatment dosage, typically on a daily schedule.
WO 60810 2014/031918 In one particular variation, the composition is a pharmaceutical composition d for oral administration, such as a tablet or a capsule or a liquid formulation, for example, a solution or suspension, adapted for oral administration. In still r particular variation, the pharmaceutical composition is a liquid formulation d for parenteral administration. nds of the present invention are inhibitors of one or more PHD isoforms, and as such are useful in the treatment and prevention of conditions associated with HIF.
In another embodiment, the invention provides methods of treating conditions associated with HIF, comprising: administering to a patient in need thereof an effective amount of a compound of the invention. In another ment, a compound of the invention is provided for use as a medicament. The invention also provides the use of a compound of the invention, including the use for the manufacture of a medicament, to treat the conditions associated with HIF described herein. The compounds of the t invention are useful as PHD tors for a variety of subjects (e. g., humans, non-human mammals and non-mammals).
As used herein terms “condition,” “disorder,” and se” relate to any unhealthy or abnormal state. The term “conditions ated with HIF” includes conditions, disorders, and diseases in which the tion of PHD provides a therapeutic benefit, such as hypoxic conditions, ing cardiovascular disorders, hematological disorders, pulmonary disorders, kidney disorders, brain disorders, and cancer.
The terms “hypoxia” and “hypoxic” refer to levels of oxygen below normal and can lead to cellular dysfunction and even cell death. Hypoxia can result from decreased blood flow, insufficient oxygen in the blood, decreased capacity of the blood to carry oxygen, and various other causes. The term “hypoxic condition” includes, but is not limited to, ischemic conditions (ischemic hypoxia). The term “ischemia” refers to a deficient supply of blood to a cell, tissue, or organ and is associated with a reduction in oxygen delivered to tissues.
Since the heart, brain, and kidney are especially sensitive to hypoxic stress inhibitors of PHD are useful in treating vascular disorders, such as ischemic events, hematological disorders, such as , and kidney disorders.
Ischemia may arise due to reduced circulation such as stroke, myocardial infarction, congestive heart failure, atherosclerosis, and formation of a thrombus in an artery or vein, blockage of an artery or vein by an embolus, vascular closure due to other causes.
Such conditions may reduce blood flow, producing a state of hypoperfusion to an organ or tissue, or block blood flow completely.
Other conditions that can lead to ischemia include tissue damage due to trauma or injury, such as, e. g., spinal cord injury; viral infection. The term “conditions associated with HIF” es the term “ischemic conditions” which refers to conditions or events that are associated with or result in ischemia. Thus, the term “conditions ated with HIF” includes conditions associated or resulting in ischemia including, but are not d to, an event selected from the group consisting of pulmonary embolism, perinatal hypoxia, atory shock including, e. g., hemorrhagic, septic, genic, etc.; mountain sickness, acute respiratory failure, intestinal infarction, acute kidney failure, renal ischemia reperfusion injury, atherosclerosis, chronic venous insufficiency, congestive heart failure, c cirrhosis, diabetes, macular degeneration, sleep apnea, Raynaud’s disease, systemic sclerosis, occlusive artery disease, ent ic attacks, chronic alcoholic liver disease, c kidney failure, peripheral vascular disorders, ulcers, burns, chronic wounds, and the like.
Ischemia can also result when individuals are placed under general anesthesia, and can cause tissue damage in organs ed for transplant.
Another embodiment is a method of treating ischemic conditions. In particular the present invention provides a method of treating myocardial infarctions, including acute myocardial infarction. The present invention provides a method of treating acute heart e.
The present invention provides a method of treating congestive heart failure. The present invention es a method of treating the exacerbation of tive heart failure with and without acute myocardial infarction. The present invention also provides a method of treating stroke. The present ion also provides a method of treating acute kidney injury of ischemic and non—ischemic etiology.
Hypoxia results from reduced oxygen content in the blood due to pulmonary disorders (hypoxic hypoxia) such as COPD, severe pneumonia, pulmonary edema, pulmonary hypertension, and the like. Hypoxia also results from anemic conditions (anemic hypoxia) such as gastric or duodenal ulcers, liver or renal disease, thrombocytopenia or blood ation disorders, cancer or other chronic illness, cancer chemotherapy and other therapeutic interventions that produce anemia, and the like, decreased concentration of hemoglobin or red blood cells, and de sickness, and the like.
] The term “conditions associated with HIF” includes specifically, but is not limited to, COPD. The term “conditions associated with HIF” includes pulmonary disorders specifically, but is not d to, diffuse parenchymal lung diseases such as idiopathic interstitial pneumonias, idiopathic ary fibrosis, usual interstitial pneumonia, desquamative pulmonary fibrosis, cryptogenic organizing pneumonia, acute interstitial pneumonia, non-specific interstitial pneumonia, atory bronchiolitis ated with institial lung disease, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, hypersensitivity pneumonitis, and decreased pulmonary function due to lupus, sarcoidosis, Wegner’s granulomatosis, radiation of the chest, and certain medications, for example, amiodarone, bleomycin, busulfan, methotrexate, and nitrofurantoin.
The term “anemia” refers to any reduction in the number of red blood cells and/or in the level of hemoglobin in blood relative to normal blood levels.
The term “conditions associated with HIF” es anemia, and specifically includes, but is not limited to, chemotherapy-induced anemia (such as treatment with antiviral drug regimens for HIV and hepatitis), anemia of chronic disease, anemia associated with cancer conditions, anemia resulting from ent for cancer, anemias of chronic immune disorders such as rheumatoid tis, inflammatory bowel e, lupus, menstruation, iron processing deficiencies, acute or chronic kidney disease, infections, ation, ation, toxins, diabetes, infection due to, e. g., virus, bacteria, and/or parasites, anemia can be associated with blood loss due to, e. g., trauma, stomach ulcers, duodenal ulcers, hemorrhoids, cancer of the stomach or large ine, injury, surgical procedures; diseases associated with bone marrow failure or decreased bone marrow function; microcytic anemia, hypochromic anemia, blastic anemia, and the like.
] The term “conditions associated with HIF” includes cancer, including leukemia (chronic myelogenous leukemia and chronic lymphocytic leukemia); breast cancer, genitourinary cancer, skin cancer, bone cancer, prostate cancer, and liver cancer; brain ; cancer of the larynx, gall bladder, rectum, parathyroid, thyroid, adrenal, neural tissue, bladder, head, neck, stomach, bronchi, and kidneys; basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteosarcoma, Ewing’s sarcoma, veticulum cell a, and Kaposi’s sarcoma; myeloma, giant cell tumor, islet cell tumor, acute and chronic cytic and granulocytic tumors, hairy-cell tumor, adenoma, medullary oma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, oid habitus tumor, Wilms’ tumor, seminoma, ovarian tumor, omater tumor, cervical sia, neuroblastoma, retinoblastoma, myelodysplastic syndrome, rhabdomyosarcoma, astrocytoma, non-Hodgkin’s ma, malignant hypercalcemia, polycythermia vera, adenocarcinoma, glioblastoma multiforma, glioma, lymphomas, and malignant melanomas, among others.
The terms “treat,” “treatment,” and “treating” include improvement of the ions described herein. The terms “treat,” “treatment,” and “treating” include all 22 l processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all ms or a cure of the condition. The terms “treat, 3’ 6‘treatment,” and “treating” are intended to include therapeutic treatment of such disorders. The terms “treat,” “treatment,” and “treating” are intended to include prophylactic treatment of such disorders.
As used herein the terms “patient” and “subject” es humans and non—human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, s, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, ians, and the like. It is understood that a more ular patient is a human. Also, more particular patients and ts are non-human mammals, such as mice, rats, and dogs.
As used herein, the term “effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous stances. In determining the effective amount, the dose, a number of factors are considered by the attending diagnostician, ing, but not limited to: the s of t; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the ular compound administered; the mode of administration; the bioavailability teristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present invention, the treatment dosage, is expected to range from 1 mg to 200 mg. Specific amounts can be ined by the skilled person. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the riate dose for a patient (e. g., an infant) whose mass falls outside of this weight range.
The compounds of the invention may be combined with one or more other pharmacologically active compounds or therapies for the treatment of one or more ers, diseases or conditions for which HIF is ted may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating arthritis, including rheumatoid arthritis and osteoarthritis, or for treating cancer, including hematological malignancies, such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma, and T-cell lymphoma, and carcinomas, such as lung cancer, pancreatic cancer, and colon cancer. Such ations may offer significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity.
The activity of compounds as PHD tors may be determined by a y of methods, including in vitro and in viva methods.
] Example A Inhibition of PHD Enzyme ] The IC50 values for the PHD2 enzyme (residues 181 — 417) were determined by mixing increasing amounts of inhibitor with a fixed amount of enzyme (SnM, final concentration) and Biotin labeled peptide (Biotin-Asp-Leu-Glu-Met-Leu-Ala-Pro-Tyr-Ile- Pro-Met-Asp-Asp-Asp-Phe—Gln-Leu, luM final concentration) and 2-Oxyglutarate (2uM final concentration) in 50mM HEPES, 50mM KCl, 0.5mM TCEP, 2uM FeClZ, 0.lmg/ml BSA, at pH 7.3. The reaction was conducted by pre—incubating the enzyme in the presence of inhibitor for 60 min at room ature. The activity of the free enzyme was measured by adding the peptide, the 2-Oxoglutarate (see above for final trations) and Ascorbic Acid (lmM final concentration). The tic ty was quenched after 60 min by adding an excess of a tight binding inhibitor to the assay mixture. The amount of product released was measured by using a LC/MS system (Agilent HPLC with d Biosystems API3000 Mass Spectrometer). Data were analyzed using the classical isotherm equation for the determination of IC50 values and are pIC50, i.e., -log(IC50), where IC50 is molar concentration and are reported as pIC50, i.e., -log(IC50), where IC50 is molar concentration.
Table A provides results for exemplified compounds in Example A.
TABLE A: PHD Inhibition (pICso) for Example (Ex) Compounds [mm- EI----------- n----------- -m------ -----------m ---------W -----------n -----------n -----------n -“---------- -----------n -----n Inn-"m“ Inn-"m“ m---------- ------------ ------------ ------------ Example B Inhibition of PHD in cells PHD inhibition is determined using (secondary assay) Cell-based HIF-alpha ization assay: H9c2 rat cardiomyocytes (ATCC) were seeded in l tissue culture microplates and ed for 24 hours prior to addition of compounds (11 point range of serial dilutions) or dimethylsulfoxide vehicle. After 24 hrs of compound incubation, whole cell extracts were prepared by lysing cells in cell extraction buffer containing protease and phosphatase inhibitors (Meso—Scale Discovery). HIFla n content was assessed by ELISA (Meso—Scale Discovery) and expressed as a % relative to the maximum response obtained from the positive l, desferrioxamine (Sigma—Aldrich). Compound ECsos were obtained by curve—fitting using XLfit4 MicroSoft Excel curve—fitting software. Compound EC50pos were obtained using XLfit4 to ate the compound concentration that results in 50% of the desferrioxamine maximum response.
Table B provides results for exemplified compounds in Example B.
TABLE B Inhibition of PHD in cells (pEC50) for Example (Ex) Compounds ECSO Ex -oEC E>< ..O‘EJ‘Q‘FU#KO-bo\IUIKOU: O -—---549 ---—-— 0‘11 -—-—-— -—----NNNN NNNN WNHO \1000 [\JNNN \OKOKOKO O\U1-I>UJ UJUJUJUJmO\O\O\O\\o<><>\1c::>< 9.059951\owm-boN-bmwg -—-—-544 [\J [\J .5 [\J \o \1 O\ [\J 00 U.) \1O O\ [\J U: “--90 Inn—l um- O\U1U1U1 \IOOOOOOO \lU‘Ifi—‘UJQ [\JNNNNN WNNNNN 0000\10U1 99992925o:momw UJUJUJUJNN OOOOKOKO WNHOKOOO >199). \I®O 0001—4 «9‘99“. OOO 9‘9“ U1U1 U14> UJUJUJUJUJUJ \l\l\l\l\l\l om5mm~ 9‘o U1 627 502 [\J U.) ._. O\ .5 U.) D.) O.5 U: U: U: U.) \1 \1 WO 60810 mm mg4.26523.3.7. mum-6.55 566565566 81290.9801 ”“55 3.663. ----—2M Imam ”“51: 53.4.5258 55555555566566666656666666 O63.615587.9.228112120.70.03.2543. 00034565975733348113189 290.84.85567777857247 In“! --6mIRE-n ”m:29.297.17.177.
Im;0.14.4.1 3333333333333333333333333333333333333333333333 0000011111111112222222222333333333344444444445 5670090123456700901234567009012345678901234567890 6655656566656666665 1188686612393442134 2368173923743430328 3333333333333333333333444444444444444444444444 77000000800008800009999999999000000000011111111112222 0090123456700901234567890123456789012345670090123 6565655555555555666NN666656656566666521560282922131 51 mm:U1U1 Jk‘k) O\\l Jk-bNN U1-l> _O\ WW U‘IU‘IU‘I 5"?" 00-1> OU1 #J>NN \]O\ 0M0565E\O\lt—‘ IM[\J b.) U1 U1 O1 1—4 .5 .5[\J 00 01 b.) O Imz00 I”6'.5 m “—-O\U1 U1U1 \OU1[\) NNNNN oooooooooo oo\1Oxm.5oa OxngxOngngle59.552000qu 5mmmxow5xo P‘Q‘Q‘P‘P‘Q‘. 00.5Hmom 0.599qu 528 [\J 00 \0 U1 . \0 3—4 DJ 0[\J O\ [\J 00 Fu-b-b-b-b-b-bUJUJUJUJUJN ngNt—‘OKO O\ O[\J U1 \0 1—4 [\J \OO .0“O.5 i0DJ iO\00 533 N\O 1—4 .0“ O 1—4 DJ 01.5 U1 1—4 1—4 591 [\J \o [\J .0“ DJ \0 DJ Oxm Ox DJ 00 Example C In vivo protection assay PHD inhibitor or vehicle was administered orally to 8—week old male C57 mice or Sprague Dawley rats. Four hours after dosing, hearts were removed quickly and perfused in a retrograde manner with modified Krebs-Henseleit buffer in a Langendorff apparatus at constant pressure (80 mmHg). To measure t size, hearts were first ed for 20 min to reach equilibrium and then subjected to a 30—minute global ischemia ow) period followed by a 60—min reperfusion period in mice or 90-min reperfusion in rats. The ventricles were cut transversely into 5 sections. The slices were stained 1% 2,3,5—triphenyl tetrazolium chloride (TTC) and scanned to e the infarct area and the total area. Cardiac injury was assessed by ing lactate dehydrogenase (LDH) release to coronary effluent during the 60-min reperfusion period (in mice only). The amount of LDH release was determined using an LDH activity assay kit (MBL International Corp.) as expressed as % of vehicle treated hearts.
The compound of Example 282 reduced area of the infarct in mice by 59% at 30 mg/kg and by 50% at 10 mg/kg as compared to the vehicle control values. ponding reduction of LDH released to the ry effluent was 56% and 51% at 30 and 10 mg/kg, respectively. The compound of Example 282 reduced area of the infarct in rats by 30% at a dose of 5 mg/kg.
Example D Determination of heart gene s for Vascular Endothelial Growth Factor (VEGF) PHD inhibitor or vehicle were stered orally to male C57BL/6 in groups of four. The compounds were formulated in 30% hydroxypropyl beta—cyclodextrin in 50mM WO 60810 Sodium Phosphate pH7.4 at doses of 30 mg/kg and 60 mg/kg. Two hours after dosing the mice were euthanized by C02 and the hearts were d quickly, ned into 2 pieces; the lower (apical) n was snap frozen and stored at -80°C and analyzed for VEGF gene changes applying qRT-PCR and using Life Technologies #4392938 and an RNA extraction protocol using Qiagen #74881 RNeasy 96 Universal Tissue Kit. Standards are made from RNA from combined vehicle treated s at a concentration of 100ug/mL, a 7 point curve is made with 1:4 dilutions and a blank. Samples are run on using RNA-to-CT 1-Step method using a StepOnePlus ime PCR System from Applied Biosystems Relative quantitation is expressed by dividing the quantity ofVEGF by the quantity of the reference gene.
Treatment groups and vehicle control were combined and ed.
Table D provides results for selected exemplified compounds in Example D.
% Increase Dose (mg/kg) Com.ared to Control __—-E_ ———m_ ———m- It is well-known that and increase in VEGF and other angiogenic factors provides protection against ic injury. Nature Med. 9, 653—660 (2003). PHD is an important regulator involved in gene expression. Biochem J. 2004, 381 (Pt 3): 761—767. At a dose of 60 mg/kg, the compound of Example 282 provides a 2 fold greater VEGF mRNA production compared to the compound of Example R1. It is also well-known that cularization stimulated by VEGF is beneficial in several important clinical contexts, including myocardial ischemia. Mol. Cell Bio. 1996 Sep; 16(9): 4604—4613.

Claims (18)

WHAT IS CLAIMED IS:
1. A compound of formula 3 or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2; s is 0, 1, or 2; R3, which occurs at every open valency of a pyridinyl moiety depicted in formula 3, each time taken is independently selected from the group consisting of en, hydroxyl, amino, C1-8 alkylamino, cyano, halo, C1-6 alkyl, and C1-4 ; R4 is ed from the group consisting of hydrogen, cyano, halo, methyl, ethyl, methoxy, and trifluoromethyl; R5 is selected from the group consisting of the formulae G is carbon; A is selected from the group consisting of N, O, S, CR6 and NR6; E is selected from the group consisting of N, O, S, and CR6; provided that only one of A and E can be O or S; or G is N and A and E are CR6; or G and A are N and E is CR6; or G, A, and E are N; R6, which is at every open valency in the formulae for R5, each time taken is independently selected from the group consisting of hydrogen, cyano, halo, C3-8 cycloalkyl, C1-6 alkyl, C1-4 alkoxy, and oromethyl; R7 is ed from the group consisting of cyano and cyanomethyl; R8, which occurs at every open valency of a ring moiety depicted in formula 3, each time taken is independently selected from the group consisting of hydrogen, cyano, halo, C1-4 alkyl, C1-4 alkoxy, and trifluoromethyl; and R9 is ed from the group consisting of hydrogen, C1-6 alkyl optionally substituted with 1 to 3 fluoro, and C3-8 cycloalkyl.
2. A compound or pharmaceutically acceptable salt thereof ing to claim 1, wherein R5 is
3. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 or 2, wherein R9 is C1-6 alkyl.
4. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, n s is 1 and q is 1.
5. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein each R8 is hydrogen.
6. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, n one of R8 is C1-4 alkyl and each other R8 is hydrogen.
7. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein one of R8 is methyl and each other R8 is hydrogen.
8. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein each R3 is hydrogen and R4 is hydrogen.
9. A compound according to claim 1, which is selected from the group of compounds ting of: 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; ydroxy(5-(4-propylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl) methylbenzonitrile; 4-(5-hydroxy(5-(4-methyl-1,4-diazepanecarbonyl)pyridinyl)-1H-pyrazolyl) methylbenzonitrile; 4-(1-(5-(4-(tert-butyl)piperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; 4-(1-(5-(6,6-difluoromethyl-1,4-diazepanecarbonyl)pyridinyl)hydroxy-1H- pyrazolyl)methylbenzonitrile; 5-(4-ethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)fluoro methylbenzonitrile; 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)fluoro methylbenzonitrile; 4-(1-(5-(4-cyclopropylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; 4-(1-(5-(4-cyclopropylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; 4-(1-(5-(4-ethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)-2,3- dimethylbenzonitrile; 4-(1-(5-(4-cyclopropylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)-2,3- dimethylbenzonitrile; 4-(1-(5-(4-(2,2-difluoroethyl)piperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)methylbenzonitrile; 4-(5-hydroxy(5-(4-(2,2,2-trifluoroethyl)piperazinecarbonyl)pyridinyl)-1H-pyrazol yl)methylbenzonitrile; 2-fluoro(5-hydroxy(5-(4-methylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl)- 3-methylbenzonitrile; 5-(4-cyclopropyl-1,4-diazepanecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl)- 2-fluoromethylbenzonitrile; (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; 4-(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; (S)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; 4-(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; 5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; (R)fluoro(5-hydroxy(5-(4-isopropylmethylpiperazinecarbonyl)pyridinyl)- azolyl)methylbenzonitrile; 2-fluoro(5-hydroxy(5-(4-isopropylmethylpiperazinecarbonyl)pyridinyl)-1H- pyrazolyl)methylbenzonitrile; (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; (S)fluoro(5-hydroxy(5-(4-isopropylmethylpiperazinecarbonyl)pyridinyl)- 1H-pyrazolyl)methylbenzonitrile; (R)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; 4-(5-hydroxy(5-(4-(pentanyl)piperazinecarbonyl)pyridinyl)-1H-pyrazolyl) methylbenzonitrile; (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)methylbenzonitrile; 4-(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; (S)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; 4-(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; 4-(1-(5-(4-cyclobutylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; (S)(5-hydroxy(5-(3-methylpropylpiperazinecarbonyl)pyridinyl)-1H-pyrazol yl)methylbenzonitrile; (R)(5-hydroxy(5-(3-methylpropylpiperazinecarbonyl)pyridinyl)-1H-pyrazol methylbenzonitrile; 4-(5-hydroxy(5-(3-methylpropylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl)- 3-methylbenzonitrile; (R)(1-(5-(4-cyclopropylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H- pyrazolyl)methylbenzonitrile; 4-(1-(5-(4-cyclopropylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol- 4-yl)methylbenzonitrile; ydroxy(5-(3,3,4-trimethylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl) methylbenzonitrile; 5-(4-ethyl-3,3-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)methylbenzonitrile; (R)(5-hydroxy(5-(4-isopropylmethylpiperazinecarbonyl)pyridinyl)-1H- pyrazolyl)methylbenzonitrile; ydroxy(5-(4-isopropylmethylpiperazinecarbonyl)pyridinyl)-1H-pyrazol yl)methylbenzonitrile; (R)(1-(5-(2,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; 4-(1-(5-(2,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)methylbenzonitrile; (S)(1-(5-(4-cyclopropylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H- pyrazolyl)methylbenzonitrile; (S)(1-(5-(2,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; (R)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) benzonitrile; (S)(5-hydroxy(5-(4-isopropylmethylpiperazinecarbonyl)pyridinyl)-1H- pyrazolyl)methylbenzonitrile; (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; 4-(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; 2-fluoro(5-hydroxy(5-(4-methylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl)- 5-methylbenzonitrile; (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; (S)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; (R)(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; 4-(1-(5-(3,4-dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; 4-(5-hydroxy(5-(4-methylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl) methylbenzonitrile; 4-(1-(5-(4-cyclopropylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; 4-(5-hydroxy(5-(4-propylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl) benzonitrile; 4-(5-hydroxy(5-(4-propyl-1,4-diazepanecarbonyl)pyridinyl)-1H-pyrazolyl) methylbenzonitrile; 4-(5-hydroxy(4-methyl(4-methylpiperazinecarbonyl)pyridinyl)-1H-pyrazol yl)benzonitrile; (S)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)fluoromethylbenzonitrile; 4-(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) fluoromethylbenzonitrile; (R)(1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)methylbenzonitrile; (1-(5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazol yl)methylbenzonitrile; and 5-(4-ethylmethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile; or a pharmaceutically able salt of any one of the above-mentioned compounds.
10. The compound according to clam 1, which is 4-(1-(5-(4-ethylpiperazine carbonyl)pyridinyl)hydroxy-1H-pyrazolyl)methylbenzonitrile or a pharmaceutically able salt thereof.
11. The compound according to clam 1, which is 4-(5-hydroxy(5-(4- methylpiperazinecarbonyl)pyridinyl)-1H-pyrazolyl)methylbenzonitrile or a pharmaceutically acceptable salt thereof.
12. The compound according to clam 1, which is 4-(1-(5-(4-(2,2- difluoroethyl)piperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile or a pharmaceutically acceptable salt thereof.
13. The compound according to clam 1, which is (S)(1-(5-(3,4- dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile or a pharmaceutically acceptable salt thereof.
14. The compound according to clam 1, which is (R)(1-(5-(2,4- dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile or a pharmaceutically acceptable salt thereof.
15. The nd ing to clam 1, which is (R)(1-(5-(3,4- dimethylpiperazinecarbonyl)pyridinyl)hydroxy-1H-pyrazolyl) methylbenzonitrile or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition sing a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 15 and a pharmaceutically acceptable excipient.
17. Use of a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 15 in the preparation of a medicament for the treatment of a condition associated with hypoxia inducible factor.
18. The compound according to claim 1, substantially as herein described with reference to any one of the Examples thereof.
NZ711522A 2013-03-29 2014-03-26 6-(5-hydroxy-1h-pyrazol-1-yl)nicotinamide derivatives and their use as phd inhibitors NZ711522B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361806806P 2013-03-29 2013-03-29
US61/806,806 2013-03-29
US201361916715P 2013-12-16 2013-12-16
US61/916,715 2013-12-16
PCT/US2014/031918 WO2014160810A1 (en) 2013-03-29 2014-03-26 6-(5-hydroxy-1h-pyrazol-1-yl)nicotinamide derivatives and their use as phd inhibitors

Publications (2)

Publication Number Publication Date
NZ711522A NZ711522A (en) 2021-02-26
NZ711522B2 true NZ711522B2 (en) 2021-05-27

Family

ID=

Similar Documents

Publication Publication Date Title
US10407409B2 (en) 6-(5-hydroxy-1H-pyrazol-1-yl)nicotinamide inhibitors of PHD
US8987273B2 (en) Substituted imidazo[1,2-B]pyridazines
CN102131809A (en) Tri-cyclic pyrazolopyridine kinase inhibitors
JP2006507253A (en) Imidazopyrazine as a cyclin-dependent kinase inhibitor
CN102131808A (en) Pyrazolopyridine kinase inhibitors
WO2021224291A1 (en) Tricyclic heterocycles useful as tead binders
AU2021312027A1 (en) Tricyclic heterocycles
IL292485A (en) Pyridylpyridone compounds
CN102159546A (en) Aminopyridine kinase inhibitors
JP2023524863A (en) tricyclic heterocycle
CA3158169A1 (en) Benzodiazepine derivatives for treating a respiratory syncytial virus (rsv) infection
NZ711522B2 (en) 6-(5-hydroxy-1h-pyrazol-1-yl)nicotinamide derivatives and their use as phd inhibitors
AU2022234998A1 (en) Pyridopyrimidine compounds and applications thereof
AU2022378910A1 (en) Tricyclic heterocycles
CN116655636A (en) Five-membered and six-membered heterocyclic compounds and application thereof as protein kinase inhibitors
EP4334319A1 (en) 2,8-dihydropyrazolo[3,4-b]indole derivatives for use in the treatment of cancer
JP2023518285A (en) Condensed Pyridine Derivatives Substituted by Amide Functionality as ACSS2 Inhibitors