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WO2025106780A1 - Rxfp1 receptor agonists - Google Patents

Rxfp1 receptor agonists Download PDF

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Publication number
WO2025106780A1
WO2025106780A1 PCT/US2024/056074 US2024056074W WO2025106780A1 WO 2025106780 A1 WO2025106780 A1 WO 2025106780A1 US 2024056074 W US2024056074 W US 2024056074W WO 2025106780 A1 WO2025106780 A1 WO 2025106780A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
disease
compound according
group
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Pending
Application number
PCT/US2024/056074
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French (fr)
Inventor
Erin Anderson
Donald Raymond CALDWELL JR.
Todd Fields
Autumn Rose FLYNN
Jeffry B. FRANCISKOVICH
Jason Eric Lamar
Maria Cynthia MARTIN
Christopher Mayne
Elizabeth A. MCFADDIN
Andrew Metcalf
Ganesh MURHADE
Zhicheng SUN
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Eli Lilly and Co
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Eli Lilly and Co
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Publication of WO2025106780A1 publication Critical patent/WO2025106780A1/en
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    • 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
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to small molecule RXFP1 agonists and uses thereof.
  • Human relaxin-2 (relaxin) is an insulin-like peptide known to regulate cardiovascular, renal, and pulmonary adaptations during pregnancy.
  • relaxin has several limitations such as poor oral bioavailability, a short half- life, and there are high costs of production, and storage.
  • relaxin family peptide receptor- 1 (RXFP1) peptide agonists require subcutaneous/intravenous administration.
  • RXFP1 agonists there remains a need to provide alternative, small molecule RXFP1 agonists.
  • RXFP1 agonists that are useful for treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
  • RXFP1 receptor agonists that exhibit better pharmacokinetic/ pharmacodynamic properties.
  • RXFP1 receptor agonists that exhibit efficacy with reduced or minimized untoward or undesired effects.
  • RXFP2 relaxin family peptide receptor-2
  • Gi is -C(Ra)- or -N-;
  • G2 is -C(Rb)- or -N-;
  • Ring A is a group of the formula wherein are unsubstituted or substituted with one or more of halogen or C1-3 alkoxy;
  • -X- is -NH- or -S-;
  • Ra is -H or -F
  • Rb is -H or -F
  • Ri is C1-3 alkoxy or cyclopropoxy, wherein C1-3 alkoxy is unsubstituted or substituted with one or more halogens;
  • R2 is a group of the formula
  • R 2 a is one or more of C1-3 alkyl, -OH, -N(R) 2 , oxo, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1 , 1 -dioxide.
  • the C1-3 alkyl is unsubstituted or substituted with one or more of -OH, oxo, or morpholine, wherein the morpholine is unsubstituted or substituted with an C1-3 alkylene bridge, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with a C1-3 alkyl, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; each R is independently a C1-3 alkyl;
  • -G3a- is -CHR 2 b- or -CH2-O-CH2-;
  • -Y- is a C 1-3 alky lene
  • R 2 b is -COOH
  • R 2 C is -H, or halogen
  • R3 is a group of the formula:
  • -G4- is -CH- or -N-;
  • R3 at each occurrence, is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
  • Rsb. at each occurrence is independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C1-4 alkyl;
  • R3C at each occurrence, is independently -H or halogen
  • R3d is -H, halogen. C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyd, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
  • R4 is -H, -CN, or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
  • Gi is -C(Ra)- or -N-;
  • G? is -C(Rb)- or -N-;
  • Ring A is a group of the formula wherein are unsubstituted or substituted with one or more of halogen or C1-3 alkoxy;
  • -X- is -NH- or -S-;
  • Ra is -H or halogen
  • Rb is -H or halogen
  • Ri is C1-3 alkoxy or cyclopropoxy, wherein C1-3 alkoxy is unsubstituted or substituted with one or more halogens;
  • R2 is a group of the formula
  • R2a is one or more of C1-3 alkyl, -OH, oxo, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1- dioxide, wherein the C1-3 alkyl is unsubstituted or substituted with one or more of -OH, oxo, or morpholine, wherein the morpholine is unsubstituted or substituted with an C1-3 alkylene badge, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with a C1-3 alky
  • the methods include administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • compounds of Formula I, and pharmaceutically acceptable salts thereof, for use in therapy are also provided herein.
  • compounds of Formula I, and pharmaceutically acceptable salts thereof for use in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
  • Also additionally provided herein is the use of compounds of Formula I, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
  • Novel RXFP1 receptor agonists are described herein. These new compounds could address some or all of the needs noted above for novel RXFP1 receptor agonists in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
  • Gi is -C(Ra)- or -N-;
  • G2 is -C(Rb)- or -N-;
  • Ring A is a group of the formula d or substituted with one or more of halogen or C1-3 alkoxy;
  • -X- is -NH- or -S-;
  • Ra is -H or halogen
  • Rb is -H or halogen
  • Ri is C1-3 alkoxy or cyclopropoxy, wherein C1-3 alkoxy is unsubstituted or substituted with one or more halogens;
  • R2 is a group of the formula
  • R2a is C1-3 alkyl, -OH, oxo. -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1 -dioxide.
  • the C1-3 alkyl is unsubstituted or substituted with one or more of -OH, oxo, or morpholine, wherein the morpholine is unsubstituted or substituted with an C1-3 alkylene bridge, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with a C1-3 alkyl, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; each R is independently a C1-3 alky l; is -CHR2b-, or -CH2-O-CH2-;
  • -Y- is a C1-3 alkylene
  • R 2 b is -COOH
  • R 2C is -H. or halogen
  • R3 is a group of the formula:
  • -G4- is -CH-, or -N-;
  • R3a is -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
  • R3b is -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN or C1-4 alky l;
  • R3c at each occurrence, is independently -H, or halogen
  • Rsa is -H, halogen, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyd, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
  • R4 is -H, -CN, or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
  • Ri is C1-3 alkoxy; or a pharmaceutically acceptable salt thereof.
  • R1 is C1-3 alkoxy; wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, pyrazine, thiomorpholine 1,1 -di oxide, wherein the pyrimidine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with a C1-3 alkyl, and wherein the pyrrole is unsubstituted or substituted with -OH; is -H, or halogen;
  • Rsa. at each occurrence is independently -H, halogen, -SF5, -SO2CF3. -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
  • R4 is -H or C1-3 alky l, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
  • Ring A is a group of the formula
  • Ra is -H or -F
  • Rb is -H or -F ;
  • R1 is C1-3 alkoxy
  • R.2 is a group of the formula wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1 -dioxi de, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
  • Rsa is -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
  • Rad is -H, halogen, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
  • R4 is -H; or a pharmaceutically acceptable salt thereof.
  • Ra is -H or -F
  • Rb is -H or -F
  • R1 is C1-3 alkoxy
  • R2 is a group of the formula R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1- dioxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
  • R 3 is a group of the formula: ; SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C 1-3 alkoxy are unsubstituted or substituted with one or more halogens; each R 3c is independently -H, or -F; and R 4 is -H; or a pharmaceutically acceptable salt thereof.
  • Ring A is selected from the group consisting of , or a pharmaceutically acceptable salt thereof. . e co pou according to any one of aspects 1-3, wherein Ring A is a group of the formula a pharmaceutically acceptable salt thereof. 8. e compoun accor ng to any one of aspects 1-3, wherein Ring A is a group of the formula r a pharmaceutically 9. The compound according to aspect 8, wherein Ring A is a group of the formula pharmaceutically acceptable salt thereof. rding to aspect 1 or 2, wherein Ring A is a group of the formula armaceutically acceptable salt thereof.
  • R2a is selected from the group consisting of , or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound as defined in any one of aspects 1-46. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a method of treating cardiovascular, pulmonary' and/or renal conditions, diseases and/or disorders in an individual comprising administering to the individual an effective amount of a compound of any one of aspects 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 47.
  • condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
  • cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
  • condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder.
  • pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary’ disease (COPD).
  • COPD chronic obstructive pulmonary’ disease
  • condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
  • kidney disease, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
  • a compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
  • a compound for use according to claim 58, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
  • a compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a pulmonary' condition, disease, or disorder.
  • a compound for use according to claim 60, wherein the pulmonary' condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
  • a compound for use according to claim 62, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
  • a compound for use of aspect 57, wherein the disease or disorder to be treated is a cardiovascular condition, disease, or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary' artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy
  • a compound for use of aspect 57, wherein the disease or disorder to be treated is a pulmonary condition, disease, or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a compound for use of aspect 57, wherein the disease or disorder to be treated is a renal condition, disease, or disorder selected from acute kidney disease, chronic kidney disease or diabetes nephropathy.
  • disease or disorder to be treated is a cardiovascular condition, disease, or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
  • disease or disorder to be treated is a pulmonary condition, disease, or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • disease or disorder to be treated is a renal condition, disease, or disorder selected from acute kidney disease, chronic kidney disease or diabetes nephropathy.
  • Ring A is a group of the formula wherein is unsubstituted or substituted with halogen; wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, pyrazine, thiomorpholine 1,1 -di oxide, wherein the pyrimidine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with a C1-3 alkyl, and wherein the pyrrole is unsubstituted or substituted with -OH; R?a.
  • each occurrence is independently -H, halogen, -SO2CF3, -SCF-3S, F C51,-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
  • R4 is -H or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
  • Ring A is a group of the formula
  • Ra is -H or -F
  • Rb is -H or -F ;
  • R2 is a group of the formula wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1 -di oxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
  • Rs a is -H. halogen, -SF5, -SO2CF3. -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; each Rsc is independently -H, or -F;
  • R3d is -H. halogen, C1-4 alkyl, or C1-3 alkoxy, w-herein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
  • R4 is -H; or a pharmaceutically acceptable salt thereof.
  • the compound of the formula is:
  • Ring A is a group of the formula
  • Ra is -H or -F
  • Rb is -H or -F
  • R2 is a group of the formula
  • R2a is -OH, -N(R) 2 , oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1- dioxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
  • R3 is a group of the formula:
  • Rsa is -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4alkyl, or Ci-s alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; or a pharmaceutically acceptable salt thereof.
  • Ring A is selected from the group consisting of , or a pharmaceutically acceptable salt thereof.
  • the compound is of the formula is substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.
  • Ring A is selected from the group consisting of , or a pharmaceutically acceptable salt thereof.
  • the compound is of the formula pharmaceutically acceptable salt thereof. odiment, the compound is of the formula pharmaceutically acceptable salt thereof.
  • Gi is -N-. or a pharmaceutically acceptable salt thereof.
  • Gi is -C(R a )-, or a pharmaceutically acceptable salt thereof.
  • Ra is -H, or a pharmaceutically acceptable salt thereof.
  • G2 is -N-, or a pharmaceutically acceptable salt thereof.
  • G2 is -C(Rb)-, or a pharmaceutically acceptable salt thereof.
  • Rb is -H, or a pharmaceutically acceptable salt thereof.
  • Ri is methoxy, or a pharmaceutically acceptable salt thereof.
  • R3 is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  • R3 is selected from the group consisting of , or a pharmaceutically acceptable salt thereof.
  • R3 is a group of the formula , or a pharmaceutically acceptable salt thereof.
  • Rsa is tert-buty l, -SF5, -SO2CF3, or -SCF3, and R3b is -H or -F, or a pharmaceutically acceptable salt thereof.
  • R? a is -F, -Cl, -Br. difluoromethyl, difluorochloromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy
  • R3b is -H, -F, -Cl, -Br, trifluoromethyl, -CN, or methyl, or a pharmaceutically acceptable salt thereof.
  • Ra a and Rsb are methoxy, or a pharmaceutically acceptable salt thereof.
  • R2 is a group of the formula or a pharmaceutically acceptable salt thereof.
  • R2a is selected from the group consisting of pharmaceutically acceptable salt thereof.
  • R2 is selected from the group consisting of pharmaceutically acceptable salt thereof.
  • R2 is selected from the group consisting of a pharmaceutically acceptable salt thereof.
  • R2 is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  • R2 is selected from the group consisting of , or a pharmaceutically acceptable salt thereof. -f>2- or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition of the compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
  • the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery 7 disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
  • the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a pulmonary 7 condition, disease, or disorder.
  • the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
  • the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in therapy.
  • a compound of Formula I for use in the treatment of cardiovascular, pulmonary 7 , and/or renal conditions, diseases, and/or disorders.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
  • the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder.
  • pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
  • a method of exhibiting agonist activity in a RXFP1 receptor in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.
  • the isotopic derivative can be prepared using any of a variety of art- recognized techniques.
  • the isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes, and/or in the examples described herein or a pharmaceutically acceptable salt thereof, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compound is a deuterium labeled compound of any one of the compounds described herein and pharmaceutically acceptable salts thereof.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • an atom is designated specifically as “H” or “hydrogen”
  • the atom is understood to have hydrogen at its natural abundance isotopic composition.
  • an atom is designated specifically as “D” or “deuterium”
  • the atom is understood to have deuterium at an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound is selected from
  • compositions comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, examples of which include, but are not limited to, the compounds disclosed herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof.
  • methods of treating cardiovascular conditions, diseases, and/or disorders comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof.
  • methods of treating pulmonary 7 conditions, diseases, and/or disorders comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof.
  • methods of treating renal conditions, diseases, and/or disorders comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof.
  • a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of cardiovascular, conditions, diseases, and/or disorders. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary conditions, diseases, and/or disorders Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of renal conditions, diseases, and/or disorders.
  • the cardiovascular conditions, diseases, and disorders include, but are not limited to, acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, and ventricular hypertrophy.
  • the pulmonary conditions, diseases, and disorders include, but are not limited to, pulmonary hypertension and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the renal conditions, diseases, and disorders include, but are not limited to, acute kidney disease, chronic kidney disease and diabetes nephropathy.
  • the methods also can include a step of administering the Compound of formula I, or a pharmaceutically acceptable salt thereof in combination with an effective amount of at least one additional therapeutic agent.
  • the standard of care for many of the conditions/diseases/disorders herein includes an anticoagulant, an ACE inhibitor, an ARB.
  • an ARNI an ARNI, a P-blocker, a diuretic, digitalis, digoxin, hydralazine/isorbide dinitrate, a MRA or other aldosterone antagonist, a SGLT2 inhibitor, a statin, and/or an anti-glycemic agent, as well as other therapeutic agents to control comorbidities, including, but not limited to, high cholesterol, high blood pressure, atrial fibrillation, diabetes and obesity.
  • the additional therapeutic agent can be administered simultaneously, separately or sequentially with the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with at least one additional therapeutic agent in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
  • Additional therapeutic agents include, but are not limited to, an anticoagulant, an ACE inhibitor, an ARB, an ARNI, a P-blocker, a diuretic, digitalis, digoxin, hydralazine/isorbide dinitrate, a MRA or other aldosterone antagonist, a SGLT2 inhibitor, a statin, and/or an anti-glycemic agent, as well as other therapeutic agents to control comorbidities, including, but not limited to, high cholesterol, high blood pressure, atrial fibrillation and diabetes.
  • the methods or uses herein can include the steps described herein, and these maybe be, but not necessarily, carried out in the sequence as described. Other sequences, however, also are conceivable. Moreover, individual or multiple steps may be carried out either in parallel, and/or overlapping in time, and/or individually or in multiply repeated steps. Furthermore, the methods may include additional, unspecified steps.
  • Such methods or uses therefore can include selecting an individual having a cardiovascular condition, disease or disorder or who is predisposed to the same.
  • the methods can include selecting an individual having a pulmonary condition, disease or disorder or who is predisposed to the same.
  • the methods can include selecting an individual having a renal condition, disease or disorder or who is predisposed to the same.
  • the methods can include selecting an individual who is diabetic, hypertensive with kidney function impairment, and/or obese.
  • the individual in need is a diabetic, hypertensive with kidney function impairment, and/or obese.
  • the methods or uses also may be combined with diet and exercise, and/or may be combined with additional therapeutic agents other than those discussed above.
  • pharmaceutically acceptable salt refers to a salt of a compound considered to be acceptable for clinical and/or veterinary use.
  • pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley- VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
  • compositions containing the compounds of Formula I, or a pharmaceutically acceptable salt thereof, as described herein may be prepared using pharmaceutically acceptable additives.
  • pharmaceutically acceptable additive(s) refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the composition or formulation and not deleterious to the patient. Examples of pharmaceutical compositions and processes for their preparation can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22nd Ed.. Mack Publishing Co., 2012.
  • Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose, alginates, gelatin, and polyvinyl-pyrrolidone; kaolin and bentonite; and polyethyl glycols.
  • “effective amount” means an amount or dose of a compound of formula I, or a pharmaceutically acceptable salt thereof that, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment (z.e., may produce a clinically measurable difference in a condition of the individual such as, for example, increased angiogenesis, increased vascular compliance, increased cardiovascular blood flow, increased hepatic blood flow, increased pulmonary blood flow, increased renal blood flow, increased glomerular filtration rate, decreased blood pressure, decreased (or prevented) inflammation and/or reduced (or prevented) fibrosis in the heart, kidney, liver or lung).
  • an effective amount can be readily determined by one of skill in the art by using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered, including, but not limited to, the species of mammal, its size, age and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual, the particular Compound of Formula I, or a pharmaceutically acceptable salt thereof administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances.
  • treating means managing and caring for an individual having a condition, disease, disorder or symptom for which Compound of formula I, or a pharmaceutically acceptable salt thereof administration is indicated for the purpose of attenuating, restraining, reversing, slowing or stopping progression or severity of the condition, disease, disorder and/or symptom. Treating includes administering a Compound of formula I, or a pharmaceutically acceptable salt thereof herein or composition containing a Compound of formula I, or a pharmaceutically acceptable salt thereof herein to the individual to prevent the onset of symptoms or complications, alleviating the symptoms or complications, or eliminating the condition, disease, disorder or symptom.
  • Treating includes administering a Compound of formula I, or a pharmaceutically acceptable salt thereof or composition containing a Compound of formula I, or a pharmaceutically acceptable salt thereof herein to the individual to result in such as, for example, increased angiogenesis, increased vascular compliance, increased cardiovascular blood flow, increased hepatic blood flow, increased pulmonary blood flow, increased renal blood flow, increased glomerular filtration rate, decreased blood pressure, decreased (or prevented) inflammation and/or reduced (or prevented) fibrosis in the heart, kidney, liver or lung).
  • the individual to be treated is a mammal, especially a human.
  • “individual,” “patient” and “subject” are used interchangeably and mean a mammal, especially a human.
  • the individual is further characterized with a condition, disease, disorder and/or symptom that would benefit from administering a Compound of formula I, or a pharmaceutically acceptable salt thereof herein.
  • halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., “C1-4 alkyl” or “C1-3 alkyl.”
  • alkyls include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso- butyl.
  • alkylene means saturated linear or branched-chain bivalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., “C 1-3 alkylene.”
  • alkylenes include, but are not limited to, methylene, ethylene, propylene, 1- propylene, and isopropylene.
  • alkoxy refers to an alkyl substituent to which an oxygen radical is attached, e.g. “C1-3 alkoxy”.
  • Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-propoxy, and isopropoxy.
  • ACN refers to acetonitrile
  • AcOH refers to acetic acid
  • BOC or “Boc” refers to tert-butoxycarbonyl
  • Boc 2 O refers to di-tert-butyl decarbonate
  • BOP-Cl refers to bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • CH 3 ONa refers to sodium methoxide
  • DCE refers to 1,2-dichloroethane
  • DEE refers to diethyl ether
  • DiPEA refers to N,N-diisopropylethylamine
  • DCM refers to dichloromethane
  • DMF refers to N,N-dimethylformamide
  • EtOAc refers to ethyl acetate
  • ES-MS refers to electrospray mass spectrometry
  • alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • C1-4 alkyl refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one, two, three, or four carbon atoms. Examples of C1-4 alkyl include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-buty l, and 2- methyl-2-propyl.
  • C1-3 alkyl refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one, two, or three carbon atoms.
  • Examples of C1-3 alkyd include, but are not limited to, methyl, ethyl, 1 -propyl, or isopropy l.
  • cycloalkyd means a saturated cyclic hydrocarbon group containing the indicated number of carbon atoms.
  • C3-6 cycloalkyl refers to a saturated cyclic hydrocarbon group having three, four, five or six carbon atoms. Examples of C3-6 cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyd, and cyclohexyl.
  • halogen refers to F (fluoro), Cl (chloro), Br (bromo), and I (iodo).
  • oxo refers to the substitution of CH2 with O to form C(O).
  • Individual isomers, enantiomers, diastereomers, and atropisomers may be separated or resolved at any convenient point in the synthesis of compounds listed below, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al.. “Enantiomers, Racemates, and Resolutions” , John Wiley and Sons. Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994).
  • Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form the acid addition salt. Salts can also form simultaneously upon deprotection of a nitrogen or oxygen, z.e., removing the protecting group. Examples, reactions and conditions for salt formation can be found in Gould, P.L., “Salt selection for basic drugs,'’ International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin. R.J., et al.
  • the compounds of the present invention, or salts thereof, may be prepared by a variety 7 of procedures, some of which are illustrated in the Schemes, Preparations, and Examples below.
  • the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different routes, to prepare compounds or salts of the present invention.
  • the products of each step in the Preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • certain intermediates described in the following preparations may contain one or more nitrogen protecting groups. It is understood that protecting groups may be varied as appreciated by one of skill in the art depending on the particular reaction conditions and the particular transformations to be performed. One skilled in the art will appreciate that a deprotected amine can be functionalized via different methodologies known in the literature. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example "Greene's Protective Groups in Organic Synthesis", Fifth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2014).
  • Ri, R2, R3, R4, Gi, G2, X, and A are as defined for Formula I.
  • Scheme 1 depicts the preparation of compounds of the present invention beginning with a suitable amine 1 and carboxylic acid 2.
  • the PG moiety on the amine of the carboxylic acid 2 is a standard amine protecting group well known to the skilled artisan, including carbamate and amide protecting groups.
  • the carboxylic acid 2 is reacted with the amine 1 under standard amide coupling conditions to prepare the amide 3 in Step 1.
  • Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of the carboxylic acid 2 and a desired amine 1 in a suitable solvent, such as ACN, with an appropriate coupling reagent, such as TCFH or PPACA.
  • the intermediate amine 4 is obtained by reacting a suitable acid, such as TFA, to a stirring solution of the amide 3 in an appropriate solvent, such as DCM, at RT for at least 18 h.
  • a suitable acid 5 (“W” representing a halogen) under amide coupling conditions known to a skilled person as illustrated in Step 3.
  • a suitable coupling reagent such as oxalyl chloride
  • DMF dimethyl methacrylate
  • the amine 4 is added, followed by an appropriate organic base, such as DiPEA, and the reaction mixture is further stirred at RT for at least 1.5 h.
  • the intermediate 6 is reacted with a suitable amine 7 under nucleophilic aromatic substitution conditions well know n to the skilled artisan to give 8.
  • Suitable nucleophilic aromatic substitution conditions include reacting a compound bearing an appropriate halogen W on an aromatic moiety, such as fluorine or chlorine, with a suitable nucleophilic reactant such as an amine.
  • a suitable organic base such as DiPEA
  • an appropriate organic solvent such as NMP or DMF
  • /iTsOH can be used in the place of DiPEA using an organic solvent such as IP A, stirring for at least 2 h at 80 °C.
  • Another alternative is to couple intermediate 6 with amine 7 under transition metal catalyzed coupling conditions, for example using dichloro[bis(2- (diphenylphosphino)phenyl)ether]palladium(II) and an inorganic base such as Na2CCh in an organic solvent, such as 1,4-dioxane, at elevated temperature, e.g. stirring for at least 16 h at 80 °r
  • the amine 13, 14 and 15 of the present invention can be prepared starting with the appropriate amine 9.
  • the PG moiety on the amine 9 is a standard amine protecting group well known to the skilled artisan, including carbamate and amide protecting groups.
  • Step 1 the amine 9 is reacted with l-bromo-2-(2-bromoethoxy)ethane under standard nucleophilic substitution conditions and include using Nal in presence of a suitable base, such as K2CO3, in an appropriate organic solvent, such as EtOH, at 95 °C at least.
  • intermediate 11 is generated by reacting the amine 9 with (vinylsulfonyl)ethene in an appropriate organic solvent, such as EtOH, under reflux conditions.
  • Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of 2-(2-chloroethoxy)acetic and the amine 9 in a suitable solvent, such as DMF, with an appropriate coupling reagent, such as HATU, in the presence of a suitable organic base, such as DiPEA, with stirring at RT for at least 16 h.
  • a suitable solvent such as DMF
  • an appropriate coupling reagent such as HATU
  • DiPEA a suitable organic base
  • the resulting intermediate is treated under standard nucleophilic substitution conditions in presence of a suitable base, such as K2CO3, in an appropriate organic solvent, such as DMF, at 80 °C at least.
  • PG moiety' is a BOC group
  • deprotection of intermediates 10, 11 and 12 is achieved under acidic conditions standard to the art.
  • the amines 13, 14 and 15 are obtained by adding a suitable acid, such as TFA. to a stirring solution of intermediate 10, 11, and 12, respectively in an appropriate solvent, such as DCM, at RT for at least 18 h.
  • Scheme 3 represents an alternative route to prepare the intermediate 4.
  • the suitable acyl chloride 16 is reacted with the appropriate amine 1 under standard amide coupling conditions with a suitable organic base, such as DiPEA, in an appropriate organic solvent, such as DCM, at RT.
  • a suitable organic base such as DiPEA
  • DCM organic solvent
  • the resulting amide 17 is treated under reductive conditions and includes reacting the amide 17 with zinc and NH4CI in a suitable organic solvent, such as MeOH. at 50 °C at least.
  • Scheme 4 depicts the preparation of compounds of the present invention starting with suitable ary l halide 18 (wherein "W” is a halogen).
  • Intermediate 18 is reacted with a suitable amine 7 under nucleophilic aromatic substitution conditions well known to the skilled person, in the presence of a suitable organic base, such as DiPEA, in an appropriate organic solvent, such as NMP or DMF, at 80 °C at least to give 19 in Step 1.
  • a suitable organic base such as DiPEA
  • an appropriate organic solvent such as NMP or DMF
  • the carboxylic acid 20 can be prepared from the suitable ester 19 under standard saponification conditions using an appropriate strong inorganic base, such as NaOH or LiOH. in a mixture of suitable organic solvents, such as THF or EtOH, with stirring at 60 °C for at least 1.5 h.
  • the carboxylic acid intermediate 20 is reacted with a suitable amine 21 under amide coupling conditions well known to the skilled artisan.
  • a suitable coupling reagent such as oxalyl chloride, is introduced to a stirring solution of the carboxylic acid 20 at 0 °C, followed by DMF added dropwise.
  • the amine 21 is added, followed by an appropriate organic base, such as DiPEA, and the reaction mixture is further stirred at RT for at least 1.5 h.
  • the ester 22 is treated under standard saponification conditions using an appropriate strong inorganic base, such as NaOH or LiOH, in a mixture of suitable organic solvents, such as THF or EtOH.
  • Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of the carboxylic acid 23 and a desired amine in a suitable solvent, such as ACN, DMF or DCM, with an appropriate coupling reagent, such as TCFH, HATU or PPACA, in the presence of a suitable organic base, such as DiPEA, TEA or NMI, with stirring at RT for at least 35 min.
  • a suitable solvent such as ACN, DMF or DCM
  • an appropriate coupling reagent such as TCFH, HATU or PPACA
  • Scheme 5 depicts the preparation of compounds of the present invention starting with suitable carboxylic acid 5.
  • the carboxylic acid 5 is reacted with a suitable amine 21 under amide coupling conditions well known to the skilled artisan.
  • a suitable coupling reagent such as oxalyl chloride, is introduced to a stirring solution of the carboxylic acid 5 at 0 °C, followed by DMF added dropwise.
  • the reaction mixture is allowed to stir at RT for at least 30 min, the amine 21 is added, followed by an appropriate organic base, such as DiPEA, and the reaction mixture is further stirred at RT for at least 1.5 h.
  • Aryl halide intermediate 24 (wherein “W” is a halogen and "Ci?
  • a suitable amine 7 under standard nucleophilic aromatic substitution conditions in presence of a suitable organic base, such as DiPEA, in an appropriate organic solvent, such as NMP or DMF, at 80 °C at least to give 22 in Step 2.
  • the carboxylic acid 23 can be prepared from the suitable ester 22 under standard saponification conditions using an appropriate strong inorganic base, such as NaOH or LiOH, in a mixture of suitable organic solvents, such as THF or EtOH, with stirring at 60 °C for at least E5 h.
  • the carboxylic acid 23 is reacted with a suitable amine 1 under standard amide coupling conditions to prepare the amide 8 in Step 4.
  • Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of the carboxylic acid 23 and a desired amine in a suitable solvent, such as ACN, with an appropriate coupling reagent, such as TCFH or PPACA, in the presence of a suitable organic base, such as DiPEA or NMI, with stirring at RT for at least 35 min.
  • a suitable solvent such as ACN
  • an appropriate coupling reagent such as TCFH or PPACA
  • a suitable organic base such as DiPEA or NMI
  • Scheme 6 shows the preparation of compounds of the present invention starting with acid intermediate 25 and amine intermediate 4 to give compound 8.
  • Suitable amide coupling conditions are well known to the skilled person and include reacting carboxylic acid 25 and amine 4 in a suitable solvent such as NMP with a coupling reagent such as PPACA and an organic base such as TEA at RT, optionally adding 4-dimethylaminopyridine and optionally heating up to 85 °C.
  • R2-group of 8 contains a carboxylic ester
  • it can be treated under standard saponification conditions using an appropriate strong inorganic base such as NaOH or LiOH in a mixture of suitable organic solvents such as THF or EtOH with stirring at 60 °C for at least 1.5 h to give the carboxylic acid.
  • Coupling of this carboxylic acid with an amine using an appropriate coupling reagent such as HATU and an organic amine base such as DIPEA gives compounds of Formula I where R2a is, for example.
  • Pentafluoro(2-fluoro-5-nitrophenyl)- ⁇ 6 -sulfane [0108] Pentafluoro(2-fluoro-5-nitrophe A mixture of pentafluoro(2-fluorophenyl)- 6 ⁇ -sulfane (5.00 g, 22.5 mmol) and sulfuric acid (18.3 g, 9.96 mL, 187 mmol) was cooled to 0 °C. Thenitric acid (14.0 g, 9.96 mL, 223 mmol) was added to the reaction mixture; after 5 min, the ice bath was removed and the reaction was stirred at 25 °C for 3 hours.
  • the reaction mixture was extracted with EtOAc (3 x 50 mL).
  • EtOAc 3 x 50 mL
  • the combined organic layers were washed with NaCl sat. aq. solution (3 x 10 mL) and dried over anhydrous Na2SC>4.
  • reaction vessel was sealed and heated at 80 °C for 18 h, then 1.3.4.6.7.8-hexahydro-2H-pyrimido[1.2-a]pyrimidine (0.200 g, 1.44 mmol) was added followed by THF (1 mL).
  • the reaction mixture was heated at 80 °C for 20 h, then combined with a reaction mixture run in the same manner on 100 pmol scale.
  • the mixture was purified by reverse-phase flash chromatography using a gradient of 10 to 100% ACN in 10 mM aq. NH4HCO3 to give the title compound (0. 135 mg, 46%) as a solid.
  • the product was the second-eluting isomer when purified by chiral chromatography [column: Phenomenex® Lux® i-Amylose-1, 30 x 150 mm, 5 pm; mobile phase: 5-20% isopropanol in heptane] .
  • the product was the second-eluting isomer when purified by chiral normal phase chromatography [column: Phenomenex® Lux® i-Amylose-3, 30 x 150 mm, 5 pm; mobile phase: 23% MeOH/CCL], c.
  • reaction mixture was stirred at 80 °C for 2 hours, then the reaction mixture was concentrated and the residue was purified directly by reverse phase column chromatography (Cl 8, 0.1% FA in water. 0.1% FA in ACN) to afford the title compound (47.8 mg, 72 pmol, 35%) as a white solid.
  • Example 52 N-(cis-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)-4-methoxy-6- ((3-morpholinobicyclo[1.1.1]pentan-1-yl)amino)pyrimidine-5-carboxamide (racemic mixture) [0212] A solution of cis-3-(4-met nobicyclo[1.1.1]pentan-1- yl)amino)pyrimidine-5-carboxamido)bicyclo[2.2.2]octane-2-carboxylic acid (racemic mixture) (95.7 mg, 0.2 mmol), HATU (110 mg) and TEA (78 ⁇ L) in DMF (1.5 mL) was stirred at 25 °C for 5 min, then 4-fluoro-3-(trifluoromethyl)aniline (41.0 mg, 0.2 mmol) was added.
  • Example 53 N-(2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-2-((3- morpholinobicyclo[1.1.1]pentan-1-yl)amino)nicotinamide [0213] To a solution of 4-methoxy- clo[1.1.1]pentan-1-yl)amino)nicotinic acid (200 mg, 626 ⁇ mol) in DCE (6.26 mL) was added oxalyl chloride (95.4 mg, 66 ⁇ L, 752 ⁇ mol), followed by dropwise addition of DMF (114 mg, 121 ⁇ L, 2 mmol).
  • racemic mixture was purified by chiral-HPLC with the following conditions (Column: Lux 5p Cellulose-2, 30*250 mm, 5.0 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NHs-MeOH)) to afford Isomer 1 (first-eluting isomer, 21.8 mg. 35%) as a white solid with 100%ee, and Isomer 2 (second-eluting isomer, 26.5 mg, 44%) as a white solid with 99.22%ee. Both isomers: 601 (M+H).
  • Example 58 4-Methoxy-N-(5-methoxy-2-((l-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan- 4yl)carbamoyl)phenyl)-6-((3-morpholinobicyclo[l.l. l]pentan-l-yl)amino)pyrimidine5- carboxamide
  • Example 86 The title compound was prepared as Example 84 using 3-oxa-6-azabicyclo[3.1 ,l]heptane hydrochloride and 4 equivalents of DIPEA. ES-MS m/z 671 (M+H). Example 86
  • Aqueous workup was performed on the reaction mixture by adding water and extracting with DCM three times, washing the combined organics with sat. aq. NaCl, then dry ing the organics over Na2SO4.
  • RXFP1 Cell cAMP HTRF Assay Relaxin family peptide receptor 1 (RXFP1) expressing cells were generated by transfecting a tetracycline-inducible RXFP1 expression cassette (Accession NM 021634.4) into HEK293 cells and single cell clones that are responsive to Human Relaxin2 (cat# H-6784.0200, Bachem, Torrance, CA) were selected. RXFP1 expressing cells were treated with 1 pg/mL doxycycline for 24 h prior to compound dosing in order to induce RXFP1 expression. At the time of cell dosing, compounds were acoustically transferred into 384-well plates (ProxiPlate, 384-well.
  • Assay buffer used for treatment was IX Stimulation Buffer (provided with the Gs cAMP HighRange kit. cat#62AM6PEJ. Revvity). diluted in distilled water and containing 500 pM 3- Isobutyl-1 -methylxanthine final (cat# I5879250MG, Sigma- Aldrich, St. Louis, MO). After 1 h incubation, cAMP levels were assessed using the CisBio Gs cAMP HighRange Kit (cat# 62AM6PEJ) according to the manufacturer's instruction (Revvity).

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Abstract

The present invention provides compounds of the formula: wherein G1, G2, -X-, R1, R2, R3, R4, and Ring A are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients for cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.

Description

RXFP1 RECEPTOR AGONISTS
FIELD OF THE INVENTION
[0001] The present invention relates to small molecule RXFP1 agonists and uses thereof.
BACKGROUND OF THE INVENTION
[0002] Human relaxin-2 (relaxin) is an insulin-like peptide known to regulate cardiovascular, renal, and pulmonary adaptations during pregnancy. Prechnical studies and recent clinical trials with a short-acting recombinant relaxin, serelaxin, have shown the promise of recombinant relaxin as a therapeutic agent in the treatment of cardiovascular and fibrotic diseases.
[0003] However, relaxin has several limitations such as poor oral bioavailability, a short half- life, and there are high costs of production, and storage. Similarly, relaxin family peptide receptor- 1 (RXFP1) peptide agonists require subcutaneous/intravenous administration.
[0004] Small molecule modulators of RXFP1 have also been sought. For example, McBride A et al. (2017) Scientific Reports 7: 10806 discusses small-molecule, positive allosteric modulators of RXFP1. WO2022/122773 discloses small molecule carboxylic acid derivatives used as RXRP1 modulators.
[0005] There remains a need to provide alternative, small molecule RXFP1 agonists. In particular, there is a need to provide orally deliverable RXFP1 agonists that are useful for treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders. Further, there is a desire to provide RXFP1 receptor agonists that exhibit better pharmacokinetic/ pharmacodynamic properties. Also, there is a need to provide RXFP1 receptor agonists that exhibit efficacy with reduced or minimized untoward or undesired effects. More particularly, there is a need to provide small molecule RXFP1 receptor agonists which are selective for RXFP1 over relaxin family peptide receptor-2 (RXFP2). The present invention addresses one or more of these needs by providing novel small molecule RXFP1 agonists. SUMMARY OF THE INVENTION
[0006] Compounds of Formula I are provided herein:
Figure imgf000003_0001
Formula I wherein:
Gi is -C(Ra)- or -N-;
G2 is -C(Rb)- or -N-;
Ring A is a group of the formula
Figure imgf000003_0002
wherein
Figure imgf000003_0003
are unsubstituted or substituted with one or more of halogen or C1-3 alkoxy;
-X- is -NH- or -S-;
Ra is -H or -F;
Rb is -H or -F;
Ri is C1-3 alkoxy or cyclopropoxy, wherein C1-3 alkoxy is unsubstituted or substituted with one or more halogens;
R2 is a group of the formula
Figure imgf000004_0001
R2a is one or more of C1-3 alkyl, -OH, -N(R)2, oxo, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1 , 1 -dioxide.
Figure imgf000004_0002
wherein the C1-3 alkyl is unsubstituted or substituted with one or more of -OH, oxo, or morpholine, wherein the morpholine is unsubstituted or substituted with an C1-3 alkylene bridge, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with a C1-3 alkyl, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; each R is independently a C1-3 alkyl;
-G3a- is -CHR2b- or -CH2-O-CH2-;
-Y- is a C 1-3 alky lene;
R2b is -COOH;
R2C is -H, or halogen;
R3 is a group of the formula:
Figure imgf000005_0001
-G4- is -CH- or -N-;
R3», at each occurrence, is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
Rsb. at each occurrence, is independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C1-4 alkyl;
R3C, at each occurrence, is independently -H or halogen;
R3d is -H, halogen. C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyd, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
R4 is -H, -CN, or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
[0007] The follow ing are further numbered aspects of the invention:
1. A compound of the formula:
Figure imgf000005_0002
Gi is -C(Ra)- or -N-;
G? is -C(Rb)- or -N-;
Ring A is a group of the formula
Figure imgf000005_0003
wherein
Figure imgf000006_0001
are unsubstituted or substituted with one or more of halogen or C1-3 alkoxy;
-X- is -NH- or -S-;
Ra is -H or halogen;
Rb is -H or halogen;
Ri is C1-3 alkoxy or cyclopropoxy, wherein C1-3 alkoxy is unsubstituted or substituted with one or more halogens;
R2 is a group of the formula
Figure imgf000006_0002
R2a is one or more of C1-3 alkyl, -OH, oxo, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1- dioxide,
Figure imgf000006_0003
wherein the C1-3 alkyl is unsubstituted or substituted with one or more of -OH, oxo, or morpholine, wherein the morpholine is unsubstituted or substituted with an C1-3 alkylene badge, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with a C1-3 alkyl, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; each R is independently a C1-3 alkyl; -G3a- is -CHR2b-, or -CH2-O-CH2-; -Y- is a C1-3 alkylene; R2b is -COOH; R2c is -H, or halogen; R3 is a group of the formula: ;
Figure imgf000007_0001
R3a, at each occurrence, is independently -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; R3b, at each occurrence, is independently -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN or C1-4 alkyl; R3c, at each occurrence, is independently -H, or halogen; R3d, at each occurrence, is independently -H, halogen, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; R4 is -H, -CN, or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof. [0008] Also provided herein are methods of using the compounds of Formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, to treat cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders. The methods include administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. [0009] Further provided herein, are compounds of Formula I, and pharmaceutically acceptable salts thereof, for use in therapy. Additionally provided herein, are the compounds of Formula I, and pharmaceutically acceptable salts thereof, for use in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders. Also additionally provided herein is the use of compounds of Formula I, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0010] Novel RXFP1 receptor agonists are described herein. These new compounds could address some or all of the needs noted above for novel RXFP1 receptor agonists in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
[0011] The present invention provides a compound of Formula I:
Figure imgf000008_0001
Formula I wherein Gi, G2, Ri, -X-, R2, Rs, R4, and Ring A, are as defined above, or a pharmaceutically acceptable salt thereof.
[0012] The following are further numbered aspects of the invention:
1. A compound of the formula:
Figure imgf000008_0002
Formula I wherein:
Gi is -C(Ra)- or -N-; G2 is -C(Rb)- or -N-;
Ring A is a group of the formula
Figure imgf000009_0001
d or substituted with one or more of halogen or C1-3 alkoxy;
-X- is -NH- or -S-;
Ra is -H or halogen;
Rb is -H or halogen;
Ri is C1-3 alkoxy or cyclopropoxy, wherein C1-3 alkoxy is unsubstituted or substituted with one or more halogens;
R2 is a group of the formula
Figure imgf000009_0002
R2a is C1-3 alkyl, -OH, oxo. -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1 -dioxide.
Figure imgf000009_0003
wherein the C1-3 alkyl is unsubstituted or substituted with one or more of -OH, oxo, or morpholine, wherein the morpholine is unsubstituted or substituted with an C1-3 alkylene bridge, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with a C1-3 alkyl, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; each R is independently a C1-3 alky l; is -CHR2b-, or -CH2-O-CH2-;
-Y- is a C1-3 alkylene;
R2b is -COOH;
R2C is -H. or halogen;
R3 is a group of the formula:
Figure imgf000010_0001
-G4- is -CH-, or -N-;
R3a is -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
R3b is -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN or C1-4 alky l;
R3c, at each occurrence, is independently -H, or halogen;
Rsa is -H, halogen, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyd, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens;
R4 is -H, -CN, or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
2. The compound according to aspect 1 wherein:
Ri is C1-3 alkoxy; or a pharmaceutically acceptable salt thereof.
3. The compound according to aspect 1 or 2 wherein Ring A is a group of the formula
Figure imgf000011_0001
wherein
Figure imgf000011_0002
is unsubstituted or substituted with halogen;
R1 is C1-3 alkoxy; wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, pyrazine, thiomorpholine 1,1 -di oxide,
Figure imgf000011_0003
wherein the pyrimidine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with a C1-3 alkyl, and wherein the pyrrole is unsubstituted or substituted with -OH; is -H, or halogen;
Rsa. at each occurrence, is independently -H, halogen, -SF5, -SO2CF3. -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
R4 is -H or C1-3 alky l, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
4. The compound according to aspect 1 or 2 wherein
Ring A is a group of the formula
Figure imgf000011_0004
Ra is -H or -F;
Rb is -H or -F ;
R1 is C1-3 alkoxy; R.2 is a group of the formula
Figure imgf000012_0001
wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1 -dioxi de, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
Rsa is -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
Rad is -H, halogen, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
R4 is -H; or a pharmaceutically acceptable salt thereof.
5. The compound according to any one of aspects 1-4 wherein Ring A is a group of the formula
Figure imgf000012_0002
Ra is -H or -F;
Rb is -H or -F;
R1 is C1-3 alkoxy;
R2 is a group of the formula
Figure imgf000012_0003
R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1- dioxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group; R3 is a group of the formula: ;
Figure imgf000013_0001
SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; each R3c is independently -H, or -F; and R4 is -H; or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of aspects 1-5 wherein Ring A is selected from the group consisting of , or a pharmaceutically acceptable salt thereof.
Figure imgf000013_0002
. e co pou according to any one of aspects 1-3, wherein Ring A is a group of the formula a pharmaceutically acceptable salt thereof.
Figure imgf000013_0003
8. e compoun accor ng to any one of aspects 1-3, wherein Ring A is a group of the formula r a pharmaceutically
Figure imgf000013_0004
9. The compound according to aspect 8, wherein Ring A is a group of the formula pharmaceutically acceptable salt thereof. rding to aspect 1 or 2, wherein Ring A is a group of the formula
Figure imgf000014_0001
armaceutically acceptable salt thereof.
11. The compound according to any one of aspects 1-10, wherein R4 is -H, or a pharmaceutically acceptable salt thereof.
12. The compound as defined in any one of aspects 1-7 of the formula pharmaceutically acceptable salt thereof. as defined in any one of aspects 1-6 or 8 of the formula
Figure imgf000014_0002
pharmaceutically acceptable salt thereof.
14. The compound as defined in any one of aspects 1-13, wherein Gi is -N-, or a pharmaceutically acceptable salt thereof.
15. The compound as defined in any one of aspects 1-13, wherein Gi is -C(Ra)-, or a pharmaceutically acceptable salt thereof.
16. The compound as defined in aspect 15, wherein Ra is -H, or a pharmaceutically acceptable salt thereof.
17. The compound as defined in any one of aspects 1-16, wherein G2 is -N-, or a pharmaceutically acceptable salt thereof. 18. The compound as defined in any one of aspects 1-16, wherein G2 is -C(Rb)-, or a pharmaceutically acceptable salt thereof.
19. The compound as defined in aspect 18, wherein Rb is -H, or a pharmaceutically acceptable salt thereof.
20. The compound as defined in any one of aspects 1-14 or 17, wherein Gi is -N-, and G2 is - N-, or a pharmaceutically acceptable salt thereof.
21. The compound as defined in any one of aspects 1-14 or 18, wherein Gi is -N-, and Gi is - C(Rb)-, or a pharmaceutically acceptable salt thereof.
22. The compound as defined in any one of aspects 1-13, or 16-17, wherein Gi is -C(H)-, and G2 is -N-, or a pharmaceutically acceptable salt thereof.
23. The compound as defined in any one of aspects 1-13, 16, 18-19, wherein Gi is -C(H)-, and G2 is -C(Rb)-, or a pharmaceutically acceptable salt thereof.
24. The compound as defined in any one of aspects 1. 6-23. wherein Ri is methoxy, difluoroethoxy, or a pharmaceutically acceptable salt thereof.
25. The compound as defined in aspect 24, wherein Ri is methoxy, or a pharmaceutically acceptable salt thereof.
26. The compound as defined in aspect 25 of the formula
Figure imgf000015_0001
, or a pharmaceutically acceptable salt thereof.
27. The compound as defined in aspect 25 of the formula
Figure imgf000015_0002
. or a pharmaceutically acceptable salt thereof.
28. The compound as defined in any one of aspects 1-4. 6-27. wherein R? is a group of the formula
Figure imgf000016_0001
, ically acceptable salt thereof.
29. The compound as defined in aspect 28, wherein R3 is a group of the formula
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof.
30. The compound as defined in aspect 29, wherein R3 is a group of the formula
Figure imgf000016_0003
. or a pharmaceutically acceptable salt thereof.
31. The compound as defined in any one of aspects 28-30, wherein R.3a is tert-butyl, -SF5 -, SO2CF3, or -SCF3, and Rsb is -H or halogen, or a pharmaceutically acceptable salt thereof.
32. The compound as defined in any one of aspects 28-30, wherein Rsa is -F, -Cl, -Br, difluoromethyl, difluorochloromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and R3b is -H, -F, -Cl, -Br, trifluoromethyl, -CN, or methyl, or a pharmaceutically acceptable salt thereof.
33. The compound as defined in any one of aspects 28-30, wherein R3a and R31, are both methoxy, or a pharmaceutically acceptable salt thereof.
34. The compound as defined in any one of aspects 1-33, wherein R3 is a group of the formula
Figure imgf000016_0004
, or a pharmaceutically acceptable salt thereof.
35. The compound according to any one of claims 1-34, wherein -X- is -NH-, or a pharmaceutically acceptable salt thereof.
36. The compound as defined in any one of aspects 1-35, wherein R2 is a group of the formula
Figure imgf000016_0005
or a pharmaceutically acceptable salt thereof. 31. The compound according to claim 36, wherein R2 is a group of the formula
Figure imgf000017_0001
and R2a is selected from the group consisting of -OH.
Figure imgf000017_0002
pharmaceutically acceptable salt thereof.
38. The compound according to claim 37, wherein R2a is selected from the group consisting of
Figure imgf000017_0003
, or a pharmaceutically acceptable salt thereof.
39. The compound as defined in any one of aspects 1-36, wherein R2 is a group of the formula
Figure imgf000017_0004
pharmaceutically acceptable salt thereof.
40. The compound as defined in aspect 39, wherein R2 is a group of the formula
Figure imgf000018_0001
pharmaceutically acceptable salt thereof.
41. The compound as defined in any one of aspects 1-36, wherein R2 is a group of the formula
Figure imgf000018_0002
or a pharmaceutically acceptable salt thereof.
42. The compound as defined in aspect 41, wherein R2 is a group of the formula
Figure imgf000018_0003
, or a pharmaceutically acceptable salt thereof.
43. The compound according to aspect 1, selected from the group consisting of
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
or a pharmaceutically acceptable salt thereof.
46. The compound according to any one of aspects 1-5 selected from
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
47. A pharmaceutical composition comprising a compound as defined in any one of aspects 1-46. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
48. A method of treating cardiovascular, pulmonary' and/or renal conditions, diseases and/or disorders in an individual, the method comprising administering to the individual an effective amount of a compound of any one of aspects 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 47.
49. A method of treating cardiovascular, pulmonary7, and/or renal conditions, diseases, and/or disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of any one of aspects 1-46. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 47.
50. The method of claim 49, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
51. The method of claim 50, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy. 52. The method of claim 49, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder.
53. The method of claim 52, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary’ disease (COPD).
54. The method of claim 49, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
55. The method of claim 54, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
56. A compound of any one of aspects 1-46 for use in a therapy.
57. A compound of any one of aspects 1-46 for use in treating cardiovascular, pulmonary' and/or renal conditions, diseases and/or disorders.
58. A compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
59. A compound for use according to claim 58, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
60. A compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a pulmonary' condition, disease, or disorder.
61. A compound for use according to claim 60, wherein the pulmonary' condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
62. A compound for use according to claim 57, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
63. A compound for use according to claim 62, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
64. A compound for use of aspect 57, wherein the disease or disorder to be treated is a cardiovascular condition, disease, or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary' artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy
65. A compound for use of aspect 57, wherein the disease or disorder to be treated is a pulmonary condition, disease, or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD). 66. A compound for use of aspect 57, wherein the disease or disorder to be treated is a renal condition, disease, or disorder selected from acute kidney disease, chronic kidney disease or diabetes nephropathy.
67. Use of a compound of any one of aspects 1-46 for the manufacture of a medicament for treating cardiovascular, pulmonary and/or renal conditions, diseases and/or disorders.
68. The use of aspect 67, wherein the disease or disorder to be treated is a cardiovascular condition, disease, or disorder selected from acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
69. The use of aspect 67, wherein the disease or disorder to be treated is a pulmonary condition, disease, or disorder selected from pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
70. The use of aspect 67. wherein the disease or disorder to be treated is a renal condition, disease, or disorder selected from acute kidney disease, chronic kidney disease or diabetes nephropathy.
[0013] In an embodiment, Ring A is a group of the formula
Figure imgf000049_0001
wherein
Figure imgf000049_0002
is unsubstituted or substituted with halogen; wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, pyrazine, thiomorpholine 1,1 -di oxide,
Figure imgf000049_0003
wherein the pyrimidine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with a C1-3 alkyl, and wherein the pyrrole is unsubstituted or substituted with -OH; R?a. at each occurrence, is independently -H, halogen, -SO2CF3, -SCF-3S, F C51,-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
R4 is -H or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
[0014] In another embodiment, Ring A is a group of the formula
Figure imgf000050_0001
Ra is -H or -F;
Rb is -H or -F ;
R2 is a group of the formula
Figure imgf000050_0002
wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1 -di oxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
Rs a is -H. halogen, -SF5, -SO2CF3. -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; each Rsc is independently -H, or -F;
R3d is -H. halogen, C1-4 alkyl, or C1-3 alkoxy, w-herein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
R4 is -H; or a pharmaceutically acceptable salt thereof.
[0015] In another embodiment, the compound of the formula is:
Figure imgf000051_0001
Ring A is a group of the formula
Figure imgf000051_0002
Ra is -H or -F;
Rb is -H or -F;
R2 is a group of the formula
Figure imgf000051_0003
R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1- dioxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
R3 is a group of the formula:
Figure imgf000051_0004
Rsa is -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4alkyl, or Ci-s alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; or a pharmaceutically acceptable salt thereof. [0016] In another embodiment. Ring A is selected from the group consisting of
Figure imgf000052_0001
, or a pharmaceutically acceptable salt thereof.
[0017] In another embodiment, the compound is of the formula
Figure imgf000052_0005
Figure imgf000052_0002
is substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.
[0018] In another embodiment, Ring A is selected from the group consisting of
Figure imgf000052_0003
, or a pharmaceutically acceptable salt thereof.
[0019] In another embodiment, the compound is of the formula pharmaceutically acceptable salt thereof. odiment, the compound is of the formula
Figure imgf000052_0004
pharmaceutically acceptable salt thereof.
[0021] In another embodiment, Gi is -N-. or a pharmaceutically acceptable salt thereof.
[0022] In another embodiment, Gi is -C(Ra)-, or a pharmaceutically acceptable salt thereof.
[0023] In another embodiment, Ra is -H, or a pharmaceutically acceptable salt thereof.
[0024] In another embodiment, G2 is -N-, or a pharmaceutically acceptable salt thereof. [0025] In another embodiment, G2 is -C(Rb)-, or a pharmaceutically acceptable salt thereof.
[0026] In another embodiment, Rb is -H, or a pharmaceutically acceptable salt thereof.
[0027] In another embodiment, Ri is methoxy, or a pharmaceutically acceptable salt thereof.
[0028] In another embodiment, R3 is selected from the group consisting of
Figure imgf000053_0001
or a pharmaceutically acceptable salt thereof.
[0029] In another embodiment, R3 is selected from the group consisting of
Figure imgf000053_0002
, or a pharmaceutically acceptable salt thereof.
[0030] In another embodiment, R3 is a group of the formula
Figure imgf000053_0003
, or a pharmaceutically acceptable salt thereof.
[0031] In another embodiment, Rsa is tert-buty l, -SF5, -SO2CF3, or -SCF3, and R3b is -H or -F, or a pharmaceutically acceptable salt thereof.
[0032] In another embodiment, R?a is -F, -Cl, -Br. difluoromethyl, difluorochloromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and R3b is -H, -F, -Cl, -Br, trifluoromethyl, -CN, or methyl, or a pharmaceutically acceptable salt thereof.
[0033] In another embodiment, Raa and Rsb are methoxy, or a pharmaceutically acceptable salt thereof.
[0034] In another embodiment, R2 is a group of the formula
Figure imgf000053_0004
or a pharmaceutically acceptable salt thereof.
[0035] In another embodiment, R2a is selected from the group consisting of
Figure imgf000053_0005
pharmaceutically acceptable salt thereof. [0036] In another embodiment, R2 is selected from the group consisting of
Figure imgf000054_0001
pharmaceutically acceptable salt thereof.
[0037] In another embodiment, R2 is selected from the group consisting of
Figure imgf000054_0002
a pharmaceutically acceptable salt thereof.
[0038] In another embodiment, R2 is selected from the group consisting of
Figure imgf000054_0003
or a pharmaceutically acceptable salt thereof.
[0039] In another embodiment, R2 is selected from the group consisting of
Figure imgf000054_0004
, or a pharmaceutically acceptable salt thereof.
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
-f>2-
Figure imgf000063_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
or a pharmaceutically acceptable salt thereof.
[0043] In another embodiment, a pharmaceutical composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
[0044] In another embodiment, a method of treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition of the compound of Formula I, or a pharmaceutically acceptable salt thereof.
[0045] In another embodiment, the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder. [0046] In another embodiment, the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery7 disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy. [0047] In another embodiment, the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a pulmonary7 condition, disease, or disorder.
[0048] In another embodiment, the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
[0049] In another embodiment, the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
[0050] In another embodiment, the method of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
[0051] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.
[0052] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular, pulmonary7, and/or renal conditions, diseases, and/or disorders.
[0053] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
[0054] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary7 artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
[0055] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder. [0056] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
[0057] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
[0058] In another embodiment, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
[0059] In another embodiment, use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
[0060] In another embodiment, the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
[0061] In another embodiment, the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy. [0062] In another embodiment, the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder.
[0063] In another embodiment, the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
[0064] In another embodiment, the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
[0065] In another embodiment, the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy. [0066] In another embodiment, a method of exhibiting agonist activity in a RXFP1 receptor in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
[0067] In the above embodiments of the compounds of Formula I, or a pharmaceutically acceptable salt thereof, the chemical drawings are shown flat without chiral information. These compounds often have multiple chiral centers and are contemplated to exist in various forms with various combinations of chiral centers. Additionally, these compounds have various enantiomers, diastereomers, and atropisomers that can exist and are included herein.
[0068] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.
[0069] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes, and/or in the examples described herein or a pharmaceutically acceptable salt thereof, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[0070] In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound is a deuterium labeled compound of any one of the compounds described herein and pharmaceutically acceptable salts thereof.
[0071] In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when an atom is designated specifically as "H" or "hydrogen", the atom is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when an atom is designated specifically as "D" or "deuterium", the atom is understood to have deuterium at an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.
[0072] A compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound is selected from
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
[0073] Also provided herein are pharmaceutical compositions comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, examples of which include, but are not limited to, the compounds disclosed herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
[0074] Further provided herein are methods of treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. Further provided herein are methods of treating cardiovascular conditions, diseases, and/or disorders, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. Further provided herein are methods of treating pulmonary7 conditions, diseases, and/or disorders, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. Further provided herein are methods of treating renal conditions, diseases, and/or disorders, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof.
[0075] Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of cardiovascular, conditions, diseases, and/or disorders. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary conditions, diseases, and/or disorders. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in therapy. Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of renal conditions, diseases, and/or disorders.
[0076] In the methods or uses herein, the cardiovascular conditions, diseases, and disorders include, but are not limited to, acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, and ventricular hypertrophy. Tn the methods or uses herein, the pulmonary conditions, diseases, and disorders include, but are not limited to, pulmonary hypertension and chronic obstructive pulmonary disease (COPD). In the methods or uses herein, the renal conditions, diseases, and disorders include, but are not limited to, acute kidney disease, chronic kidney disease and diabetes nephropathy.
[0077] The methods also can include a step of administering the Compound of formula I, or a pharmaceutically acceptable salt thereof in combination with an effective amount of at least one additional therapeutic agent. Briefly, the standard of care for many of the conditions/diseases/disorders herein includes an anticoagulant, an ACE inhibitor, an ARB. an ARNI, a P-blocker, a diuretic, digitalis, digoxin, hydralazine/isorbide dinitrate, a MRA or other aldosterone antagonist, a SGLT2 inhibitor, a statin, and/or an anti-glycemic agent, as well as other therapeutic agents to control comorbidities, including, but not limited to, high cholesterol, high blood pressure, atrial fibrillation, diabetes and obesity. In some instances, the additional therapeutic agent can be administered simultaneously, separately or sequentially with the compound of formula I, or a pharmaceutically acceptable salt thereof.
[0078] Further provided herein is a compound according to Formula I or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with at least one additional therapeutic agent in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders. Additional therapeutic agents include, but are not limited to, an anticoagulant, an ACE inhibitor, an ARB, an ARNI, a P-blocker, a diuretic, digitalis, digoxin, hydralazine/isorbide dinitrate, a MRA or other aldosterone antagonist, a SGLT2 inhibitor, a statin, and/or an anti-glycemic agent, as well as other therapeutic agents to control comorbidities, including, but not limited to, high cholesterol, high blood pressure, atrial fibrillation and diabetes. [0079] The methods or uses herein can include the steps described herein, and these maybe be, but not necessarily, carried out in the sequence as described. Other sequences, however, also are conceivable. Moreover, individual or multiple steps may be carried out either in parallel, and/or overlapping in time, and/or individually or in multiply repeated steps. Furthermore, the methods may include additional, unspecified steps.
[0080] Such methods or uses therefore can include selecting an individual having a cardiovascular condition, disease or disorder or who is predisposed to the same. Alternatively, the methods can include selecting an individual having a pulmonary condition, disease or disorder or who is predisposed to the same. Alternatively, the methods can include selecting an individual having a renal condition, disease or disorder or who is predisposed to the same. In certain instances, the methods can include selecting an individual who is diabetic, hypertensive with kidney function impairment, and/or obese.
[0081] In some instances, the individual in need is a diabetic, hypertensive with kidney function impairment, and/or obese.
[0082] The methods or uses also may be combined with diet and exercise, and/or may be combined with additional therapeutic agents other than those discussed above.
[0083] The term “pharmaceutically acceptable salt" as used herein refers to a salt of a compound considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley- VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
[0084] Pharmaceutical compositions containing the compounds of Formula I, or a pharmaceutically acceptable salt thereof, as described herein may be prepared using pharmaceutically acceptable additives. The term “pharmaceutically acceptable additive(s)” as used herein for the pharmaceutical compositions, refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the composition or formulation and not deleterious to the patient. Examples of pharmaceutical compositions and processes for their preparation can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22nd Ed.. Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose, alginates, gelatin, and polyvinyl-pyrrolidone; kaolin and bentonite; and polyethyl glycols. [0085] As used herein, “effective amount” means an amount or dose of a compound of formula I, or a pharmaceutically acceptable salt thereof that, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment (z.e., may produce a clinically measurable difference in a condition of the individual such as, for example, increased angiogenesis, increased vascular compliance, increased cardiovascular blood flow, increased hepatic blood flow, increased pulmonary blood flow, increased renal blood flow, increased glomerular filtration rate, decreased blood pressure, decreased (or prevented) inflammation and/or reduced (or prevented) fibrosis in the heart, kidney, liver or lung). An effective amount can be readily determined by one of skill in the art by using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered, including, but not limited to, the species of mammal, its size, age and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual, the particular Compound of Formula I, or a pharmaceutically acceptable salt thereof administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances.
[0086] As used herein, “treating” or “to treat” means managing and caring for an individual having a condition, disease, disorder or symptom for which Compound of formula I, or a pharmaceutically acceptable salt thereof administration is indicated for the purpose of attenuating, restraining, reversing, slowing or stopping progression or severity of the condition, disease, disorder and/or symptom. Treating includes administering a Compound of formula I, or a pharmaceutically acceptable salt thereof herein or composition containing a Compound of formula I, or a pharmaceutically acceptable salt thereof herein to the individual to prevent the onset of symptoms or complications, alleviating the symptoms or complications, or eliminating the condition, disease, disorder or symptom. Treating includes administering a Compound of formula I, or a pharmaceutically acceptable salt thereof or composition containing a Compound of formula I, or a pharmaceutically acceptable salt thereof herein to the individual to result in such as, for example, increased angiogenesis, increased vascular compliance, increased cardiovascular blood flow, increased hepatic blood flow, increased pulmonary blood flow, increased renal blood flow, increased glomerular filtration rate, decreased blood pressure, decreased (or prevented) inflammation and/or reduced (or prevented) fibrosis in the heart, kidney, liver or lung). The individual to be treated is a mammal, especially a human. [0087] As used herein, “individual,” “patient” and “subject” are used interchangeably and mean a mammal, especially a human. In certain instances, the individual is further characterized with a condition, disease, disorder and/or symptom that would benefit from administering a Compound of formula I, or a pharmaceutically acceptable salt thereof herein. [0088] As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., “C1-4 alkyl” or “C1-3 alkyl.” Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso- butyl. As used herein, the term alkylene means saturated linear or branched-chain bivalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., “C1-3 alkylene.” Examples of alkylenes include, but are not limited to, methylene, ethylene, propylene, 1- propylene, and isopropylene. As used herein, the term alkoxy refers to an alkyl substituent to which an oxygen radical is attached, e.g. “C1-3 alkoxy”. Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-propoxy, and isopropoxy. [0089] Certain abbreviations are defined as follows: “ACN” refers to acetonitrile; “AcOH” refers to acetic acid; “BOC” or “Boc” refers to tert-butoxycarbonyl; “Boc2O” refers to di-tert-butyl decarbonate; “BOP-Cl” refers to bis(2-oxo-3-oxazolidinyl)phosphinic chloride; “CH3ONa” refers to sodium methoxide; “DCE” refers to 1,2-dichloroethane; “DEE” refers to diethyl ether; “DiPEA” refers to N,N-diisopropylethylamine; “DCM” refers to dichloromethane; “DMF” refers to N,N-dimethylformamide; “EtOAc” refers to ethyl acetate; “ES-MS” refers to electrospray mass spectrometry; “EtOH” refers to ethanol; “FA” refers to formic acid; “h” refers to hour(s); “HATU” refers to hexafluorophosphate azabenzotriazole tetramethyl uronium; “HPLC” refers to high-performance liquid chromatography; “IPA” refers to isopropanol; “KOtBu” refers to potassium tert-butoxide; “LDA” refers to lithium diisopropylamide; “mCPBA” refers to meta- chloroperoxybenzoic acid; “MeOH” refers to methanol; “min” refers to minute(s); “MTBE” refers to methyl tert-butyl ether; “NaBH3CN” refers to sodium cyanoborohydride; “NMI” refers to N-methylimidazole; “NMP” refers to N-methyl-2-pyrrolidone; “PG” refers to protecting group; “PPACA” refers to 1-propanephosphonic anhydride; “prep-HPLC” refers to preparatory high-performance liquid chromatography; “prep-TLC” refers to preparatory thin layer chromatography; “pTsOH” refers to para-toluenesulfonic acid; “RT” refers to room temperature; “sat.” refers to saturated; “SCX” refers to strong cation exchange; “TCFH” refers to chloro- N,N,N',N'-tetramethylformamidinium hexafluorophosphate; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “TFAA” refers to trifluoroacetic anhydride; and “THF” refers to tetrahydrofuran.
[0090] As used herein, the term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, the term "C1-4 alkyl" as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one, two, three, or four carbon atoms. Examples of C1-4 alkyl include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-buty l, and 2- methyl-2-propyl. For example, the term "C1-3 alkyl" as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one, two, or three carbon atoms. Examples of C1-3 alkyd include, but are not limited to, methyl, ethyl, 1 -propyl, or isopropy l.
[0091] As used herein, the term “cycloalkyd” means a saturated cyclic hydrocarbon group containing the indicated number of carbon atoms. For example, the term “C3-6 cycloalkyl” as used herein refers to a saturated cyclic hydrocarbon group having three, four, five or six carbon atoms. Examples of C3-6 cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyd, and cyclohexyl.
[0092] As used herein the term "halogen" refers to F (fluoro), Cl (chloro), Br (bromo), and I (iodo).
[0093] As used herein the term “oxo” refers to the substitution of CH2 with O to form C(O). [0094] Individual isomers, enantiomers, diastereomers, and atropisomers may be separated or resolved at any convenient point in the synthesis of compounds listed below, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al.. "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons. Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). This description is intended to include all of the isomers, enantiomers, diastereomers, and atropisomers possible for the compounds disclosed herein or that could be made using the compounds disclosed herein. In the molecules described herein, only molecules in which the absolute conformation of a chiral center (or atropisomer conformation) is known have used naming conventions or chemical formula that are drawn to indicate the chirality or atropisomerism. Those of skill in the art will readily understand when other chiral centers are present in the molecules described herein and be able to identify the same.
[0095] Compounds of any one of Formula I that are chemically capable of forming salts are readily converted to and may be isolated as a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form the acid addition salt. Salts can also form simultaneously upon deprotection of a nitrogen or oxygen, z.e., removing the protecting group. Examples, reactions and conditions for salt formation can be found in Gould, P.L., “Salt selection for basic drugs,'’ International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin. R.J., et al. “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977).
[0096] The compounds of the present invention, or salts thereof, may be prepared by a variety7 of procedures, some of which are illustrated in the Schemes, Preparations, and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different routes, to prepare compounds or salts of the present invention. The products of each step in the Preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
[0097] Additionally, certain intermediates described in the following preparations may contain one or more nitrogen protecting groups. It is understood that protecting groups may be varied as appreciated by one of skill in the art depending on the particular reaction conditions and the particular transformations to be performed. One skilled in the art will appreciate that a deprotected amine can be functionalized via different methodologies known in the literature. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example "Greene's Protective Groups in Organic Synthesis", Fifth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2014).
[0098] Examples of known procedures and methods include those described in general reference texts such as Comprehensive Organic Transformations, VCH Publishers Inc, 1989; Compendium of Organic Synthetic Methods, Volumes 1-10, 197 4-2002, Wiley Interscience; Advanced Organic Chemistry, Reactions Mechanisms, and Structure, 5th Edition, Michael B. Smith and Jerry March, Wiley Interscience, 2001; Advanced Organic Chemistry, 4th Edition. Part B, Reactions and Synthesis, Francis A Carey and Richard J. Sundberg, Kluwer Academic/ Plenum Publishers, 2000, etc., and references cited therein.
[0099] In the following schemes, Ri, R2, R3, R4, Gi, G2, X, and A are as defined for Formula I.
Figure imgf000089_0001
[0100] Scheme 1 depicts the preparation of compounds of the present invention beginning with a suitable amine 1 and carboxylic acid 2. The PG moiety on the amine of the carboxylic acid 2 is a standard amine protecting group well known to the skilled artisan, including carbamate and amide protecting groups. The carboxylic acid 2 is reacted with the amine 1 under standard amide coupling conditions to prepare the amide 3 in Step 1. Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of the carboxylic acid 2 and a desired amine 1 in a suitable solvent, such as ACN, with an appropriate coupling reagent, such as TCFH or PPACA. in the presence of a suitable organic base, such as DiPEA or NMI, with stirring at RT for at least 35 min. The removal of the PG moiety on the amine of the amide 3 is achieved under conditions standard to the art. For example, if PG is BOC, the intermediate amine 4 is obtained by reacting a suitable acid, such as TFA, to a stirring solution of the amide 3 in an appropriate solvent, such as DCM, at RT for at least 18 h. The resulting amine 4 is reacted with a suitable acid 5 (“W” representing a halogen) under amide coupling conditions known to a skilled person as illustrated in Step 3. A suitable coupling reagent, such as oxalyl chloride, is introduced to a stirring solution of the carboxylic acid 5 at 0 °C, followed by DMF added dropwise. Once the reaction mixture is stirred at RT for at least 30 min, the amine 4 is added, followed by an appropriate organic base, such as DiPEA, and the reaction mixture is further stirred at RT for at least 1.5 h. [0101] In Step 4, the intermediate 6 is reacted with a suitable amine 7 under nucleophilic aromatic substitution conditions well know n to the skilled artisan to give 8. Suitable nucleophilic aromatic substitution conditions include reacting a compound bearing an appropriate halogen W on an aromatic moiety, such as fluorine or chlorine, with a suitable nucleophilic reactant such as an amine. The reaction occurs in the presence of a suitable organic base, such as DiPEA, in an appropriate organic solvent, such as NMP or DMF, at 60 °C at least. Alternatively, /iTsOH can be used in the place of DiPEA using an organic solvent such as IP A, stirring for at least 2 h at 80 °C. Another alternative is to couple intermediate 6 with amine 7 under transition metal catalyzed coupling conditions, for example using dichloro[bis(2- (diphenylphosphino)phenyl)ether]palladium(II) and an inorganic base such as Na2CCh in an organic solvent, such as 1,4-dioxane, at elevated temperature, e.g. stirring for at least 16 h at 80 °r
Scheme 2
Figure imgf000090_0001
[0102] In Scheme 2. the amine 13, 14 and 15 of the present invention can be prepared starting with the appropriate amine 9. The PG moiety on the amine 9 is a standard amine protecting group well known to the skilled artisan, including carbamate and amide protecting groups. In Step 1, the amine 9 is reacted with l-bromo-2-(2-bromoethoxy)ethane under standard nucleophilic substitution conditions and include using Nal in presence of a suitable base, such as K2CO3, in an appropriate organic solvent, such as EtOH, at 95 °C at least. In Step 2, intermediate 11 is generated by reacting the amine 9 with (vinylsulfonyl)ethene in an appropriate organic solvent, such as EtOH, under reflux conditions. The amine 9 is reacted with 2-(2-chloroethoxy)acetic acid under standard amide coupling conditions in Step 3. Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of 2-(2-chloroethoxy)acetic and the amine 9 in a suitable solvent, such as DMF, with an appropriate coupling reagent, such as HATU, in the presence of a suitable organic base, such as DiPEA, with stirring at RT for at least 16 h. The resulting intermediate is treated under standard nucleophilic substitution conditions in presence of a suitable base, such as K2CO3, in an appropriate organic solvent, such as DMF, at 80 °C at least. When the PG moiety' is a BOC group, deprotection of intermediates 10, 11 and 12 is achieved under acidic conditions standard to the art. The amines 13, 14 and 15 are obtained by adding a suitable acid, such as TFA. to a stirring solution of intermediate 10, 11, and 12, respectively in an appropriate solvent, such as DCM, at RT for at least 18 h.
Scheme 3
Figure imgf000091_0001
[0103] Scheme 3 represents an alternative route to prepare the intermediate 4. The suitable acyl chloride 16 is reacted with the appropriate amine 1 under standard amide coupling conditions with a suitable organic base, such as DiPEA, in an appropriate organic solvent, such as DCM, at RT. The resulting amide 17 is treated under reductive conditions and includes reacting the amide 17 with zinc and NH4CI in a suitable organic solvent, such as MeOH. at 50 °C at least.
Figure imgf000092_0001
[0104] Scheme 4 depicts the preparation of compounds of the present invention starting with suitable ary l halide 18 (wherein "W" is a halogen). Intermediate 18 is reacted with a suitable amine 7 under nucleophilic aromatic substitution conditions well known to the skilled person, in the presence of a suitable organic base, such as DiPEA, in an appropriate organic solvent, such as NMP or DMF, at 80 °C at least to give 19 in Step 1. The carboxylic acid 20 can be prepared from the suitable ester 19 under standard saponification conditions using an appropriate strong inorganic base, such as NaOH or LiOH. in a mixture of suitable organic solvents, such as THF or EtOH, with stirring at 60 °C for at least 1.5 h. The carboxylic acid intermediate 20 is reacted with a suitable amine 21 under amide coupling conditions well known to the skilled artisan. A suitable coupling reagent, such as oxalyl chloride, is introduced to a stirring solution of the carboxylic acid 20 at 0 °C, followed by DMF added dropwise. Once the reaction mixture is allowed to stir at RT for at least 30 min, the amine 21 is added, followed by an appropriate organic base, such as DiPEA, and the reaction mixture is further stirred at RT for at least 1.5 h. In Step 4, the ester 22 is treated under standard saponification conditions using an appropriate strong inorganic base, such as NaOH or LiOH, in a mixture of suitable organic solvents, such as THF or EtOH. with stirring at 60 °C for at least 1.5 h. The carboxylic acid 23 is reacted with a suitable amine 1 under standard amide coupling conditions to prepare the amide 8 in Step 5. Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of the carboxylic acid 23 and a desired amine in a suitable solvent, such as ACN, DMF or DCM, with an appropriate coupling reagent, such as TCFH, HATU or PPACA, in the presence of a suitable organic base, such as DiPEA, TEA or NMI, with stirring at RT for at least 35 min.
Scheme 5
Figure imgf000093_0001
[0105] Scheme 5 depicts the preparation of compounds of the present invention starting with suitable carboxylic acid 5. The carboxylic acid 5 is reacted with a suitable amine 21 under amide coupling conditions well known to the skilled artisan. A suitable coupling reagent, such as oxalyl chloride, is introduced to a stirring solution of the carboxylic acid 5 at 0 °C, followed by DMF added dropwise. Once the reaction mixture is allowed to stir at RT for at least 30 min, the amine 21 is added, followed by an appropriate organic base, such as DiPEA, and the reaction mixture is further stirred at RT for at least 1.5 h. Aryl halide intermediate 24 (wherein “W” is a halogen and "Ci? " is N) is reacted with a suitable amine 7 under standard nucleophilic aromatic substitution conditions in presence of a suitable organic base, such as DiPEA, in an appropriate organic solvent, such as NMP or DMF, at 80 °C at least to give 22 in Step 2. The carboxylic acid 23 can be prepared from the suitable ester 22 under standard saponification conditions using an appropriate strong inorganic base, such as NaOH or LiOH, in a mixture of suitable organic solvents, such as THF or EtOH, with stirring at 60 °C for at least E5 h. The carboxylic acid 23 is reacted with a suitable amine 1 under standard amide coupling conditions to prepare the amide 8 in Step 4. Suitable amide coupling conditions are well known to the skilled person and include reacting a solution of the carboxylic acid 23 and a desired amine in a suitable solvent, such as ACN, with an appropriate coupling reagent, such as TCFH or PPACA, in the presence of a suitable organic base, such as DiPEA or NMI, with stirring at RT for at least 35 min.
Scheme 6
Figure imgf000094_0001
[0106] Scheme 6 shows the preparation of compounds of the present invention starting with acid intermediate 25 and amine intermediate 4 to give compound 8. Suitable amide coupling conditions are well known to the skilled person and include reacting carboxylic acid 25 and amine 4 in a suitable solvent such as NMP with a coupling reagent such as PPACA and an organic base such as TEA at RT, optionally adding 4-dimethylaminopyridine and optionally heating up to 85 °C.
[0107] In Schemes 1, 4, 5, and 6, if the R2-group of 8 contains a carboxylic ester, it can be treated under standard saponification conditions using an appropriate strong inorganic base such as NaOH or LiOH in a mixture of suitable organic solvents such as THF or EtOH with stirring at 60 °C for at least 1.5 h to give the carboxylic acid. Coupling of this carboxylic acid with an amine using an appropriate coupling reagent such as HATU and an organic amine base such as DIPEA gives compounds of Formula I where R2a is, for example.
Figure imgf000095_0001
Preparation 1 Pentafluoro(2-fluoro-5-nitrophenyl)-λ6-sulfane [0108] Pentafluoro(2-fluoro-5-nitrophe A mixture of pentafluoro(2-fluorophenyl)- 6
Figure imgf000095_0002
λ -sulfane (5.00 g, 22.5 mmol) and sulfuric acid (18.3 g, 9.96 mL, 187 mmol) was cooled to 0 °C. Then nitric acid (14.0 g, 9.96 mL, 223 mmol) was added to the reaction mixture; after 5 min, the ice bath was removed and the reaction was stirred at 25 °C for 3 hours. Next the reaction mixture was poured onto 300 mL of ice and the resulting mixture was extracted with DEE (300 mL). The combined organic layers were washed with sat. aq. NaCl (150 mL), dried over MgSO4, filtered and concentrated to give the title compound (2.5 g, 9.3 mmol, 41%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.71 (dd, J = 5.8, 2.7 Hz, 1H), 8.45 (dt, J = 9.2, 3.2 Hz, 1H), 7.44 (t, J = 9.5 Hz, 1H). Preparation 2 4-Fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline [0109] A mixture of pentafluoro(2-fluo
Figure imgf000095_0003
yl)-λ6-sulfane (2.5 g, 9.4 mmol), iron (2.6 g, 47 mmol), EtOH (60 mL) and concentrated HCl (2.4 mL) was heated at 105 °C under reflux for 3 hours. The mixture was then filtered, cooled to RT, and made slightly basic by the addition of NH4OH. The solvent was evaporated in vacuum, and the remaining residue was washed with water (100 mL) and extracted with a 4:1 mixture chloroform:iPrOH (600 mL). The organic layer was dried MgSO4, filtered and concentrated under reduced pressure and then purified directly by reverse phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN), followed by a second column (C18, 0.1% FA in H2O, 0.1% FA in ACN) to afford the title compound (1.56 g, 6.58 mmol, 70%) as a brown solid. ES-MS m/z 238 (M+H). Preparation 3 tert-Butyl (3-(1,1-dioxidothiomorpholino)bicyclo[1.1.1]pentan-1-yl)carbamate [0110] To a refluxing solution of t o[1.1.1]pentan-1-yl)carbamate (1.00
Figure imgf000096_0001
g, 5.04 mmol) in EtOH (5 mL) was added drop wise a solution of (vinylsulfonyl)ethene (596 mg, 524 μL, 5.04 mmol) in EtOH (5 mL). The resulting mixture was stirred at reflux for 4 hours, cooled to RT and concentrated under reduced pressure. The resulting solid was triturated with MTBE and dried under reduced pressure to give the title compound (1.05 g, 3.32 mmol, 66 %) as a white solid. ES-MS m/z 317 (M+H). Preparation 4 tert-Butyl (3-morpholinobicyclo[1.1.1]pentan-1-yl)carbamate [0111] A mixture of tert-butyl (3
Figure imgf000096_0002
n-1-yl)carbamate (2.0 g, 10 mmol), 1- bromo-2-(2-bromoethoxy)ethane (2.7 g, 12 mmol), sodium iodide (1.5 g, 10 mmol), and potassium carbonate (2.8 g, 20 mmol) in DMF (6.7 mL) was sealed and heated at 95 °C. After 75 min, the mixture was quenched with water (125 mL), extracted with EtOAc (250 mL), dried over MgSO4, filtered and concentrated, to give the title compound (2.0 g, 7.5 mmol, 74%) as a light yellow oil.1H NMR (400 MHz, CDCl3) δ 3.73 – 3.67 (m, 4H), 2.42 (dd, J = 5.7, 3.8 Hz, 4H), 1.98 (s, 6H), 1.42 (s, 9H). Preparation 5 tert-Butyl (3-(2-(2-chloroethoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate [0112] A mixture of 2-(2-chlo
Figure imgf000096_0003
, 7 μmol), tert-butyl (3- aminobicyclo[1.1.1]pentan-1-yl)carbamate (199 mg, 1.00 mmol), HATU (382 mg, 1.00 mmol), and DiPEA (216 mg, 292 μL, 1.67 mmol) was stirred in DMF (4.19 mL). After 16 hours, the reaction was quenched with water and extracted with EtOAc. The combined organic phase washed with water, a saturated solution of NaHCO3, then sat. aq. NaCl. The crude was dried over MgSO4, filtered, and concentrated to dryness to obtain the title compound that was used as-is in next step (337 mg, quantitative yield). ES-MS m/z 319 (M+H). Preparation 6 tert-Butyl (3-(3-oxomorpholino)bicyclo[1.1.1]pentan-1-yl)carbamate [0113] A mixture of tert-butyl (3- mido)bicyclo[1.1.1]pentan-1-
Figure imgf000097_0001
yl)carbamate (50 mg, 0.16 mmol) and K2CO3 (43 mg, 0.31 mmol) was stirred in DMF (0.78 mL) at 80°C. The reaction mixture was cooled, diluted with EtOAc and filtered to remove solids. The filtrate was collected and washed with water, then sat. aq. NaCl. The organics were dried over MgSO4, filtered, and concentrated to dryness to obtain the title compound (30 mg, 0.11 mmol, 69%). ES-MS m/z 283 (M+H). Preparation 7 N-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-nitrobenzamide [0114] To a solution of 2-nitrobenz
Figure imgf000097_0002
.95 mmol) in DCM (23.2 mL), was added 4-fluoro-3-(trifluoromethyl)aniline (1.25 g, 6.95 mmol) and DIPEA (2.70 g, 3.63 mL, 20.9 mmol) at ambient temperature. After 3 hours, the crude mixture was concentrated under vacuum and the residue was purified by normal phase chromatography (EtOAc/heptanes 0-100%) to afford the title compound (1.98 g, 6.03 mmol, 87%). ES-MS m/z 329 (M+H). Preparation 8 2-Amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide [0115] To a solution of N-(4-fluoro enyl)-2-nitrobenzamide (1.98 g, 6.03
Figure imgf000098_0001
mmol) in MeOH (20.1 mL), was added zinc (3.94 g, 60.3 mmol) and NH4Cl (3.23 g, 60.3 mmol) at ambient temperature. The reaction was heated to 50 °C and stirred for 3 hours. The reaction mixture was cooled and filtered through diatomaceous earth. The filter cake was rinsed with MeOH and the filtrate was collected and concentrated under vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (1.68 g, 5.63 mmol, 93%). ES- MS m/z 299 (M+H). Preparation 9 tert-Butyl ((1S,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-λ6- sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate [0116] To a mixture of (1R,2S,3R,
Figure imgf000098_0002
bonyl)amino)bicyclo[2.2.1]heptane-2- carboxylic acid (2.02 g, 7.89 mmol) and 4-fluoro-3-(pentafluoro-λ6-sulfaneyl)aniline (1.56 g, 6.58 mmol) was added TCFH (2.21 g, 7.89 mmol) and 1-methylimidazole (1.30 g, 1.25 mL, 15.8 mmol) in ACN (26.3 mL). The reaction mixture was stirred at 25 °C for 35 min. The reaction mixture was then concentrated and the residue was purified by reverse phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to afford the title compound (1.50 g, 3.16 mmol, 48%) as a tan solid. ES-MS m/z 473 (M+H). [0117] The following were prepared essentially as described in Preparation 9 using the appropriate aniline:
Figure imgf000099_0001
Figure imgf000100_0002
Preparation 15 (lR,2S,3R,4S)-3-Amino-N-(4-fluoro-3-(pentafluoro-X6-sulfaneyl)phenyl)bicyclo[2.2. l]heptane- 2-carboxamide
[0118] A solution of /e/7-butyl ((lS,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-X6- sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamate (1.50 g 3.16 mmol) in DCM (25 mL) and TFA (6.32 mL) was stirred at 25 °C for 1 hour. The solution was concentrated and purified by reverse phase C18 column chromatography (Cl 8. 0.1% FA in H2O, 0.1% FA in ACN) to afford the title compound (1.06 g, 2.83 mmol, 90%) as a white solid. ES-MS m/z 375 (M+H).
[0119] The following were prepared essentially as described in Preparation 15 using the appropriate BOC-protected starting material:
Figure imgf000100_0001
Figure imgf000101_0001
Preparation 24
4-Chloro-N-((lS,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-X6- sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxypyrimidine-5-carboxamide
Figure imgf000102_0001
[0120] To a solution of 4-chloro-6-methoxypyrimidine-5-carboxylic acid (72.1 mg, 382 μmol) in DCM (15 mL). oxalyl dichloride (58.2 mg, 39.3 μL, 459 μmol) was added, followed by dropwise addition of DMF (27.9 mg, 29 pL. 382 μmol). After bubbling stopped, (lR,2S.3R,4S)-3-amino- N-(4-fluoro-3-(pentafluoro-k6-sulfaneyl)phenyl)bicyclo[2.2. l]heptane-2-carboxamide (196.9 mg, 526.0 μmol) was added, followed by DiPEA (148 mg, 0.20 mL, 1.15 mmol). The reaction was stirred for 20 minutes, then loaded directly onto silica gel and purified in 0-100% EtOAc/heptane to give the title compound (130 mg, 239 μmol, 62%). ES-MS m/'z 545 (M+H).
[0121] The following were prepared essentially as described in Preparation 24 using the appropriate amine and carboxylic acid:
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000104_0001
Preparation 35
Methyl 6-((5-(((lS,2R,3S,4R)-3-((4-fluoro-3-
(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-6-methoxypyrimidin-
4-yl)amino)spiro[3.3]heptane-2-carboxylate (mixture of isomers)
Figure imgf000105_0001
[0122] To a solution of 4-chloro-N-((lS,2R,3S,4R)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxypyrimidine-5- carboxamide (226.3 mg, 464.8 μmol) and methyl 6-(chloro-15-azaneyl)spiro[3.3]heptane-2- carboxylate (mixture of isomers, 141.1 mg, 686.0 μmol) in DMF (3 mL) was added DiPEA (360.5 mg, 0.49 mL, 2.789 mmol) and the reaction was stirred at 60 °C for 2.5 hours. Upon reaction completion, the reaction was cooled to ambient temperature and partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0-100% EtOAc in heptane to give the title compound (194.8 mg, 314.4 pmol, 68%). ES-MS m/z 620 (M+H).
[0123] The following were prepared essentially as described in Preparation 35 using the appropriate aniline/amine and carboxylic acid:
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0002
Preparation 43 (lR,2S,3R,4S)-3-(4-Methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5- carboxamido)bicyclo[2.2. l]heptane-2-carboxylic acid
Figure imgf000108_0001
[0124] To a stirring solution of methyl (lR,2S,3R,4S)-3-(4-methoxy-6-((3- morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5-carboxamido)bicyclo[2.2. l]heptane-2- carboxylate (1090 mg, 2.311 mmol) in THF (10 mL) was added LiOH (553.6 mg, 1 1.56 mL, 23. 11 mmol) and EtOH (1.9 mL). The reaction mixture was heated to 60 °C and stirred for 1.5 hour. After 1.5 hour, IM HC1 was added until mixture shows pH=2. The reaction mixture was concentrated under reduced pressure and then purified directly by reverse phase column chromatography (C18, 0.1% FA in H2O, 0.1% FA in ACN) to afford the title compound (896 mg, 1.96 mmol, 85%) as an off-white solid. ES-MS mJz 458 (M+H). Preparation 44
4-Chloro-6-methoxy-2-methylpyrimidine-5-carbaldehyde
Figure imgf000109_0001
[0125] To a stirred solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (3 g, 16 mmol) in MeOH (30 mL) was added CH?ONa (933.35 mg, 17.28 mmol) in portions at 0 °C under N2 atmosphere. The reaction mixture was stirred overnight at RT under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaCl sat. aq. solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (33% EtOAc in petroleum ether) to afford the title product (600 mg, 20%) as a white solid. ES-MS m ; 187 (M+H).
[0126] The following compounds were prepared essentially as described in Preparation 44:
Figure imgf000109_0003
Preparation 46
Methyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate
Figure imgf000109_0002
[0127] A solution of 4-chloro-6-methoxy-2-methylpyrimidine-5-carbaldehyde (300 mg, 2 mmol) in MeOH (3 mL) was treated with I2 (1224. 16 mg, 4.82 mmol) in MeOH (3 mL) at 0 °C under N2 atmosphere, followed by the addition of KOH (270.60 mg, 4.82 mmol) in MeOH (3 mL) dropwise at 0 °C. The reaction mixture was stirred for 1.5 h at RT under N2 atmosphere. The reaction mixture was quenched with NaHSOs sat. aq. solution at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and filtered. The filter cake was washed with H2O (3 x 20 mL). The resulting solid was dried under reduced pressure to give the title product (140 mg, 37%) as a yellow solid. ES-MS /nz 217 (M+H).
Preparation 47
Methyl 4-methoxy-2-methyl-6-((3-morpholinobicyclo[l .1. 1] pentan- l-yl)amino)py rimidine-5- carboxylate
Figure imgf000110_0001
[0128] A solution of methyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate (140 mg, 1 mmol), 3-(morpholin-4-yl)bicyclo[l. l. l]pentan-l-amine (217.46 mg, 0.97 mmol) and DiPEA (417.66 mg, 3.23 mmol) in NMP (25 mL) was stirred overnight at 80 °C under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL), and was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaCl sat. aq. solution (50 mL) and dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue w as purified by silica gel column chromatography (50% EtOAc in petroleum ether) to afford the title product (130 mg, 55%) as a white solid. ES-MS m/'z 349 (M+H).
[0129] The following compound w as prepared essentially as described in Preparation 47:
Figure imgf000110_0002
Preparation 49
4-Chloro-2,5-difluoronicotinic acid
Figure imgf000111_0001
[0130] A solution of 4-chloro-2,5-difluoropyridine (11 g, 74 mmol) in THF (150 mL) was treated with LDA (55. 18 mL, 110.35 mmol. 2M in THF) for 1 h at -78 °C under N2 atmosphere followed by the addition of dry ice (CO2, 1 g) in portions at -78 °C. The resulting mixture was stirred for 1 h at RT under N2 atmosphere. The reaction was quenched with NH4CI sat. aq. solution at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM/MeOH (10: 1, 200 mL). The resulting mixture was washed with H2O (2 x 50 mL) and NaCl sat. aq. solution (50 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% MeOH in DCM) to afford the title product (17 g) as ayellow solid. ES- MS m/z 194 (M+H).
[0131] The following compounds were prepared essentially as described in Preparation 49:
Figure imgf000111_0003
Preparation 51
4-Methoxy-6-((3-morpholinobicyclo[l .1. l]pentan-l -yl)amino)pyrimidine-5-carboxylic acid
Figure imgf000111_0002
-I l l-
[0132] To a stirred solution of w-butyllithium (2.5 M, 700 uL, 1.75 mmol) in diethyl ether (2.0 mL) at -40 °C was added 5-bromo-6-methoxy-N-(3-morpholinobicyclo[l. l. l]pentan-l- yl)pyrimidin-4-amine (176 mg, 0.495 mmol) in solution in anhydrous THF (2.0 mL) dropwise. The reaction mixture was stirred at -40°C for lOmin, then under carbon dioxide atmosphere for 20 min at 0°C. The reaction mixture was quenched with water (5 mL) and was acidified with sat. aq. NH4CI (until pH ~ 7), then CHCh:iPrOH 3: 1 (10 mL) was added. The aq. layers were extracted with CHCh :iPrOH 3: 1 (3 x 10 mL). The combined organics layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was split into two halves. One half of the residue was purified by silica gel chromatography using a gradient of MeOH in DCM from 0% to 35% with 1 % of AcOH to give the title compound (20 mg) as a white solid. A second crop of the title compound w as obtained as follow s: the aqueous phase was acidified with a 3 N aq. solution of citric acid (until pH ~ 5) and CHChiPrOH 3: 1 (10 mL) was added. The aqueous layers were extracted with CHChiPrOH 3: 1 (3 x 10 mL). The combined organics layers were dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound (62 mg) as a white solid. ES-MS m'z 321 (M+H).
Preparation 52 Methyl 4-chloro-2,5-difluoronicotinate
Figure imgf000112_0001
[0133] To a solution of 4-chloro-2,5-difluoronicotic acid (17 g) and K2CO3 (72.84 g, 527.05 mmol) in 1,4-dioxane (200 mL) w as added CH3I (27.34 mL, 439.21 mmol) dropwise at RT. The reaction mixture was stirred overnight at 80 °C under N2 atmosphere. The resulting mixture was filtered, the filter cake was w ashed with 1,4-dioxane (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% EtOAc in petroleum ether) to afford the title compound (7 g, 47%) as a yellow oil. ’H NMR (400 MHz, DMSO-cL) 5 8.66-8.61 (m, 1H), 3.98 (s, 3H). [0134] The following compound was prepared essentially as described in Preparation 52:
Figure imgf000113_0003
Preparation 54
Benzyl 2-fluoro-4-methoxynicotinate
Figure imgf000113_0001
[0135] A solution of 2-fluoro-4-methoxynicotinic acid (19 g, 111 mmol), benzy l bromide (94.95 g, 555.15 mmol) and TEA (77.17 mL, 555.15 mmol) in DCM (500 mL) was stirred overnight at RT under N2 atmosphere. The reaction mixture was diluted with H2O (300 mL), and extracted with DCM (3 x 500 mL). The combined organic layers were washed with NaCl sat. aq. solution (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-66% EtOAC in petroleum ether) to afford the title product (20 g. 69%) as a white solid. ES-MS m/z 262 (M+H).
Preparation 55
2-Chloro-A-(2-chloroethyl)-A-methylacetamide
Figure imgf000113_0002
[0136] To a stirred solution of (2-chloroethyl)(methyl)amine hydrochloride (5 g, 39 mmol) and TEA (11.68 g, 115.38 mmol) in DCM (100 mL) was added chloroacetyl chloride (4.78 g, 42.31 mmol) dropwise at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (700 mL). The resulting mixture was extracted with DCM/MeOH (4/1) (5 x 150 mL). The combined organic layers were washed with NaCl sat. aq. solution (2 x 50 mL) and dried over anhydrous Na2SC>4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH in DCM) to afford the title product (3 g, 33%) as a light yellow oil. ES-MS m'z 170 (M+H).
Preparation 56
Ze/7-Butyl (3-(3-hydroxypyrrolidin-l-yl)bicyclo[l. l. l]pentan-l-yl)carbamate (racemic mixture)
Figure imgf000114_0001
[0137] To a stirred mixture of /c/7-butyl JV-(3-aminobicyclo[l. l. l]pentan-l-yl)carbamate (3 g, 15 mmol) and l,4-dichlorobutan-2-ol (racemic mixture) (2.60 g, 18.16 mmol) in DMF (30 mL) were added CS2CO3 (9.86 g, 30.26 mmol) and KI (2.51 g, 15.13 mmol) in portions at RT. The reaction mixture was stirred at 90 °C for 5 h. The reaction was quenched with H2O (150 mL) at RT. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with NaCl sat. aq. solution (2 x 100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue w as purified by silica gel column chromatography (10-25% MeOH in DCM) to afford the title compound (1.0 g. 25%) as a light brown oil. ES-MS m'z 269 (M+H).
[0138] The following compound was prepared essentially as described in Preparation 56:
Figure imgf000115_0002
a. 2-Chloro-N-(2-chloroethyl)-N-methylacetamide was used as starting material
Preparation 58
/e/7- Butyl (3-(hydrazinecarbonyl)bicyclo[l. 1. l]pentan-l-yl)carbamate
Figure imgf000115_0001
[0139] To a stirred solution of methyl 3-((te/7-butoxycarbonyl)amino)bicyclo[l.l.l]pentane-l- carboxylate (1 g. 4 mmol) in MeOH (20 mL) was added hydrazine hydrate (778.03 mg, 12.43 mmol) dropwise at RT. The reaction mixture was stirred for 30 min at RT, then stirred for additional 3 h at 80 °C. The resulting mixture was concentrated under vacuum to afford the title product (970 mg, 97%) as a white solid. ES-MS m/z 242 (M+H).
Preparation 59
/c/V-Biityl (3-(l,3,4-oxadiazol-2-yl)bicyclo[l. l. l]pentan-l-yl)carbamate
Figure imgf000116_0001
[0140] A solution of tert-butyl (3-(hydrazinecarbonyl)bicyclo[l.l. l]pentan-l-yl)carbamate (0.97 g, 4.02 mmol) and pTsOH (69.23 mg, 0.40 mmol) in triethyl orthoformate (20 mL) was stirred for 3 h at 80 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-50% EtOAc in petroleum ether) to afford the title product (700 mg, 69%) as a white solid. ES-MS m/z 252 (M+H).
Preparation 60 tert-Butyl (3-carbamoylbicyclo[l. l. l]pentan-l-yl)carbamate
Figure imgf000116_0002
[0141] A solution of methyl 3-((/e/7-butoxycarbonyl)amino|bicyclo| 1 . 1. 1] pentane- 1 -carboxylate (1 g, 4 mmol) in NH3 (g) in MeOH (20 mL, 7M) was stirred for overnight at RT under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford the title product (900 mg) as a white solid. ES-MS m/z 227 (M+H). Preparation 61 tert-Butyl (3-(4H-1,2,4-triazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate [0142] A solution of tert-butyl (3-carbam [1.1.1]pentan-1-yl)carbamate (900 mg, 4
Figure imgf000117_0001
mmol) in (dimethoxymethyl)dimethylamine (10 mL) was stirred for 1 h at 100 °C under N2 atmosphere. The reaction mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (15 mL) and added hydrazine hydrate (637.31 mg, 15.91 mmol) at RT. The reaction mixture was stirred for 1 h at 100 °C under N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was diluted with DCM (100 mL), washed with NaHCO3 sat. aq. solution (3 x 50 mL) and NaCl sat. aq. solution (2 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% MeOH in DCM) to afford the title product (160 mg, 15%) as a white solid. ES-MS m/z 251 (M+H). Preparation 62 tert-Butyl (3-carbamothioylbicyclo[1.1.1]pentan-1-yl)carbamate [0143] A mixture of tert-butyl (3-carbam
Figure imgf000117_0002
.1.1]pentan-1-yl)carbamate (1.00 g, 4.42 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (2.68 g, 6.63 mmol) in THF (10 mL) was stirred for 2 h at 80 °C under N2 atmosphere. The reaction mixture was allowed to cool down to RT. The reaction mixture was basified to pH = 8 with NaHCO3 sat. aq. solution. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaCl sat. aq. solution (3 x 10 mL) and dried over anhydrous Na2SC>4.
After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-50% EtOAc in petroleum ether) to afford the title product (440 mg, 41%) as a white solid. ES-MS m/z 243 (M+H).
Preparation 63
/er/- Butyl (3-(thiazol-2-yl)bicyclo[l .1.1] pentan- l-yl)carbamate
Figure imgf000118_0001
[0144] To a stirred solution of /c/7-butyl (3-carbamothioylbicyclo[l.l. l]pentan-l-yl)carbamate (430 mg, 2 mmol) and /iTsOH (1070 mg, 6 mmol) in EtOH (3 mL) was added 2-bromo-l,l- dimethoxy -ethane (600 mg, 4 mmol) dropwise at RT under N2 atmosphere. The reaction mixture was stirred for 3 h at 80 °C under N2 atmosphere. The reaction mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM (3 mL), and BOC2O was added (504 mg, 2 mmol) and TEA (539 mg, 5 mmol) was added dropwise at RT. The reaction mixture was stirred for additional 2 h at RT. The resulting mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with NaCl sat. aq. solution (3 x 5 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-50% EtOAc in petroleum ether) to afford the title product (140 mg, 30%) as a yellow solid. ES-MS m/z 267 (M+H).
Preparation 64
4-Fluoro-A-(4-fluoro-3-(trifluoromethyl)phenyl)-2-nitrobenzamide
Figure imgf000118_0002
[0145] To a solution of 4-fluoro-2-nitrobenzoic acid (1. 12 g, 6.05 mmol) in DCM (25 mL), were added oxalyl chloride (960 mg, 662 pf. 8 mmol), and DMF (22.1 mg, 23 303 μmol). The μL, reaction mixture was stirred at RT for 90 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (25 mL) and a solution of 4-fluoro-3- (trifhioromethyl)aniline (1.08 g, 6.05 mmol) and DiPEA (1.56 g, 2.11 mL, 12.1 mmol) in DCM (25 mL) was added at RT. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with H2O, NaCl sat. aq. solution (3 x 10 mL) and dried over anhydrous MgSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and the precipitate was filtered and rinsed with DCM. The filtrate was purified by silica gel chromatography (0-50% EtOAc in cyclohexane) to afford the title product (1.6 g, 76%) as a yellow' crystalline solid. ES-MS m/z 345 (M+H).
Preparation 65
2-Amino-4-fluoro-A-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide
Figure imgf000119_0001
[0146] To a solution of Pd/C (197 mg, 924 μmol) in EtOAc (10 mL) was added a solution of 4- fluoro-jV-(4-fluoro-3-(trifluoromethyl)phenyl)-2-nitrobenzamide (1.60 g, 4.62 mmol) in EtOAc (30 mL). The flask was then evacuated twice with N2 and then placed under 276 KPa of H2 (gas) (9.34 mg, 4.62 mmol). The reaction was stirred at RT for 6 h. The reaction mixture was filtered through a pad of diatomaceous earth and the solvent removed under reduced pressure. The residue w as diluted with EtOAc, heated and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-20% EtOAc in cyclohexane) to give the title product (1 .08 g, 65%) as a white solid. ES-MS m/z 315 (M+H).
[0147] The following compounds were prepared essentially as described in Preparation 64:
Figure imgf000119_0002
Figure imgf000120_0002
a. Starting materials used: 2-amino-4-fluoro-N-(4-fluoro-3-
(trifluoromethyl)phenyl)benzamide and 2-fluoro-4-methoxynicotinic acid
Preparation 67 tert-Buh l (R)-3-((3-((5-fluoro-2-((4-fluoro-3-
(trifluoromethyl)phenyl)carbamoyl)phenyl)carbamoyl)-4-methoxypyri din-2 -yl)amino)piperidine-
1 -carboxylate
Figure imgf000120_0001
[0148] A solution of /e/7-butyl (R)-3-aminopiperidine-l -carboxylate (320.0 mg, 1.6 mmol), 2- fluoro-A-(5-fluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4- methoxynicotinamide (500.0 mg, 1.1 mmol), NMP (5 ml), and DiPEA (275.4 mg, 371 pL, 2.1 mmol) was stirred at 80 °C overnight. The reaction mixture was cooled to RT, and extracted with EtOAc. The combined organic layers were washed with EI2O. NaCl sat. aq. solution and dried over anhydrous MgSCh. After filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel chromatography (0-30% EtOAc in DCM) to afford the title product (480.0 mg. 69%) as a white solid. ES-MS m/z 650 (M+H). Preparation 68
3-(l,3,4-Oxadiazol-2-yl)bicyclo[l. l.l]pentan-l-amine; hydrochloride
Figure imgf000121_0001
[0149] A solution of /e/7-Butyl (3-(l,3,4-oxadiazol-2-yl)bicyclo[l. l.l]pentan-l-yl)carbamate (700 mg, 3 mmol) in HCI (4 M solution in 1,4-di oxane, 20 mL) was stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure to afford the title compound (500 mg) as a white solid. ES-MS m/z 152 (M+H).
[0150] The following compounds were prepared essentially as described in Preparation 68 using the appropriate BOC-protected starting material:
Figure imgf000121_0002
Figure imgf000122_0002
Preparation 74
Methyl 2,5-difluoro-4-((3-morpholinobicyclo[L L l]pentan-l-yl)amino)nicotinate
Figure imgf000122_0001
[0151] A solution of 3-morpholinobicyclo[l.l. l]pentan-l-amine (3.49 g, 14.45 mmol), methyl 4- chloro-2.5-difluoronicotinate (2 g. 10 mmol) and DiPEA (8.39 mL. 48.18 mmol) in NMP (200 mL) was stirred for 2 h at 50 °C. The reaction mixture was diluted with H2O (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with NaCl sat. aq. solution (2 x 500 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue w as purified by reversed-phase flash chromatography (Cl 8; ACN in H2O) to give the title compound (1.45 g, 42%) as a white solid. ES-MS m/z 340 (M+H). [0152] The following compounds were prepared essentially as described in Preparation 74 using the appropriate aryl chloride:
Figure imgf000123_0001
a. Starting material used: benzyd 2-fluoro-4-methoxypyridine-3 -carboxylate Preparation 78
4-Methoxy-2-((3-morpholinobicyclo[l .1. l]pentan-l -yl)amino)nicotinic acid
Figure imgf000124_0001
[0153] A solution of benzyl 4-methoxy-2-((3-morpholinobicyclo[l. l .l]pentan-l- yl)amino)nicotinate (15 g, 37 mmol) and Pd/C (15 g) in MeOH (250 mL) was stirred at RT for 16 h under H2 atmosphere. The Reaction mixture was filtered and the filter cake was washed with MeOH (2 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (50 mL). The precipitated solids were collected by filtration, washed with EtOAc (2 x 30 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-20% MeOH in DCM) to afford the title product (4.3295 g) as an off-white solid. ES-MS m/z 320 (M+H).
Preparation 79
Methyl 5-fluoro-2-methoxy-4-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)nicotinate
Figure imgf000124_0002
[0154] A solution of methyl 2,5-difluoro-4-((3-morpholinobicyclo[l.l.l]pentan-l- yl)amino)nicotinate (500 mg, 2 mmol) and NaOMe (95.52 mg, 1.77 mmol) in MeOH (50 mL) was stirred overnight at 80 °C. The reaction mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with NaCl sat. aq. solution (2 x 100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to afford the title compound (300 mg, 55%) as a white solid. ES-MS m,z 352 (M+H).
[0155] The following compound was prepared essentially as described in Preparation 79:
Figure imgf000125_0002
Preparation 81
Methyl cA-3-(4-methoxy-6-((3-morpholinobicyclo[ 1.1.1 ]pentan- l-yl)amino)pyrimidine-5- carboxamido)bicvclo[2.2.2]octane-2-carboxvlate (racemic mixture)
Figure imgf000125_0001
[0156] A solution of 4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine- 5-carboxylic acid (98.0 mg), methyl cA-3-aminobicyclo[2.2.2]octane-2-carboxylate; hydrochloride (racemic mixture) (60.8 mg) and DiPEA (120 0.687 mmol) inμ AL,CN (1.9 mL) was stirred at 100 °C for 3 min. A solution of TCFEI (80.4 mg) and NMI (65.0 0.815 mmol) μL, in ACN (1.9 mL) was added to the reaction mixture, and was stirred at 100 °C for 30 min. The reaction mixture was cooled to 25 °C, then H2O (10 mL) and EtOAc (10 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried using a phase separator and concentrated under vacuum. The residue was purified by silica gel chromatography (1-50% EtOH/EtOAc (3: 1) in w-heptane). Fractions were combined and concentrated under reduced pressure to afford the title product (69.0 mg, 59%) as a pale yellow gum. ES-MS m/z 486 (M+H).
Preparation 82
Methyl 2-(4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5- carboxamido)benzoate
Figure imgf000126_0001
[0157] To a solution of 4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l- yl)amino)pyrimidine-5-carboxylic acid (400 mg, 1 mmol), methyl 2-aminobenzoate (283 mg, 242 μL, 2 mmol), BOP-CI (381 mg, 2 mmol) in NMP (12.5 mL) was added DiPEA (968 mg, 1.31 mL, 8 mmol). The reaction mixture was stirred at 50 °C for 12 h. After 12 h, the solvent was removed and the residue was purified directly by reverse phase column chromatography (Cl 8. 0.1% FA in H2O, 0.1% FA in ACN) to afford the title product (335 mg, 53%) as a white solid. ES-MS m z 454 (M+H).
Preparation 83 4-Methoxy-2-methyl-6-((3-morpholinobicy clo[ 1. 1. 1 ]pentan- 1 -yl)amino)pyrimidine-5-carboxylic acid
0
HN_N^
OH Ox
[0158] To a stirred solution of methyl 4-methoxy-2-methyl-6-((3- morpholinobicyclo[l.l.l]pentan-l-yl)amino)pyrimidine-5-carboxylate (120 mg) in THF (10 mL) was added LiOH.FbO (28.90 mg, 0.69 mmol) in H2O (10 mL) dropwise at 0 °C. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure to give the title product (100 mg) as a white solid. ES-MS m/z 335 (M+H).
[0159] The following compounds were prepared essentially as described in Preparation 83 using the appropriate ester:
Figure imgf000127_0001
Figure imgf000128_0001
Preparation 88
Methyl 4-methoxy-2-(methylsulfonyl)-6-((3-morpholinobicyclo[l. l. l]pentan-l- yl)amino)pyrimidine-5-carboxylate
Figure imgf000129_0001
[0160] A solution of methyl 4-methoxy-2-(methylthio)-6-((3-morpholinobicyclo[l. l. l]pentan-l- yl)amino)pyrimidine-5-carboxylate (1.2 g, 3.2 mmol) and m-CPBA (1.31 g, 7.57 mmol) in DCM (30 mL) was stirred overnight at RT under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (8- 10% MeOH in DCM) to afford the title product (1.2 g, 92%) as a light yellow solid. ES-MS m/z 413 (M+H).
Preparation 89
Methyl 2-cyano-4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5-
Figure imgf000129_0002
[0161] To a stirred mixture of methyl 4-methoxy-2-(methylsulfonyl)-6-((3- morpholinobicyclo[l.l.l]pentan-l-yl)amino)pyrimidine-5-carboxylate (700 mg, 2 mmol) and trimethylsilanecarbonitrile (336.7 mg, 3.4 mmol) in ACN (20 mL) was added KO/Bu (95.2 mg, 0.9 mmol) in portions at RT under N2 atmosphere. The reaction mixture was stirred for additional 3 h at RT. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with NaCl sat. aq. solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and bis(pinacolato)diboron (2154.8 mg, 8.5 mmol) was added dropwise at RT. The reaction mixture was stirred for additional 3 h at RT. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with NaCl sat. aq. solution (100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-50% EtOAc in petroleum ether) to afford the title product (350 mg, 57%) as a white solid. 'H NMR (400 MHz, DMSO-ife) 5 8.70 (s, 1H), 3.92 (s, 3H), 3.81 (s. 3H), 3.58 (t, 4H), 2.38 (t, 4H). 2.09 (s. 6H).
Preparation 90
N5-(( 1 S,2R,3S,4R)-3-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1 ]heptan-2- yl)-4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-2,5-di carboxamide
Figure imgf000130_0001
[0162] A solution of methyl 2-cyano-4-methoxy-6-((3-morphohnobicyclo[l. 1. l]pentan-l- yl)amino)pyrimidine-5-carboxylate (300 mg) and LiOH.H2O (70.05 mg, 1.67 mmol) in THF (10 mL)/H20 (10 mL) was stirred overnight at 50 °C under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL). The mixture was acidified to pH = 5 with concentrated HC1. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with NaCl sat. aq. solution (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To a stirred solution of the residue (200 mg) and (lR,2S,3R,4S)-3-amino-A-(4-fluoro-3-(trifluoromethyl)phenyl)bicyclo[2.2.1 ]heptane- 2-carboxamide (274.76 mg, 0.87 mmol) in ACN (30 mL) were added NMI (190. 19 mg, 2.32 mmol) and TCFH (324.97 mg, 1.16 mmol) dropwise at RT under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with NaCl sat. aq. solution (2 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography (Cl 8; mobile phase. 20- 30% ACN in H2O (0.1% FA)). The resulting mixture was concentrated under reduced pressure to afford the title product (130 mg, 36%) as a light yellow solid. ES-MS m/z 662 (M+H).
Preparation 91
2-Amino-4-methoxy-n-(l-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzamide
Figure imgf000131_0001
[0163] To a reaction vessel was added l-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan-4-amine hydrochloride (2.77 g, 12.0 mmol), 2-amino-4-methoxybenzoic acid (2.00, 12.0 mmol), PyBOP (9.34 g, 18.0 mmol) and EtOAc (20 mL), followed by DIPEA (4.64 g, 6.26 mL, 35.9 mmol). The reaction was warmed to 30 °C for 18 h. then EtOAc was added. The mixture was washed twice with HO (1 M aq., 100 mL), then sat. aq. NaCl. The organics were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (2 g, 50%). ES-MS m/z 345 (M+H).
Preparation 92
6-Amino-2,2-difluoro-N-(l-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan-4- y l)benzo[d] [ 1 ,3] dioxole-5 -carboxamide
Figure imgf000131_0002
[0164] The title compound was prepared essentially as described in Preparation 91 using 6- amino-2,2-difluorobenzo[d][L3]dioxole-5-carboxylic acid. ES-MS m/z 395 (M+H). Preparation 93 tert-Butyl (4-((2,2-difluorobenzo[d][l,3]dioxol-5-yl)carbamoyl)-6-methoxypyridin-3- yl)carbamate
Figure imgf000132_0001
[0165] The title compound was prepared essentially as described in Preparation 91 using 5-((tert- butoxycarbonyl)amino)-2-methoxyisonicotinic acid and
2,2-difluorobenzo[d][l,3]dioxol-5-amine, using NMP as solvent and heating the reaction to 60 °C for 18 h. ES-MS m 'z 424 (M+H).
Preparation 94
Methyl 2-methoxy-5-(4-methoxy-2-((3-morpholinobicyclo[l . 1. l]pentan-l- yl)amino)nicotinamido)isonicotinate
Figure imgf000132_0002
[0166] To a solution of 4-methoxy-2-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)nicotinic acid (1 .55 g, 4.85 mmol), methyl 5-amino-2-methoxyisonicotinate (884 mg, 4.85 mmol) and TEA (1.47 g, 2.03 rnL, 14.6 mmol) in NMP (15 mL) was added PPACA (50% solution in EtOAc, 15.4 g, 14.3 mL, 24.3 mmol) dropwise and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was allowed to cool down to RT and washed with water, then extracted with DCM (4 x 15 mL) and purified via reverse phase flash chromatography eluting with a gradient of 50 to 70% ACN (+ 0.1% FA) in 0.1% aq. FA to give the title compound (1.25 g, 53%) as a solid. ES-MS m z 484 (M+H). Preparation 95 N-(4-Fluoro-3-(trifluoromethyl)phenyl)-4-methoxy-2-nitrobenzamide [0167] To a solution of 4-metho mg, 1.53 mmol) and 4-fluoro-3-
Figure imgf000133_0001
(trifluoromethyl)aniline hydrochloride (363 mg, 1.69 mmol) in NMP (5 mL) was added PPACA (50 wt% solution in EtOAc, 2.92 g, 3 mL, 4.60 mmol) and TEA (930 mg, 1.3 mL, 9.19 mmol) were added and the reaction was stirred at 60 °C for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated to give the title compound (549 mg, quantitative yield). ES-MS m/z 359 (M+H). Preparation 96 tert-Butyl (4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)carbamate [0168] To a mixture of 5-((tert-
Figure imgf000133_0002
thoxyisonicotinic acid (0.500 g, 1.86 mmol), 4-fluoro-3-(trifluoromethyl)aniline (.670 g, 3.74 mmol), 1-methylimidazole (0.37 g, .36 mL, 4.5mmol), and N,N,N‘,N‘-tetramethylchloroformamidinium hexafluorophosphate (.630 g, 2.25 mmol) was added acetonitrile (10 mL) and the mixture was stirred for 16 h. The reaction mixture was concentrated and the residue was dissolved taken up in ethyl acetate. The organics were washed with sat. aq. NaHCO3, sat. aq. NH4Cl, then sat. aq. NaCl. The organics were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0 to 100% ethyl acetate in cyclohexane to give the title compound (0.725 g, 91 %) as a yellow solid. ES-MS m/z 330 (M+H). [0169] The following compounds were prepared essentially as described in Preparation 96 using the appropriate amine and carboxylic acid. Preparation Compound name Struc ES-MS number ture m/z ) 7 ) )
Figure imgf000134_0002
Preparation 100 tert-Butyl (6-methoxy-4-((1-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamoyl)pyridin- 3-yl)carbamate [0170] A mixture of 5-((tert-buto
Figure imgf000134_0001
oxyisonicotinic acid (2.0 g, 7.5 mmol), TCFH (2.5 g, 8.9 mmol), 1-(tert-butyl)-2-oxabicyclo[2.2.2]octan-4-amine (2.0 g, 11 mmol) and 1-methylimidazole (1.5 g, 1.5 mL, 19 mmol) in ACN (40 mL) was stirred at RT overnight. Water (75 mL) was added and the reaction mixture was stirred for 45 min. The resulting solid was filtered, washed with water, and dried under reduced pressure at 40 °C for 1 h. The solid was stirred in diethyl ether for 20 min, then filtered and dried under reduced pressure at 40 °C for 2 h to give the title compound (1.5 g) as a pale yellow solid. ES-MS m/z 446 (M+H). Preparation 101 5-Amino-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-methoxyisonicotinamide [0171] To a solution of tert-but 3]dioxol-5-yl)carbamoyl)-6-
Figure imgf000135_0001
methoxypyridin-3-yl)carbamate (623 mg, 1.47 mmol) in DCM (2 mL) was added TFA (721 mg, 487 μL, 7.36 mmol). After 20 min the reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (476 mg, quantitative yield). ES- MS m/z 324 (M+H). [0172] The following compounds were prepared essentially as described in Preparation 101 using the appropriate Boc-protected amine. Preparation Compound name Str ES-MS number ucture m/z ) ) )
Figure imgf000135_0002
flash chromatography using a gradient of 10 to 100% ACN in 10 mM aq. NH4HCO3 [0173] The following compounds were prepared essentially as described in Preparation 8 using the appropriate aryl or heteroaryl nitrate, using acetone and water as the reaction solvent and stirring the reaction at 30 °C for 1 h.
Figure imgf000136_0002
Preparation 107
2-Fluoro-N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)-4- methoxynicotinamide
Figure imgf000136_0001
[0174] To a mixture of 2-fluoro-4-methoxynicotinic acid (0.400 g, 2.34 mmol) and DCM (10 mL) was added oxalyl chloride (0.29 g, 0.20 mL, 2.3 mmol) followed by DMF (0.2 g, 0.2 mL, 3 mmol) drop-wise and stirred for 30 min. A solution of 5-amino-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2-methoxyisoni cotinamide (0.93 g, 2.8 mmol) dissolved in THF (5 mL) was added at 0 °C followed by DIPEA (0.89 g, 1.2 mL, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 16 h, then diluted with EtOAc. The mixture was washed with sat. aq. NaHCCh. water, then sat. aq. NaCl. The organic phase was concentrated, then the residue was mixed with a minimal amount of EtOAc with sonication. The solid was collected and rinsed with cold EtOAc. The solid was dried under reduced pressure to give the title compound (0.853 g, 76 %) as white solid. ES-MS m z 483 (M+H). [0175] The following compounds were prepared essentially as described in Preparation 107 using the appropriate acid and amine.
Figure imgf000137_0002
Preparation 111 terLButyl (3-(2-(2-chloroethoxy)acetamido)bicyclo[l.l. l]pentan-l-yl)carbamate
Figure imgf000137_0001
[0176] To a reaction vessel was added tert-butyl (3-aminobicyclo[l.l.l]pentan-l-yl)carbamate (0.380 g, 1.92 mmol), DMF (8 mL), 2-(2-chloroethoxy)acetic acid (0.220 g, 1.59 mmol), and HATU (0.73 g, 1.9 mmol). DIPEA (0.45 g, 0.60 mL, 3.4 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with EtOAc and washed three times with water, then sat. aq. NaCl. The organics were dried over MgSO4, fdtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (0.300 g, 60%). ES-MS m/z 319 (M+H). Preparation 112 tert- Butyl (3-(3-oxomorpholino)bicyclo[l. l. l]pentan-l-yl)carbamate
Figure imgf000138_0001
[0177] A mixture oftert-butyl (3-(2-(2-chloroethoxy)acetamido)bicyclo[l. l. l]pentan-l- yl)carbamate (0.295 g, 925 μmol), DMF (5.0 mL), and K2CO3 (0.260 g, 1.88 mmol) was heated to 80 °C for 23 h, then cooled to RT. The mixture was fdtered and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (0.295 g. quantitative yield). ES-MS m/z 283 (M+H)
Preparation 113
4-(3-Aminobicyclo[l. 1. 1] pentan- l-yl)morpholin-3 -one
Figure imgf000138_0002
[0178] A mixture oftert-butyl (3-(3-oxomorpholino)bicyclo[l. l. l]pentan-l-yl)carbamate (261 mg, 0.925 mmol), DCM (1.5 mL), and TFA (2.2 g, 1.5 mL, 19 mmol) was stirred for 3 h, then concentrated under reduced pressure. The residue was purified by loading it as a MeOH solution onto SCX resin, which was flushed with MeOH. The colum was then eluted with a solution of NH3 in MeOH and the eluate was concentrated under reduced pressure to give the title compound (0.180 g, quantitative yield). ES-MS m,'z 183 (M+H).
Preparation 114
3-((3-((4-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)carbamoyl)-4- methoxypyridin-2-yl)amino)bicyclo[l .1. 1] pentane- 1 -carboxylic acid
Figure imgf000139_0001
[0179] To a mixture of 2-fluoro-N-(4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6- methoxypyridin-3-yl)-4-methoxynicotinamide (0.222 g, 460 μmol) and methyl 3- aminobicyclo[l. l. l]pentane-l-carboxylate (0.134 g, 949 μmol) in NMP (2.0 mL) was added DIPEA (0.22 g, 0.30 mL, 1.7 mmol). The reaction vessel was sealed and heated at 80 °C for 18 h, then 1.3.4.6.7.8-hexahydro-2H-pyrimido[1.2-a]pyrimidine (0.200 g, 1.44 mmol) was added followed by THF (1 mL). The reaction mixture was heated at 80 °C for 20 h, then combined with a reaction mixture run in the same manner on 100 pmol scale. The mixture was purified by reverse-phase flash chromatography using a gradient of 10 to 100% ACN in 10 mM aq. NH4HCO3 to give the title compound (0. 135 mg, 46%) as a solid. ES-MS mz 590 (M+FI).
Preparation 115
Methyl 5-(2-fluoro-4-methoxynicotinamido)-2-methoxyisonicotinate
Figure imgf000139_0002
[0180] A mixture of 2-fluoro-4-methoxynicotinic acid (1.35 g, 7.89 mmol), DCM (60.0 mL), oxalyl dichloride (1.44 g, 960 11.3 mμLm,ol), and DMF (23.6 mg, 25.0 323 μmol) was μL, stirred at RT under nitrogen for 68 h. The mixture was concentrated under reduced pressure, then the residue was dissolved in DCM (30 mL). The resulting solution was added dropwise to a solution of methyl 5-amino-2-methoxyisoni cotinate (1.18 g, 6.48 mmol) and DIPEA (2.52 g 3.40 mL, 19.5 mmol) in DCM (30 mL). The mixture was stirred for 2 h, then washed with HO (0.5 N aq. solution), sat. aq. NaHCO3, and then sat. aq. NaCl. The organics were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in DCM to give the title compound (2.00 g, 92%) as a solid. ES-MS m/z 336 (M+H).
Preparation 116
Methyl 2-methoxy-5-(4-methoxy-6-((3-morpholinobicyclo[l.l.l]pentan-l-yl)amino)pyrimidine-
5-carboxamido)isonicotinate
Figure imgf000140_0001
[0181] To a stirred solution of 4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l- yl)amino)pyrimidine-5-carboxylic acid (5.60 g, 17.5 mmol) in DMF (56 mL) was added hydroxybenzotriazole (2.84 g, 21 mmol) and methyl 5-amino-2-methoxyisonicotinate (3.82 g, 21 mmol). The mixture was stirred at 20 to 30 °C for 5 min followed by the addition of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (4.03 g. 21 mmol). The reaction mixture was stirred at 20 to 30 °C for 15 h, then water (112 mL) was added droppwise. The solid which formed was then collected by filtration, rinsed with water (30 mL), and dried at 45 °C for 16 h to give the title compound (8.33 g, 98%) as a solid. ES-MS m,'z 485 (M+H). Preparation 117
Methyl (R)-5-(2-((l-(tert-butoxycarbonyl)piperidin-3-yl)amino)-4-methoxynicotinamido)-2- methoxyisonicotinate
Figure imgf000141_0001
[0182] A mixture of methyl 5-(2-fluoro-4-methoxynicotinamido)-2-methoxyisonicotinate (500.0 mg, 1.491 mmol), tert-butyl (R)-3 -aminopiperidine- 1 -carboxylate (525.0 mg, 2.621 mmol), DIPEA (579 mg. 780 4μ.4L8, mmol), and NMP (6.0 mL) was stirred at 80 °C for 22 h. Water was added and the reaction mixture was extracted three times with EtOAc. The combined organics were washed three times with water and once with sat. aq. NaCl, then dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in DCM to give the title compound (525 mg, 69%) as a solid. ES-MS m/z 516 (M+H).
Preparation 118
Methyl (R)-2-methoxy-5-(4-methoxy-2-(piperidin-3-ylamino)nicotinamido)isonicotinate
Figure imgf000141_0002
[0183] The title compound was prepared essentially as described in Preparation 101 using methyl (R)-5-(2-((l-(tert-butoxycarbonyl)piperidin-3-yl)amino)-4-methoxynicotinamido)-2- methoxyisonicotinate. The reaction mixture was loaded onto SCX resin, rinsed with MeOH, then eluted, collected, and concentrated a solution of NH3 in MeOH to give the title compound. ES- MS m/z 416 (M+H). Preparation 119 Methyl (R)-2-methoxy-5-(4-methoxy-2-((1-(oxetan-3-yl)piperidin-3- yl)amino)nicotinamido)isonicotinate [0184] To a solution of methyl (R)- oxy-2-(piperidin-3-
Figure imgf000142_0001
ylamino)nicotinamido)isonicotinate (450.0 mg, 82 wt%, 888.2 μmol) in MeOH (4.50 mL) was added acetic acid (52.45 mg, 50.00 μL, 873.4 μmol) and oxetan-3-one (190.0 mg, 2.637 mmol). The mixture was stirred for 20 min, then sodium cyanoborohydride (220 mg, 3.50 mmol) was added. The reaction was stirred at RT for 3 h, then concentrated under reduced pressure. The residue was partitioned between EtOAc and sat. aq. NaHCO3. The organics were washed twice with sat. aq. NaHCO3, then sat. aq. NaCl. The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a gradient of 10 to 100% ACN in water + 0.1% formic acid to give the title compound (250 mg, 60%) as a solid.1H-NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.05 (d, J= 7.0 Hz, 1H), 8.77-8.67 (m, 1H), 8.11 (d, J= 5.7 Hz, 1H), 7.20 (s, 1H), 6.47 (d, J= 5.8 Hz, 1H), 4.51 (td, J= 6.5, 2.5 Hz, 2H), 4.42 (dt, J= 9.9, 6.1 Hz, 2H), 4.24-4.18 (m, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.42 (quintet, J= 6.4 Hz, 1H), 2.62-2.57 (m, 1H), 2.34-2.29 (m, 1H), 2.17-2.15 (m, 1H), 2.01-1.97 (m, 1H), 1.81-1.76 (m, 2H), 1.57-1.49 (m, 2H). Preparation 120
(R)-2-Methoxy-5-(4-methoxy-2-((l-(oxetan-3-yl)piperidin-3-yl)amino)nicotinamido)isonicotinic acid
Figure imgf000143_0001
[0185] A mixture of methyl (R)-2-methoxy-5-(4-methoxy-2-((l-(oxetan-3-yl)piperidin-3- yl)amino)nicotinamido)isonicotinate (250.0 mg, 530.2 μmol), THF (4.50 mL), water (0.500 mL), and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (151.3 mg, 1.087 mmol) was heated to 60 °C for 18 h, then the mixture was acidified to pH 4-5 and the volatile solvents were removed by passing a stream of nitrogen over the mixture at 45 °C. The remaining aqueous solution was purified by reversed phase flash chromatography using a gradient of 5 to 95% ACN in aq. NH4HCO3 (10 mM) + 5% MeOH to give the title compound (217 mg, 89%) as a solid. ES-MS m z 458 (M+H).
Preparation 121
2-Methoxy-5-(4-methoxy-2-((3-morpholinobicyclo[l. l. l]pentan-l- yl)amino)nicotinamido)isonicotinic acid
Figure imgf000143_0002
[0186] A solution of methyl 2-methoxy-5-(4-methoxy-2-((3-morpholinobicyclo[l.l. l]pentan-l- yl)amino)nicotinamido)isonicotinate (146 mg, 302 μmol) in THF (1 mL) was added LiOH (2 M aq. solution, 72.3 mg, 1.51 mL, 3.02 mmol) and EtOH (0.2 mL). The reaction mixture was stirred overnight. 1 M aq. HC1 was added to bring pH to 2, then the mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness give the title compound (119.9 mg, 85%) as a solid. ES-MS m/z 458 (M+H).
Preparation 122
2-Methoxy-5-(4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5- carboxamido)isonicotinic acid
Figure imgf000144_0001
[0187] The title compound was prepared essentially as described in Preparation 121 using methyl 2-methoxy-5-(4-methoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5- carboxamido)isonicotinate. ES-MS m/z 471 (M+H).
Preparation 123
5-Amino-N-(2,2-difluoro-1.3-benzodioxol-5-yl)-3-fluoro-2-methoxypyridine-4-carboxamide
Figure imgf000144_0002
[0188] To a stirred mixture of 5-bromo-N-(2,2-difluoro-l,3-benzodioxol-5-yl)-3-fluoro-2- methoxypyridine-4carboxamide (500 mg, 1.24 mmol) and L-proline (42.63 mg, 0.370 mmol,) in DMSO (3 mL) were added Cui (47.01 mg, 0.247 mmol) and ammonium hydroxide (25%, 3.46 g, 24.7 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 5h under nitrogen atmosphere, then diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 * 100 mL). The combined organic layers were washed with sat. aq. (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using a gradient of 65 to 70% ACN in 10 mM NH4HCO3), 65% to 70% gradient to give the title compound (200 mg, 47%) as a yellow solid. ES-MS m/z 342 (M+H).
Preparation 124
Methyl 4-chloro-6-isopropoxypyrimidine-5-carboxylate
Figure imgf000145_0001
[0189] To a 250 mL round bottom flask equipped with stir bar under an atmosphere of nitrogen was added: 2-propanol (1.60 g, 2.03 mL, 26.6 mmol) and THF (50 mL). The solution was cooled to 0 °C and NaH (60 wt% in mineral oil, 1.06 g, 26.6 mmol) was added portion- wise. The reaction mixture stirred 30 min in an ice bath, then methyl 4,6-dichloropyrimidine-5- carboxylate (5.00 g, 24.2 mmol) was added in one portion and reaction continued to stir in an ice bath. The reaction was stirred slowly warming to ambient temperature, then stirred 22 h. The reaction was quenched with sat. aq. NH4CI and stirred 5 min, then diluted with minimal water and EtOAc. The organic phase was washed with sat. aq. NaHCO3, then sat. aq. NaCl. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (1.91 g. 27%) as an oil. ES-MS m/z 231 (M+H).
[0190] The following compounds were prepared as described in Preparation 124 using the appropriate alcohol.
Figure imgf000145_0002
Figure imgf000146_0002
a. Silica gel chromatography gradient: 0 to 25% EtOAc in hexanes
Preparation 128
4-Isopropoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5-carboxylic acid
Figure imgf000146_0001
[0191] To a mixture of methyl 4-chloro-6-isopropoxypyrimidine-5-carboxylate (0.835 g, 3.62 mmol) and 3-morpholinobicyclo[l. l. l]pentan-l-amine (1.05 g. 6.24 mmol) was added NMP (10 rnL) followed by DIPEA (1.3 g, 1.8 mL, 10 mmol). The reaction vessel was sealed and heated at 80 °C for 16 h, then cooled to ambient temperature and diluted with water and EtOAc. The organics were washed with sat. aq. NaHCOa. water, and then sat. aq. NaCl. The organic phase was dried over MgSO4, filtered, and concentrated. To the residue was added 1, 3, 4, 6.7.8- hexahydro-2H-pyrimido[l,2-a]pyrimidine (1.51 g, 10.8 mmol), THF (5 rnL), and water (1 mL). The solution was heated to 50 °C and stirred for 90 min, then concentrated under a stream of nitrogen and added 10% aq. citric acid (2 mL). The solution was purified by reverse phase flash chromatography using agradient of 10 to 100% ACN in aq. NH4HCO3 (10 mM) to give the title compound (1.26 g, 48%). ES-MS m/z 349 (M+H).
[0192] The following compounds were prepared as described in Preparation 128 using the appropriate heteroaryl halide.
Figure imgf000146_0003
Figure imgf000147_0001
b. The product was further purified by slurry ing in EtOAc and EtOH, and the solid was filtered and dned under reduced pressure.
Preparation 131
4-Ethoxy-6-((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)pyrimidine-5-carboxylic acid
Figure imgf000147_0002
[0193] A mixture of methyl 4-chloro-6-ethoxypyrimidine-5-carboxylate (0.600 g, 2.77 mmol), 3- morpholinobicyclo[l.l.l]pentan-l-amine (0.660 g, 3.92 mmol) and DIPEA (0.74 g, 1.0 mL, 5.7 mmol) in NMP (10 mL) was heated to 80 °C for 4 days, then cooled to RT and diluted with water and EtOAc. The organic phase was washed with sat. aq. NaHCO3. water, then sat. aq. NaCl.
The organics were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give methyl 4- ethoxy-6-((3-morpholinobicyclo[l.l. l]pentan-l-yl)amino)pyrimidine-5-carboxylate, which was mixed with l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (0.280 g, 2.01 mmol), THF (3 mL), and water (0.5 mL). The mixture was heated to 50 °C for 2 h. then cooled to RT and adjusted to pH 5 with 10% aq. citric acid. The mixture was concentrated under a stream of nitrogen to reduce the volume of THF, then purified by reverse phase flash chromatography using a gradient of 10 to 100% ACN in 10 mM aq. NH4HCO3 to give the title compound (0. 151 g, 68%). ES-MS m/z 335 (M+H).
Preparation 132
Benzyl 2-((3-((tert-butoxycarbonyl)amino)bicyclo[l . 1 .1 ]pentan-l -yl)amino)-4- methoxynicotinate
Figure imgf000148_0001
[0194] A solution of tert-butyl N-{3-aminobicyclo[l. l.l]pentan-l-yl}carbamate (5.69 g, 28.709 mmol) and DIPEA (7.42 g, 57.417 mmol) in DMSO (20 mL) was stirred at RT for 20 min under N2 atmosphere. To the reaction mixture was added benzyl 2-fluoro-4-methoxypyridine-3- carboxylate (5 g, 19. 139 mmol) dropwise at RT. The resulting mixture was stirred at 90 °C for additional 16 h. The resulting mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H2O (2 x 100 mL) and dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure to afford the title product (10 g) as a yellow oil. ES-MS m/z 440 (M+H).
Preparation 133
Benzyl 2-((3-aminobicyclo[l. 1. l]pentan-l-yl)amino)-4-methoxynicotinate hydrochloride
Figure imgf000149_0001
[0195] To a solution of benzyl 2-({3-[(to7-butoxycarbonyl)amino]bicyclo[l. l.l]pentan-l- yl}amino)-4-methoxypyridine-3-carboxylate (2.5 g. 5.68 mmol) in ACN (100 mL) was added HC1 (4 M solution in 1,4-di oxane, 25 mL) dropwise and the resulting mixture was stirred at RT for 2 h. The resulting mixture was concentrated under reduced pressure to give the title product (2 g, 72%) as a solid. ES-MS m/z 340 (M+H).
Preparation 134
Benzyl 2-((3-(3-hydroxypyrrolidin-l-yl)bicyclo[l. 1.1] pentan- l-yl)amino)-4-methoxynicotinate (Isomer 1)
Figure imgf000149_0002
[0196] To a stirred mixture of benzyl 2-((3-aminobicyclo[l. l.l]pentan-l-yl)amino)-4- methoxynicotinate (2 g, 5.80 mmol) and l,4-dichlorobutan-2-ol (racemic mixture, 1.00 g, 7.05 mmol) in DMF (50 mL) were added CS2CO3 (3.77 g, 11.60 mmol) and KI (0.962 g, 5.80 mmol) in portions at RT. The resulting mixture was stirred at 90 °C for 5h. The reaction was quenched by the addition of water (150 mL) at RT, then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL). dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using a gradient of 10 to 80% ACN in 0.1% aq. NH4OH to give the title compound (0.78 g, 33 %) as a racemic mixture. The product was purified by chiral HPLC [column: CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 pm; mobile phase: solvent A - hexanes + 0.1% diethylamine, solvent B - IPA; gradient: isocratic 10% solvent B in solvent A] to give the title compound (76 mg) as the first-eluting isomer (white solid). ES-MS m/z 410 (M+H).
Preparation 135
Benzyl 2-((3 -( 1 , 1 -dioxidothiomorphohno)bicyclo[l . 1. 1 ]pentan- 1 -yl)amino)-4-methoxynicotinate
Figure imgf000150_0001
[0197] The title compound was prepared as described in Preparation 134 using l-chloro-2-(2- chloroethanesulfonyl)ethane. DCM was used in the aqueous extraction step instead of EtOAc, and the product was purified by reverse phase flash chromatography using a gradient of 70 to 75% ACN in 0. 1% aq. formic acid. ES-MS m/z 458 (M+H).
Preparation 136 2-((3-(3-Hydroxypyrrolidin-l-yl)bicyclo[l.l.l]pentan-l-yl)amino)-4- methoxynicotinic acid (Isomer 1)
Figure imgf000150_0002
[0198] To a stirred solution of benzyl 2-((3-(3-hydroxypyrrolidin-l-yl)bicyclo[l. l. l]pentan-l- yl)amino)-4-methoxynicotinate (Isomer 1, 76 mg, 0.185 mmol) in MeOH (20 mL) was added 10% palladium on carbon (20 mg) at RT. The resulting mixture was stirred at RT for 1 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with methanol (3 x io mL). and the filtrate was concentrated under reduced pressure to afford the title compound (40 mg, 68%) as a white solid. ES-MS m/z 320 (M+H). Preparation 137
2-((3-(l,l-Dioxidothiomorpholino)bicyclo[l.l.l]pentan-l-yl)amino)-4-methoxynicotinic acid
Figure imgf000151_0001
[0199] The title compound was prepared as described in Preparation 136 using benzy l 2-((3-(l,l- dioxidothiomorpholino)bicyclo[l.l.l]pentan-l-yl)amino)-4-methoxyni cotinate, stirring the reaction for 3 h under hydrogen atmosphere. ES-MS m/z 368 (M+H).
EXAMPLES
Example 1
N-((lS,2R,3S,4R)-3-((4-Cyano-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-
4-methoxy-6-((3-morpholinobicyclo[l.l.l]pentan-l-yl)amino)pyrimidine-5-carboxamide
Figure imgf000151_0002
[0200] To a mixture of (lR,2S,3R,4S)-3-(4-methoxy-6-((3-morpholinobicyclo[l.l.l]pentan-l- yl)amino)pyrimidine-5-carboxamido)bicyclo[2.2. l]heptane-2-carboxylic acid (50 mg, 0.11 mmol) and 4-amino-2-(trifluoromethyl)benzonitrile (22 mg, 0.12 mmol) was added TCFH (34 mg, 0.12 mmol) and 1 -Methylimidazole (20 mg, 19 0.24 mmol) inμ AL,CN (1.1 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was then concentrated and purified directly by reverse phase column chromatography (Cl 8, 0.1% FA in H2O, 0.1% FA in ACN) to afford the title compound (14.0 mg, 21 pmol, 19%) as a white solid. ES-MS m/z 626 (M+H).
[0201] The following were prepared essentially as described in Example 1 using the appropriate carboxylic acid and aniline:
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Example 12
N-((lS,2R,3S,4R)-3-((4-Fluoro-3-(pentafluoro-X6-sulfaneyl)phenyl)carbamoyl) bicyclo[2.2.1]heptan-2-yl)-4-methoxy-6-((3-morpholinobicyclo[l.l.l]pentan-l- yl)amino)pyrimidine-5-carboxamide
Figure imgf000156_0001
[0202] To a mixture of 4-chloro-N-((lS,2R,3S,4R)-3-((4-fluoro-3-(pentafluoro-X6- sulfaneyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxypyrimidine-5-carboxamide (64.1 mg, 118 μmol), 3-morpholinobicyclo[l. l. l]pentan-l-amine dihydrochloride (33.2 mg, 138 μmol) and DiPEA (89.0 mg, 688pmol, 0.12 mL) were dissolved in DMF (4 mL). The reaction was stirred at 80 °C for 3 hours. Upon reaction completion, the reaction was partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0-100% EtOAc in heptane then 0-20% MeOH in DCM. then the product was repurified via reverse phase chromatography using 0-100% ACN/H2O (0.1% FA modifier in both eluents) to give title compound (14.4 mg, 21.3 pmol, 19%). ES-MS m/z 677 (M+H).
[0203] The following were prepared essentially as described in Example 12 using the appropriate aryl halide and amine:
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0002
Example 29
(lS,3R)-3-((6-Methoxy-5-((2-((3-
((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)pyrimidin-4- yl)amino)cyclohexane-l-carboxylic acid
Figure imgf000162_0001
[0204] To a solution of methyl (lS,3R)-3-((6-methoxy-5-((2-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)carbamoyl)pyrimidin-4-yl)amino)cyclohexane- 1 -carboxylate (295 mg, 464 μmol) in THF (1 mL) was added LiOH (2 M aq., I l l mg, 2.32 mL, 4.64 mmol) and EtOH (0.2 mL). The reaction mixture was heated to 60 °C and stirred for 45 minutes. IM HC1 was added to bring the mixture to pH=2. The mixture was extracted with EtOAc (30mL) and the combined organic layers were concentrated. The residue was purified via reverse phase chromatography (Cl 8) eluting with a gradient of 45% to 85% 0.1% aqueous FA in 0.1% FA in ACN to give the title compound (57.5 mg, 92.5 pmol, 20%) as an off-white solid. ES-MS m z 622 (M+H). [0205] The following were prepared essentially as described in Example 29 using the appropriate ester starting material:
Figure imgf000163_0002
Figure imgf000163_0001
Figure imgf000164_0001
a. The product was the second-eluting isomer when purified by chiral chromatography [column: Phenomenex® Lux® i-Amylose-1, 30 x 150 mm, 5 pm; mobile phase: 5-20% isopropanol in heptane] . b. The product was the second-eluting isomer when purified by chiral normal phase chromatography [column: Phenomenex® Lux® i-Amylose-3, 30 x 150 mm, 5 pm; mobile phase: 23% MeOH/CCL], c. The product was the second-eluting isomer when purified by chiral chromatography [column: Phenomenex® Lux® i-Amylose-1, 30 x 150 mm, 5 pm; mobile phase: 10-20% isopropanol in heptane] . Example 36
N-((lS,2R.3S,4R)-3-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-
4-methoxy-6-((4-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)amino)pyrimidine-5- carboxamide
Figure imgf000165_0001
[0206] To a mixture of 4-chloro-N-((lS,2R,3S,4R)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxypyrimidine-5- carboxamide (100 mg. 205 μmol). 3-(4-aminophenyl)-l,2,4-oxadiazol-5(4H)-one HC1 (48.3 mg. 226 μmol) was added p-toluenesulfonic acid monohydrate (39.1 mg, 205 μmol) in isopropanol (2 mL). The reaction mixture was stirred at 80 °C for 2 hours, then the reaction mixture was concentrated and the residue was purified directly by reverse phase column chromatography (Cl 8, 0.1% FA in water. 0.1% FA in ACN) to afford the title compound (47.8 mg, 72 pmol, 35%) as a white solid.
Example 37 4-((4-(l,3,4-Thiadiazol-2-yl)phenyl)amino)-N-((lS,2R,3S,4R)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-6-methoxypyrimidine-5- carboxamide
Figure imgf000166_0001
[0207] The title compound was prepared essentially as described in Example 36 using -(1,3,4- thiadiazol-2-yl)aniline. ES-MS m'z 628 (M+H).
Example 38
N-((lS,2R,3S,4R)-3-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-
4-methoxy-6-((3-morpholino-l,2,4-thiadiazol-5-yl)amino)pyrimidine-5-carboxamide
Figure imgf000166_0002
[0208] To a mixture of 4-chloro-N-((lS,2R.3S,4R)-3-((4-fluoro-3-
(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2. l]heptan-2-yl)-6-methoxypyrimidine-5- carboxamide (48.9 mg, 100 μmol), morpholino-l,2,4-thiadiazol-5-amine (20.3 mg, 109 μmol) was added dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (76.9 mg, 107 μmol) and Na2CO3 (44.0 mg, 415 μmol). The reaction vessel was sealed and purged with argon, then anhydrous, degassed 1,4-dioxane (1.00 mL) was added via syringe. The reaction was purged with argon for an additional 2 minutes before being stirred at 80 °C for 16 hours. The mixture was then partitioned between EtOAc (50 mL) and water (10 mL). The organic layer was dried over Na2SOr, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0- 100% EtOAc in heptane, then the product was re-purified by reversed phase HPLC using ACN and 0.1% FA in water to give the title compound (32.8 mg, 51.5 pmol, 51%). ES-MS m/z 637 (M+H).
[0209] The following were prepared essentially as described in Example 1 using the appropriate carboxylic acid and (lR,2S,3R,4S)-3-amino-N-(4-fluoro-3- (trifluoromethyl)phenyl)bicyclo[2.2.1]heptane-2-carboxamide:
Figure imgf000167_0001
Figure imgf000168_0001
[0210] The following were prepared essentially as described in Example 12 using the appropriate aryl halide and amine:
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Example 51
7V-(2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-6-((3- morpholinobicy clo[l .1. l]pentan-l -yl)amino)pyrimidine-5-carboxamide
Figure imgf000172_0001
[0211] To a solution of 4-fluoro-3-(trifluoromethyl)aniline (42.8 mg, 239 μmol), 2-(4-methoxy- 6-((3-morpholinobicyclo[l.l. l]pentan-l-yl)amino)pyrimidine-5-carboxamido)benzoic acid (100 mg, 228 μmol), PPACA (217 mg, 201 341 μmμoLl,) in DCM (2.28 mb) was added DiPEA (118 mg, 159 μL 9,10 μmol) and the reaction mixture was stirred at 50 °C for 2 h. After 2 h, the reaction mixture was concentrated and then purified directly by reverse phase column chromatography (Cl 8. 0.1% FA in H2O, 0.1% FA in ACN) to give the title product (83 mg, 58%) as a white solid. ES-MS m/z 601 (M+H).
Example 52 N-(cis-3-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.2]octan-2-yl)-4-methoxy-6- ((3-morpholinobicyclo[1.1.1]pentan-1-yl)amino)pyrimidine-5-carboxamide (racemic mixture) [0212] A solution of cis-3-(4-met nobicyclo[1.1.1]pentan-1-
Figure imgf000173_0001
yl)amino)pyrimidine-5-carboxamido)bicyclo[2.2.2]octane-2-carboxylic acid (racemic mixture) (95.7 mg, 0.2 mmol), HATU (110 mg) and TEA (78 µL) in DMF (1.5 mL) was stirred at 25 °C for 5 min, then 4-fluoro-3-(trifluoromethyl)aniline (41.0 mg, 0.2 mmol) was added. The reaction mixture was stirred at 65 °C for 100 min. The reaction mixture was cooled to 25 °C, quenched with H2O (20 mL), and EtOAc (20 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried using a phase separator and concentrated under vacuum. The residue was purified by silica gel chromatography (1-40% EtOAc/EtOH (3:1) in n-heptane). Fractions were combined and concentrated under reduced pressure. The product was purified again by prep-TLC (5% MeOH in DCM) to afford a first isomer (26.0 mg, 21%) as a white foam. ES-MS m/z 633 (M+H).
Example 53 N-(2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-2-((3- morpholinobicyclo[1.1.1]pentan-1-yl)amino)nicotinamide [0213] To a solution of 4-methoxy- clo[1.1.1]pentan-1-yl)amino)nicotinic
Figure imgf000174_0001
acid (200 mg, 626 μmol) in DCE (6.26 mL) was added oxalyl chloride (95.4 mg, 66 μL, 752 μmol), followed by dropwise addition of DMF (114 mg, 121 μL, 2 mmol). After bubbling stopped, 2-amino-N-(4-fluoro-3-(trifluoromethyl)phenyl)benzamide (224 mg, 752 μmol) was added, followed by DiPEA (243 mg, 327 μL, 2 mmol). The reaction mixture was stirred for 20 min, then the mixture was purified directly by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title product (59 mg, 15%). ES-MS m/z 600 (M+H).
Example 54 2-Cyano-N-((1S,2R,3S,4R)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-4-methoxy-6-((3- morpholinobicyclo[1.1.1]pentan-1-yl)amino)pyrimidine-5-carboxamide [0214] To a stirred mixture of N5-( luoro-3-
Figure imgf000175_0001
(trifluoromethyl)phenyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)-4-methoxy-6-((3- morpholinobicyclo[1.1.1]pentan-1-yl)amino)pyrimidine-2,5-dicarboxamide (100 mg) and pyridine (23.91 mg, 0.30 mmol) in toluene (20 mL) was added TFAA (47.6 mg, 0.2 mmol) at RT under N2 atmosphere. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure. A solution of the residue (80 mg) and TEA (43.7 mg, 0.4 mmol) in DMF (2 mL) was stirred for 3 h at 50 °C under N2 atmosphere. The mixture was purified by prep-HPLC (Column: RP18 OBD, 30*150 mm, 5μm; Mobile Phase A: H2O (10 mmol/L NH4HCO3), Mobile Phase B: ACN). The pure fraction was lyophilized to afford the title product (24.8 mg, 26%) as a white solid. ES-MS m/z 644 [M+H]; [a]D25= +91.5 (c=1.0, in MeOH)
Example 55
(R)-A-(5-Fluoro-2-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-2-((l-
(oxetan-3-yl)piperidin-3-yl)amino)ni cotinamide
Figure imgf000176_0001
[0215] To a solution of (R)-A-(5-fluoro-2-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-4-methoxy-2-(piperidin-3-ylamino)nicotinamide (50.0 mg, 91.0 μmol) in MeOH (0.750 mL) was added AcOH (5.46 mg, 91.0 μmol) and oxetan- 3-one (19.7 mg, 273 μmol). The reaction mixture was stirred for 15 min at RT then treated with NaBFECN (17.2 mg, 273 μmol). The reaction mixture was stirred at RT overnight. The solvent was removed under a stream of N2 at 40 °C. The residue was purified by reverse-phase HPLC using a gradient of 40 to 77% ACN in 10 mM aq. NH4HCO3 + 5% MeOH to give the title product (41.1 mg, 75%). ES-MS m/z 606 (M+H).
Example 56 and 57
A-(2-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-4-((3-(3-hydroxypyrrolidin-l- yl)bicyclo[l. l. l]pentan-l-yl)amino)-6-methoxypyrimidine-5-carboxamide (Isomer 1 - Example
56 and Isomer 2 - Example 57)
Figure imgf000177_0001
[0216] To a stirred solution of l-(3-aminobicyclo[l. l. l]pentan-l-yl)pyrrolidin-3-ol; hydrochloride (racemic mixture) (131.00 mg, 0.64 mmol) in DMF (10 mL) was added TEA (88.95 pL. 0.64 mmol) dropwise at RT under N2 atmosphere. The reaction mixture was stirred at RT for 2 h under N2 atmosphere. To the reaction mixture were added 4-chloro-A-(2-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-6-methoxypyrimidine-5-carboxamide (200 mg) and CsF (12.96 mg, 0.09 mmol) in portions at RT. The reaction mixture was stirred at RT for 16 h under N2 atmosphere. The reaction mixture was stirred at 50 °C for another 2 days under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) at RT. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaCl sat. aq. solution (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18, ACN in H2O (0.1% NH3.H2O)) and by prep-HPLC (RP18 OBD Column, ACN in H2O) to afford a racemic mixture of the title product (60 mg, 23%) as a white solid. Then the racemic mixture was purified by chiral-HPLC with the following conditions (Column: Lux 5p Cellulose-2, 30*250 mm, 5.0 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NHs-MeOH)) to afford Isomer 1 (first-eluting isomer, 21.8 mg. 35%) as a white solid with 100%ee, and Isomer 2 (second-eluting isomer, 26.5 mg, 44%) as a white solid with 99.22%ee. Both isomers:
Figure imgf000177_0002
601 (M+H). Example 58 4-Methoxy-N-(5-methoxy-2-((l-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan- 4yl)carbamoyl)phenyl)-6-((3-morpholinobicyclo[l.l. l]pentan-l-yl)amino)pyrimidine5- carboxamide
Figure imgf000178_0001
[0217] To a mixture of 2-amino-4-methoxy-N-(l-(trifluoromethyl)-2-oxabicyclo[2.2.2]octan-4- yl)benzamide (100 mg, 290 μmol) and 4-methoxy-6-((3-morpholinobicyclo[l. 1. l]pentan-l- yl)amino)pyrimidine-5-carboxylic acid (93.0 mg, 290 μmol) dissolved in EtOAc (2 mL) was added 2,4,6-tripropyl-l,3,5,2,4,6trioxatriphosphinane 2,4,6-trioxide (924 mg, 1 mL, 50% Wt, 1.45 mmol) and DIPEA (113 mg, 0.15 mL, 871 μmol) and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was partitioned between EtOAc and water, then the organic layer was dried over Na2SO4, filtered, and concentrated. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptanes, followed by 0 to 20% MeOH in EtOAc to give the title compound (43 mg, 23%). ES-MS m'z 647 (M+H).
[0218] The following examples were prepared essentially as described in Example 58 using the appropriate carboxylic acid and amine:
Figure imgf000179_0001
Figure imgf000180_0001
a. The product was purified by reverse-phase HPLC using a gradient of (50-55 starting %B) to (75-81 ending %B) ACN in 10 mM aq. NH4HCO3 + 5% MeOH.
-I SO-
Example 64
N-(4-((2,2-Difluorobenzo[d][l,3]dioxol-5-yl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxy-2-
((3-morpholinobicyclo[l. l. l]pentan-l-yl)amino)nicotinamide
Figure imgf000181_0001
10219] To a mixture of 5-amino-N-(2.2-difluorobenzo[d][l,3]dioxol-5-yl)-2- methoxyisonicotinamide (80.0 mg, 247 μmol), DIPEA (128 mg, 0.17 mL, 990 μmol), and ((1H- benzo[d][l,2,3]triazol-l-yl)oxy)tri(pyrrolidin-l-yl)phosphonium hexafluorophosphate(V) (386 mg, 742 μmol) in EtOAc (2 mL) was added DIPEA (128 mg, 0.17 mL, 990 μmol) and N,N- dimethylpyridin-4-amine (36.3 mg, 297 μmol). The mixture was stirred for 60 °C for 1 h, then cooled to RT and partitioned between EtOAc (5 mL) and water (5 mL). The organic layer was washed with water (2 x 5 mL), concentrated and the residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (52 mg, 34%). ES-MS m/z 623 (M-H).
Example 65
N-(2,2-Difluoro-l,3-benzodioxol-5-yl)-3-fluoro-2-methoxy-5-(4-methoxy-2-{[3-(morpholin-4- yl)bicyclo[l. l. l]pentan-l-yl]amino}pyridine-3-amido)pyridine-4-carboxamide
Figure imgf000182_0001
[0220] To a stirred mixture of 5-amino-N-(2,2-difluoro-l,3-benzodioxol-5-yl)-3-fluoro-2- methoxypyridine-4-carboxamide (100 mg, 0.293 mmol. 1 equiv.) and 4-methoxy-2-((3- morph olinobicyclo[ 1.1.1] pentan- 1 -yl)amino)nicotinic acid (102.95 mg, 0.322 mmol) in ACN (5 mL) was added TCFH (164.44 mg, 0.586 mmol) and 1 -methyl- IH-imidazole (96.24 mg, 1.172 mmol) at RT under nitrogen atmosphere, and the mixture was stirred for 4 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. aq. (3 x 100 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using a gradient of 45 to 55% ACN in 10 M NH4HCO3 + 0.05% NH4OH to give the title compound (141.3 mg, 75%) as a solid. ES-MS m/z 643 (M+H).
Example 66
4-Isopropoxy-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)-6- ((3 -morpholinobi cy clo [ 1.1.1] pentan- 1 -yl)amino)pyrimidine-5 -carboxamide
Figure imgf000183_0001
[0221] The title compound was prepared essentially as described in Example 65 using 4- isopropoxy-6-((3-morpholinobicyclo[l. 1. l]pentan-l-yl)amino)pyrimidine-5-carboxylic acid and 5-amino-2-methoxy-N-(3-((trifluoromethyl)sulfonyl)phenyl)isonicotinamide. ES-MS m 'z 706 (M+H).
[0222] The following examples were prepared essentially as described in Example 12 using the appropriate aryl halide and amine:
Figure imgf000183_0002
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0002
Example 77
N-(4-((2,2-Difluorobenzo[d][1.3]dioxol-5-yl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxy-6- ((3-morpholinobicyclo[l .1 .1 ]pentan- 1 -yl)amino)pyrimidine-5-carboxamide
Figure imgf000187_0001
[0223] To a mixture of 2-methoxy-5-(4-methoxy-6-((3-morpholinobicyclo[l. l.l]pentan-l- yl)amino)pyrimidine-5-carboxamido)isonicotinic acid (125.6 mg. 267.0 μmol) and 2,2- difluorobenzo[dJ[l,3]dioxol-5-amine (137 mg, 791 μmol) in NMP (2 mL) was added PPACA (339.8 mg, 0.5 mL, 50 wt%, 533.9 μmol) and TEA (108.1 mg, 0.15 mL, 1.068 mmol) and the reaction mixture was stirred at 20 °C for 1 h. The mixture was partitioned between EtOAc and water and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC using a gradient of 38 to 63% ACN in 0.1 % aq. formic acid to give the title compound (15.3 mg, 9%). ES-MS mJz 626 (M+H).
[0224] The following examples were prepared as described in Example 77 using the appropriate amine and carboxylic acid.
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0002
a. 4-Dimethylaminopyridine (1.07-1.9 equivalents) was added when the reaction was set up, and the reaction mixture was heated to 80-85 °C for 18 h - 4 days. The reaction mixture was purified by reverse phase flash chromatography without workup, using a gradient of ACN (5-10 starting %, 95-100 ending %) in 10 mM aq. NH4HCO3 (with optional addition of 5% MeOH). b. The product was purified by reverse phase HPLC using a gradient of 46-71% ACN in 10 mM aq. ammonium acetate + 5% MeOH.
Example 84
N-(4-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxy-2-((3-
(morpholine-4-carbonyl)bicyclo[l. l. l]pentan-l-yl)amino)nicotinamide
Figure imgf000190_0001
[0225] To a mixture of 3-((3-((4-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6- meth oxypyri din-3 -yl)carbamoyl)-4-methoxypyri din-2 -yl)amino)bicyclo [1.1.1] pentane- 1- carboxylic acid (0.049 g, 83 μmol) and morpholine (0.015 g, 0.17 mmol) in NMP (1.0 mL) was added HATU (0.039 g, 0.10 mmol) and DIPEA (22 mg, 0.030 mL, 0.17 mmol). The reaction mixture was stirred at RT for 3 days, then diluted with water and EtOAc. Saturated aq. NH4CI was added to the mixture and the layers were separated. The organics were washed sat. aq. NaHCCh, water, then sat. aq. NaCl. The organics were dried over MgSO-i. filtered, and concentrated. The residue was purified by reverse phase flash chromatography using a gradient of 10 to 100% ACN in 10 mM aq. NH4HCO3. Fractions containing the product were concentrated, then the residue was taken up in EtOAc and the organics were washed with water and sat. aq. NaCl. The organics were dried over MgSO4, filtered, and concentrated to give the title compound (0.024 g, 44%) as a solid. ES-MS m/z 659 (M+H).
Example 85
2-((3-(3-Oxa-6-azabicyclo[3.1.1]heptane-6-carbonyl)bicyclo[l. l. l]pentan-l-yl)amino)-N-(4-((4- fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-6-methoxypyridin-3-yl)-4-methoxy nicotinamide
Figure imgf000191_0001
[0226] The title compound was prepared as Example 84 using 3-oxa-6-azabicyclo[3.1 ,l]heptane hydrochloride and 4 equivalents of DIPEA. ES-MS m/z 671 (M+H). Example 86
4-Methoxy-N-(6-methoxy-4-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)-2-
((3-(5-oxo-4,5-dihydro-1.2,4-oxadiazol-3-yl)bicyclo[l.l.l]pentan-l-yl)amino)nicotinamide
Figure imgf000192_0001
[0227] 2-Fluoro-4-methoxy-N-(6-methoxy-4-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)nicotinarnide (83 mg, 0.16 mmol) and 3-(3-aminobicyclo[l.1.1] pentan- l-yl)-l, 2, 4-oxadiazol-5(4H)-one hydrochloride (38 mg, 0.19 mmol) were combined in N,N-dimethylacetamide and treated with K2HPO4 (82 mg, 0.47 mmol) and the mixture was stirred at 70 °C overnight. The reaction mixture was purified by reverse phase HPLC using a gradient of 48 to 73% ACN in 0.1% aq. formic acid to give the title compound (3.2 mg, 3%). ES-MS m'z 676 (M+H).
Example 87
4-(2,2-Difluoroethoxy)-N-(6-methoxy-4-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)pyridin-3-yl)-6-((3- morpholinobicyclo[l .1. l]pentan- 1 -yl)amino)pyrimidine-5-carboxamide
Figure imgf000193_0001
[0228] To a mixture of 4-(2,2-difluoroethoxy)-6-((3-morpholinobicyclo[l.l. l]pentan-l- yl)amino)pyrimidine-5-carboxylic acid (75 mg, 0.20 mmol), 5-amino-2-methoxy-N-(3- ((trifluoromethyl)sulfonyl)phenyl)isonicotinamide (100 mg, 266 μmol) and TCFH (85 mg, 0.30 mmol) was added ACN (1 mb) and 1 -methylimidazole (67 mg, 0.82 mmol). The mixture was stirred at RT overnight, then purified by reverse phase flash chromatography using a gradient of 10 to 100% ACN in 10 mM aq. NH4HCO3 to give the title compound (66 mg, 45%) as an off- white solid. ES-MS m/z 728 (M+H).
[0229] The following examples were prepared as described in Example 87 using the appropriate amine and carboxylic acid.
Figure imgf000193_0002
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
a. Aqueous workup was performed on the reaction mixture by adding EtOAc and washing the organics with water and sat. aq. NaCl. b. The product was purified by reverse phase HPLC using a gradient of 47 to 49% ACN in 10 mM aq. NH4HCO3 + 0.05% NH4OH. c. After reverse-phase flash purification, the product was slurried in ACN, filtered and dried under reduced pressure.
Aqueous workup was performed on the reaction mixture by adding water and extracting with DCM three times, washing the combined organics with sat. aq. NaCl, then dry ing the organics over Na2SO4.
[0230] Biological Assay: The following assay demonstrate that the exemplified compounds are RXFP1 receptor agonists.
[0231] Human RXFP1 Cell cAMP HTRF Assay : Relaxin family peptide receptor 1 (RXFP1) expressing cells were generated by transfecting a tetracycline-inducible RXFP1 expression cassette (Accession NM 021634.4) into HEK293 cells and single cell clones that are responsive to Human Relaxin2 (cat# H-6784.0200, Bachem, Torrance, CA) were selected. RXFP1 expressing cells were treated with 1 pg/mL doxycycline for 24 h prior to compound dosing in order to induce RXFP1 expression. At the time of cell dosing, compounds were acoustically transferred into 384-well plates (ProxiPlate, 384-well. cat #6008289, Revvity, Waltham, MA) using the ECHO acoustic liquid handler (Beckman, Brea, CA). Cells were dosed in 10-point dose-response curves (3-fold dilution) starting at 10 pM for 1 h at 37 °C. Final DMSO concentration was 0.6% in a 10 pL assay volume.
[0232] Assay buffer used for treatment was IX Stimulation Buffer (provided with the Gs cAMP HighRange kit. cat#62AM6PEJ. Revvity). diluted in distilled water and containing 500 pM 3- Isobutyl-1 -methylxanthine final (cat# I5879250MG, Sigma- Aldrich, St. Louis, MO). After 1 h incubation, cAMP levels were assessed using the CisBio Gs cAMP HighRange Kit (cat# 62AM6PEJ) according to the manufacturer's instruction (Revvity). Briefly, 5 pL of D2-labeled cAMP and 5 pL of Eu3+-Cryptate-labeled anti-cAMP antibody diluted in lysis buffer (kit provided) were added to each well. Cell lysis solutions were incubated for 1 h at RT prior to detection on a PHERAstar FSX microplate reader (BMG, Ortenberg, Germany,). The EITRF ratio (Emission 665 nm/Emission 620 nm x 10.000) was converted to cAMP units using a cAMP standard curve. Relative ECsos were calculated relative to the top and bottom of the individual concentration response curves, determined via non-linear regression using a four-parameter logistic fit using Genedata Ver. 18.0.8 (Genedata, Basel, Switzerland).
[0233] In the above assay, compounds of Examples 1-98 exhibited an agonist activity in the RXFP1 receptor with a relative ECso of <50 nM. This data shows that compounds of Formula I as described herein are RXFP1 agonists in this human HEK293 cells.

Claims

We claim:
1. A compound of the formula:
Figure imgf000199_0001
wherein:
Gi is -C(Ra)- or -N-;
G2 is -C(Rb)- or -N-;
Ring A is a group of the formula
Figure imgf000199_0002
ed or substituted with one or more of halogen or C1-3 alkoxy;
-X- is -NH- or -S-;
Ra is -H or halogen;
Rb is -H or halogen;
Ri is C1-3 alkoxy or cyclopropoxy, wherein C1-3 alkoxy is unsubstituted or substituted with one or more halogens;
R2 is a group of the formula
Figure imgf000200_0001
R.2a is C1-3 alky l, -OH, oxo, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, piperazine, pyrrolidine, pyrazine, thiomorpholine 1,1 -dioxide.
Figure imgf000200_0002
wherein the C1-3 alkyl is unsubstituted or substituted with one or more of -OH, oxo, or morpholine, wherein the morpholine is unsubstituted or substituted with an C1-3 alkylene bridge, wherein the oxadiazole, thiadiazole, pyrimidine, piperazine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine, piperazine, and pyrazine are unsubstituted or substituted with a C1-3 alkyl, wherein the pyrrolidine is unsubstituted or substituted with -OH, and wherein the pyrrole is unsubstituted or substituted with -OH; each R is independently a C1-3 alkyl;
-G3a- is -CHR2b- or -CH2-O-CH2-;
-Y- is a Ci-? alkylene;
R2b is -COOH; r halogen;
R3 is a group of the formula: ;
Figure imgf000201_0001
R3a is -H, halogen, -SF5, -SO2CF3, -SCF3, C1-4 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; R3b is -H, halogen, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CN, or C1-4 alkyl; R3c, at each occurrence, is independently -H or halogen; R3d is -H, halogen, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; R4 is -H, -CN, or C1-3 alkyl, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1 wherein: R1 is C1-3 alkoxy; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2 wherein: Ring A is a group of the formula ,
Figure imgf000201_0002
wherein is unsubstituted or substituted with halogen; R1 is C1
Figure imgf000201_0003
; R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, pyrrole, triazole, thiazole, pyrimidine, pyrazine, thiomorpholine 1,1-dioxide, ,
Figure imgf000201_0004
wherein the pyrimidine, pyrazine, or morpholine are unsubstituted or substituted with an oxo group, wherein the pyrimidine and pyrazine are unsubstituted or substituted with a C 1-3 alkyl, and wherein the pyrrole is unsubstituted or substituted with -OH;
R3a. at each occurrence, is independently -H, halogen, -SF5, -SO2CF3. -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and
R4 is -H or C1-3 alkyd, wherein C1-3 alkyl is unsubstituted or substituted with -CN; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 or 2 wherein:
Ring A is a group of the formula
Figure imgf000202_0001
Ra is -H or -F;
Rb is -H or -F ;
Ri is C1-3 alkoxy;
R2 is a group of the formula
Figure imgf000202_0002
wherein R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1 -di oxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
Rsa is -H. halogen, -SF5, -SO2CF3. -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; each Rsc is independently -H, or -F;
Rjd is -H. halogen, C1-4 alkyl, or C1-3 alkoxy, w-herein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; and R.4 is -H; or a pharmaceutically acceptable salt thereof.
5. The compound according to any one of claims 1-4 wherein:
Ring A is a group of the formula
Figure imgf000203_0001
Ra is -H or -F;
Rb is -H or -F;
Ri is C1-3 alkoxy;
R2 is a group of the formula
Figure imgf000203_0002
R2a is -OH, -N(R)2, oxetane, oxadiazole, thiadiazole, morpholine, or thiomorpholine 1,1- dioxide, wherein the oxadiazole, thiadiazole, or morpholine are unsubstituted or substituted with an oxo group;
Rs is a group of the formula:
Figure imgf000203_0003
Rsa is -H, halogen, --SSOF25,CF3, -SCF3, C1-4 alkyl, or C1-3 alkoxy, wherein the C1-4 alkyl, or C1-3 alkoxy are unsubstituted or substituted with one or more halogens; each Rsc is independently -H, or -F; and
R4 is -H; or a pharmaceutically acceptable salt thereof.
6. The compound according to any one of claims 1-5 wherein Ring A is selected from the group consisting of
Figure imgf000204_0001
, or a pharmaceutically acceptable salt thereof.
7. The compound according to any one of claims 1 -3, wherein Ring A is a group of the formula
Figure imgf000204_0002
acceptable salt thereof.
8. The compound according to any one of claims 1 -3, wherein Ring A is a group of the formula
Figure imgf000204_0003
pharmaceutically acceptable salt thereof.
9. The compound according to claim 8. wherein Ring A is a group of the formula pharmaceutically acceptable salt thereof. rding to claim 1 or 2, wherein Ring A is a group of the formula
Figure imgf000204_0004
armaceutically acceptable salt thereof.
11. The compound according to any one of claims 1-10, w herein R4 is -H, or a pharmaceutically acceptable salt thereof.
12. The compound according to any one of claims 1-1 1, wherein Gi is -N-, or a pharmaceutically acceptable salt thereof.
13. The compound according to any one of claims 1-11, wherein Gi is -C(Ra)-, or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 13, wherein Ra is -H, or a pharmaceutically acceptable salt thereof.
15. The compound according to any one of claims 1-14, wherein G? is -N-, or a pharmaceutically acceptable salt thereof.
16. The compound according to any one of claims 1-14, wherein G2 is -C(Rb)-, or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 16, wherein Rb is -H, or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1. 6-17. wherein Ri is methoxy, difluoroethoxy. or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 18, wherein Ri is methoxy, or a pharmaceutically acceptable salt thereof.
20. The compound according to any one of claims 1-19. wherein R3 is selected from the group consisting of
Figure imgf000205_0001
, or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 20, wherein R3a is tert-butyl, -SF5, -SO2CF3. or -SCF3, and R3b is -H or -F, or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 20, wherein R3a is -F, -Cl, -Br, difluoromethyl, difluorochloromethyl, trifluoromethyl, trill uoromethoxy, or difluoromethoxy, and Rab is - H, -F, -Cl, -Br, trifluoromethyl, -CN, or methyl, or a pharmaceutically acceptable salt thereof.
23. The compound according to claim 20, wherein Raa and Rab are methoxy, or a pharmaceutically acceptable salt thereof.
24. The compound according to any one of claims 1-23. wherein -X- is -NH-, or a pharmaceutically acceptable salt thereof.
25. The compound according to any one of claims 1-24, wherein R2 is a group of the formula
Figure imgf000205_0002
, or a pharmaceutically acceptable salt thereof.
26. The compound according to any one of claims 1-24, wherein R2 is a group of the formula
Figure imgf000206_0001
, and R2a is selected from the group consisting of -OH,
Figure imgf000206_0002
pharmaceutically acceptable salt thereof.
27. The compound according to claim 26, wherein R2a is selected from the group consisting of
Figure imgf000206_0003
, or a pharmaceutically acceptable salt thereof.
28. The compound according to any one of claims 1-24. wherein R2 is selected from the group consisting of
Figure imgf000206_0004
pharmaceutically acceptable salt thereof.
29. The compound according to claim 28, wherein R2 is selected from the group consisting of
Figure imgf000207_0001
a pharmaceutically acceptable salt thereof.
30. The compound according to any one of claims 1-24, wherein R2 is selected from the group consisting of
Figure imgf000207_0002
or a pharmaceutically acceptable salt thereof.
31. The compound according to claim 30, wherein R2 is selected from the group consisting of
Figure imgf000207_0003
, or a pharmaceutically acceptable salt thereof.
32. The compound according to claim 1, selected from the group consisting of
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
or a pharmaceutically acceptable salt thereof.
33. A pharmaceutical composition comprising a compound according to any one of claims 1-
32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
34. A method of treating cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of any one of Claims 1-32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim
33.
35. The method of claim 34. wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
36. The method of claim 34, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder, wherein the pulmonary condition, disease, or disorder is pulmonary' hypertension or chronic obstructive pulmonary disease (COPD).
37. The method of claim 34, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
38. A compound according to any one of Claims 1-32, or a pharmaceutically acceptable salt thereof, for use in therapy.
39. A compound according to any one of Claims 1-32, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular, pulmonary, and/or renal conditions, diseases, and/or disorders.
40. A compound for use according to claim 39, wherein the condition, disease, or disorder to be treated is a cardiovascular condition, disease, or disorder.
41. A compound for use according to claim 40, wherein the cardiovascular condition, disease, or disorder is acute heart failure, chronic heart failure, atherosclerosis, coronary artery disease, diabetes, stroke, hypercholesterolemia, hypertension, ischemia, vasoconstriction, or ventricular hypertrophy.
42. A compound for use according to claim 39, wherein the condition, disease, or disorder to be treated is a pulmonary condition, disease, or disorder.
43. A compound for use according to claim 42, wherein the pulmonary condition, disease, or disorder is pulmonary hypertension or chronic obstructive pulmonary disease (COPD).
44. A compound for use according to claim 39, wherein the condition, disease, or disorder to be treated is a renal condition, disease, or disorder.
45. A compound for use according to claim 44, wherein the renal condition, disease, or disorder is acute kidney disease, chronic kidney disease or diabetes nephropathy.
46. A method of exhibiting agonist activity7 in a RXFP1 receptor in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of any one of Claims 1-33 or a pharmaceutical composition of Claim 34.
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