Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—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
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems

Definitions

• the present invention relates generally to novel diazaspiro compounds and their analogues thereof, which are inhibitors of Rho kinases, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of disorders associated with aberrant Rho kinase activity.
• Rho-Kinase is a member of the serine-threonine protein kinase family.
• ROCK exists in two isoforms, ROCK1 and ROCK2 (Ishizaki, T. et al., EMBO J. , 15: 1885-1893 (1996)).
• ROCK has been identified as an effector molecule of RhoA, a small GTP-binding protein (G protein) that plays a key role in multiple cellular signaling pathway s.
• RhoA a small GTP-binding protein
• ROCK and RhoA are ubiquitously expressed across tissues.
• the RhoA/ROCK signaling pathway is involved in a number of cellular functions, such as ACTIN® organization, cell adhesion, cell migration, and cytokinesis (Riento, K. et al., Nat. Rev. Mol. Cell Biol , 4:446-456 (2003)).
• RhoA Upon activation of its receptor, RhoA is activated, and, in turn, it activates ROCK. Activated ROCK phosphorylates the myosin-binding subunit of myosin light chain phosphatase, which inhibits activity of the phosphatase and leads to contraction. Contraction of the smooth muscle in the vasculature increases blood pressure, leading to hypertension.
• Rho A/ROCK signaling pathway plays an important role in signal transduction initiated by several vasoactive factors, for example angiotensin II (Yamakawa, T. et al. , Hypertension, 35:313-318
• ROCK inhibitors fasudrl Asano, T. et al., J. Pharmacol. Exp. Then , 241 : 1033-1040 (1987)) or Y-27632 (Uehata, M. et al, Nature, 389:990-994 (1997)) further illustrate the link between ROCK and cardiovascular disease.
• ROCK expression and activity have been shown to be elevated in spontaneously hypertensive rats, suggesting a link to the development of hypertension in these animals (Mukai, Y. ei & ⁇ ., FASEB J. , 15: 1062-1064 (2001)).
• the ROCK inhibitor Y-27632 (Uehata, M.
• ROCK inhibitor Y-27632 also inhibited neointimal formation in rats (Sawada, N. et al. , Circulation, 101 :2030-2033 (2000)).
• ROCK inhibitor would be useful in treating other cardiovascular diseases.
• fasudil was shown to reduce both the infarct size and neurologic deficit (Toshima, Y., Stroke, 31 :2245-2250 (2000)).
• the ROCK inhibitor Y-27632 was shown to improve ventricular hypertrophy, fibrosis and function in a model of congestive heart failure in Dahl salt- sensitive rats (Kobayashi, N. et al. Cardiovascular Res. , 55:757-767 (2002)).
• ROCK ROCK-related diseases
• coronary vasospasm Shiokawa, H. et al., Cardiovasc. Res., 43: 1029-1039 (1999)
• cerebral vasospasm Sato, M. et al., Circ. Res., 87: 195-200 (2000)
• ischemia/reperfusion injury (Yada, T. et al., J. Am. Coll. Cardiol., 45:599-607 (2005)), pulmonary hypertension (Fukumoto, Y. et al., Heart, 91 :391-392 (2005)), angina (Shimokawa, H. et al., J. Cardiovasc. Pharmacol , 39:319-327 (2002)), renal disease (Satoh, S. et al, Eur. J. Pharmacol. , 455: 169-174 (2002)) and erectile dysfunction (Gonzalez-Cadavid, N.F. et al., Endocrine, 23: 167-176 (2004)).
• RhoA/ROCK signaling pathway allows formation of multiple competing lamellipodia that disrupt the productive migration of monocytes (Worthylake, R.A. et al. , J. Biol. Chem. , 278: 13578- 13584 (2003)). It has also been reported that small molecule inhibitors of Rho Kinase are capable of inhibiting MCP-1 mediated chemotaxis in vitro (lijima, H., Bioorg. Med. Chem. , 15: 1022-1033 (2007)). Due to the dependence of immune cell migration upon the RhoA/ROCK signaling pathway one would anticipate inhibition of Rho Kinase should also provide benefit for diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
• ROCK inhibitors may also be useful in other diseases involving smooth muscle hyper-reactivity, including asthma and glaucoma (Shimokawa, H. et al., Arterioscler. Thromb. Vase. Biol , 25: 1767-1775 (2005)).
• Rho- kinase has been indicated as a drug target for the treatment of various other diseases, including airway inflammation and hyperresponsiveness (Henry, P.J. et al., Pulm.
• CVD cardiovascular diseases
• WO2017/123860 all of which are assigned to the present applicant.
• fasudil is the only marketed ROCK inhibitor at this time.
• An i . v. formulation was approved in Japan for treatment of cerebral vasospasm.
• ROCK inhibitors for the treatment of cardiovascular diseases, cancer, neurological diseases, renal diseases, fibrotic diseases, bronchial asthma, erectile dysfunction, and glaucoma.
• the present invention provides novel diazaspiro compounds and their analogues, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as selective inhibitors of Rlio kinases.
• the 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 in the treatment and/or prophylaxis of conditions associated with aberrant ROCK activity.
• 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 a condition associated with aberrant ROCK activity.
• the present invention is directed to a method of treating a cardiovascular or related disease which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.
• diseases include, for example, hypertension, atherosclerosis, restenosis, stroke, heart failure, renal failure, coronary artery disease, peripheral artery disease, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injur ', pulmonary hypertension, angina, erectile dysfunction and renal disease.
• the present invention is directed to a method of treating diseases involving smooth muscle hyper reactivity including asthma, erectile dysfunction and glaucoma, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.
• the present invention is directed to a method of treating diseases mediated at least partially by Rho kinase including fibrotic diseases, oncology, spinal- cord injury, Alzheimer's disease, multiple sclerosis, stroke, neuropathic pain, rheumatoid arthritis, psoriasis and inflammatory bowel disease, which method comprises
• the present invention is directed at pharmaceutical compositions comprising the above-mentioned compounds, processes for preparing the above-mentioned compounds and intermediates used in these processes.
• 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 present invention provides, inter alia, compounds of Formula
• Ring A is selected from
• Ji, , , and h are independently selected from N, CR3, and CR4; provided no more than two of Ji, h, h, and J4 are N;
• L is selected from -C(O)-, -C(0)NH-, and -S(0) P -;
• Ri at each occurrence, is independently selected from H, F, CI, Br, OH, CN, NRaRa, -OCi-4 alkyl substituted with 0-3 Re, and Ci-4 alkyl substituted with 0-3 R e ;
• R2 at each occurrence, is independently selected from H, - ⁇ ( ' ! 1 ⁇ ⁇ :ORb. (CH 2 )rS(0) P Rc, -(CH 2 )rC(-0)Rb, -(CH 2 )iNRaRa, -(CH 2 )iCN,
• R3 at each occurrence, is independently selected from H, F, CI, Br, CN, C 1-4 alkyl
• R 4 at each occurrence, is independently selected from H, F, CI, Br, OH, CN, OCM alkyl substituted with 0-3 Re, NRaRa, and CM alkyl substituted with 0-3 R e ;
• Rs is selected from C3-10 carbocyclyl substituted with 0-5 Re and heterocyclyl comprising carbon atoms and 1-6 heteroatoms selected from N, NRea, S, and O, and substituted with 0-6 Re;
• R? at each occurrence, is independently selected from H, Ci-e alkyl substituted with 1-5 Ra, C 2 -6 aikenyl substituted with 1-5 R a , C 2 -6 aikynyi substituted with 1 -5 R 3 , -(CH2)r-C3-iocarbocyclyl substituted with 1-5 Ra, and -(CH2)r-heterocyclyl substituted with 1-5 R a : or R? and R? together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 1-5 Ra;
• Rb at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, C2--6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)r-C3-iocarbocyclyl substituted with 0-5 R e , and -(CH2)r-heterocyclyl substituted with 0-5 R e :
• Re at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 R e , C 2 -6alkenyl substituted with 0-5 R e , C2-ealkyny] substituted with 0-5 Re, tVecarbocyclyl, and heterocyciyl;
• Rci at each occurrence, is independently selected from H and C i-4aikyl substituted with 0-5 R e ;
• Ci-salkyl (optionally substituted with F, CI, Br, OI L OCi-4 alkyl, NR g R g ), -(CH 2 )i-C3-iocarbocy cly 1 and -(CH 2 )r-heterocyclyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with
• R at each occurrence, is independently selected from H and Ci-salkyl
• n is an integer of zero, 1 or 2;
• p is an integer of zero, 1 or 2;
• q is an integer of zero or 1;
• r is an integer of zero, 1, 2, 3 or 4;
• t is an integer of zero, 1 or 2.
• the present invention provides compounds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Ri, at each occurrence, is independently selected from H, F, CI, Br, OH, CN, NRaRa,
• R2 at each occurrence, is independently selected from H, -(CH2)rORb, (CH2)rS(0) P R c ,
• RJ at each occurrence, is independently selected from H, F, CI, Br, CN, Ci-4 alkyl
• R7 at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 1-5 Ra, C2-6 alkenyl substituted with 1 -5 Ra, C2-6 alkynyl substituted with 1-5 R a , -(CH2)r-C3-iocarbocyclyl substituted with 1-5 Ra, and -(CHbjr-heterocyciyl substituted with 1-5 R a ; or R? and R? together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 1-5 R a ;
• Rb at each occurrence, is independently selected frorn H, Ci-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH2)r-C3-iocarbocyclyl substituted with 0-5 R e , and -(CH 2 )r-heterocyclyl substituted with 0-5 R e ;
• Rc at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 Re, ( ' . ⁇ t.alkeny! substituted with 0-5 R e , C2-6alkynyl substituted with 0-5 R e ,
• Rd at each occurrence, is independently selected fror H and substituted with
• Rf at each occurrence, is independently selected from H, F, CI, Br, CN, OH, Ci-5alkyl (optionally substituted with F, CI, Br, OH, and OCi-4 alkyl, -NRgRg), -(CH2)r-C3-iocarbocyclyl, and -(CH2)r-heteroeyclyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with Cwalk l;
• R g at each occurrence, is independently selected from H and Ci-salkyl
• the present invention provides compounds of Formula (II):
• Ring A is selected from
• h and are independently selected from N, CRs, and CR4;
• L is selected from -C(O)- and -S(Q) P -:
• Ri at each occurrence, is independently selected from H, F, CI, Br, CN, NRaRa, and
• R2 at each occurrence, is independently selected from H, F, CI, Br, OH, CN, NRaRa, anc Ci-4aikyl substituted with 0-4 R e ;
• R3 at each occurrence, is independently selected from H, F, CI, Br, CN, C1-4 alkyl
• R 4 at each occurrence, is independently selected from H, F, CI, Br, OH, CN, OCM alkyl substituted with 0-3 R e , and CM alkyl substituted with 0-3 R e ;
• Re at each occurrence, is independently selected from F, CI, Br, Chalky i, C 2- 4alkenyl, CiMaikynyi, mtro, -(CHR d )rS(0)pRc, -(CHRd)rS(Q),NRaRa, -iCHR d NRaS(Q c , -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa,
• Rea at each occurrence, is independently selected from H, Cwalkyl, -S(0)pR c ,
• R'7 is independently selected from H, Ci-6 alkyl substituted with 0-5 Ra, C?.-6 alkenyl substituted with 1-5 Ra, C?. ⁇ 6 alkynyl substituted with 1-5 Ra, - CH2)r-C3-iocarbocyclyl substituted with 1-5 Ra, and -(CH 2 )r-heterocyclyl substituted with 1-5 R a ; or R? and R?
• Rb at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, C2--6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH 2 )r-C3-iocarbocyclyl substituted with 0-5 Re, and -(CH 2 )r-heterocyclyl substituted with 0-5 R e ;
• Rc at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 Re, C2-6aIkenyl substituted with 0-5 R e , Cj-ealkynyl substituted with 0-5 Re,
• Rf at each occurrence, is independently selected from H, F, CI, Br, CN, OH, C1-.5 alkyl (optionally substituted with F, CI, Br, OH, and OCi-4 alky], -NR g R g ), -(CH 2 )r-
• R g at each occurrence, is independently selected from H and Ci-salkyl
• h is selected from N, CR3, and CR 4 ;
• L is selected from -C(0) ⁇ and -S(0) P -;
• Rj at each occurrence, is independently selected from H, F, CI, Br, CM, NR a Ra, and
• R2 at each occurrence, is independently selected from H and substituted with
• Rs at each occurrence, is independently selected from H, F, CI, Br, CN, Ci -4 alkyl
• R 4 at each occurrence, is independently selected from H, F, CI, Br, OH, CN, OCi-4 alkyl substituted with 0-3 Re, and Ci-4 alkyl substituted with 0-3 R e :
• Re at each occurrence, is independently selected from F, CI, Br, C1-4 alkyl, -(CH 2 )iORb,
• R7 is independently selected from H, Ci-& alkyl substituted with 1-5 Ra, C 2 -6 alkenyl substituted with 1-5 R a , C 2 ,-6 alkynyl substituted with 1-5 R a ,
• Rb at each occurrence, is independently selected from H, Ci-6 alky! substituted with 0-5
• Rc at each occurrence, is independently selected from C i-6 alkyl substituted with 0-5 Re,
• Rf at each occurrence, is independently selected from H, F, CI, Br, CN, OH, C1-5 alkyl
• R g at each occurrence, is independently selected from H and Ci-saikyl:
• the present invention provides compounds of Formula (IV).
• h is selected from N and CH;
• R3 is selected from H, CN, Ci-4 alkyl, -OC1-3 alkyl, and -Cs-ecycloalkyl:
• R7 is independently selected from H, Ci-6 alkyl substituted with 1-5 Ra, C2-6 alkenyl substituted with 1-5 R a , C2-6 alkynyl substituted with 1-5 Ra,
• Rb at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, -(CH 2 )r-C3-iocarbocyclyl substituted with 0-5 Re, and -(CH 2 )r-heterocyclyl substituted with 0-5 R e ;
• Rg at each occurrence, is independently selected from H and Ci-salkyl:
• r is an integer of zero, 1, 2 or 3.
• the present invention provides compounds of Formula (V):
• Ring A is selected from
• Ri is selected from H, F, CI, Br, NR a Ra, and
• R? at each occurrence, is independently selected from H, Ci-e alkyl substituted with 1-5 Ra; or R? and R? together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from
• Rb at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, -(CH2)r-C3-iocarbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 R e ;
• Rf at each occurrence, is independently selected from H, H, F, CI, Br, CN, OH, C (optionally substituted with F, CI, Br, OH, OCi-4 alkyl, NR g R g ), --(CH 2 ⁇ C3-6cycloalkyl, and -(CH 2 )r-phenyi;
• R g at each occurrence, is independently selected from H and Ci-salkyl:
• r is an integer of zero, 1, 2 or 3.
• the present invention provides compounds of Formula (VI):
• Ring A is selected from
• Ri is selected from H, F, CI, Br, NRaRa, and
• Ra is selected from H, Ci-ealkyl substituted with 0-5 Re,
• Rf at each occurrence, is independently selected from H, F, CI, Br, CN, OH, C1-5 alkyl
• R at each occurrence, is independently selected from H and Ci-salkyl; and r is an integer of zero, 1 , 2 or 3.
• the present invention provides compoiinds of Formula (VI), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• Rf at each occurrence, is independently selected from H, F, CI, Br, CN, OH, and Ci-5 alkyl (optionally substituted with F, CI, Br, OH, QCi-4 alkyl, and NRgRg), and ⁇ ( ( ! ! > ⁇ :-pheii ! .
• R at each occurrence, is independently selected from H and
• r is an integer of zero, 1, 2 or 3.
• the present invention provides compounds of Formula (VII):
• Re at each occurrence, is independently selected from F, CI, Br, Chalky i, C 2- 4alkenyl, C 2 -4aikynyl, mtro, -(CH 2 )rS(Q)pRe, -(CH2 S(0)/,NRaRa, -(CH 2 )rNRaS(C3 ⁇ 4Rc, -(CH 2 )rORb, -(CH 2 )iCN, -(CH 2 )rNRaRa, ⁇ ! ( ⁇ ] i > i,NRaC ⁇ ⁇ ))3 ⁇ 4.
• Rea at each occurrence, is independently selected from H, Cwalkyl, -S(Q)pR c ,
• p is an integer of zero, 1 or 2;
• r is an integer of zero, 1, 2 or 3;
• the present invention provides compounds of Formula (VII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• R6a at each occurrence, is independently selected froni H and CM alkyl ;
• the present invention provides compounds of Formula (VIII);
• L is selected from -C(O)- and -S(0) P -;
• Re at each occurrence, is independently selected from F, CI, Br, Ci-4alkyl, C 2- 4alkeny], mtro, -(CHRd)rS(Q) P Rc, -(CHRd)rNR,S(0) «R c ,
• Rea at each occurrence, is independently selected from H and Cwalkyl;
• Ra at each occurrence, is independently selected from H and Ci-e alkyl substituted with
• R at each occurrence, is independently selected from H and Ci-e alkyl substituted with 0-5 R e ;
• Rc at each occurrence, is independently selected from Ci-e alkyl substituted with 0-5 Re, C2-ealkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
• Rf at each occurrence, is independently selected from H, F, CI, Br, CN, OH, C1-5 alkyl (optionally substituted with F, CI, Br, OH, and OCi-4 alkyl, NRgRg),
• Rg at each occurrence, is independently selected from H and Ci-salkyl
• p is an integer of zero, 1 or 2;
• r is an integer of zero, 1 , 2 or 3.
• the invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all
• the present invention provides a compound selected from any subset list of compounds exemplified in the present application.
• the compounds of the present invention have ROCK ICso values ⁇ 10 ⁇ .
• the compounds of the present invention have ROCK ICso values ⁇ I ⁇ .
• the compounds of the present invention have ROCK ICso values ⁇ 0.1 ⁇ .
• the compounds of the present invention have ROCK ICso values ⁇ 0,05 ⁇ .
• the compounds of the present invention have ROCK ICso values ⁇ 0.01 ⁇ .
• the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate, thereof.
• the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable earner and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
• the present invention provides a process for making a compound of the present invention.
• the present invention provides an intermediate for making a compound of the present invention.
• the present invention provides a pharmaceutical
• composition further comprising additional therapeutic agent(s).
• the present invention provides a method for the treatment and/or prophylaxis of a condition associated with aberrant ROCK activity comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at l east one of the compounds of the present inventi on or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
• the term "patient” encompasses all mammalian species.
• treating cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e. , arresting it development; and/or (b) relieving the disease-state, i.e. , causing regression of the disease state.
• prophylaxis covers the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state.
• Patients are selected for preventative therapy based on factors that are known to increase risk 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 patient that has 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.
• the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.
• Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present in vention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form.
• a free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers.
• Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecul es are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
• stereoisomer refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.
• enantiomer refers to one of a pair of molecular” species that are mirror images of each other and are not superimposable.
• 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 acti vity.
• R and S represent the configuration of substituents around a clnral carbon atom(s).
• the isomeric descriptors “R” and “S” are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).
• 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.
• 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 “CMO alkyi” (or alkylene) is intended to include Ci, C2, C3, C4, Cs, Ce, C7, Cs, C9, 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 pentyl (e.g. , n-pentyl, isopentyl, neopentyl).
• Me methyl
• Et ethyl
• propyl e.g. , n-propyl and isopropyl
• butyl e.g. , n-butyl, isobutyl, /-butyl
• pentyl e.g. , n-pentyl, isopentyl, neopentyl.
• alkenyl or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain.
• C?. to C6 alkenyl or “C2-6 alkenyl” (or alkenylene) is intended to include C2, C3, Ci, Cs, and Ce. alkenyl groups.
• alkenyl examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyi-2- propenyl, and 4-methyl-3-pentenyl.
• Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon-carbon 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, CJ, CA, Cs, and Ce alkynyl groups: such as ethynyl, propynyl, butynyl, pentynyl, and hexyn l.
• alkoxy refers to an -O-alkyl group.
• C i to Ce alkoxy or "Ci -6 alkoxy” (or alkyloxy) is intended to include Ci, C2, C3, C 4 , Cs, and Ce alkoxy groups.
• Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g. , n-propoxy and isopropoxy), and /-butoxy.
• alkyithio or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge: for example methyl-S- and ethyi-S-.
• Halo or “halogen” includes fluoro (F), chloro (CI), bromo (Br), and iodo (I).
• haioalkyi is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens.
• haioalkyi include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichioromethyl, pentafluoroethyi, pentachloroethyl, 2,2,2-trifluoroethyl, heptafiuoropropyl, and heptachioropropyl.
• haioalkyi also include "fluoroalkyl” that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
• Haloalkoxy or "haloalkyloxy” represents a haioalkyi group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
• Ce to Ce haloalkoxy or “Ci-6 haloalkoxy”
• Ci Ci
• C2, C3, C 4 Cs
• Ce haloalkoxy groups examples include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.
• haloalkylthio or “thiohaioalkoxy” represents a haioalkyi group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example
• cycloalkyl refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. " C3 to C? cycloalkyl” or “ C3-7 cycloalkyl” is intended to include C3, C4, C5, C.6, and C? cycloalkyl groups.
• Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyelobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".
• carrier or “carbocyclic residue” is intended to mean any- stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bi cyclic 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.
• carbocycles include, but are not limited to, cyclopropyl, cyelobutyl, cyclobutenyl, cyclopentyl, cyciopentenyl, cyclohexyl, cydoheptenyl, cycioheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,
• bridged rings are also included in the definition of carbocycle (e. g. ,
• Preferred carbocycles are cyclopropyl, cyelobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
• 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 always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the rmg may also be present on the bridge.
• bicyclic carbocycle 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 stmcture.
• the bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable.
• bicyclic carbocyclic group examples include, but not limited to, naphthyl, 1 ,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
• Aryl groups refer to monocyclic or poly cyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl. And 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).
• Cio aryl or “Ce-io aryl” refers to phenyl and naphthyl. Unless otherwise specified, "aryl”, “Ce or Cio aryl” or “Ce-io aryl” or “aromatic residue” may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH3, CI, F, Br, 1, CN, NO2, NH2, N(CHs)H, N(CH 3 )?., CFs, Oi l- :.. C( ⁇ ⁇ ! :. SCFI3, S! ())( ' !
• benzyl refers to 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, OH, OCHs, CI, F, Br, I, CN, NO2, Ni N(CH3)H, N(CH 3 ) 2 , CF3, OCF3, ( i ( ) )( ! ! .. SCH3, Si 0)0 ⁇ . Si O H i CH3, CH2CH3, CO2H, and CO2CH3.
• heterocyclic group is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 1 1 -, 12-, 13-, or 14-membered poly cyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any poly cyclic 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.
• the nitrogen atom may be substituted or unsubstituted (i.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 heterocvcle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocvcle 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 heterocvcle is not more than 1.
• heterorocvcle it is intended to include heteroaryl.
• heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyi, benzothiofuranyl, benzothiophenyl, benzoxazolyi, benzoxazolinyl, benzthiazolyl, benztriazolyl, benzietrazolyl,
• Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, Iriazinyl, triazolyl, benzimidazolyl, lH-indazolyl, benzofuranyl, benzothiofuranyl, benzietrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyi, oxindolyl, benzoxazolinyl,
• Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indoiyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazoiidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and tnazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
• bicyclic heterocycle 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.
• 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 heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).
• 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 substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle 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 heterocycle is not more than 1.
• bicyclic heterocyclic group examples include, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indoiyl, isoindolyl, indolinyl, lH-indazolyl, benzimidazolyl, 1 ,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8- tetrahydro-qumoiinyl, 2,3-dihydro-benzofuranyL chromanyl, 1,2,3,4-tetrahydro- quinoxalinyl, and 1 ,2,3,4-tetrahydro-quinazolinyl.
• aromatic heterocyclic group or "heteroaryl” is intended to mean stable monocyclic and poly cyclic 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, fury], quinolvl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indoiyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyi, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4- thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, mdolinyl,
• benzodioxolanyl, and benzodioxane, Heteroaryl groups are substituted or un substituted.
• the nitrogen atom is substituted or unsubstituted ( .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 ⁇ 0 and S(0) P , wherein p is 0, 1 or 2).
• Bridged rings are also included in the definition of heterocycle.
• a bridged ring occurs when one or more atoms (i.e. , C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
• Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbo -nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
• counterion is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
• a dotted ring When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated.
• 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 (N— >()) 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.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxyiic acids.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, paraoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, paraoic, maleic, hydroxy maleic, phenylacetic, glutamic,
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.
• compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e. , a compound of formula I) is a prodrug within the scope and spirit of the invention.
• a prodrug within the scope and spirit of the invention.
• Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
• esters of compounds of formula ! include Ci-ealkyl, Ci-ealkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, Ci-e alkanoyioxy-Ci-ealkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), Ci-6alkoxycarbonyloxy-Ci-6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenyiglycyloxymethyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)-methyl), and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared
• prodrugs Preparation of prodrugs is well known in the art and described in, for example. King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al, Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and E ymo!ogy, VCHA and Wile -VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).
• the present invention is intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hy drogen include deuterium and tritium.
• Deuterium has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen.
• Deuterium can be represented by symbols such as " 2 H” or "D”.
• Isotopes of carbon include C and l4 C.
• Isotopically -labeled compounds of the invention 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 otherwise employed. Such compounds have a variety of potential uses, e.g. , as standards and reagents in determining the ability of a potential
• “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that compounds of the present invention do not contain a N-halo, S(0) 2 H, or S(0)H group.
• solvate means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• the solvent molecules in the solvate may be present in a regular arrangement and'or a non-ordered arrangement.
• the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
• “Solvate” encompasses both solution-phase and isolable solvates. Exemplar ⁇ ' solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
• the effectiveness of compounds of the present invention as ROCK inhibitors can be determined in a 30 ⁇ assay containing 20 mM HEPES, pH 7.5, 20 mM MgCk, 0.015% Brij-35, 4 mM DTT, 5 ⁇ ATP and 1.5 ⁇ peptide substrate (FITC-AHA- AKRRRLS SLR A-OH) (SEQ ID No. 1), Compounds were dissolved in DMSO so that the final concentration of DMSO was ⁇ 2%, and the reaction was initiated with Rho kinase variants.
• the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
• composition means a composition comprising a compound of the 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, antibacterial agents, antifungal 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 patient to which the agent- containing composition is to be administered; the intended route of administration 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. Descriptions of suitable
• the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent 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.
• a physician or veterinarian can determine and prescribe the effecti ve amount of the drug required to prevent, counter, or arrest the progress of the disorder.
• the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/'day.
• the most preferred doses will range from about 0.001 to about 10 mg kg/minute dunng 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.
• Compounds of this invention can also be administered by parenteral
• administration e.g. , intra-venous, intra-arterial, intramuscularly, or subcutaneously.
• intra-venous or intra-arterial the dose can be given continuously or intermittent.
• formulation can be developed for intramuscularly and subcutaneous delivery that ensure a gradual release of the active pharmaceutical ingredient.
• Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• 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.
• the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert earner such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components ca be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate,
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
• the compounds of the present invention can also be administered in the form of liposome delivery' systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
• Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
• soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
• the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, poly lactic acid, polygly colic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals.
• biodegradable polymers useful in achieving controlled release of a drug, for example, poly lactic acid, polygly colic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals.
• Dosage forms suitable for administration may contain from about 1 milligram to about 1000 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.
• Gelatin capsules may contain the active ingredient and powdered earners, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
• powdered earners such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
• Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
• Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
• parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
• Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
• Anti oxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
• citric acid and its salts and sodium EDTA are also used.
• parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl -paraben, and
• the compounds of the present invention can be administered alone or in
• administered in combination or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
• each component may be administered at the same time or sequentially in any order at different points in time.
• each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
• the compounds of the present invention are also useful as standard or reference compounds, for example as a qualit ' standard or control, in tests or assays involving the inhibition of ROCK.
• Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving ROCK.
• 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 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, comprising: 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 a cardiovascular and/or inflammatory disorder (as defined previously).
• the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat cardiovascular and/or inflammatory disorder.
• 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 within 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.
• the 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 information 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 article of manufacture is to be sold (e.g. , the United States Food and Drug
• 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 the present invention may be synthesized by methods available to those skilled in the art of organic chemistry (Maffrand, J. P. et al, Heterocycles , 16(l ):35-37 (1981)).
• General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds. Examples of compounds of the present invention prepared by methods described in the general schemes are given in the intermediates and examples section set out hereinafter.
• homochiral compounds may be prepared by separation of racemic products by chiral phase preparative HPLC.
• the example compounds may be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functionalities into racemic intermediates which serve to control the diastereoselectivity of transformations, providing enantio-enriched products upon cleavage of the chiral auxiliary'.
• the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
• the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
• the reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
• Representative 2,8-diazaspiro[4.5]decan-l-one compounds 3c of this invention can also be prepared as shown in Scheme 3 in which the Suzuki coupling of the hinge ar l group was performed in the last step of the synthesis. Deprotecting Boc group of lc yields 3a, which can be coupled with either acetyl chlorides or carboxylic acids to givi 3b. Suzuki coupling of 3b with aryl boronic acids or boronic esters to give 3 ⁇ .
• GGrraaddiieenntt : 00--2200%% BB oovveerr 1199 mmiinnuutteess,, tthheenn aa 55--mmiinnuuttee hhoolldd aatt 110000%% BB;; FFllooww:: 2200 mmLL//mmiinn.. FFrraaccttiioonnss ccoonnttaaiinniinngg tthhee ddeessiirreedd pprroodduuccttt
• IInn aa ssccaallaabbllee rreeaaccttiioonn ttuubbee wwaass aaddddeedd 11 --bbrroommoo--44--iiooddoobbeennzzeennee ((1111122 m mgg,, 33..9933 mmmmooll)),, tteerrtt--bbuuttyyll ll--ooxxoo--22,,88--ddiiaazzaassppiirroo[[44..55] jddeeceaannee--88--ccaarrbbooxxyyllaattee ((550000 n migg,, 11..996666 m mmmooll)),, cceessiiuumm ccaarrbboonnaattee ((11228811 mmgg,, 33..9933 mmmmooll))
• TThhee oorrggaanniicc llaayyeerr w waass sseeppaarraatteedd,, wwaasshheedd wwiitthh wwaatteerr ((22 xx 3300 m mll)) aanndd bbrriinnee ((3300 mmll)),, ddrriieedd oovveerr MMggSS00 44 ,
• IInntteerrmmeeddiiaattee 22 : PPrreeppaarraattiioonn ooff tteerrtt--bbuuttyyll 22--((44--bbrroommoo--33--mmeetthhooxxyypphheeinryyll))--ll--ooxxoo--22,,88--
• the reaction was purged with argon and sealed. The reaction was then subjected to microwave oven and stirred at 120 °C for 45 mm. The reaction was partitioned between EtOAc (30 ml) and water (20 ml). The organic layer was separated, washed with water (15 ml) and brine (15 ml), dried over MgSiX filtered and concentrated. The residue was purified uisng ISCO system (0-100% EtOAc Hex gradient) to give ! en-busy!
• TThhee rreeaaccttiioonn wwaass ppuurrggeedd wwiitthh aarrggoonn aanndd sseeaalleedd.
• TThhee rreeaaccttiioonn wwaass ppuurrggeedd wwiitthh aarrggoonn aanndd sseeaalleedd.
• TToo aa rroouunndd bboottttoomm fl flaasskk wwaass aaddddeedd 33AA ((2255 mmgg,, 00..005599 mmmmooll)),, TOTOFF ((11 mmLL)),, 22-- mmeetthhooxxyybbeennzzooyyll cchhlloorriiddee ((1111..0000 m mgg,, 00..006644 mmmmooll)) aanndd EE ⁇ 33NN ((00..001122 mmLL,, 00..008888 mmmmooll)).
• Example 14 Preparatiosi of 8-(3-f1 oro-4-methoxYbes3 ⁇ 4zoYl)-2-i3-met oxY-4-(lH- Dyrazol-4-yl)phenvH -2,8-diazaspiro [4.51 decan- 1-one
• Example 17 Preparatiosi of 8-(2-fluoro-4-methoxybenzoyl)-2-[3-metho3 ⁇ 4v-4-(l.H- pyrazol-4-yl)phenyl j -2,8-diazaspiro 4.5 j decan- 1-one
• Example 22 Preparatiosi of 8-(3-chloro-4-methoxybeiizoyl)-2-[3-methoxy-4-(lH- pyrazol-4-yl) phenyl] -2,8-diazaspiro [4.5] deearc- 1-one
• Example 24 To a round bottom flask was added Example 24 (55 mg, 0.1 13 mmol), THF (1 mL), water (0. 1 mL) and LiOH (2.70 mg, 0.113 mmol). The reaction was stirred at rt overnight. The reaction was concentrated to give 4-(2-(3-methoxy-4-(lH-pyrazol-4- yl)phenyl)-l-oxo-2,8-diazaspiro[4.5]decane-8-carbonyl)benzoic acid, lithium salt (48 mg, 0.090 mmol, 80 % yield) as a white solid.
• 2211 11 22..4444 ( (bbrr.. ss..,, 44HH)),, 22..1144 ((bbrr.. ss.., 22HH)),, 11..9911 ((ss,, 22HH)),, 11..7788 -- 11..6644 ((mm,, 22HH)),, 11..5577 ((bbrr.. ss..,, 22HH));; MMSS ((EESSII)) mm//zz:: 449999,,44 ((MM++HH)) ++ ;; AAnnaall..
• the reaction was purged with nitrogen and sealed. The reaction was then subjected to microwave oven and stirred at 120 °C for 40 mm. The reaction was partitioned between EtO Ac (50 ml) and water (20 ml). The organic layer was separated, washed with water (20 ml) and brine (30 ml), dried over MgS04, filtered and concentrated.
• reaction mixtures were purified via preparative LC/MS with the following conditions: Column: XBridge C 18, 19 x 100 mm, 5- ⁇ particles; Mobile Phase A: 5 :95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 2-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. ** Gradient varied for each reaction depending on polarity of compound.
• Method 1 Column: Waters Acquity UPLC BEH CI 8, 2.1 x 50 mm, 1.7-um particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate;
• Mobile Phase B 95:5 acetonitriieiwater with 10 mM ammonium acetate; Temperature: 50 °C: Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
• Method 2 Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-um particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1 ,0 mL/min; Detection: UV at 220 nm.
• ROCK lCso 2.1nM.
• Example 55 Preparatiosi of 4-(2-?3-methoxy-4-(lII-pyr3 ⁇ 43 ⁇ 4ol-4-yI)phe83 ⁇ 4vIl-l-oxo-2,8- diazaspiro[4.5jde €a8ie-8-carboi3 ⁇ 4vnbe!izes3 ⁇ 4e-l-siiIfo 3 ⁇ 43 ⁇ 4Bic!e
• Example 63 Preparatiosi of 8-(furan-2-carboiiYl)-2-f3-metfaoxy-4-(lH-pyrazol-4- yl)phei3 ⁇ 4yll-2,8-dt3 ⁇ 4zaspiro [4,51 dee3 ⁇ 4n-l -one
• Example 65 Preparatiosi of 8-(furan-3-carboiiyl)-2-f3-methoxy-4-(lH-pyrazol-4- yl)phenyll-2,8-diazaspiro [4,51 dee3 ⁇ 4 -l -one
• HHzz,, 22HH );
• MMSS EESSII m m//zz 442211..22 ((MM++HH));
• Example 72 Preparation of 2-[3-m ti3 ⁇ 4oxy-4-(lH-pyr3 ⁇ 4zoI-4-yl)pi3 ⁇ 4er8yll-8-(6- methylpyrMiae-3-car osivg)-2. -diaz3 ⁇ 4spsroi4,5jdeca!3 ⁇ 4-l-0!3 ⁇ 4e
• HH NNMMRR ((550000 M MHHzz,, DDMMSSOO--cckk)) ⁇ 99..5577 ((ss,, 1IHH)),, 88..0022 ((bbrr ss,, 22HH)),, 77..6677 -- 77..5533 ((mm,, 22HH)),, 77..1166 ((dddd,, 88..44..
• Example 86 Preparatiosi of 8-(2.,6-d3 ⁇ 4sHet!ioxypyr ii3 ⁇ 4e--3-car!>osiyI)-2-[3-metlioxy-4- (lII-pyr3 ⁇ 43 ⁇ 4oI-4-yI)phe83 ⁇ 4vIl-2,8-diazaspiro4.5]deeas3 ⁇ 4-l-083 ⁇ 4e
• EExxaammppllee 8822 : PPrreeppaarraattiioossii ooff 22--ii33--mmeetthhoox.xyv--44--((llHH--ppyyrraa3 ⁇ 43 ⁇ 4ooll--44--yvII))pphheess3 ⁇ 43 ⁇ 4vyIIll--88--((44----
• HH NNMMRR ((550000 MMHHzz,, DDMMSSOO--cckk)) ⁇ 88..0022 ((bbrr ss,, 22HH)),, 77..6666 -- 77..5588 ((mm,, 22HH)),, 77..3344 ((ss,, I l Hi s))., 77..2255 ((88,, I l Hi s))., 77..1166 ((dddd,, 88 55.. 11 ,.66 HHzz, IIHH)),, 44,, 1199 ((bbrr dd,, ,,// ii !!
• Example 84 Preparatiosi of 2-i3-methoxy-4-(lH-PYr3 ⁇ 43 ⁇ 4ol-4-vI)phepyIl-8-(2-phe?3 ⁇ 4Yl- 13-tW3 ⁇ 4zoIe-4- €3 ⁇ 4rbo!3 ⁇ 4Yl)-2,8--diazaspiro?4.5

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