WO2023077070A1 - Rxfp1 agonists - Google Patents

Rxfp1 agonists Download PDF

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Publication number
WO2023077070A1
WO2023077070A1 PCT/US2022/078879 US2022078879W WO2023077070A1 WO 2023077070 A1 WO2023077070 A1 WO 2023077070A1 US 2022078879 W US2022078879 W US 2022078879W WO 2023077070 A1 WO2023077070 A1 WO 2023077070A1
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WIPO (PCT)
Prior art keywords
substituted
alkyl
halo
mmol
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2022/078879
Other languages
English (en)
French (fr)
Inventor
Adam James Clarke
Todd J. Friends
Arvind Mathur
Michael C. Myers
Jianqing Li
Donald J.P. Pinto
Kumar Balashanmuga PABBISETTY
Shun Su
Benjamin P. VOKITS
Durga Buchi Raju BARRE
II Leon M. SMITH
Michael J. Orwat
Scott A. SHAW
Sreekantha Ratna KUMAR
Hima Kiran POTTURI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Filing date
Publication date
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to ES22813850T priority Critical patent/ES3062200T3/es
Priority to KR1020247017525A priority patent/KR20240091018A/ko
Priority to JP2024525593A priority patent/JP2024540163A/ja
Priority to US18/701,270 priority patent/US20250011288A1/en
Priority to EP22813850.9A priority patent/EP4423068B1/en
Priority to CN202280083558.3A priority patent/CN118510758A/zh
Publication of WO2023077070A1 publication Critical patent/WO2023077070A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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Definitions

  • the present disclosure relates to novel compounds which are relaxin family peptide receptor 1 (RXFP1) agonists, compositions containing them, and methods of using th em, for example in th e treatment of heart fai lure, fibroti c diseases, an d related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), and hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
  • RXFP1 relaxin family peptide receptor 1
  • the human relaxin hormone (also called relaxin or H2 relaxin) is a 6-kDa peptide composed of 53 amino acids whose activity was initially discovered when Frederick Hisaw in 1926 injected crude extracts from swine corpus luteum into virgin guinea pigs and observed a relaxation of the fibrocartilaginous pubic symphysis joint (Hisaw FL., Proc. Soc. Exp. Biol. Med., 1926, 23, 661-663).
  • Hie relaxin receptor was previously known as Lgr7 but is now officially termed the relaxin family peptide receptor 1 (RXFP1) and was deorphanized as a receptor for relaxin in 2002 (Hsu SY., et al.
  • RXFP1 is reasonably well conserved between mouse and human with 85% amino acid identity and is essentially ubiquitously expressed in humans and in other species (Halls ML., etal, Br. J. Pharmacol, 2007, 150, 677-691).
  • the cell signaling pathways for relaxin and RXFP1 are cell type dependent and quite complex (Halls ML., etal, Br. J. Pharmacol., 2007, 150, 677-691; Halls ML., etal. Ann. N Y Acad. Sci., 2009, 1160, 108-1 11; Halls ML., Ann NY Acad. Sci., 2007, 1160, 117-120).
  • the best studied pathway is the relaxin-dependent increase in cellular levels of cAMP in which relaxin functions as an RXFP1 agonist to promote GDS coupling and activation of adenylate cyclase (Halls ML., et al, Mol. Pharmacol, 2006, 70, 214-226).
  • Additional vascular adaptations include an -30% increase in global arterial compliance that is important for maintaining efficient ventricular-arterial coupling, as well as an -50% increase in both renal blood flow (RBF) and glomerular filtration rate (GFR), important for metabolic waste elimination (Jeyabalan AC., K.P., Renal and Electolyte Disorders. 2010, 462-518), (Poppas A., et al., Circ., 1997, 95, 2407-2415). Both pre-clinical studies in rodents as well as clinical studies performed in a variety' of patient settings, provide evidence that relaxin is involved, at least to some extent, in mediating these adaptive physiological changes (Conrad KI’., Regul. Integr. Comp.
  • Heart failure defined hemodynamically as “systemic perfusion inadequate to meet the body's metabolic demands as a result of impaired cardiac pump function”, represents a tremendous burden on today’s health care system with an estimated United States prevalence of 5.8 million and greater than 23 million worldwide (Roger VL., et al., Circ. Res., 2013, 113, 646-659). It is estimated that by 2030, an additional 3 million people in the United States alone will have HF, a 25% increase from 2010. The estimated direct costs (2008 dollars) associated with HF for 2010 was $25 billion, projected to grow to $78 B by 7 2030 (Heidenreich PA., etal., Circ., 2011, 123, 933-944).
  • Hie symptoms of HF are the result of inadequate cardiac output and can be quite debilitating depending upon the advanced stage of the disease.
  • Major symptoms and signs of HF include: 1) dyspnea (difficulty in breathing) resulting from pulmonary edema due to ineffective forward flow from the left ventricle and increased pressure in the pulmonary capillary bed; 2) lower extremity edema occurs when the right ventricle is unable to accommodate systemic venous return; and 3) fatigue due to the failing heart’s inability to sustain sufficient cardiac output (CO) to meet the body's metabolic needs (Kemp CD., & Conte JV., Cardiovasc. Pathol., 2011, 21, 365-371).
  • HF patients are often described as “compensated” or “decompensated”.
  • symptoms are stable, and many overt features of fluid retention and pulmonary 7 edema are absent.
  • Decompensated heart failure refers to a deterioration, which may present as an acute episode of pulmonary 7 edema, a reduction in exercise tolerance, and increasing breathlessness upon exertion (Millane T., etal., BMJ 2000, 320, 559-562).
  • HF was primarily described as “systolic HF” in which decreased left-ventricular (LV) contractile function limits the expulsion of blood and hence results in a reduced ejection fraction (EF is stroke volume/end diastolic volume), or “diastolic HF” in which active relaxation is decreased and passive stiffness is increased limiting LV filling during diastole, however overall EF is maintained (Borlaug BA. & Paulus WJ., Eur Heart J., 2011, 32, 670-679).
  • HFrEF heart failure with reduced ejection fraction
  • HFpEF heart failure with preserved ejection fraction
  • Serelaxin an intravenous (IV) formulation of the recombinant human relaxin peptide with a relatively short first-phase pharmacokinetic half-life of 0.09 hours, is currently being developed for the treatment of HF (Novartis, 2014). Serelaxin has been given to normal healthy volunteers (NHV) and demonstrated to increase RBF (Smith MC., et al., J. Am. Soc. Nephrol. 2006, 17, 3192-3197) and estimated GFR (Dahlke M., et al., J. Clin. Pharmacol., 2015, 55, 415-422). Increases in RBF were also observed in stable compensated HF patients (Voors AA., etal., Cir.
  • kidney Garber SL., et al., Kidney Int., 2001, 59, 876-882
  • liver injury' Biller RG., Liver Int., 2014, 34, 416-426.
  • a large body of evidence supports a role for relaxin-dependent agonism of RXFP1 mediating the adaptive changes that occur during mammalian pregnancy, and that these changes translate into favorable physiological effects and outcomes when relaxin is given to HF patients.
  • Additional preclinical animal studies in various disease models of lung, kidney, and liver injury provide evidence that relaxin, when chronically administered, has the potential to provide therapeutic benefit for multiple indications in addition to HI’. More specifically, chronic relaxin administration could be of benefit to patients suffering from lung disease (e.g., idiopathic pulmonary' fibrosis), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., nonalcoholic steatohepatitis and portal hypertension).
  • lung disease e.g., idiopathic pulmonary' fibrosis
  • kidney disease e.g., chronic kidney disease
  • hepatic disease e.g., nonalcoholic steatohepatitis and portal hypertension.
  • the present invention provides novel substituted norbomyl compounds, their analogues, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as RXFP1 receptor agonists.
  • Hie present invention also provides processes and intermediates for making the compounds of the present invention.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.
  • the compounds of the invention may be used, for example, in the treatment and/or prophylaxis of heart failure, fibrotic diseases, and related diseases, such as: lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidneydisease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
  • lung disease e.g., idiopathic pulmonary fibrosis
  • kidney disease e.g., chronic kidneydisease
  • hepatic disease e.g., non-alcoholic steatohepatitis and portal hypertension.
  • the compounds of the present invention may be used in therapy.
  • the compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of heart failure.
  • the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
  • the invention encompasses compounds of Formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them.
  • the present invention provides, inter alia, compounds of Formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them.
  • the present invention provides, inter alia, compounds of Formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them.
  • the present invention provides, inter alia, compounds of Formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them.
  • L is O- or NH-
  • R 1 is Ci-3 alkyl substituted with 1 aryl or C 3 -r, cycloalkyl substituent
  • R 3 is H, halo, -OH, CM alkyl substituted with 0-5 halo substituents, or -OCM alkyl substituted with 0-5 halo substituents;
  • R 6a is halo, -OIL -OCM alkyl, CM alkyl, aryl, or C.3-6 cycloalkyl substituted with 0-4 halo substituents;
  • R 6b is H, C i-4 alkyl substituted with 0-1 aryl, or C3-6 cycloalkyl substituted with 0-4 halo substituents;
  • R 7 is H or CM alkyl
  • A is -O-, -S-, -CH2O-, or -OCH2-;
  • R c is C1-6 alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 R e , C2-6 alkynyl substituted with 0-5 R e , C3-6 carbocyclyl, or 3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S( ::: O) P , and N;
  • R d is H, CM alkyl, or C3-6 cycloalkyl;
  • R g is halo, CN, -OH, Ci-e alkyl, C3-6 cycloalkyl, or aryl; n is zero, 1, 2, or 3; and p is zero, 1 , or 2.
  • R 6 is halo, Ci-7 alkyl substituted with 0-3 R 6a , C3-6 cycloalkyl substituted with 0-3 R 14 , C3-
  • R 6a is halo, -OH, C3-6 cycloalkyl, or aryl
  • R 7 is II or C1-3 alkyl
  • R 10 is halo, CN, C1-4 alkyl, -OH, or -OC1-4 alkyl;
  • R 14 is halo, CN, C1-4 alkyl substituted with 0-3 halo substituents, -OC1-4 alkyl substituted with 0-3 halo substituents;
  • R 16 is H, C1-3 alkyl substituted with 0-4 R 16a , or ary l substituted with 0-4 R 16a ;
  • R f is H, C1-5 alkyl, C3-6 cycloalkyl, or aryl; or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclyl;
  • R g is halo, CN, -OH, C1-6 alkyl, C3-6 cycloalkyl, or aryl; n is zero, 1 , 2, or 3; and p is zero, 1, or 2.
  • the present invention provides compounds of Formula (III): (HI) or pharmaceutically acceptable salts thereof, wherein:
  • R 4 is halo or C1-3 alkyl substituted with 0-4 halo substituents
  • R 6 is halo, C1-4 alkyl substituted with 0-3 R 6a , C.3-6 cycloalkyl, phenyl substituted with 0-3 R 14 , naphthyl, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;
  • R 6a is halo, -OH, or C3-6 cycloalkyl
  • R 7 is H
  • R 8 is -OC1-4 alkyl substituted with 0-5 halo or -OH substituents
  • R 10 is halo, CN, C1-4 alkyl, or -OH;
  • R a is H, C1-6 alkyl substituted with 0-5 R e , -(CH2)n-phenyl substituted with 0-5 R e , or -(CH2)n-heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-5 R s ;
  • R b is H, C1-6 alkyl substituted with 0-5 R e , -(CH2.)O-I-C3-6 cycloalkyl substituted with 0-5 R e , -(CH2)o-i-phenyl substituted with 0-5 R e , or -(CHzJn-heterocyclyl substituted with 0-5 R e ;
  • R f is H or C1-3 alkyl and n is zero, 1, 2, or 3.
  • the present invention provides compounds of Formula (III), or pharmaceutically acceptable salts thereof, wherein:
  • R 4 is halo or Ci-4 alkyl substituted with 0-4 F substituents
  • R 6 is Ci-3 alkyl substituted with 0-3 R 6a , C3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, S, and N;
  • R 6a is halo; substituted with 0-4 halo or OH substituents; 1 5 ⁇
  • R 10 is halo
  • R a is H, C1-5 alkyl substituted with 0-4 R e , -(CHzJn-phenyl substituted with 0-4 R e , or -(CH2)n-heterocyclyl substituted with 0-4 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-4 R e ;
  • R b is H, C1-5 alkyl substituted with 0-4 R e , -(CH2)n-phenyl substituted with 0-4 R e , or -(CH2)n-heterocyclyl substituted w 7 ith 0-4 R c ;
  • R c is Ci-5 alkyl substituted with 0-4 R e ;
  • the present invention provides compounds of Formula (III), or pharmaceutically acceptable salts thereof, wherein:
  • R 4 is F or CF3
  • R 6 is CF3, cyclopropyl, phenyl, or
  • R 8 is -OCi-4alkyl substituted with 0-2 OH substituents
  • R 9 is R 11
  • R 10 is F
  • R 12 is halo, -C(
  • R a is H, Ci-4 alkyl, C3-6 cycloalkyl, or phenyl
  • R b is H or C1-3 alkyl.
  • R 4 is halo or Ci-4 alkyl substituted with 0-4 halo
  • R 6 is Ci-4 alkyl substituted with 0-3 R 6a , C3-6 cycloalkyl, phenyl substituted with 0-3 R 14 , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;
  • R 6a is halo
  • R 7 is H
  • R 8 is -OC1-4 alkyl substituted with 0-5 halo or OH substituents
  • R 9 is halo, CN, CM alkyl substituted with 0-3 R 10 , or phenyl substituted with 0-3 R 10 and 0-2 R 11 ;
  • R 10 is halo, CN, or CM alkyl
  • R 16 is H, CM alkyl substituted with 0-4 R 16a , or phenyl substituted with 0-4
  • R 16a is halo
  • R b is H or Ci -4 alkyl
  • R c is C1-3 alkyl.
  • R 4 is halo or Ci-4 alkyl substituted with 0-4 halo substituents
  • R 6 is Ci-4 alkyl substituted with 0-3 R 6a , C3-6 cycloalkyl, phenyl substituted with 0-3 R 14 , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;
  • R 7 is H
  • R 8 is -OC1-4 alkyl substituted with 0-5 halo or OH substituents
  • R 9 is halo, CN, or C1-4 alkyl substituted with 0-3 R 10 ;
  • R 10 is halo
  • R 16 is H, C1-4 alkyl substituted with 0-4 R ', or aryl substituted with 0-4 R 16a ;
  • R 4 is halo or Ci-4 alkyl substituted with 0-4 halo substituents
  • R 6 is Ci-4 alkyl substituted with 0-3 R 6a , Ca-6 cycloalkyl, phenyl substituted with 0-3 R 14 , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;
  • R 7 is H
  • R 8 is -OCi-4 alkyl substituted with 0-5 halo or OH substituents
  • R 9 is halo or CN
  • the present invention provides compounds of Formula (III): A (R 8 )O-2
  • R 4 is halo or Ci-4 alkyl substituted with 0-4 halo
  • R 6 is Ci-4 alkyl substituted with 0-3 R 6a , C3-6 cycloalkyl, phenyl substituted with 0-3 R 14 , or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N;
  • R 7 is H
  • R 8 is -OC1-4 alkyl substituted with 0-5 halo or OH substituents
  • R 9 is halo or CN
  • R 16 is H or C1-4 alkyl substituted with 0-4 R 16a ;
  • R 16a is halo
  • the present invention provides compounds of Formula (IV): or pharmaceutically acceptable salts thereof, wherein:
  • R 10 is halo, CN, C1-4 alkyl, or -OH;
  • R 13 is -OH
  • R 17 is II or C1-2 alkyl substituted with 0-3 R i0 and 0-2 R 11 ; or R 17 and R 17 together with the nitrogen atom to which they are both attached form
  • R a is H or Ci-3 alkyl
  • R b is H, Ci-3 alkyl substituted with 0-5 R e , or -(CH2)O-I-C3-6 cycloalkyl substituted with
  • the present invention provides compounds of Fonnula (V):
  • R 3 is C1-4 alkyl substituted with 0-3 R 4 , -(CHR d )n-C.3-6-carbocyclyl substituted with 0-3 R 4 ;
  • R 4 is halo, CN, or C1-4 alkyl substituted with 0-5 halo substituents
  • R 6 is halo, C1-4 alkyl substituted with 0-3 R 6a , C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N, and substituted with 0-5 R 14 ;
  • R 6a is halo or OH
  • R 7 is H
  • R 8 is -OC1-3 alkyl
  • R 10 is halo, CN, Ci-4 alkyl, or -OH:
  • R 11 is Ci-3 alkyl substituted with 0-3 R 12 and 0-2 R 13 , CN, or OR b ;
  • R 12 is halo
  • R 13 is - OR b or C.3-6 carbocyclyl
  • R 14 is halo, CN, or C1-4 alkyl substituted with 0-3 halo substituents
  • R b is H or C1-3 alkyl substituted with 0-5 R e ;
  • R d is H or Ci-4 alkyl
  • R e is halo or OH; and n is zero or 1 .
  • the present invention provides compounds of Formula (VI): or pharmaceutically acceptable salts thereof, wherein:
  • R 3 is Ci-4 alkyl substituted with 0-3 R 4 , -(CHR d )n-C.3-6-carbocyclyl substituted with 0-3 R 4 ;
  • R 4 is halo, CN, or Ci-4 alkyl substituted with 0-5 halo substituents;
  • R 6 is halo, Ci-4 alkyl substituted with 0-3 R 6a , C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S, and N, and substituted wi th 0-5 R 14 ;
  • R 6a is halo or -OH
  • R 7 is H
  • R 8 is C1-3 alkyl
  • R 10 is halo, CN, C1-4 alkyl, or -OH;
  • R 11 is C1-3 alkyl substituted with 0-3 R 12 and 0-2 R 13 , CN, or OR b ;
  • R 12 is halo
  • R 13 is - OR b or C3-6 carbocyclyl
  • R 14 is halo, CN, or C1-4 alkyl substituted with 0-3 halo substituents
  • R b is H or Ci-3 alkyl substituted with 0-5 R e ;
  • R d is H or Ci-4 alkyl
  • R e is halo or OH; and n is zero or 1 .
  • the present invention provides compounds of Formula (VII): or pharmaceutically acceptable salts thereof, wherein:
  • R 3 is -(CHR d )n-C3-w-carbocyclyl substituted with 0-5 R 4 ;
  • R 6 is Ci-4 alkyl substituted with 0-3 R 6a or C3-6 cycloalkyl substituted with 0-5 R 14 ;
  • R 6a is halo
  • R 7 is H
  • R 8 is C1-3 alkyl or -OC1-3 alkyl
  • R 14 is halo
  • R a is H, Ci -6 alkyl substituted with 0-5 R e , Ca-w carbocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-5 R e ;
  • R b is H or Ci-4 alkyl substituted with 0-5 R e ;
  • R c is Ci-4 alkyl
  • R d is H or Ci-3 alkyl
  • R f is H or C1-4 alkyl
  • R g is halo, CN, -OH, or Ci-4 alkyl; n is zero or 1; and p is zero, 1, or 2.
  • R 3 is -CHR d -C3-6 cycloalkyl substituted with 0-2 R 4 or phenyl substituted with 0-2 R 4 ;
  • R 4 is F, CH3, or CF 3 ;
  • R 6 is C1-4 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl substituted with 0- 3 halo substituents;
  • R 7 is H
  • R 8 is -OCII3
  • R 10 is halo
  • R lla is H or CM alkyl substituted with 0-3 R nb ;
  • R llb is -OH
  • R 12 is CM alkyl substituted with 0-3 halo substituents
  • R 14 is halo
  • R a is H, Ci-4 alkyl substituted with 0-4 R e , C3-10 carbocyclyl substituted with 0-4 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclyl substituted with 0-4 R e ;
  • R b is H or Ci -3 alkyl
  • R c is C1-3 alkyl
  • R d is C1-2 alkyl
  • R f is CM alkyl; and p is zero, 1, or 2.
  • R 6 is phenyl substituted with 0-1 R 14 ;
  • R 7 is H;
  • R 14 is halo, -OCi-4 alkyl, or phenyl.
  • R 6 is 5- membered heterocyclyl comprising 1-3 heteroatoms selected from O and N;
  • R 7 is II.
  • R 7 is H.
  • R 3 is Ci-e alkyl.
  • R 3 is methyl, ethyl, propyl, or butyl, or pentyl.
  • R 3 is .
  • R 3 is C3-6 cycloalkyl substituted with 0-2
  • R 3 is C3-6 cycloalkenyl substituted with 0-2
  • R 3 is
  • R 3 is -(CR d R d )i-2-phenyl substituted with 0-2 R 4 ; R 4 is halo, CF3 or OCF3; R d is H or methyl.
  • R 3 is -(CHR d )-C3-6 cycloalkyl substituted with 0-2 R 4 ; R 4 is halo or C1-2 alkyl; Rd is H or C1-2 alkyl .
  • R 3 is ;
  • R 4 is C1-2 alkyl.
  • R 3 is 1/Vx ' v V' ;
  • R 4 is halo or CN.
  • R 3 is -(CR d R d )i-2-5-membered heterocyclyl comprising 1 -2 heteroatoms selected from O and N; R d is II or methyl.
  • R 4 is halo, CN, C1-2 alkyl substituted with 0-3 halo substituents.
  • R 3 is cyclopropyl, cyclobutyl, cyclopentyl substituted with 0-1 R 4 , or cyclohexyl; R 4 is CN or C1-2 alkyl.
  • R 5 is H, halo, or OH.
  • R 6 is CH3 or CF3
  • R 6 is C3-6 cycloalkyl substituted with 0-3 halo substituents.
  • R 14 is C1-3 alkyl substituted with 0-3 halo substituents.
  • R 7 is H or CHs.
  • R 8 is halo or -OCFfe.In one embodiment of .( R4 ) 2 R 14
  • R 3 is ;
  • R 4 is halo, CF3, or -OCF3;
  • R 6 is C3-6 cycloalkyl or C1-3 alkyl substituted with 0-3 R 6a ;
  • R 6a is halo;
  • R 14 is C1-2 alkyl substituted with 0-3 halo substituents;
  • R 7 is H;
  • R 8 is -OC1-3 alkyl substituted with 0-1 CF3 or -OCH3 substituent;
  • R 9 is
  • VxF “(R 10 )o-i -"O"(R 1 °)0-2
  • R1 1 O-I ;
  • R 10 is Ci-4 alkyl, CN, or OH;
  • R 11 is C1-3 alkyl substituted with 0-3 R 1 and 0-2 R 13 ;
  • R 12 is halo; and
  • R 13 is OH or C3-6 cycloalkyl.
  • R 3 is ;
  • R 4 is halo, CF3, or -
  • R 6 is C3-6 cycloalkyl or C1-3 alkyl substituted with 0-3 R 6a ; R 6a is halo; R 14 is C1-2 alkyl substituted with 0-3 halo substituents; R 7 is H; R 8 is -OC1-3 alkyl substituted with 0-1 CF3 or -OCH3 substituents; R 9 is
  • R 11 is Ci-4 alkyl, CN, or OH
  • R 11 is Ci-a alkyl substituted with 0-3 R 1 1 2 and 0-2 R 13
  • R 12 is halo
  • R 13 is OH or Ca-e cycloalkyl.
  • R 3 is R d or ;
  • R 4 is
  • R 14 N ( .0 halo, CN, or C1-2 alkyl substituted with 0-3 halo;
  • R d is C1-2 alkyl;
  • R 6 is , Ca-e cycloalkyl substituted with 0-3 R 6a , or Ci-a alkyl substituted with 0-3 R 6a ;
  • R 6a is halo or OH;
  • R 14 is Ci-2 alkyl substituted with 0-3 halo substituents;
  • R 7 is H;
  • R 8 is -OC1-2 alkyl substituted with 0-1 Ca-e cycloalkyl substituent;
  • R 9 is alkyl or OH;
  • R 11 is Ci-a alkyl substituted with 0-3 R 12 and 0-2 R 13 ;
  • R 12 is halo; and
  • R L3 is OH or C.a-6 cycloalkyl.
  • the invention includes combinations of the different aspects.
  • Halo includes fluoro, chloro, bromo, and iodo.
  • Alkyl or alkylene is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci to Cio alkyl or “Ci-io alkyl” (or alkylene)
  • Ci Ci, C2, C3, C4, C5, Ce, C7, Cs, Cs>, and Cio alkyl groups.
  • Ci to Ce alkyl or "Ci-Ce alkyl” denotes alkyl having 1 to 6 carbon atoms.
  • Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group.
  • Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, /-butyl), and pentyd (e.g., n-pentyl, isopentyd, neopentyl).
  • methyl Me
  • Et ethyl
  • propyl e.g., n-propyl and isopropyl
  • butyl e.g., n-butyl, isobutyl, /-butyl
  • pentyd e.g., n-pentyl, isopentyd, neopentyl.
  • Alkenyl or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carboncarbon double bonds that may 7 occur in any stable point along the chain.
  • C2 to Ce alkenyl or “C2-6 alkenyl” (or alkenylene) is intended to include C2, C3, C4, C5, and Ce alkenyl groups; such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably 7 one to three, carboncarbon triple bonds that may occur in any stable point along the chain.
  • C2 to Ce alkynyl or “C2-6 alkynyl” (or alkynylene) is intended to include C2, Ci, C4, Cs, and Ce alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • Carbocycle is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11 -, 12-, or 13 -membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic.
  • carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin).
  • bridged rings are also included in the definition of carbocyclyl (e.g;, [2.2.2
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • Preferred bridges are one or two carbon atoms. It is noted that a bridge ahvays converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for tiie ring may also be present on the bridge.
  • carbocyclyl When the term “carbocyclyl” is used, it is intended to include “aryl,” “cycloalkyl,” “spirocycloalkyl”, and “cycloalkenyl.” Preferred carbocyclyls, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
  • Cycloalkyl is intended to mean cyclized alkyl groups, including mono-, bi- or multicyclic ring systems. "C3 to C? cycloalkyl” or “C3-7 cycloalkyl” is intended to include C3, C4, C5, Ce, and C? cycloalkyl groups.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Non-limiting examples of multicyclic cycloalkyls include 1 -decalinyl, norbomyl and adamantyl.
  • Cycloalkenyl is intended to mean cyclized alkenyl groups, including mono- or multi-cyclic ring systems that contain one or more double bonds in at least one ring: although, if there is more than one, th e doubl e bonds cann ot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl,” as defined herein).
  • C3 to C? cycloalkenyl or “C.3-7 cycloalkenyl” is intended to include C3, C4, C5, Ce, and C7 cycloalkenyl groups.
  • “Spirocycloalkyl” is intended to mean hydrocarbon bicyclic ring systems with both rings connected through a single atom.
  • the ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • Bicyclic carbocyclyl or "bicyclic carbocyclic group” is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated.
  • the bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure.
  • the bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
  • Aryl groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl .. Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley’s Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997).
  • Benzyl is intended to mean a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted with 1 to 5 groups, preferably 1 to 3 groups.
  • Heterocycle is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-., or 15-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N— >0 and S(O) P , wherein p is 0, 1 or 2).
  • the nitrogen atom may be substituted or unsubstituted (z. e. , N or NR wherein R is H or another substituent, if defined).
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocyclyl may optionally be quatemized.
  • heterocyclyl when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocyclyl is not more than 1. Bridged rings are also included in the definition of heterocyclyl. When the term “heterocyclyl” is used, it is intended to include heteroaryl.
  • heterocyclyls include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a/7-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2/7,677-1,5,2- dithiazinyl, dihydrofuro[2,3-6]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 177-indazo
  • “Bicyclic heterocyclyl” "bicyclic heterocyclyl” or “bicyclic heterocyclic group” is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5 -membered heteroaryl ring, a 6- membered heteroaryl ring or a benzo ring, each fused to a second ring.
  • the second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocyclyl, a 6-membered heterocyclyl or a carbocyclyl (provided the first ring is not benzo when the second ring is a carbocyclyl).
  • the bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the bicyclic heterocyclic group described herein may be substi tuted on carbon or on a nitrogen atom if the resulting compotmd is stable. It is preferred that when the total number of S and O atoms in the heterocyclyl exceeds 1 , then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocyclyl is not more than 1.
  • bicyclic heterocyclic group examples include quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, IH-indazolyl, benzimidazolyl, 1 ,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 5, 6,7,8- tetrahydroquinolinyl, 2,3 -dihydrobenzofuranyl , chromanyl, 1 ,2,3,4- tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.
  • Heteroaryl is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fiiryl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1 ,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxan
  • Heteroaiyl groups are substituted or unsubstituted.
  • the nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N-+O and S(O) P , wherein p is 0, 1 or 2).
  • substituted means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • a ring system e.g., carbocyclic or heterocyclic
  • nitrogen atoms e.g., amines
  • these may be converted to N-oxides by treatment with an oxidizing agent (e.g. , mCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
  • an oxidizing agent e.g. , mCPBA and/or hydrogen peroxides
  • shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (NL.1O) derivative.
  • any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • a group is shown to be substituted with 0-3 R groups, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.
  • R is selected independently from the definition of R.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • a given chemical formula or nam e shall encompass all stereo and optical isom ers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Enantiomers and diastereomers are examples of stereoisomers.
  • the term "enantiomer” refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The tenn “diastereomer” refers to stereoisomers that are not mirror images.
  • racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
  • the invention includes all tautomeric forms of the compounds, atropi somers and rotational isomers.
  • chiral refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image.
  • homochiral refers to a state of enantiomeric purity.
  • optical activity refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light.
  • the invention is in tended to include all isotopes of atoms occurring in the compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically- labeled compounds of the in vention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwi se employed .
  • Such compounds may have a vari ety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • Human embiyonic kidney cells 293 (HEK293) cells and HEK293 cells stably expressing human RXFP1 were cultured in MEM medium supplemented with 10% qualified FBS, and 300 L lg/ml hygromycin (Life Technologies). Cells were dissociated and suspended in assay buffer.
  • the assay buffer was BBSS buffer (with calcium and magnesium) containing 20 mM HEPES, 0.05% BSA, and 0.5 mM IBMX.
  • Cells (3000 cells per well, except 1500 cell per well for HEK293 cells stably expressing human RXFP1) were added to 384-well Proxiplates (Perkin-Elmer). Cells were immediately treated with test compounds in DMSO (2% final) at final concentrations in the range of 0.010 nM to 50 DM. Cells were incubated for 30 min at room temperature. The level of intracellular cAMP was determined using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to manufacturer’s instructions. Solutions of cryptate conjugated anti-cAMP and d2 fluorophore-labelled cAMP were made in a supplied lysis buffer separately.
  • the cells were lysed with equal volume of the d2-cAMP solution and anti-cAMP solution. After a 1 h room temperature incubation, time-resolved fluorescence intensity was measured using the Envision (Perkin-Elmer) at 400 nm excitation and dual emission at 590 nm and 665 nm. A calibration curve was constructed with an external cAMP standard at concentrations ranging from 2.7 DM to 0.1 pM by plotting the fluorescent intensity ratio from 665 nm emission to the intensity from the 590 nm emission against cAMP concentrations. The potency and activity of a compound to inhibit cAMP production was then determined by fitting to a 4-parametric logistic equation from a plot of cAMP level versus compotmd concentrations.
  • the compounds of Formula (I) are RXFP1 receptor agonists and may find use in the treatment of medical indications such as heart failure (e.g., HFREF and HFpEF ), fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary' fibrosis or pulmonary hypertension), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
  • heart failure e.g., HFREF and HFpEF
  • fibrotic diseases e.g., fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary' fibrosis or pulmonary hypertension), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
  • the compounds of Formular (I) can also be used to treat disorders that are a result of or a cause of arterial stiffness, reduced arterial elasticity, reduced arterial compliance and distensibility including hypertension, kidney disease, peripheral arterial disease, carotid and cerebrovascular disease (i.e stroke and dementia), diabetes, microvascular disease resulting in end organ damage, coronary artery' disease, and heart failure.
  • disorders that are a result of or a cause of arterial stiffness, reduced arterial elasticity, reduced arterial compliance and distensibility including hypertension, kidney disease, peripheral arterial disease, carotid and cerebrovascular disease (i.e stroke and dementia), diabetes, microvascular disease resulting in end organ damage, coronary artery' disease, and heart failure.
  • the compounds described herein may also be used in the treatment of pre-eclampsia.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) for the treatment of a relaxin-associated disorder and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method of treating a cardiovascular disease comprising adm inistering an effective amount of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is a method of treating heart failure comprising administering an effective amount of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is a method of treating fibrosis comprising administering a therapeutically' effective amoimt of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is a method of treating a disease associated with fibrosis comprising administering a therapeutically effective amoimt of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is a method of treating idiopathic pulmonary' fibrosis comprising administering a therapeuti cally effective am ount of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is a method of treating a kidney disease (e.g., chronic kidney disease), comprising admini stering a therapeuticall y effecti ve amount of a compound of Formula (I) to a patient in need thereof.
  • a kidney disease e.g., chronic kidney disease
  • Another aspect of the invention is a method of treating or preventing kidney failure, comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is a method of improving, stabilizing or restoring renal function in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I) to the patient.
  • Another aspect of the invention is a method of treating a hepatic disease comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is a method of treating non-alcoholic steatohepatitis and portal hypertension comprising administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
  • Another aspect of the invention is use of a compound of Formula (I) for prophylaxis and/or treatment of a relaxin-associated disorder.
  • Another aspect of the invention is a compound of Formula (I) for use in tiie prophylaxis and/or treatment of a relaxin-associated disorder.
  • patient refers to any human or non-human organism that could potentially benefit from treatment with a RXFP1 agonist as understood by practitioners in this field.
  • exemplary subjects include human beings of any age with risk factors for cardiovascular disease. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arrhythmia, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS).
  • PCOS polycystic ovary syndrome
  • Treating" or “treatment” cover the treatment of a disease-state as understood by practitioners in this field and include the following: (a) inhibiting the disease-state, i.e., arresting it development; (b) relieving the disease-state, i.e., causing regression of the disease state; and/or (c) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it.
  • Preventing cover the preventive treatment (i.e., prophylaxis and/or risk reduction) of a subclinical disease-state aimed at reducing the probability of the occurrence of a clinical disease-state as understood by practi tioners in this field.
  • Patients are selected for preventative therapy based on factors that are known to increase ri sk of suffering a clinical disease state compared to the general population.
  • "Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention.
  • Primary prevention is defined as treatment in a subject that lias not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
  • “Risk reduction” or “reducing risk” covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.
  • “Therapeutically effecti ve amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination with other agents to treat disorders as understood by practitioners in this field. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.
  • “Disorders of the cardiovascular system” or “cardiovascular disorders” include for example the following disorders: hypertension (high blood pressure), peripheral and cardiac vascular disorders, coronary heart disease, stable and unstable angina pectoris, heart attack, myocardial insufficiency, abnormal heart rhythms (or ardiythmias), persistent ischemic dysfunction ("hibernating myocardium”), temporary postischemic dysfunction ("stunned myocardium”), heart failure, disturbances of peripheral blood flow, acute coronary syndrome, heart failure, heart muscle disease (cardiomyopathy), myocardial infarction and vascular disease (blood vessel disease).
  • Heart failure includes both acute and chronic manifestations of heart failure, as well as more specific or related types of disease, such as advanced heart failure, postacute heart failure, cardio-renal syndrome, heart failure with impaired kidney function, chronic heart failure, chronic heart failure with mid-range ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, heart failure associated with combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardio
  • Fibrotic disorders encompasses diseases and disorders characterized by fibrosis, including among others tire following diseases and disorders: hepatic fibrosis, cirrhosis of the liver, NASH, pulmonary fibrosis or lung fibrosis, cardiac fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitreoretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • Relaxin-associated disorders include but are not limited to disorders of tire cardiovascular system and fibrotic disorders.
  • the compounds of this invention can be administered by any suitable means, for example, orally, such as tablets, capsul es (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrastemal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories.
  • suitable means for example, orally, such as tablets, capsul es (each of which includes sustained release or timed release formulations), pills, powders
  • “Pharmaceutical composition” means a composition comprising a compound of tiie invention in combination with at least one additional pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • adjuents such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary' skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of adm inistration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary' skill in the art.
  • the dosage regimen for the compotmds of the present invention will, of course, vary' depending upon known factors, such as the ph armacodynamic characteristics of the particular agen t and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.01 to about 5000 mg per day, preferably between about 0.1 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day.
  • the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • Dosage forms (pharmaceutical compositions) suitable for administration may con tain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
  • a typi cal capsule for oral admini stration contains at least one of the compounds of the present in vention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • a typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
  • the compounds may be employed in combination with other suitable therapeutic agents useful in the treatment of diseases or disorders including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, memoiy enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, and anti-inflammatory agents.
  • the additional therapeutic agents may include ACE inhibitors, P-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine Al receptor agonists, partial adenosine Al receptor, dopamine P-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with biased agonism for select cell signaling pathways, combinations of angiotensin II receptor antagonists and neprilysin enzyme inhibitors, neprilysin enzyme inhibitors, soluble guanylate cyclase activators, myosin ATPase activators, rho-kinase 1 inhibitors, rho-kinase 2 inhibitors, apelin receptor agonists, nitroxyl donating compounds, calcium-dependent kinase II inhibitors, antifibrotic agents, galectin-3 inhibitors, vasopressin receptor antagonist
  • the additional therapeutic agents may also include nintedanib, Pirfenidone, LPA1 antagonists, LPA1 receptor antagonists, GLP1 analogs, tralokinumab (IL- 13, AstraZeneca), vismodegib (hedgehog antagonist, Roche), PRM-151 (pentraxin-2, TGF beta-1, Promedior), SAR-156597 (bispecific Mab IL-4&IL-13, Sanofi), pumpuzumab ((anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inh./pentoxifylline/NAC oral control, release, Pacific Ther.), omipalisib (oral PI3K/mT0R inhibitor, GSK), IW-001 (oral sol.
  • bovine type V collagen mod. ImmuneWorks
  • STX-100 integrated alpha V/ beta-6 ant, Stromedix/ Biogen
  • Actimmune IFN gamma
  • PC-SOD midismase; inhaled, LIT Bio-Pharma / CKD Pharm
  • lebrikizumab anti-IL-13 SC humanized mAb, Roche
  • AQX-1125 SHIP1 activator, Aquinox), CC-539 (JNK inhibitor, Celgene), FG-3019 (FibroGen), SAR-100842 (Sanofi), and obeticholic acid (OCA or INT-747, Intercept).
  • the potential exi sts for a chemical interaction between the combined active ingredients.
  • the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced).
  • one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
  • One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would invol ve the formulation of a combination product in which the one component is coated with a sustained and/or en teric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
  • HPMC hydroxypropyl methylcellulose
  • the polymer coating serves to form an additional barrier to interaction with the other component.
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving RXFP1 .
  • Such compounds may be provided in a commercial ki t, for example, for use in pharmaceutical research involving RXFP1.
  • a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
  • compounds according to the present invention could be used to test their effectiveness.
  • the compounds of the present invention may also be used in diagnostic assays involving RXFP1.
  • the present invention also encompasses an article of manufacture.
  • article of manufacture is intended to include, but not be limited to, kits and packages.
  • the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises a first therapeutic agent, compri sing a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemias and the sequelae thereof.
  • the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment of dyslipidemias and the sequelae thereof.
  • the article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located witbin the first and second containers means that the respective container holds the item within its boundaries.
  • the first container is a receptacle used to hold a pharmaceutical composition.
  • This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
  • First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
  • Hie second container is one used to hold the first container and, optionally, the package insert.
  • the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
  • the package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container.
  • the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.
  • the package insert is a label, tag, marker, etc. that recites infonnation relating to the pharmaceutical composition located within the first container.
  • the information recited will usually be determined by the regulatory agency governing the area in which the arti cle of manufacture is to be sold (e.g., the United States Food and Drug Administration).
  • the package insert specifically recites the indications for which the pharmaceutical composition has been approved.
  • the package insert may be made of any material on which a person can read information contained therein or thereon.
  • the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g. , printed or applied).
  • the compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section.
  • the structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification.
  • the variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.
  • Reverse phase preparative HPLC was carried out using Cl 8 columns with UV 220 nm or prep LCMS detection eluting with gradients of Solvent A (90% water, 10% MeOH, 0.1% TEA) and Solvent B (10% water, 90% MeOH, 0.1% TFA) or with gradients of Solvent A (95% water, 5% ACN, 0.1% TFA) and Solvent B (5% water, 95% ACN, 0.1% TEA) or with gradients of Solvent A (95% water, 2% ACN, 0.1% HCOOH) and Solvent B (98% ACN, 2% water, 0.1% HCOOH) or with gradients of Solvent A (95% water, 5% ACN, 10 mM NH ⁇ OAc) and Solvent B (98% ACN, 2% water, 10 mM NH4OAC) or with gradients of Solvent A. (98% water, 2% ACN, 0.1% NII4OII) and Solvent B (98% ACN, 2% water, 0. 1%
  • the methyl ester was converted to the amide via treatment with 4-fluoro-3 -trifluoromethylaniline and trime thyl aluminum to furnish 1-6.
  • Deprotection of the trifluoroacetamide using K2CO3 and MeOH produced amine 1-7.
  • Detector wavelength 220 nm; Injections details: 4 injections of 3.5 mL of 59 g / 490 mL MeOELDCM (4:1) 120 mg/mL in IPA. Analytical chromatographic conditions:
  • the norbomyl intermediate IIa-8 could also be prepared by the general route shown in Scheme la from furan-2,5 -dione and ferrocenium hexafluorophosphate. Diels Alder condensation, followed by hydrolysis to IIa-2, Curtius rearrangement to the intermediate amine which was reduced tmder hydrogenation conditions and subsequently protected to generate intermediate Ila- 3. Cleavage of the benzyl ester and cross coupling to NHR1R2 generated intermediates with the general structure IIa-5. Conversion of the C7 hydroxygroup to the ketone followed by Wittig olefination generated major isomer intermediate IIa-8. The major isomer was separated from the minor isomer by chromatography and the racemate separated into enantiopure IIa-8 (-).
  • Racemic II-4 (4 grams) was produced as outlined above and separated into individual enantiomers using chiral SFC.
  • Scheme III demonstrates the diversification possible with a variety of reagents for example, alkyl lithium, alkyl magnesium, Wittig reaction, Homer-Wadsworth Emmons, but not limited to these.
  • Scheme IV demonstrates installation of cycloalkyl and heterocycle bridgehead functionality in similar manner as scheme II, in this example, isoxazole and cyclopropyl groups, but not limited to these groups.
  • Scheme V demonstrates functionalizing the C7 position with a trifluoromethyl group.
  • Intermediate V-1 was prepared from II-4. To a 250 mL round bottom flask charged with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.5 mL, 20 mmol) in anhydrous DMF (50 mL) was added dropwise via dropping funnel to a suspension of II-4 and Cui (2.3 g, 12 mmol) in anhydrous DMF (100 mL) and IIMPA (8.0 mL, 19 mmol) and the reaction mixture heated at 75 °C under an inert nitrogen atmosphere for 16 h. The cooled reaction mixture was filtered and purified by silica gel chromatography to produce V-1 (3.0 g, 6.1 mmol, 77% yield).
  • Intermediate V-2 was prepared from V-l .. MeOH (1.5 mL) and acetyl chloride (2. 1 mmol) were charged into a 2 dram vial and stirred at 23 °C for 5 min. V-l was added to the reaction vial and the contents heated at 40 °C for 24 h.
  • Scheme VI demonstrates a general method of preparing heterocyclic carboxylic acids for amide to coupling with intermediates for example, V-2 utilizing coupling agents such as HATU (not limited to). Additionally the carboxylic acids can be assembled in an alternate order or using an alternate protection strategy.
  • Intermdiate MI-3 To a solution of methyl MI-2 (0.022 g, 0.099 mmol) dissolved in THF (0.8 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (4 mg, 0.1 mmol) and stirred 16 h. The reaction was neutralized by the addition of IM HCl and extracted into EtOAc. The organic layer was separated, dried over Na?.SO4, and the fluid was decanted and concentrated under reduced pressure. The residue was used without further purification: 5-(3-hydroxypropyl)-2-methoxynicotinic acid (0.02 g, 0.1 mmol, 100 % yield). MS (ESI) m/z TlTl (M+H).
  • Scheme VIII demonstrates a general route to amides from generic aniline amide VIII-1 .
  • Analogs were prepared by activating amine VIII-1 with B0C2C) in the presence of DMAP, and subsequently displacing the activated amide, VIII-2 with an amine. Further derivitizes are prepared by treatment of VIII-3 with acid, and subsequent amide bond formation is prepared between amine VIII-4 and a carboxyllic acid with cross coupling reagents, for example HATU, but not limited to.
  • reaction mixture was heated under microwave irradiation at 100 °C for 30 min, then cooled to RT, partitioned between water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic portions were dried over Na2SO4, filtered, concentrated and purified by HPLC to afford 20 (7.8 mg, 0.013 mmol, 71 % yield).
  • Example 26 To a solution of IV-2 (10 mg, 0.025 mmol), 26-3 (11 mg, 0.030 mmol), MeCN (0.25 mL), and DIEA (0.02 mL, 0.09 mmol) was added HAITI (11 mg, 0.028 mmol). The reaction mixture was stirred at rt for 3 h, concentrated under reduced pressure and redissolved in 20% TEA in DCM (1 mL).
  • Example 33 3-(5- ⁇ [(2R,3S,7Z)-3- ⁇ [4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl ⁇ -7- (2,2,2-trifluoroethyhdene)bicyclo[2.2.1]heptan-2-yl]carbamoyl ⁇ -4,5-dihydro-l,2-oxazol- 3-yl)benzoic acid was prepared by the coupling method described for example 1 using the trifluoromethyl norbomyl intennediate V-2 and 33-2 followed by deprotection with TEA as in the procedure to prepare example 26. (4.7 mg, 7.7 mmol, 20 % yield).
  • Example 34 was prepared from coupling 34-5 with V-2 under HATU conditions similar to example 1 to produce N-[(2R,3S,7Z)-3- ⁇ [4-fluoro-3-
  • Tire reaction mixture was concentrated under reduced pressure and purified via silica gel chromatography to furnish methyl 5-bromo-2-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)nicotinate (0.20 g, 0.56 mmol, 43 % yield) MS (ESI) m/z 383.7 (M+Na).
  • N-[(2R,3S,7Z)-3- ⁇ [4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl ⁇ -7-(2,2,2- trifluoroethylidene)bicyclo[2.2. l]heptan-2-yl] -5 -(3 -hydroxyprop- 1 -yn- 1 -yl)-2- methoxypyridine-3-carboxamide was prepared viaHATU coupling between 5-2 and 49-2 as described in the general procedure for example 1.
  • N-[(2R,3S,7Z)-3- ⁇ [4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl ⁇ -7-(2,2,2- trifluoroethylidene)bicyclo[2.2.1]heptan-2-yl]-5-(3-hydroxypropyl)-2-methoxypyridine- 3 -carboxamide was prepared via HATU coupling between V-2 and VII-3 as described by the general procedure for example 1. (21 mg, 0.035 mmol, 31 % yield).
  • reaction mixture was concentrated under reduced pressure to afford 7-cyano-4,5-dihydro-lH-benzo[g]indazole-3-carboxylic acid which was redissolved in a mixture of toluene/THF (8:3, 15 mL) and Nall (60% wt in dispersion oil) (83 mg, 2.07 mmol) was added.
  • the reaction mixture was stirred at rt for 1 h followed by the addition of the difluoroethyltriflate (440 mg, 2. 1 mmol).
  • the reaction mixture was heated at 70 °C for 18h, allowed to cool.
  • Example 55 7-cyano-l-(2,2-difluoroethyl)-N-((lR,2R,3S,4R,Z)-3-((4-fluoro-3- (trifluoromethyl)phenyl)carbamoyl)-7-(2,2,2-trifluoroethylidene)bicyclo[2.2.1]heptan-2- yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide was prepared by the general coupling method described for example 1 using the trifluoromethyl norbomyl intermediate V-2 and intermediate 55-2.
  • N,N-dimethylformarnide di-tert-butyl acetal (2.5 mL, 11 mmol) was added dropwise to a solution of 59-4 (340 mg, 1.9 mmol) dissolved in toluene (0.5 mL). The solution was heated to 80 °C for 30h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (30 mL), dried over NaiSCh , filtered and then concentrated under reduced pressure.
  • Example 59 To a solution of 59-11 (13 mg, 0.051 mmol) and 59-2 hydrogen chloride salt (9.7 mg, 0.031 mmol) dissolved in DMF (0.4 mL) was added BOP (16 mg, 0.037 mmol) and DIEA (0.027 mL, 0.15 mmol) and stirred for 1.5 h.

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WO2025077841A1 (zh) * 2023-10-13 2025-04-17 江苏恒瑞医药股份有限公司 酰胺取代的环烷基类化合物、其制备方法及其在医药上的应用
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WO2026041118A1 (zh) * 2024-08-22 2026-02-26 江苏恒瑞医药股份有限公司 酰胺取代的环烷基类化合物、其制备方法及其在医药上的应用
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025031481A1 (zh) * 2023-08-10 2025-02-13 深圳信立泰药业股份有限公司 一种rxfp1受体调节剂及其制备方法和医药用途
WO2025077841A1 (zh) * 2023-10-13 2025-04-17 江苏恒瑞医药股份有限公司 酰胺取代的环烷基类化合物、其制备方法及其在医药上的应用
WO2025128938A1 (en) 2023-12-15 2025-06-19 Eli Lilly And Company Benzothiazole derivatives useful as rxfp1 receptor agonists
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WO2026041118A1 (zh) * 2024-08-22 2026-02-26 江苏恒瑞医药股份有限公司 酰胺取代的环烷基类化合物、其制备方法及其在医药上的应用
WO2026064271A1 (en) * 2024-09-23 2026-03-26 Fmc Corporation Substituted bicyclic amide derivatives as herbicides

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