WO2015002915A1 - Tricyclic pyri do-carboxam i d e derivatives as rock inhibitors - Google Patents

Tricyclic pyri do-carboxam i d e derivatives as rock inhibitors Download PDF

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WO2015002915A1
WO2015002915A1 PCT/US2014/044988 US2014044988W WO2015002915A1 WO 2015002915 A1 WO2015002915 A1 WO 2015002915A1 US 2014044988 W US2014044988 W US 2014044988W WO 2015002915 A1 WO2015002915 A1 WO 2015002915A1
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substituted
independently selected
alkyl
chr
heterocyclyl
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PCT/US2014/044988
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French (fr)
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Mimi L. Quan
Zilun Hu
Cailan Wang
Sharanabasappa PATIL
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Bristol-Myers Squibb Company
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Priority to JP2016524303A priority Critical patent/JP6434968B2/en
Priority to EP14741757.0A priority patent/EP3016951B1/en
Priority to CN201480047827.6A priority patent/CN105492444B/en
Priority to ES14741757.0T priority patent/ES2633987T3/en
Priority to US14/900,238 priority patent/US9914740B2/en
Publication of WO2015002915A1 publication Critical patent/WO2015002915A1/en

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to novel tricyclic carboxamide derivatives, 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. ,
  • 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 pathways. ROCK and RhoA are ubiquitously expressed across tissues. The RhoA/ROCK signaling pathway is involved in a number of cellular functions, such as actin
  • 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.
  • RhoA/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 (2000)), urotension II (Sauzeau, V. et al, Circ. Res., 88: 1 102-1104 (2001)), endothelin-1 (Tangkijvanich, P. et al, Hepatology, 33 :74-80 (2001)), serotonin (Shimokawa, H., Jpn. Circ. J., 64: 1-12 (2000)), norepinephrine (Martinez, M.C. et al, Am. J.
  • PDGF platelet-derived growth factor
  • ROCK inhibitors fasudil (Asano, T. et al, J. Pharmacol. Exp. Ther., 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. et al, 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, Cardiovasc. Res., 55:757-767 (2002)).
  • ROCK cardiovascular disease 2019
  • 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 Shiokawa, H. et al, J. Cardiovasc.
  • 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 (Iijima, FL, Bioorg. Med.
  • Rhokinase 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
  • ROCK inhibitors Although there are many reports of ROCK inhibitors under investigation (see, for example, U.S. Publication No. 2008/0275062 Al), fasudil is the only marketed ROCK inhibitor at this time. An i.v. formulation was approved in Japan for treatment of cerebral vasospasm. There remains a need for new therapeutics, including 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 tricyclic carboxamide derivatives including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as selective inhibitors of Rho 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 injury, 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
  • Ai, A 2 , and A 3 are independently selected from N and CRi; provided no more than one Ai, A 2 , and A 3 is N;
  • B is independently selected from -(CR 3 R4)mCR 3 R4-, -(CR 3 R4) m O(CR 3 R4) n -,
  • L is independently selected from - -(CR6R7) s O(CR6R7) q -, and
  • Ri and R 2 are independently selected from H, F, CI, Br, CN, NR a R a , -OC 1 -4 alkyl
  • Re and R7 are independently selected from H, substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • Rs is selected from C 3 -1 0 carbocyclyl and heterocyclyl, each substituted with 0-5 R 9 ;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -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 heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, C e 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 , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e ,
  • Rj at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • R f at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • n and n at each occurrence, are independently selected from zero, 1, and 2; provided m + n ⁇ 2;
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1, and 2; provided when s and q are in the same term, s + q ⁇ 3;
  • B is independently selected from -(CR 3 R4)mO(CR 3 R4)n-, -(CR 3 R4)m Ra(CR 3 R4)n-, -(CR 3 R4) m S(0) p (CR 3 R4) dislike-, -(CR 3 R4) m C(0)0(CR 3 R4) readily-,
  • the present invention provides compounds of Formula (III):
  • L is independently selected from -(CR 6 R7) q -, -(CR 6 R7) S NR 5 -, -(CR6R?)sO-, and
  • Ri and R2 are independently selected from H, F, CI, Br, CN, RaRa, -OC1-4 alkyl
  • R 3 and R4 are independently selected from H, F, OH, CN, and Ci_ 4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 R e , and Ci_ 4 alkynyl substituted with 0-3
  • Re and R7 are independently selected from H, substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • Rs is selected from aryl, C 3 _ 6 cycloalkyl, and heterocyclyl, each substituted with 0-5 R 9 ;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ; Rb, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 R e , C2- 6 alkynyl substituted with 0-5 Re,
  • Rd at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • Rf at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1 and 2.
  • the present invention provides compounds of Formula (IV):
  • Ri and R 2 are independently selected from H, F, CI, Br, OH, CN, NR a R a , -OCi_ 4 alkyl substituted with 0-3 Re, and C 1-4 alkyl substituted with 0-3 Re;
  • R3 is independently selected from H and C 1-4 alkyl substituted with 0-3 R e , C 1-4 alkenyl substituted with 0-3 Re, and C 1-4 alkynyl substituted with 0-3 R e ;
  • R6 and R7 are independently selected from H, Ci_ 4 alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -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 heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, Ci_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 , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
  • R c at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 R e , C 2 - 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 R e ,
  • Rd at each occurrence, is independently selected from H and Ci-4alkyl substituted with
  • R e at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C 2 _6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) r -C 3 _io carbocyclyl,
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
  • the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • Ri and R 2 are H;
  • R3 is independently selected from H and Me
  • R 5 is H; Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C 2 _6 alkenyl substituted with 0-5 Re, C 2 _6 alkynyl substituted with 0-5 R e , -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 R e , C2- 6 alkynyl substituted with 0-5 Re,
  • Rd at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • R6 and R7 are independently selected from H and Ci_ 4 alkyl substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -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 heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, C e 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 , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e , C 2 - 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 R e ,
  • Rj at each occurrence, is independently selected from H and Ci-4alkyl substituted with
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • the present invention provides compounds of Formula (V):
  • L is independently selected from -(CR 6 R 7 ) q , -(CR 6 R 7 )s R 5 -, -(CR 6 R 7 ) s O-, and
  • Ri and R2 are independently selected from H, F, CI, Br, CN, NR a R a , -OC1-4 alkyl
  • R3 and R4 are independently selected from H, F, OH, CN, and C 1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 R e , and C 1 -4 alkynyl substituted with 0-3
  • Re and R7 are independently selected from H, substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; Rs is selected from aryl, C 3 _ 6 cycloalkyl, and heterocyclyl, each substituted with 0-5 Rg;
  • two adjacent Rg groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 R e , C 2 - 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 Re,
  • Ra at each occurrence, is independently selected from H and Ci-4alkyl substituted with
  • Rf at each occurrence, is independently selected from H, F, CI, Br, Ci- 5 alkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1 and 2.
  • the present invention provides compounds of Formula (VI):
  • Ri and R 2 are independently selected from H, F, CI, Br, OH, CN, NR a R a , -OCi_ 4 alkyl substituted with 0-3 Re, and Ci_ 4 alkyl substituted with 0-3 Re;
  • R3 is independently selected from H and C1-4 alkyl substituted with 0-3 R e , C1-4 alkenyl substituted with 0-3 Re, and Ci_ 4 alkynyl substituted with 0-3 R e ;
  • Re and R7 are independently selected from H, Ci- 4 alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 R e , C 2 _ 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 Re,
  • Rd at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
  • the present invention provides compounds of Formula (VII):
  • L is independently selected from -(CR 6 R7) q , -(CR6R7) S NR 5 -, -(CR6R?) s O-, and
  • Ri and R 2 are independently selected from H, F, CI, Br, CN, NR a R a , -OCi_ 4 alkyl
  • R6 and R7 are independently selected from H, Ci_ 4 alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 R e , -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C 2 _6 alkenyl substituted with 0-5 Re, C 2 _6 alkynyl substituted with 0-5 R e , -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 R e , C 2 _ 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 Re,
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1, and 2.
  • the present invention provides compounds of Formula (VIII):
  • L is independently selected from -(CR 6 R7) q , -(CR6R7) S NR 5 -, -(CR6R?) s O-, and
  • Ri and R 2 are independently selected from H, F, CI, Br, CN, NR a R a , -OCi_ 4 alkyl
  • Re and R7 are independently selected from H, substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C 2 _6 alkenyl substituted with 0-5 Re, C 2 _6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5
  • R c at each occurrence, is independently selected from C e 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 ,
  • Rd at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • Rf at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1, and 2.
  • the present invention provides compounds of Formula (IX):
  • L is independently selected from -(CR 6 R7) q , -(CR6R7) S NR 5 -, -(CR6R?) s O-, and
  • Ri and R 2 are independently selected from H, F, CI, Br, CN, NR a R a , -OCi_ 4 alkyl substituted with 0-3 R e , C 1-4 alkyl substituted with 0-3 R e , and -(CH 2 ) r OR b ;
  • R3 and R4 are independently selected from H, F, and C 1-4 alkyl substituted with 0-3 R e , Ci-4 alkenyl substituted with 0-3 R e , and C 1-4 alkynyl substituted with 0-3 R e ;
  • R6 and R7 are independently selected from H, Ci_ 4 alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ;
  • R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -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 heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, Ci_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 , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
  • R c at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 R e , C 2 - 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 R e ,
  • Rd at each occurrence, is independently selected from H and Ci-4alkyl substituted with
  • R e at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C 2 _6 alkenyl, C 2 _6 alkynyl, -(CH 2 ) r -C 3 _io carbocyclyl,
  • R f at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1, and 2.
  • the present invention provides compounds of Formula (IX), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • L is -(CR 6 R 7 ) q ;
  • Ri and R 2 are H;
  • R3 and R4 are independently selected from H, F, and Ci_ 4 alkyl substituted with 0-3 R e ;
  • R 5 is H;
  • Re and R7 are independently selected from H and substituted with 0-3 R e ;
  • Rs is selected from aryl and heterocyclyl, each substituted with 0-5 R 9 ;
  • R 9 is independently selected from F, CI, Br, CN, C 1-4 alkyl, OH, OC 1 -4 alkyl,
  • the present invention provides compounds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • A3 is independently selected from and CRi;
  • B is independently selected from -0-, -CR 3 R 4 O-, -OCR 3 R 4 -, -NR a -, -C(0)0-, -OC(O)-, -C(0)NR a -, -NR a C(0)-, and -S-;
  • L is independently selected from -(CR 6 R 7 ) q ,
  • Ri is independently selected from H, F, CI, Br, CN, NR a R a , -OC 1 -4 alkyl substituted with 0-3 R e , Ci_4 alkyl substituted with 0-3 R e , -(CH 2 ) r OR b , (CH 2 ) r S(0) p R c ,
  • R 2 is independently selected from H, F, CI, Br, CN, NR a R a , -OC 1 -4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 R e , and -(CH 2 ) r OR b ;
  • Re and R7 are independently selected from H, substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • Rs is selected from C 3 -1 0 carbocyclyl and heterocyclyl, each substituted with 0-5 R 9 ;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C 2 _ 6 alkenyl substituted with 0-5 Re, C 2 _ 6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • Rb at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e , C 2 - 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 Re,
  • Ra at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • Rf at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1, and 2; provided when s and q are in the same term, s + q ⁇ 3.
  • the present invention provides compounds of Formula (II), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • B is independently selected from -O- and -NR a -;
  • L is -(CR 6 R 7 ) q ;
  • Ri is independently selected from H, F, CI, Br, CN, NR a R a , -OC1-4 alkyl substituted with
  • Ci_4 alkyl substituted with 0-3 R e , and -(CH 2 ) r OR b ;
  • R2 is independently selected from H, F, CI, Br, CN, NR a R a , -OC1-4 alkyl substituted with
  • Ci_4 alkyl substituted with 0-3 R e , and -(CH 2 ) r OR b ;
  • R5 is independently selected from H and C1-4 alkyl
  • Re and R7 are independently selected from H, substituted with 0-4 R e , and
  • R 9 is independently selected from F, CI, Ci- 4 alkyl substituted with 0-5 R e ,
  • R a is independently selected from H, Ci_6 alkyl substituted with 0-5
  • R b at each occurrence, is independently selected from H and Ci_6 alkyl substituted with
  • R e at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), F, CI, Br, CN, N0 2 , -(CH 2 ) r OCi_ 5 alkyl, and -(CH 2 ) r OH; p, at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
  • the present invention provides compounds of Formula (III), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • L is independently selected from -(CR 6 R 7 ) q -, -(CR 6 R7)sNR 5 -, -(CR6R 7 ) s O-, and
  • R 2 is independently selected from H, F, CI, Br, CN, NR a R a , -OC1-4 alkyl substituted with 0-3 R e , Ci_4 alkyl substituted with 0-3 R e , and -(CH 2 ) r OR b ;
  • R3 and R4 are independently selected from H, F, OH, CN, and C 1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 R e , and C 1-4 alkynyl substituted with 0-3
  • Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • Rs is selected from aryl, C 3 _ 6 cycloalkyl, and heterocyclyl, each substituted with 0-5 R 9 ;
  • R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 Re, C2- 6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • Rb at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e , C 2 - 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 Re,
  • Rf at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1 and 2.
  • R2 is independently selected from H, F, CI, Br, CN, and NR a R a ;
  • R3 is independently selected from H and C1-4 alkyl substituted with 0-3 R e , Ci_ 4 alkenyl substituted with 0-3 Re, and Ci_ 4 alkynyl substituted with 0-3 R e ;
  • Re and R7 are independently selected from H, Ci- 4 alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • R a is independently selected from H, C e alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 Re, C2- 6 alkynyl substituted with 0-5 R e ,
  • R b at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e ,
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e , C 2 - 6 alkenyl substituted with 0-5 R e , C 2 _ 6 alkynyl substituted with 0-5 Re,
  • R d is independently selected from H and Ci-4alkyl substituted with
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
  • the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Ri and R2 are H;
  • R3 is independently selected from H and Me
  • R 5 is H
  • 3 ⁇ 4 and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 R e ,
  • R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C 2 _6alkenyl substituted with 0-5 Re, -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -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 heterocyclic ring substituted with 0-5 Re;
  • R b at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C 2 _6 alkenyl substituted with 0-5 Re, C 2 _6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e ,
  • Rd at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • Rf at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • R7 are independently selected from H and Ci_ 4 alkyl substituted with 0-4 R e ;
  • R a is independently selected from H, C e alkyl substituted with 0-5 R e , C2-6alkenyl substituted with 0-5 Re, -(CH 2 ) r -C3_io carbocyclyl substituted with
  • Rb at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e ,
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 R e , C2- 6 alkynyl substituted with 0-5 Re,
  • Rd at each occurrence, is independently selected from H and Ci-4alkyl substituted with
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • the present invention provides compounds of Formula (V), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
  • L is independently selected from -(CR 6 7) q , -(CR6R7) S NR 5 -, -(CR6R?)sO-, and
  • R 2 is independently selected from H, F, CI, Br, CN, NR a R a , -OC 1 -4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 R e , and -(CH 2 ) r OR b ;
  • R3 and R4 are independently selected from H, F, CI, Br, OH, CN, C 1 - 4 alkyl substituted with 0-3 R e , and C3-6 carbocyclyl substituted with 0-3 Re, C1-4 alkenyl substituted with 0-3 R e , and C 1 - 4 alkynyl substituted with 0-3 Re;
  • R 7 are independently selected from H, Ci- 4 alkyl substituted with 0-4 R e ,
  • R6 and R 7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 R e ; alternatively, when q is 2 or 3, two adjacent R 6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
  • Rs is selected from aryl, C 3 _ 6 cycloalkyl, and heterocyclyl, each substituted with 0-5 R 9 ;
  • Rg groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C2-6alkenyl substituted with 0-5 Re, -(CH 2 ) r -C3_io carbocyclyl substituted with 0-5 Re, and -(CH2) r -heterocyclyl substituted with 0-5 R e ; or R a and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
  • R b at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 R e , C2- 6 alkynyl substituted with 0-5 Re,
  • R ⁇ i at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • R e at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH 2 ) r -C3_io carbocyclyl,
  • R f at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
  • s at each occurrence, is independently selected from 1 and 2.
  • the present invention provides compounds of Formula (Via):
  • R 2 is independently selected from H, F, CI, Br, OH, CN, and NR a R a ;
  • R3 and R4 are independently selected from H, Ci_ 4 alkyl substituted with 0-3 R e , and -(CH 2 )r-C3_6 carbocyclyl substituted with 0-3 R e ;
  • Re and R7 are independently selected from H, Ci- 4 alkyl substituted with 0-4 R e ,
  • two adjacent R 9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0) p , wherein the carbocyclic and heterocyclic rings are substituted with 0-4 R e ;
  • R a is independently selected from H, Ci_6 alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 Re, C2- 6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
  • R b is independently selected from H, Ci-6 alkyl substituted with 0-5 R e , C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 R e , -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH 2 ) r -heterocyclyl substituted with 0-5 Re;
  • R c at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 R e , C2- 6 alkenyl substituted with 0-5 R e , C2- 6 alkynyl substituted with 0-5 Re,
  • R f is independently selected from H, F, CI, Br, Ci-5alkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from 1 and 2;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
  • the present invention provides compounds of Formula (X)
  • L is -(CR 6 R 7 ) q ;
  • Ri and R 2 are independently selected from H, F, CI, Br, CN, RaRa, -OC1-4 alkyl
  • R5 is independently selected from H and Ci_ 4 alkyl
  • 3 ⁇ 4 and R7 are independently selected from H and Ci_ 4 alkyl substituted with 0-4 R e ; Rs is aryl substituted with 0-5 R 9 ;
  • R a at each occurrence, is independently selected from H, C e alkyl substituted with 0-5
  • R e -(CH 2 )r-C3_io carbocyclyl substituted with 0-5 R e , and -(CH 2 ) r -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 heterocyclic ring substituted with 0-5 R e ;
  • R b at each occurrence, is independently selected from H, C e alkyl substituted with 0-5
  • R c at each occurrence, is independently selected from C e alkyl substituted with 0-5 R e ,
  • Ra at each occurrence, is independently selected from H and Ci_ 4 alkyl substituted with
  • R f is independently selected from H, F, CI, Br, Ci-salkyl, and
  • p at each occurrence, is independently selected from zero, 1, and 2;
  • q at each occurrence, is independently selected from zero, 1, 2, and 3;
  • r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
  • the present invention provides a compound selected from the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
  • the present invention provides a compound selected from any subset list of compounds within the scope of the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
  • the present invention provides a group of compounds having ROCK2 IC 50 values ⁇ 10 ⁇ .
  • the present invention provides a group of compounds having ROCK2 IC 50 values ⁇ 1 ⁇ .
  • the present invention provides a group of compounds having ROCK2 IC 50 values ⁇ 0.1 ⁇ .
  • the present invention provides a group of compounds having ROCK2 IC 50 values ⁇ 0.05 ⁇ .
  • the present invention provides a group of compounds having ROCK2 IC 50 values ⁇ 0.01 ⁇ . II. OTHER EMBODIMENTS OF THE INVENTION
  • 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 carrier 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 least one of the compounds of the present invention 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 invention 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 molecules 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 activity.
  • R and S represent the configuration of substituents around a chiral carbon atom(s).
  • 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 alkyl” (or alkylene) is intended to include Ci, C 2 , C3, C 4 , C5, Ce, C 7 , C 8 , C9, and C 10 alkyl groups.
  • Ci to Ce alkyl or “C ⁇ -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, t- butyl), and 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 2 to Ce alkenyl or “C 2 -6 alkenyl” (or alkenylene) is intended to include C 2 , C3, C 4 , C5, 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-methyl-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.
  • C 2 to Ce alkynyl or “C 2 -6 alkynyl” (or alkynylene) is intended to include C 2 , C3, C 4 , C5, and Ce alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • alkoxy or “alkyloxy” refers to an -O-alkyl group.
  • Ci to Ce alkoxy or “Ci-6 alkoxy” (or alkyloxy) is intended to include Ci, C 2 , C3, C 4 , C5, and Ce alkoxy groups.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and ?-butoxy.
  • alkylthio 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 ethyl-S-.
  • Halo or halogen includes fluoro (F), chloro (CI), bromo (Br), and iodo (I).
  • Haloalkyl 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.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • haloalkyl 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 haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • Ce to Ce haloalkoxy or "C e haloalkoxy” is intended to include Ci, C 2 , C 3 , C 4 , C5, and Ce haloalkoxy groups.
  • haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.
  • haloalkylthio or “thiohaloalkoxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl- S-, and pentafluoroethyl-S-.
  • cycloalkyl refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems.
  • C 3 to C7 cycloalkyl or “C 3 -7 cycloalkyl” is intended to include C 3 , C 4 , C5, Ce, and C7 cycloalkyl groups.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
  • Branched cycloalkyl groups such as 1 -methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • carbocycle As used herein, “carbocycle”, “carbocyclyl” or “carbocyclic residue” is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 1 1-, 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, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
  • carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
  • carbocyclyl When the term “carbocyclyl” is used, it is intended to include “aryl”.
  • 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 ring may also be present on the bridge.
  • 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). "Ce or C 10 aryl” or “C6-10 aryl” refers to phenyl and naphthyl.
  • aryl may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH 3 , CI, F, Br, I, CN, N0 2 , NH 2 , N(CH 3 )H,
  • heterocycle As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclic ring” 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 eye lie 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 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(0) p , wherein p is 0, 1 or 2).
  • 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 heterocycle may optionally be quaternized. 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.
  • heterocycle it is intended to include heteroaryl.
  • heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
  • 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, triazinyl, triazolyl, benzimidazolyl, lH-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, 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, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. 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 quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, lH-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8- tetrahydro-quinolinyl, 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 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, furyl, 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 benzodioxane.
  • Heteroaryl 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 ⁇ 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 carbon-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
  • Ring double bonds are double bonds that are formed between two adjacent ring atoms (e.g.,
  • 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 ⁇ 0) 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 carboxylic 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, pamoic, maleic, hydroxymaleic, 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, pamoic, maleic, hydroxymaleic, 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:
  • Bundgaard, H. Chapter 5, “Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 1 13-191, Krosgaard-Larsen, P. et al, eds., Harwood Academic Publishers (1991);
  • Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se.
  • Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes.
  • Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically
  • hydrolyzable esters of compounds of formula I include Ci- 6 alkyl, Ci_ 6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, Ci_6 aikanoyloxy-Ci_ 6 alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), Ci- 6 alkoxycarbonyloxy- Ci- 6 alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
  • esters used, for example, in the penicillin and cephalosporin arts.
  • esters may be prepared by conventional techniques known in the art.
  • 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 Enzymology, VCHA and Wiley-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 hydrogen 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”.
  • deuterated herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom.
  • Isotopes of carbon include 13 C and 14 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)2H, 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. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
  • Mass Spec for mass spectrometry
  • ESI electrospray ionization mass spectroscopy
  • HR for high resolution
  • HRMS for high resolution mass spectrometry
  • LCMS liquid chromatography mass spectrometry
  • HPLC high pressure liquid

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Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

Description

TRICYCLIC PYRI DO-CARBOXAMI D E DERIVATIVES AS ROCK INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
This application is entitled to priority pursuant to 35 U.S. C. § 119(e) to U.S. provisional patent application No. 61/842,098, filed on July 2, 2013, which is incorporated herein in its entirety.
FIELD OF THE INVENTION
The present invention relates to novel tricyclic carboxamide derivatives, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of disorders associated with aberrant Rho kinase activity.
BACKGROUND OF THE INVENTION
Rho-Kinase (ROCK) 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 pathways. 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)). It is also directly involved in regulating smooth muscle contraction (Somlyo, A.P., Nature, 389:908-911 (1997)). 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.
There is considerable evidence in the literature that the RhoA/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 (2000)), urotension II (Sauzeau, V. et al, Circ. Res., 88: 1 102-1104 (2001)), endothelin-1 (Tangkijvanich, P. et al, Hepatology, 33 :74-80 (2001)), serotonin (Shimokawa, H., Jpn. Circ. J., 64: 1-12 (2000)), norepinephrine (Martinez, M.C. et al, Am. J. Physiol, 279:H1228-H1238 (2000)) and platelet-derived growth factor (PDGF) (Kishi, H. et al, J. Biochem., 128:719-722 (2000)). Many of these factors are implicated in the pathogenesis of cardiovascular disease.
Additional studies in the literature, some using the known ROCK inhibitors fasudil (Asano, T. et al, J. Pharmacol. Exp. Ther., 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. For example, 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. et al, FASEB J., 15: 1062-1064 (2001)). The ROCK inhibitor Y-27632 (Uehata, M. et al, Nature, ibid.) was shown to significantly decrease blood pressure in three rat models of hypertension, including the spontaneously hypertensive rat, renal hypertensive rat and deoxycortone acetate salt hypertensive rat models, while having only a minor effect on blood pressure in control rats. This reinforces the link between ROCK and hypertension.
Other studies suggest a link between ROCK and atherosclerosis. For example, gene transfer of a dominant negative form of ROCK suppressed neointimal formation following balloon injury in porcine femoral arteries (Eto, Y. et al, Am. J. Physiol. Heart Circ. Physiol, 278:H1744-H1750 (2000)). In a similar model, ROCK inhibitor Y-27632 also inhibited neointimal formation in rats (Sawada, N. et al, Circulation, 101 :2030-2033 (2000)). In a porcine model of IL- 1 beta- induced coronary stenosis, long term treatment with the ROCK inhibitor fasudil was shown to progressively reduce coronary stenosis, as well as promote a regression of coronary constrictive remodeling (Shimokawa, H. et al, Cardiovasc. Res., 51: 169-177 (2001)).
Additional investigations suggest that a ROCK inhibitor would be useful in treating other cardiovascular diseases. For example, in a rat stroke model, 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, Cardiovasc. Res., 55:757-767 (2002)).
Other animal or clinical studies have implicated ROCK in additional diseases including coronary vasospasm (Shimokawa, 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)).
In another study, it has been demonstrated that inhibition of the 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 (Iijima, FL, 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.
The above studies provide evidence for a link between ROCK and cardiovascular diseases including hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension and angina, as well as renal disease and erectile dysfunction. Given the demonstrated effect of ROCK on smooth muscle, 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)). Furthermore, 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.
Pharmacol. Ther., 18:67-74 (2005)), cancer (Rattan, R. et al, J. Neurosci. Res., 83:243- 255 (2006); Lepley, D. et al, Cancer Res., 65:3788-3795 (2005)), fibrotic diseases (Jiang, C. et al., Int. J. Mol. Sci., 13:8293-8307 (2012); Zhou, L. et al, Am. J. Nephrol, 34:468- 475 (2011)), as well as neurological disorders, such as spinal-cord injury, Alzheimer disease, multiple sclerosis, stroke and neuropathic pain (Mueller, B.K. et al, Nat. Rev. Drug Disc, 4:387-398 (2005); Sun, X. et al, J. Neuroimmunol. , 180: 126-134 (2006)).
There remains an unmet medical need for new drugs to treat cardiovascular disease. In the 2012 update of Heart Disease and Stroke Statistics from the American Heart Association (Circulation, 125:e2-e220 (2012)), it was reported that cardiovascular disease accounted for 32.8% of all deaths in the US, with coronary heart disease accounting for ~1 in 6 deaths overall in the US. Contributing to these numbers, it was found that -33.5% of the adult US population was hypertensive, and it was estimated that in 2010 -6.6 million US adults would have heart failure. Therefore, despite the number of medications available to treat cardiovascular diseases (CVD), including diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin blockers and calcium channel blockers, CVD remains poorly controlled or resistant to current medication for many patients.
Although there are many reports of ROCK inhibitors under investigation (see, for example, U.S. Publication No. 2008/0275062 Al), fasudil is the only marketed ROCK inhibitor at this time. An i.v. formulation was approved in Japan for treatment of cerebral vasospasm. There remains a need for new therapeutics, including ROCK inhibitors, for the treatment of cardiovascular diseases, cancer, neurological diseases, renal diseases, fibrotic diseases, bronchial asthma, erectile dysfunction, and glaucoma.
SUMMARY OF THE INVENTION
The present invention provides novel tricyclic carboxamide derivatives including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as selective inhibitors of Rho 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. In another aspect, 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.
Examples of such diseases that may be treated include, for example, hypertension, atherosclerosis, restenosis, stroke, heart failure, renal failure, coronary artery disease, peripheral artery disease, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina, erectile dysfunction and renal disease.
In another aspect, 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.
In another aspect, 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
administering to a patient in need of such treatment a compound of the present invention as described above.
In yet additional aspects, 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).
These and other features of the invention will be set forth in expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE INVENTION
I. COMPOUNDS OF THE INVENTION
In one aspect, the present invention provides, inter alia, compounds of Formula
(I):
Figure imgf000007_0001
(I)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
Ai, A2, and A3 are independently selected from N and CRi; provided no more than one Ai, A2, and A3 is N;
B is independently selected from -(CR3R4)mCR3R4-, -(CR3R4)mO(CR3R4)n-,
-(CR3R4)mNRa(CR3R4)„-, -(CR3R4)mS(0)p(CR3R4)„-, -(CR3R4)mC(0)(CR3R4)„-, -(CR3R4)mC(0)0(CR3R4)„-, -(CR3R4)mC(0)NRa(CR3R4)„-,
-(CR3R4)mOC(0)(CR3R4)„-, -(CR3R4)mNRaC(0)(CR3R4)„-,
-(CR3R4)mNRaS(0)p(CR3R4)n-, and -(CR3R4)mS(0)pNRa(CR3R4)n-;
L is independently selected from - -(CR6R7)sO(CR6R7)q-, and
Figure imgf000007_0002
Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl
substituted with 0-3 Re, C1-4 alkyl substituted with 0-3 Re, -(CH2)rORb,
(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa, -(CH2)rC(=0)NRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, (CH2)rCN, -(CH2)rNRaC(=0)Rb,
-(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa,
-(CH2)rC(=0)ORb, -(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa,
-(CH2)rNRaS(0)pRc, (CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and
-(CH2)r-heterocyclyl substituted with 0-3 Re;
R3 and R4 are independently selected from H, F, OH, CN, NRaRa, C1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3 Re, -(CH2)rORb, (CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)NRaRa, -(CH2)rC(=0)(CH2)rNRaRa, (CH2)rCN, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa,
-(CH2)rC(=0)ORb, -(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc, (CH2)r-C3-6 carbocyclyl substituted with 0-3 Re, and
-(CH2)r-heterocyclyl substituted with 0-3 Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000008_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from C3-10 carbocyclyl and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br,
Figure imgf000008_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re,
C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rj, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl,
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
m and n, at each occurrence, are independently selected from zero, 1, and 2; provided m + n < 2;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
s, at each occurrence, is independently selected from 1, and 2; provided when s and q are in the same term, s + q < 3;
provided when Ai is CRi, A3 is N, and B is -CH2C(0)NH-, Ri is not -NH-substituted phenyl. In another aspect, the present invention provides compounds of Formula (II):
Figure imgf000010_0001
(Π)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
B is independently selected from -(CR3R4)mO(CR3R4)n-, -(CR3R4)m Ra(CR3R4)n-, -(CR3R4)mS(0)p(CR3R4)„-, -(CR3R4)mC(0)0(CR3R4)„-,
-(CR3R4)mC(0)NRa(CR3R4)„-, -(CR3R4)mOC(0)(CR3R4)„-, and
-(CR3R4)mNRaC(0)(CR3R4)„-;
other variables are as defined in Formula (I) above.
In another aspect, the present invention provides compounds of Formula (III):
Figure imgf000010_0002
(III)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is independently selected from -(CR6R7)q-, -(CR6R7)SNR5-, -(CR6R?)sO-, and
-(CR6R7)SC(0)-;
Ri and R2 are independently selected from H, F, CI, Br, CN, RaRa, -OC1-4 alkyl
substituted with 0-3 Re, C1-4 alkyl substituted with 0-3 Re, and -(CH2)rORb; R3 and R4 are independently selected from H, F, OH, CN, and Ci_4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and Ci_4 alkynyl substituted with 0-3
Re; R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000011_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br,
Figure imgf000011_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci-6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000012_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1 and 2.
In another aspect, the present invention provides compounds of Formula (IV):
Figure imgf000012_0002
(IV)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Ri and R2 are independently selected from H, F, CI, Br, OH, CN, NRaRa, -OCi_4 alkyl substituted with 0-3 Re, and C1-4 alkyl substituted with 0-3 Re;
R3 is independently selected from H and C1-4 alkyl substituted with 0-3 Re, C1-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3 Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
R6 and R7 are independently selected from H, Ci_4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
Figure imgf000013_0001
-(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb,
Figure imgf000013_0002
-(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and
S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re; Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl,
-(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
Ri and R2 are H;
R3 is independently selected from H and Me;
R5 is H; Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
other variables are as defined in Formula (IV) above.
In another aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
R6 and R7 are independently selected from H and Ci_4alkyl substituted with 0-4 Re;
R9 is independently selected from F, CI, Br, Ci_4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, =0, nitro, -(CHRd)rS(0)pRc, -(CHRd)rS(0)pNRaRa, -(CHRd)rNRaS(<¾Re, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa,
-(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb,
-(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb, -(CHRd)rC(=0)NRaRa,
-(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl, -(CHRd)r-aryl, and
-(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re; alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rj, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl,
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi-4alkyl, and S(0)pCi-4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
other variables are as defined in Formula (IV) above.
In another aspect, the present invention provides compounds of Formula (V):
Figure imgf000018_0001
(V)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is independently selected from -(CR6R7)q, -(CR6R7)s R5-, -(CR6R7)sO-, and
-(CR^ O)-;
Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl
substituted with 0-3 Re, C1 -4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H, F, OH, CN, and C1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and C1 -4 alkynyl substituted with 0-3
Re;
R5 is independently selected from H and C1 -4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000018_0002
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 Rg;
Rg is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent Rg groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Ra, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-5alkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1 and 2.
In another aspect, the present invention provides compounds of Formula (VI):
Figure imgf000020_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
Ri and R2 are 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 Re;
R3 is independently selected from H and C1-4 alkyl substituted with 0-3 Re, C1-4 alkenyl substituted with 0-3 Re, and Ci_4 alkynyl substituted with 0-3 Re;
R5 is independently selected from H and Ci_4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe, (CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br, Ci_4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2_6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present invention provides compounds of Formula (VII):
Figure imgf000022_0001
(VII)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is independently selected from -(CR6R7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
Figure imgf000022_0002
Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OCi_4 alkyl
substituted with 0-3 Re, C1-4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R5 is independently selected from H and Ci_4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
R6 and R7 are independently selected from H, Ci_4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9; R9 is independently selected from F, CI, Br,
Figure imgf000023_0001
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2_6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl; ¾, at each occurrence, is independently selected from H and Ci-4alkyl substituted with 0-5 Re;
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1, and 2.
In another aspect, the present invention provides compounds of Formula (VIII):
Figure imgf000024_0001
(VIII)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is independently selected from -(CR6R7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
Figure imgf000024_0002
Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OCi_4 alkyl
substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R5 is independently selected from H and Ci_4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000025_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb,
-(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9; R9 is independently selected from F, CI, Br,
Figure imgf000025_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000026_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi-4alkyl, and S(0)pCi-4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1, and 2.
In another aspect, the present invention provides compounds of Formula (IX):
Figure imgf000026_0002
(IX)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is independently selected from -(CR6R7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
-(CR6R7)SC(0)-; Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OCi_4 alkyl substituted with 0-3 Re, C1-4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H, F, and C1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3 Re; R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, -NRaS(0)pRe, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
R6 and R7 are independently selected from H, Ci_4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3-6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9; R9 is independently selected from F, CI, Br, Ci_4alkyl substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Re, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb,
Figure imgf000027_0001
-(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, - CHR^ OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re; Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl,
-(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1, and 2.
In another aspect, the present invention provides compounds of Formula (IX), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is -(CR6R7)q;
Ri and R2 are H;
R3 and R4 are independently selected from H, F, and Ci_4alkyl substituted with 0-3 Re; R5 is H;
Re and R7 are independently selected from H and substituted with 0-3 Re;
Rs is selected from aryl and heterocyclyl, each substituted with 0-5 R9; and
R9 is independently selected from F, CI, Br, CN, C1-4alkyl, OH, OC1-4 alkyl,
-C(=0)OCi_4 alkyl, -C(=0)NH2, -C(=0)NHCi_4 alkyl, -C(=0)NHC3-6 cycloalkyl,
C3_6cycloalkyl, heterocyclyl, aryl, and heteroaryl;
other variables are as defined in Formula (IX) above.
In another aspect, the present invention provides compounds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
Figure imgf000029_0001
A3 is independently selected from and CRi;
B is independently selected from -0-, -CR3R4O-, -OCR3R4-, -NRa-, -C(0)0-, -OC(O)-, -C(0)NRa-, -NRaC(0)-, and -S-;
L is independently selected from -(CR6R7)q,
Figure imgf000029_0002
Figure imgf000029_0003
and -(CR6R7)sC(0)(CR6R7)q-;
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, (CH2)rS(0)pRc,
-(CH2)rC(=0)Rb, -(CH2)rNRaRa, -(CH2)rC(=0)NRaRa, -(CH2)rC(=0)(CH2)rNRaRa,
(CH2)rCN, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb, -(CH2)rS(0)pNRaRa,
-(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc, (CH2)r-C3-6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H, F, OH, CN, NRaRa, C1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3 Re, -(CH2)rORb, (CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)NRaRa, -(CH2)rC(=0)(CH2)rNRaRa, (CH2)rCN, -(CH2)rNRaC(=0)Rb,
-(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa,
-(CH2)rC(=0)ORb, -(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc, (CH2)r-C3-6 carbocyclyl substituted with 0-3 Re, and
-(CH2)r-heterocyclyl substituted with 0-3 Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000030_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from C3-10 carbocyclyl and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br,
Figure imgf000030_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2_6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Ra, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
s, at each occurrence, is independently selected from 1, and 2; provided when s and q are in the same term, s + q < 3.
In another aspect, the present invention provides compounds of Formula (II), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
B is independently selected from -O- and -NRa-;
L is -(CR6R7)q; Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with
0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with
0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R5 is independently selected from H and C1-4 alkyl;
Re and R7 are independently selected from H,
Figure imgf000032_0001
substituted with 0-4 Re, and
-(CH2)rC(=0)ORb;
Rs is selected from phenyl, C3-6 cycloalkyl and heterocyclyl, each substituted with 0-5 R9 R9 is independently selected from F, CI, Ci-4alkyl substituted with 0-5 Re,
-NRaS(<¾Ci_4 alkyl, -ORb, and -CN;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5
Re, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H and Ci_6 alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), F, CI, Br, CN, N02, -(CH2)rOCi_5 alkyl, and -(CH2)rOH; p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present invention provides compounds of Formula (III), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is independently selected from -(CR6R7)q-, -(CR6R7)sNR5-, -(CR6R7)sO-, and
-(CR6R7)SC(0)-;
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NRaC(=0)Rb, and -NRaC(=0)ORb;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb; R3 and R4 are independently selected from H, F, OH, CN, and C1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3
Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re; Ra, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1 and 2.
In another aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NRaC(=0)Rb, and -NRaC(=0)ORb;
R2 is independently selected from H, F, CI, Br, CN, and NRaRa;
R3 is independently selected from H and C1-4 alkyl substituted with 0-3 Re, Ci_4 alkenyl substituted with 0-3 Re, and Ci_4 alkynyl substituted with 0-3 Re;
R5 is independently selected from H and Ci_4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br, Ci_4alkyl substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
Figure imgf000035_0001
-(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHR<i)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re; alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
-(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOCi-5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000036_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4. In another aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Ri and R2 are H;
R3 is independently selected from H and Me;
R5 is H;
¾ and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
Figure imgf000037_0001
-(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHR<i)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2_6alkenyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re,
C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000038_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi-4alkyl, and S(0)pCi-4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
other variables are as defined in Formula (IV) above.
In another aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
¾ and R7 are independently selected from H and Ci_4alkyl substituted with 0-4 Re;
R9 is independently selected from F, CI, Br, Ci_4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, =0, nitro, -(CHRd)rS(0)pRc, -(CHRd)rS(0)pNRaRa, -(CHRd)rNRaS(<¾Re, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa,
-(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb,
-(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb, -(CHRd)rC(=0)NRaRa,
-(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl, -(CHRd)r-aryl, and
-(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re; alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with
0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOCi-5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000039_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
other variables are as defined in Formula (IV) above. In another aspect, the present invention provides compounds of Formula (V), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is independently selected from -(CR6 7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
-(CR^ O)-;
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NRaC(=0)Rb, and -NRaC(=0)ORb;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H, F, CI, Br, OH, CN, C1-4 alkyl substituted with 0-3 Re, and C3-6 carbocyclyl substituted with 0-3 Re, C1-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3 Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
¾ and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro, -(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent Rg groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re; Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
R<i, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl,
-(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2; q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1 and 2.
In another aspect, the present invention provides compounds of Formula (Via):
Figure imgf000042_0001
(Via)
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OCi_4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NHC(=0)Rb, and
-NHC(=0)ORb;
R2 is independently selected from H, F, CI, Br, OH, CN, and NRaRa;
R3 and R4 are independently selected from H, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re;
R5 is independently selected from H and Ci_4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re; alternatively, ¾ and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
Figure imgf000043_0001
-(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
R<i, at each occurrence, is independently selected from H and Ci-4alkyl substituted with Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl, -(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-5alkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present invention provides compounds of Formula (X)
Figure imgf000044_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
L is -(CR6R7)q;
Ri and R2 are independently selected from H, F, CI, Br, CN, RaRa, -OC1-4 alkyl
substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R5 is independently selected from H and Ci_4 alkyl;
¾ and R7 are independently selected from H and Ci_4alkyl substituted with 0-4 Re; Rs is aryl substituted with 0-5 R9;
R9 is independently selected from F, CI, Br, Ci_4alkyl substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(0)pRc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl, -(CHRa)r-aryl, and -(CHR<i)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5
Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re,
C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Ra, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present invention provides a compound selected from the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. In another aspect, the present invention provides a compound selected from any subset list of compounds within the scope of the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
In another embodiment, the present invention provides a group of compounds having ROCK2 IC50 values < 10 μΜ.
In another embodiment, the present invention provides a group of compounds having ROCK2 IC50 values < 1 μΜ.
In another embodiment, the present invention provides a group of compounds having ROCK2 IC50 values < 0.1 μΜ.
In another embodiment, the present invention provides a group of compounds having ROCK2 IC50 values < 0.05 μΜ.
In another embodiment, the present invention provides a group of compounds having ROCK2 IC50 values < 0.01 μΜ. II. OTHER EMBODIMENTS OF THE INVENTION
In another embodiment, 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.
In another embodiment, the present invention provides 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.
In another embodiment, the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier 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.
In another embodiment, the present invention provides a process for making a compound of the present invention.
In another embodiment, the present invention provides an intermediate for making a compound of the present invention.
In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s). In another embodiment, 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 least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. As used herein, the term "patient" encompasses all mammalian species.
As used herein, "treating" or "treatment" 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.
As used herein, "prophylaxis" or "prevention" 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. In another embodiment, 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.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
III. CHEMISTRY Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers 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. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. 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 invention 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 molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. 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 term "diastereomer" refers to stereoisomers that are not mirror images. The term "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 symbols "R" and "S" represent the configuration of substituents around a chiral 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)).
The term "chiral" refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image. The term "homochiral" refers to a state of enantiomeric purity. The term "optical activity" refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light.
As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci to Cio alkyl" or "CMO alkyl" (or alkylene), is intended to include Ci, C2, C3, C4, C5, Ce, C7, C8, C9, and C10 alkyl groups. Additionally, for example, "Ci to Ce alkyl" or "C\-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, t- butyl), and 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. For example, "C2 to Ce alkenyl" or "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5, and Ce alkenyl groups. Examples of alkenyl 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-methyl-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. For example, "C2 to Ce alkynyl" or "C2-6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5, and Ce alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "Ci to Ce alkoxy" or "Ci-6 alkoxy" (or alkyloxy), is intended to include Ci, C2, C3, C4, C5, and Ce alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and ?-butoxy. Similarly, "alkylthio" 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 ethyl-S-.
"Halo" or "halogen" includes fluoro (F), chloro (CI), bromo (Br), and iodo (I). "Haloalkyl" 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. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl 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 haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "Ci to Ce haloalkoxy" or "C e haloalkoxy", is intended to include Ci, C2, C3, C4, C5, and Ce haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl- S-, and pentafluoroethyl-S-.
The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. "C3 to C7 cycloalkyl" or "C3-7 cycloalkyl" is intended to include C3, C4, C5, Ce, and C7 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1 -methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".
As used herein, "carbocycle", "carbocyclyl" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 1 1-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles 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). As shown above, bridged rings are also included in the definition of carbocycle (e.g.,
[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term "carbocyclyl" is used, it is intended to include "aryl". 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 ring may also be present on the bridge.
As used herein, the term "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). "Ce or C10 aryl" or "C6-10 aryl" refers to phenyl and naphthyl. Unless otherwise specified, "aryl", "Ce or C10 aryl" or "Οβ-ιο aryl" or "aromatic residue" may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH3, CI, F, Br, I, CN, N02, NH2, N(CH3)H,
N(CH3)2, CF3, OCF3, C(=0)CH3, SCH3, S(=0)CH3, S(=0)2CH3, CH3, CH2CH3, C02H, and C02CH3. The term "benzyl", as used herein, 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, OCH3, CI, F, Br, I, CN, N02, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=0)CH3, SCH3, S(=0)CH3, S(=0)2CH3, CH3, CH2CH3, C02H, and C02CH3.
As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic ring" 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 eye lie 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 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(0)p, wherein p is 0, 1 or 2). 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 heterocycle may optionally be quaternized. 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. When the term "heterocycle" is used, it is intended to include heteroaryl.
Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H- 1,5,2- dithiazinyl, dihydrofuro[2,3-£]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,
oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2- pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3 -triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
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, triazinyl, triazolyl, benzimidazolyl, lH-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.
Examples of 5- to 6-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, triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term "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. 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 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.
Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, lH-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8- tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro- quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.
As used herein, the term "aromatic heterocyclic group" or "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, furyl, 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 benzodioxane. Heteroaryl 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→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 carbon-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.
The term "counterion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated.
As referred to herein, the term "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. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g.,
C=C, C=N, or N=N).
In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, 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. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→0) derivative.
When 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. Thus, for example, if 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. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The phrase "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.
As used herein, "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 carboxylic 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. For example, 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, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, and isethionic.
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. Generally, 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.
In addition, 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. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al, eds., Methods in Enzymology, 112:309-396, Academic Press (1985);
b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 1 13-191, Krosgaard-Larsen, P. et al, eds., Harwood Academic Publishers (1991);
c) Bundgaard, FL, Adv. Drug Deliv. Rev., 8: 1-38 (1992);
d) Bundgaard, H. et al, J. Pharm. Set, 77:285 (1988); and
e) Kakeya, N. et al, Chem. Pharm. Bull, 32:692 (1984).
Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes.
Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically
hydrolyzable esters of compounds of formula I include Ci-6alkyl, Ci_6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, Ci_6 aikanoyloxy-Ci_6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), Ci-6alkoxycarbonyloxy- Ci-6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo- 1 ,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 by conventional techniques known in the art.
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 Enzymology, VCHA and Wiley-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. By way of general example and without limitation, isotopes of hydrogen 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 "2H" or "D". The term "deuterated" herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom. Isotopes of carbon include 13C and 14C.
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
pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.
"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)2H, or S(0)H group.
The term "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. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
Abbreviations as used herein, are defined as follows: " 1 x" for once, "2 x" for twice, "3 x" for thrice, "°C" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "μί" for microliter or microliters, "N" for normal, "M" for molar, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "cone." for concentrate, "sat" or "saturated" for saturated, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomeric excess, "MS" or
"Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid
chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tic" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "lH" for proton, "δ" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.
Me Methyl
Et Ethyl
Pr Propyl
/-Pr Isopropyl
Bu Butyl
i-Bu Isobutyl
t-Bu tert-butyl
Ph Phenyl
Bn Benzyl
Boc tert-butyloxycarbonyl
AcOH or HO Ac acetic acid
A1C13 aluminum chloride
AIBN Azobisisobutyronitrile
BBr3 boron tribromide
BCI3 boron trichloride
BEMP 2-tert-butylimino-2-diethylamino-l,3-dimethylperhydro-l,3,2- diazaphosphorine BOP reagent benzotriazol- l-yloxytris(dimethylamino)phosphonium
hexafluorophosphate
Burgess reagent 1 -methoxy-N-triethylammoniosulfonyl-methanimidate
CBz Carbobenzyloxy
CH2CI2 Dichloromethane
CH3CN or ACN Acetonitrile
CDCI3 deutero-chloroform
CHCI3 Chloroform
mCPBA or m-CPBA meto-chloroperbenzoic acid
CS2CO3 cesium carbonate
Cu(OAc)2 copper (II) acetate
Cy2 Me N-cyclohexyl-N-methylcyclohexanamine
DBU l ,8-diazabicyclo[5.4.0]undec-7-ene
DCE 1 ,2 dichloroethane
DCM dichloromethane
DEA diethylamine
Dess-Martin 1, 1 , 1 -tris(acetyloxy)- 1 , 1 -dihydro- 1 ,2-beniziodoxol-3 -( 1 H)-one
DIC or DIPCDI diisopropylcarbodiimide
DIEA, DIPEA or diisopropylethylamine
Hunig's base
DMAP 4-dimethylaminopyridine
DME 1 ,2-dimethoxyethane
DMF dimethyl formamide
DMSO dimethyl sulfoxide
cDNA complimentary DNA
Dppp (R)-(+)- 1 ,2-bis(diphenylphosphino)propane
DuPhos (+)- l,2-bis((2S,5S)-2,5-diethylphospholano)benzene
EDC N-(3 -dimthylaminopropyl)-N'-ethylcarbodiimide
EDCI N-(3 -dimthylaminopropyl)-N'-ethylcarbodiimide hydrochloride
EDTA ethylenediaminetetraacetic acid
(S;S EtDuPhosRh(I) (+)- l ,2-bis((2S,5S)-2,5-diethylphospholano)benzene(l,5- cyclooctadiene)rhodium(I) trifluoromethanesulfonate Et3N or TEA triethylamine
EtOAc ethyl acetate
Et20 diethyl ether
EtOH Ethanol
GMF glass microfiber filter
Grubbs (II) (l,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro
(phenylmethylene)(triycyclohexylphosphine)ruthenium
HC1 hydrochloric acid
HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HEPES 4-(2-hydroxyethyl)piperaxine- 1 -ethanesulfonic acid
Hex Hexane
HOBt or HOBT 1 -hydroxybenzotriazole
H2S04 sulfuric acid
K2C03 potassium carbonate
KOAc potassium acetate
K3P04 potassium phosphate
LAH lithium aluminum hydride
LG leaving group
LiOH lithium hydroxide
MeOH Methanol
MgS04 magnesium sulfate
MsOH or MSA methylsulfonic acid
NaCl sodium chloride
NaH sodium hydride
NaHC03 sodium bicarbonate
Na2C03 sodium carbonate
NaOH sodium hydroxide
Na2S03 sodium sulfite
Na2S04 sodium sulfate
NBS N-bromosuccinimide
NCS N-chlorosuccinimide NH3 Ammonia
NH4CI ammonium chloride
NH4OH ammonium hydroxide
OTf triflate or trifluoromethanesulfonate
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2 palladium(II) acetate
Pd/C palladium on carbon
Pd(dppf)Ci2 [l, -bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
Ph3PCl2 triphenylphosphine dichloride
PG protecting group
POCI3 phosphorus oxychloride
i-PrOH or IPA isopropanol
PS polystyrene
PyBOP benzotriazol- 1 -yl-oxytripyrrolidinophosphonium
hexafluorophosphate
SEM-C1 2-(trimethysilyl)ethoxymethyl chloride
S1O2 silica oxide
SnCl2 tin(II) chloride
TBAF tetra-M-butylammonium fluoride
TBAI tetra-w-butylammonium iodide
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TMSCFIN2 trimethylsilyldiazomethane
T3P propane phosphonic acid anhydride
TRIS tris (hydroxymethyl) aminomethane
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. IV. BIOLOGY
In vitro Assays The effectiveness of compounds of the present invention as ROCK inhibitors can be determined in a 30 μϊ^ assay containing 20 mM HEPES, pH 7.5, 20 mM MgCi2, 0.015% Brij-35, 4 mM DTT, 5 μΜ ATP and 1.5 μΜ peptide substrate (FITC-AHA- AKRRRLSSLRA-OH). Compounds were dissolved in DMSO so that the final concentration of DMSO was < 2%, and the reaction was initiated with Rho kinase variants. After incubation, the reaction was terminated by the addition of EDTA and the phosphorylated and non-phosphorylated peptides separated using a LABCHIP® 3000 Reader (Caliper Life Sciences). Controls consisted of assays that did not contain compound, and backgrounds consisted of assays that contained enzyme and substrate but had EDTA from the beginning of the reaction to inhibit kinase activity. Compounds were tested in dose-response format, and the inhibition of kinase activity was calculated at each concentration of compound. The inhibition data were fit using a curve-fitting program to determine the IC50; i.e., the concentration of compound required to inhibit 50% of kinase activity.
Representative Examples were tested in the ROCK assay described above and found having ROCK inhibitory activity. A range of ROCK inhibitory activity (IC50 values) of < 50 μΜ (50000 nM) was observed. Table A below lists the ROCK2 IC50 values measured for the following Examples.
Table A
Figure imgf000063_0001
Example No. ROCK2 IC50 (nM)
1-12 664
1-13 979
1-14 149
1-15 7440
1-16 3920
1-17 165
1-18 37.2
1-19 75.0
1-20 199
1-21 177
1-22 29.4
1-23 158
1-24 50.7
1-25 41.3
1-26 300
1-27 6.32
1-28 59.8
1-29 1640
1-30 349
1-31 2100
1-32 55.5
1-33 291
1-34 1040
1-35 602
1-36 282
1-37 198
1-38 404
1-39 1370
1-40 7090
1-41 38.0 Example No. ROCK2 IC50 (nM)
1-42 537
1-43 643
1-44 1790
1-45 258
1-46 233
1-47 55.5
1-48 3170
1-49 717
1-50 38.1
1-51 3.23
1-52 1640
1-53 318
1-54 137
1-55 174
1-56 19.9
1-57 4910
1-58 95.9
1-59 113
1-60 36.7
1-61 98.3
1-62 7610
1-63 63.2
1-64 2150
1-65 198
1-66 92.3
1-67 54.5
1-68 37.6
1-69 75.5
1-70 0.81
1-71 12.3 Example No. ROCK2 IC50 (nM)
1-72 224
1-73 5980
1-74 24.8
1-75 159
1-76 493
1-77 17.5
1-78 4440
1-79 184
1-80 81.4
1-81 4180
1-82 2410
1-83 7.69
1-84 4.95
1-85 25.2
1-86 471
1-87 4340
1-88 4080
1-89 5650
1-90 49.7
1-91 607
1-92 682
1-93 315
1-94 260
1-95 31.9
1-96 2970
1-97 2210
1-98 1200
1-99 657
I- 100 695
I- 101 1320 Example No. ROCK2 IC50 (nM)
1-102 1170
1-103 1620
1-104 4460
1-105 62.1
1-106 10.6
1-107 429
1-108 8.54
1-109 131
1-110 218
1-111 3.62
1-112 615
1-113 1340
1-114 106
1-115 3210
1-116 1080
1-117 368
1-118 15.1
1-119 845
1-120 2280
1-121 973
1-122 2780
1-123 688
1-124 7.28
1-125 9.52
1-126 16.8
1-127 27.7
1-128 141
1-129 6310
1-130 170
1-131 411 Example No. ROCK2 IC50 (nM)
1-132 3780
1-133 1990
1-134 5320
1-135 1980
1-136 6580
1-137 4470
1-138 176
1-139 24.5
1-140 1620
1-141 6270
1-142 550
1-143 5090
1-144 9920
1-145 3420
1-146 106
1-147 835
1-148 640
1-149 593
1-150 589
1-151 458
1-152 8190
1-153 7070
1-154 378
1-155 8640
1-156 1210
1-157 810
1-158 6.18
1-159 194
1-160 3.68
1-161 875 Example No. ROCK2 IC50 (nM)
1-162 22.4
1-163 32.5
1-164 14.0
1-165 5.14
1-166 1490
II- 1 15.5
II-2 16.2
II-3 25.4
II-4 55.1
II-5 458
II-6 9070
II-7 51.2
II-8 6070
II-9 42.6
11-10 6930
11-11 541
11-12 516
11-13 382
11-14 36.0
11-15 756
11-16 35.2
III-l 2.51
III-2 25.5
III-3 1.70
III-4 2.24
III-5 2.54
III-6 281
III-7 120
III-8 33.8
III-9 497 Example No. ROCK2 IC50 (nM)
Ill- 10 684
III- 11 583
III- 12 429
III- 13 2.58
III- 14 18.8
III- 15 191
III- 16 66.9
III- 17 377
III- 18 18.2
III- 19 15.5
IV- 1 107
IV-2 72.5
IV-3 321
IV-4 276
IV-5 1590
IV-6 44.5
IV-7 111
IV-8 1220
IV-9 12.4
IV- 10 30.2
IV- 11 108
IV- 12 12.8
IV- 13 35.2
IV- 14 77.9
IV- 15 74.3
IV- 16 371
IV- 17 52.5
IV- 18 370
IV- 19 187
V-l 30.2 Example No. ROCK2 IC50 (nM)
V-2 169
V-3 23.1
V-4 664
V-5 4.71
V-6 15.9
V-7 24.3
V-8 42.4
V-9 8.97
V-10 53.9
V-l l 80.3
V-12 3.90
VI- 1 1.05
VI-2 2.78
VI-3 6.23
VI-4 6.36
VI-5 2.80
VI-6 1.32
VI-7 0.35
VI-8 19.9
VI-9 11.4
VI- 10 7.31
VI- 11 5.66
VI- 12 56.0
VII- 1 1.29
VII-2 2.87
VII-3 2.25
VII-4 3.73
VII-5 0.80
VII-6 1.34
VII-7 1.50 Example No. ROCK2 IC50 (nM)
VII-8 2.54
VII-9 0.78
VII- 10 12.6
VII- 11 1.14
VII- 12 1.82
VIII- 1 0.59
VIII-2 4.09
VIII-3 1.99
VIII-4 0.34
VIII-5 0.85
VIII-6 0.85
VIII-7 0.85
VIII-8 0.85
VIII-9 2.55
VIII- 10 6.35
VIII- 11 2.54
VIII- 12 0.85
VIII- 13 0.85
VIII- 14 0.79
VIII- 15 0.56
VIII- 16 0.60
VIII- 17 13.8
VIII- 18 5.16
VIII- 19 4.10
VIII-20 14.3
VIII-21 11.2
VIII-22 18.8
VIII-23 0.72
VIII-24 12.4
VIII-25 4.18 Example No. ROCK2 IC50 (nM)
VIII-26 13.1
VIII-27 11.9
VIII-28 4.74
VIII-29 41.5
VIII-30 13.2
VIII-31 11.0
VIII-32 12.8
VIII-33 4.38
VIII-34 4.37
VIII-35 18.6
VIII-36 1.70
VIII-37 9.03
IX- 1 9.66
IX-2 3.74
IX-3 2.39
IX-4 20.9
IX-5 18.7
IX-6 17.7
IX-7 231
IX-8 27.6
IX-9 46.3
X-l 90.2
X-2 138
X-3 13.3
X-4 2.71
X-5 104
XI- 1 452
XI-2 19.3
XI-3 25.2
XI-4 10.3 Example No. ROCK2 IC50 (nM)
XI- 1 452
XI-2 19.3
XI-3 25.2
XI-4 10.3
XI-5 33.1
XI-6 637
XI-7 17.1
XI-8 61.4
XI-9 122.6
XI- 10 73.8
XI- 11 93.1
XI- 12 12.6
XI- 13 9.03
XI- 14 32.6
XI- 15 1112
XI- 16 0.52
XI- 17 0.18
XI- 18 176
XI- 19 3.79
XI-20 1.81
XI-21 0.65
XI-22 7.34
XI-23 2.95
XI-24 20.4
XI-25 4.69
XI-26 9.28
XI-27 3.94
XI-28 239
XI-29 362
XI-30 15.9 Example No. ROCK2 IC50 (nM)
XI-31 1.44
XI-32 935
XI-33 51.7
XI-34 472
XI-35 229
XI-36 265
XI-37 494
XI-38 130
XII- 1 1480
XII-2 1750
XII-3 957
XII-4 782
XII-5 49.3
XII-6 620
XIII- 1 68.9
XIII-2 882
XIII-3 337
XIII-4 781
XIII-5 792
XIII-6 47.9
XIII-7 583
XIII-8 68.9
XIII-9 1840
XIII- 10 175
XIV- 1 3.91
XIV-2 16.3
XIV-3 13.7
XIV-4 1.29
XIV-5 89.6
XIV-6 6.98 Example No. ROCK2 IC50 (nM)
XIV-7 13.7
XIV-8 13.5
XIV-9 2.32
XIV- 10 12.2
XIV- 11 7.16
XIV- 12 1020
XIV- 13 43.2
XIV- 14 48.8
XIV- 15 33.6
XIV- 16 3.69
XIV- 17 15.2
XIV- 18 45.9
XIV- 19 80.8
XIV-20 1.01
XIV-21 15.0
XIV-22 27.7
XIV-23 8.09
XIV-24 25.3
XIV-25 38.8
XIV-26 144
XIV-27 34.2
XIV-28 46.6
XIV-29 1490
XIV-30 213
XIV31 1.16
XIV-32 5.70
XIV-33 7.43
XIV-34 66.3
XIV-35 33.1
XIV-36 2.66 Example No. ROCK2 IC50 (nM)
XIV-37 297
XV- 1 2.85
XV-2 49.4
XV-3 44.2
XV-4 49.2
XV-5 460
XV-6 552
XV-7 1140
XV-8 606
XV-9 161
XV- 10 77.8
XV- 11 965
XV- 12 28.6
XV- 13 81.0
XV- 14 26.4
XV- 15 224
XV- 16 1070
XVI- 1 20.3
XVI-2 36.9
XVI-3 7.40
XVI-4 2230
XVI-5 61.5
XVI-6 34.3
V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND
COMBINATIONS
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.
The term "pharmaceutical 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
pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington 's Pharmaceutical Sciences, 18th Edition (1990).
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 effective amount of the drug required to prevent, counter, or arrest the progress of the disorder.
By way of general guidance, 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. Intravenously, the most preferred doses will range from about 0.001 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.
Compounds of this invention can also be administered by parenteral
administration (e.g., intra-venous, intra-arterial, intramuscularly, or subcutaneously. When administered intra-venous or intra-arterial, the dose can be given continuously or intermittent. Furthermore, 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. When administered in the form of a transdermal delivery system, 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.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier 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 can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, 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,
carboxymethylcellulose, polyethylene glycol, waxes, and the like. 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. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, 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, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 1000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions 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 carriers, 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.
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. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and
chlorobutanol.
The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. By "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. When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time. Thus, 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 quality 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. For example, 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 experimentor 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. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. The present invention also encompasses an article of manufacture. As used herein, 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). In another embodiment, 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. Examples of 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. Alternatively, 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
Administration). Preferably, 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. Preferably, 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).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof. The following Examples have been prepared, isolated and characterized using the methods disclosed herein.
VI. GENERAL SYNTHESIS INCLUDING SCHEMES
The compounds of the present invention may be synthesized by many 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. Preparation of homochiral examples may be carried out by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products by chiral phase preparative HPLC. Alternatively, 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 affected. 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.
It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley- Interscience (2006)).
Scheme 1
Figure imgf000085_0001
Compounds of this invention with the structure of If could be prepared as shown in Scheme 1. Suzuki-Miyaura coupling between 4-halopyridine derivative la and fluorophenyl boronic acid or boronate lb, in the presence of a base such as K3PO4, and a Pd catalyst such as PdCl2(dppf), affords intermediate lc. Aldehyde lc is either reduced using a reducing reagent such as NaBH4, or treated with an alkyl metal reagent such as a Grignard's reagent, to afford alcohol Id. Ring closure of Id by treatment with a base, such as NaH, CS2CO3, etc, followed by aqueous basic workup to afford the tricyclic acid common intermediate le. Amide formation affords target If by coupling intermediate le with an appropriate amine in the presence of a coupling reagent, such as HATU or EDC, and a base such as DIEA.
Scheme 2
Figure imgf000086_0001
Alternatively, the common intermediate le can be prepared as shown in Scheme 2. Suzuki-Miyaura coupling between 4-halopyridine derivative la and methoxyphenyl boronic acid or boronate 2a, in the presence of a base such as K3PO4, and a Pd catalyst such as PdCl2(dppf), affords intermediate 2b. Aldehyde 2b is either reduced using a reducing reagent such as NaBH4, or treated with an alkyl metal reagent such as a Grignard's reagent, to afford alcohol 2c. Ring closure of 2c by treatment with a strong acid, such as HBr, followed by aqueous basic workup to afford the tricyclic acid le.
Scheme 3
Figure imgf000087_0001
3f 1e
Alternatively, intermediate le can be prepared as shown in Scheme 3. Suzuki- Miyaura coupling between 4-halopyridine derivative la and methoxy aniline boronic acid or boronate 3a, in the presence of a base such as K3PO4, and a Pd catalyst such as PdCl2(dppf), affords intermediate 3b. Aldehyde 3b is either reduced using a reducing reagent such as NaBH4, or treated with an alkyl metal reagent such as a Grignard's reagent, to afford alcohol 3c. Ring closure of 3c by treatment with a strong acid, such as HBr, to afford tricyclic aniline 3d. Conversion of the amino group of 3c to iodide in 3e, followed by cyanization provides 3f. The cyano group is hydrolyzed to the acid by treating 3f with an aqueous base such NaOH, or an aqueous acid such as HCl, to give the tricyclic acid le.
Scheme 4
Figure imgf000088_0001
Compounds of this invention with the structure of 4f could be prepared as shown in Scheme 4. Suzuki-Miyaura coupling between 4-pyridine boronic acid or boronate derivative 4a and bromobenzaldehyde derivative 4b, or other appropriate Suzuki coupling partners, in the presence of a base such as K3PO4, and a Pd catalyst such as PdCl2(dppf), affords intermediate 4c. Aldehyde 4c is either reduced using a reducing reagent such as NaBH4, or treated with an alkyl metal reagent such as a Grignard's reagent, to afford alcohol 4d. Ring closure of 4d by treatment with a base, such as NaH, CS2CO3, etc, followed by aqueous basic workup to afford the tricyclic acid common intermediate 4e. Amide formation affords target 4f by coupling intermediate 4e with an appropriate amine in the presence of a coupling reagent, such as HATU or EDC, and a base such as DIEA. Scheme 5
Figure imgf000089_0001
5d 5e
Figure imgf000089_0002
5h
Compounds of this invention with the structure of 5h could be prepared as shown in Scheme 5. Aldehyde 5a is either reduced using a reducing reagent such as NaBH4, or treated with an alkyl metal reagent such as a Grignard's reagent, to afford alcohol 5b. The alcohol is protected using a protecting group such as TBS to give 5c, which is then converted to boronic acid or boronate 5d under Miyaura condition. Suzuki-Miyaura coupling between 5d and chloropyrimidine derivative 5e, in the presence of a base such as Κ.3Ρ04, and a Pd catalyst such as Pd(PPli3)4, affords intermediate 5f. Removal of the TBS protecting group and closure of the ring by treating 5f with TBAF followed by ester conversion by treating with an aqueous base such as LiOH, affords common intermediate 5g. Amide formation affords target 5h by coupling intermediate 5g with an appropriate amine in the presence of a coupling reagent, such as HATU or EDC, and a base such as DIEA. Scheme 6
Figure imgf000090_0001
Compounds of this invention with the structure of 6d could be prepared as shown in Scheme 6. Amide formation provides compound 6b by coupling intermediate le or 4e or 5g with amino ester 6a in the presence of a coupling reagent, such as HATU or EDC, and a base such as DIEA. Ester 6b is converted to acid 6c when treated with a base such as LiOH. Target 6d is afforded by coupling 6c with an appropriate amine using a coupling reagent, such as HATU or EDC, and a base such as DIEA.
Scheme 7
Figure imgf000090_0002
Compounds of this invention with the structure of 7d could be prepared as shown in Scheme 7. Amide formation of intermediate le, or 4e, or 5g with 7a provides intermediate 7b. Suzuki-Miyaura coupling between 7b and an appropriate aromatic boronic acid or boronate derivative, in the presence of a base such as K3PO4, and a Pd catalyst such as PdCl2(dppf), affords 7d. Alternatively, 7b can be converted to boronic acid or boronate 7c. Then 7c can couple with aromatic halides following Suzuki-Miyaura coupling condition to afford target 7d.
Scheme 8
Figure imgf000091_0001
8d 8e 8f
Compounds of this invention with the structure of 8f could be prepared as shown in Scheme 8. Suzuki-Miyaura coupling between 8a and 8b, in the presence of a base such as K3PO4, and a Pd catalyst such as Pd(PPh3)4, affords intermediate 8c. Substitution of the lactam by treating 8c with an appropriate alkylating reagent at the presence of a base such as NaH, affords 8d. Ester conversion by treatment with an aqueous base such as LiOH, affords common intermediate 8e. Amide formation affords target 8f by coupling intermediate 8e with an appropriate amine in the presence of a coupling reagent, such as HATU or EDC, and a base such as DIEA.
Scheme 9
Figure imgf000092_0001
9d 8d
Alternatively, intermediate 8d could be prepared as shown in Scheme 9. Suzuki- Miyaura coupling between 9a and 9b, in the presence of a base such as K3PO4, and a Pd catalyst such as Pd(PPh3)4, affords intermediate 9c. Amide formation affords 9d by coupling intermediate 7c with an appropriate amine in the presence of a coupling reagent, such as HATU, EDC or T3P, and a base such as DIEA. Ring closure by treating 9d with a base such as NaH, followed by aqueous base treatment of the ester, affords 8d. Purification of intermediates and final products was carried out via either normal or reverse phase chromatography. Normal phase chromatography was carried out using prepacked Si02 cartridges eluting with either gradients of hexanes and EtOAc or DCM and MeOH, or DCM and EtOAc unless otherwise indicated. Reverse phase preparative HPLC was carried out using CI 8 columns eluting with gradients of Solvent A (90% H20, 10% MeOH, 0.1% TFA) and Solvent B (10% H20, 90% MeOH, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (90% H20, 10% ACN, 0.1% TFA) and Solvent B (10% H20, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (98% H20, 2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2% H20, 0.05% TFA, UV 220 nm) (or) SunFire Prep C18 OBD 5μ 30x100mm, 25 min gradient from 0-100% B. A =
H20/ACN/TFA 90: 10:0.1. B = ACN/H20/TFA 90: 10:0.1 (or) Waters XBridge CI 8, 19 x 200 mm, 5-μιη particles; Guard Column: Waters XBridge CI 8, 19 x 10 mm, 5-μιη particles; Solvent A: water with 20-mM ammonium acetate; Solvent B: 95:5
acetonitrile:water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min or with gradients of Solvent A (5:95 acetonitrile:water with 0.1% formic acid) and Solvent B (95:5 acetonitrile: water with 0.1% formic acid).
Unless otherwise stated, analysis of final products was carried out by reverse phase analytical HPLC.
Method A: SunFire C18 column (3.5 μιη C18, 3.0 x 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 10 min and then 100% Solvent B for 5 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).
Method B: XBridge Phenyl column (3.5 μιη C18, 3.0 x 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 10 min and then 100% Solvent B for 5 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).
Method C: Waters BEH C18, 2.1 x 50 mm, 1.7-μτη 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; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min.
Method C-l : Waters BEH C 18, 2.1 x 50 mm, 1.7-μιη particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min.
Method D: Waters BEH C18, 2.1 x 50 mm, 1.7-μιη particles; Mobile Phase A: 5:95 methanohwater with 10 mM ammonium acetate; Mobile Phase B: 95:5
methanohwater with 10 mM ammonium acetate; Temperature: 40 °C; Gradient: 0.5 min hold at 0%B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min.
Method E: Waters BEH C18, 2.1 x 50 mm, 1.7-μιη particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes; Flow: 1.1 1 mL/min. Method F: Waters BEH CI 8, 2.1 x 50 mm, 1.7-μτη 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; Temperature: 50 °C; Gradient: 0- 100% B over 3 minutes; Flow: 1.1 1 mL/min.
Method G: SunFire C18 column (3.5 μιη, 4.6 x 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 18 min and then 100% Solvent B for 5 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm).
Method H: XBridge Phenyl column (3.5 μιη, 4.6 x 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 18 min and then 100% Solvent B for 5 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm).
Method I: SunFire C18 column (3.5 μιη, 4.6 x 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm).
Method J: XBridge Phenyl column (3.5 μιη, 4.6 x 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm).
Method K: SunFire C18 column (3.5 μιη, 4.6 x 150 mm). Gradient elution (1.0 mL/min) from 0-50% Solvent B over 15 min, 50-100% Solvent B over 3 min, and then 100%) Solvent B for 5 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm).
Method L: XBridge Phenyl column (3.5 μιη, 4.6 x 150 mm). Gradient elution (1.0 mL/min) from 0-50% Solvent B over 15 min, 50-100% Solvent B over 3 min, and then 100%) Solvent B for 5 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm).
Method M: Ascentis Express C18 (2.7 μτη, 4.6 x 50 mm). Gradient elution (4.0 mL/min) from 0-100% Solvent B over 4 min. Solvent A is (95% water, 5% acetonitrile, 0.1% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.1% TFA, UV 220 nm). Method N: Ascentis Express CI 8 (2.7 μηι, 4.6 x 50 mm). Gradient elution (4.0 mL/min) from 0-100% Solvent B over 4 min. Solvent A is (95% water, 5% acetonitrile, 10 mM NH4OAc) and Solvent B is (5% water, 95% acetonitrile, 10 mM NH4OAc, UV 220 nm).
Intermediate 1 : 5H- e-8-carboxylic acid
Figure imgf000095_0001
Intermediate la:
Figure imgf000095_0002
To a stirred solution of 4-bromo-3-methoxyaniline (50 g, 247 mmol) in THF (1.5 L) were added B0C2O (69 mL, 297 mmol) and TEA (45 mL, 322 mmol). The reaction mixture was refluxed for 12 h. The solvent was removed and the residue was taken in ethyl acetate. It was washed with water and brine, and then dried over sodium sulfate and concentrated. The crude mixture was purified by normal phase chromatography to give Intermediate la as white solid (60.0 g, 78%). LC-MS (ESI) m/z: 302.0 [M+H]"; ¾ NMR (400MHz, DMSO-d6) δ 9.48 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 6.96 (dd, J=8.4, 2.0 Hz, 1H), 3.79 (s, 3H), 1.48 (s, 9H).
Intermediate lb: tert-Butyl (3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)carbamate
Figure imgf000095_0003
To a stirred solution of la (25 g, 83 mmol) in DMF (750 mL) were added KOAc (24.36 g, 248 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (31.5 g, 124 mmol) and PdCi2(dppf)-CH2Ci2 adduct (6.76 g, 8.27 mmol). The reaction was heated at 100 °C for 12 h. The DMF was removed and the residue was taken in ethyl acetate. It was washed with water and brine, dried over sodium sulfate and concentrated. The crude mixture was purified by normal phase chromatography to provide Intermediate lb as white solid (15.0 g, 48%). XH NMR (400MHz, DMSO-d6) δ 9.45 (s, IH), 7.41 (d, J=8.0 Hz, IH), 7.17 (d, J=1.6 Hz, IH), 7.00 (dd, J=8.0, 1.6 Hz, IH), 3.68 (s, 3H), 1.48 (s, 9H), 1.24 (s, 12H).
Figure imgf000096_0001
To a stirred solution of lb (15.54 g, 44.5 mmol) in 1,4-dioxane (450 mL) and ¾0 (75mL) were added 4-chloronicotinaldehyde (6.0 g, 42.4 mmol), K3PO4 (36.0 g, 170 mmol), and PdC dppfj-Q LC . adduct (2.77 g, 3.39 mmol). The reaction mixture was heated at 100 °C for 1 h under nitrogen. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and then concentrated. Purification by normal phase chromatography provided Intermediate lc as yellow solid (12.0 g, 84%). LC-MS (ESI) m/z: 329.2 [M+H]+; ¾ NMR (400MHz, DMSO-d6) δ 9.75 (d, J=0.4 Hz, IH), 9.63 (s, IH), 8.89 (s, IH), 8,79 (d, J=6.8 Hz, IH), 7.43-7.40 (m, 2H), 7.29 (d, J=l 1.2 Hz, IH), 7.20 (dd, J=11.2, 2.4 Hz, IH), 3.67 (s, 3H), 1.50 (s, 9H).
Intermediate Id: tert-Butyl (4-(3-(hydroxymethyl)pyridin-4-yl)-3-methoxyphenyl) carbamate
Figure imgf000096_0002
To a stirred solution of lc (30 g, 91 mmol) in MeOH (500 mL) was added NaBH4 (4.15 g, 110 mmol) at 0 °C under N2. The reaction was stirred at rt for 1 h. The reaction was quenched with water (150mL) and methanol was removed. The residue was extracted with ethyl acetate (2x200 mL). The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude solid was further washed with hot 50% ethyl acetate in petroleum ether (50 mL) to provide Intermediate 1 d as off-white solid (30 g, 98%). LC-MS (ESI) m/z: 329.2 [M-H]"; 'H NMR (400MHZ, DMSO-d6) δ 9.45 (s, IH), 8.67 (d, J=0.4 Hz, IH), 8.43 (d, J=6.4 Hz, IH), 7.38 (d, J=1.6 Hz, IH), 7.12-7.03 (m, 3H), 5.14 (t, J=7.2 Hz, IH), 4.03 (d, J=7.6 Hz, IH), 3.68 (s, 3H), 1.50 (s, 9H).
Intermediate le: 5H-Chromeno[3,4-c]pyridin-8-amine
Figure imgf000097_0001
A suspension of Id (30 g, 91 mmol) in HBr (63% in water, 8.0 mL, 91 mmol) was heated at 100 °C overnight. The reaction mixture was concentrated. The residue was dissolved in water and it was basified with sodium hydroxide solution and then extracted with DCM (2x300 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude solid was washed with 20% of ethyl acetate in petroleum ether and then dried to give Intermediate le as yellow solid (15 g, 83%). LC-MS (ESI) m/z: 199.1 [M+H]+; ¾ NMR (400MHz, DMSO-d6) δ 8.40 (d, J=6.8 Hz, IH), 8.31 (m, IH), 7.57 (d, J=11.2 Hz, IH), 7.50 (d, J=6.8 Hz, IH), 6.33 (dd, J=1 1.2, 2.8 Hz, IH), 6.14 (d, J=2.8 Hz, IH), 5.72 (s, 2H), 5.06 (s, 2H).
Intermediate -Iodo-5H-chromeno[3,4-c]pyridine
Figure imgf000097_0002
To a stirred solution of le (15 g, 76 mmol) in acetonitrile (150 mL) was added p- toluenesulfonic acid monohydrate (43.2 g, 227 mmol) at rt. After stirred for 10 min, an aqueous solution of NaN02 (13.05 g, 189 mmol) and KI (25.1 g, 151 mmol) was added slowly. After the addition was completed, the reaction was stirred at rt for 1 h. The reaction was basified with saturated sodium carbonate solution and then it was extracted with EtOAc (2x50 mL). The combined organic layer was washed with saturated sodium thiosulfate solution, water and brine, dried over sodium sulfate and concentrated.
Purification by normal phase chromatography provided If as off-white solid (17.5 g,
74%). LC-MS (ESI) m/z: 310.0 [M+H]+; XH NMR (400MHz, DMSO-d6) δ 8.59 (d, J=5.2 Hz, IH), 8.50 (s, IH), 7.81 (d, J=5.2 Hz, IH), 7.76 (d, J=8.4 Hz, IH), 7.50 (dd, J=8.0, 1.6 Hz, IH), 7.44 (s, IH), 5.23 (s, IH).
Intermediate lg -Chromeno[3,4-c]pyridine-8-carbonitrile
Figure imgf000098_0001
To a stirred solution of If (17 g, 55.0 mmol) in dry DMF (160 mL) was added CuCN (7.39 g, 82 mmol) as a single portion at rt under nitrogen. The reaction was heated at 150 °C overnight. The reaction was cooled to rt and then quenched with saturated aqueous ammonia solution (500 mL). The solid formed was collected by filtration and it was washed with water and then dried to afford lg (9.0 g, 78%). LC-MS (ESI) m/z: 209.2 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 8.65 (d, J=4.8 Hz, IH), 8.56 (s, IH), 8.18 (d, J=8.0 Hz, IH), 8.18 (d, J=4.8 Hz, IH), 7.59-7.56 (m, 2H), 5.32 (s, 2H).
Intermediate 1
Figure imgf000098_0002
To a stirred solution of lg (8.5 g, 40.8 mmol) in H20 (80 mL) was added H2S04 (80 mL) as a single lot and the reaction was heated at 80 °C overnight. The reaction mixture was diluted with water (200 mL). The solid formed was collected by filtration, washed with water and dried. The crude solid was triturated with methanol at 50 °C and then cooled to rt. The solid was filtered and dried to give Intermediate 1 as light yellow solid (8.2 g, 86%). LC-MS (ESI) m/z: 228.1 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 8.78 (d, J=5.6 Hz, IH), 8.71 (s, IH), 8.22-8. 18 (m, 2H), 7.70 (dd, J=8.0, 1.6 Hz, IH), 7.53 (d, J=1.6 Hz, IH), 5.37(s, 2H).
Intermediate 2: 6H-Isochromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000098_0003
Intermediate 2a: Methyl 4-(3-fluoropyridin-4-yl)-3-formylbenzoate
Figure imgf000099_0001
To a solution of methyl 4-bromo-3-formylbenzoate (500 mg, 2.057 mmol) in dioxane (15 mL) were added 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (551 mg, 2.469 mmol), K3P04 (6.17 mL, 6.17 mmol), and XPhos-G2-PreCat (81 mg, 0.103 mmol) at rt. The reaction was stirred under argon at 80 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with ]¾0 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to provide Intermediate 2a as pale solid (362 mg, 68%). LCMS (ESI) m/z: 260.0 [M+H]+; XH NMR (400MHz, CDC13) δ 9.96 (d, J=2.4 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H), 8.60 (d, J=1.3 Hz, 1H), 8.57 (dd, J=4.8, 0.9 Hz, 1H), 8.36 (dd, J=7.9, 1.8 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.31 (dd, J=6.1, 5.0 Hz, 1H), 4.00 (s, 3H); 19F NMR (376MHz, CDC13) δ -129.71 (s, IF).
Intermediate 2b: Methyl 4-(3-fluoropyridin-4-yl)-3-(hydroxymethyl)benzoate
Figure imgf000099_0002
To a solution of Intermediate 2a (1.57g, 6.06 mmol) in MeOH (15 mL) was added NaBH4 (0.229 g, 6.06 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for 30 min. LCMS showed the reaction was completed. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase
chromatography to give Intermediate 2b as clear colorless oil (0.82 g, 52%). LCMS (ESI) m/z: 262.0 [M+H]+; 'H NMR (400MHZ, CDC13) δ 8.57 (d, J=1.3 Hz, 1H), 8.51 (dd, J=4.8, 0.9 Hz, 1H), 8.33 (d, J=l. l Hz, 1H), 8.07 (dd, J=7.9, 1.8 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.30 (dd, J=6.1, 5.0 Hz, 1H), 4.60 (d, J=5.1 Hz, 2H), 3.97 (s, 3H), 1.98 (t, J=5.6 Hz, 1H).
Intermediate 2:
Figure imgf000100_0001
To a solution of Intermediate 2b (0.82 g, 3.14 mmol) in THF (10 mL) was added NaH (0.251 g, 6.28 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for 1 hr. Then it was stirred at rt overnight. Water (5 mL) was added carefully to quench the reaction and stirred for another hour at RT. The solvent was removed. The crude product was purified by reverse phase chromatography to provide Intermediate 2 as light brown solid (770 mg, 77%). LCMS (ESI) m/z: 228.0 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 8.27 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.85 - 7.80 (m, 2H), 7.75 (d, J=0.9 Hz, 1H), 5.24 (s, 2H).
Intermediate 3: 6H-I ine-8-carboxylic acid
Figure imgf000100_0002
Intermediate 3 a: Methyl 4-bromo-3-(hydroxymethyl)benzoate
Figure imgf000100_0003
To a solution of methyl 4-bromo-3-formylbenzoate (1.53 g, 6.29 mmol) in MeOH (20 mL) was added NaBH4 (0.238 g, 6.29 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for 30 min. LCMS showed the reaction was completed. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated to give Intermediate 3 a as clear colorless oil (1.50 g, 97%). LCMS (ESI) m/z: 244.9/246.9 [M+H]+; 'H NMR (400MHZ, CDC13) δ 8.17 (d, J=2.0 Hz, 1H), 7.82 (dd, J=8.4, 2.2 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 4.79 (s, 2H), 3.93 (s, 3H). Intermediate 3b: Methyl 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)benzoate
Figure imgf000101_0001
To a solution of Intermediate 3a (1.49 g, 6.08 mmol) in DMF (10 mL) were added imidazole (0.621 g, 9.12 mmol) and TBS-C1 (1.100 g, 7.30 mmol) at 0 °C. The reaction was stirred under argon at rt overnight. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to give 3b (1.89 g, 87%). LCMS (ESI) m/z: 359.0/360.9 [M+H]+; 'H NMR (400MHZ,
CDC13) δ 8.26 - 8.21 (m, 1H), 7.79 (dd, J=8.4, 2.2 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 4.76 (s, 2H), 3.93 (s, 3H), 1.00 (s, 9H), 0.16 (s, 6H).
Intermediate 3c: Methyl 3-(((/er/-butyldimethylsilyl)oxy)methyl)-4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)benzoate
Figure imgf000101_0002
To a solution of Intermediate 3b (1.41 g, 3.92 mmol) in acetonitrile (15 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.196 g, 4.71 mmol), KOAc (0.770 g, 7.85 mmol), and PdCl2(dppf) (0.144 g, 0.196 mmol) at rt. The reaction was stirred under argon at 90 °C for 5 h. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 3c as clear colorless oil (1.18 g, 74%). LCMS (ESI) m/z: 407.1 [M+H]+; XH NMR (400MHz, CDC13) 5 8.14 (d, J=0.9 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.74 - 7.68 (m, 1H), 4.91 (s, 2H), 3.81 (s, 3H), 1.24 (s, 12H), 0.86 (s, 9H), 0.00 (s, 6H).
Intermediate 3d: Methyl 3-(((ter/-butyldimethylsilyl)oxy)methyl)-4-(5-fluoropyrimidin-4- yl)benzoate
Figure imgf000101_0003
To a solution of Intermediate 3c (285 mg, 0.701 mmol) in dioxane (2 mL) were added 4-chloro-5-fluoropyrimidine (93 mg, 0.701 mmol), K3PO4 (447 mg, 2.104 mmol) and Pd(Pli3P)4 (81 mg, 0.070 mmol) at rt. The reaction was stirred under argon at 90 °C for 3 h. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to give Intermediate 3d as clear colorless oil (225 mg, 85%). LCMS (ESI) m/z: 377.1 [M+H]+; 'H NMR (400MHZ, CDCI3) δ 9.14 (d, J=2.9 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.33 (d, J=l. l Hz, 1H), 8.09 (dd, J=7.9, 1.8 Hz, 1H), 7.55 (dd, J=8.0, 1.4 Hz, 1H), 4.87 (s, 2H), 3.99 (s, 3H), 0.85 (s, 9H), 0.00 (s, 6H).
Intermediate -isochromeno[4,3-d]pyrimidine-8-carboxylate
Figure imgf000102_0001
To a solution of Intermediate 3d (225 mg, 0.598 mmol) in THF (3 mL) was added TBAF (1 M in THF, 2.99 ml, 2.99 mmol) at rt. The reaction was stirred under argon at rt for 30 min. LCMS showed the reaction was completed. The solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 3e as white solid (142 mg, 98%). LCMS (ESI) m/z: 243.1 [M+H]+; XH NMR (400MHz, CDC13) δ 8.91 (s, 1H), 8.44 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.14 (dd, J=8.0, 1.7 Hz, 1H), 7.87 (d, J=0.9 Hz, 1H), 5.37 (s, 2H), 3.97 (s, 3H).
Intermediate
Figure imgf000102_0002
To a solution of Intermediate 3e (142 mg, 0.586 mmol) in THF (6 mL) and H2O (2 mL) was added LiOH (70.2 mg, 2.93 mmol) at RT. The reaction was stirred under argon at rt for 2 h. The solvent was removed to give Intermediate 3 as white solid (134 mg, 100%). LCMS (ESI) m/z: 229.1 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 8.82 (s, IH), 8.46 (s, IH), 8.04 (d, J=8.1 Hz, IH), 7.95 (d, J=8.1 Hz, IH), 7.77 (d, J=1.0 Hz, IH), 5.39 (s, 2H)
Intermediate 4: 5-Methyl-5H- e-8-carboxylic acid, TFA salt
Figure imgf000103_0001
Intermediate 4a: Methyl 3-fluoro-4-(3-formylpyridin-4-yl)benzoate
Figure imgf000103_0002
To a solution of (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (441 mg, 2.225 mmol) in dioxane (6 mL) and ¾0 (1.6 mL) were added 4-chloronicotinaldehyde (300 mg, 2.119 mmol), K3PO4 (990 mg, 4.66 mmol), and XPhos-G2-PreCat (66.8 mg, 0.085 mmol) at rt. The reaction was heated at 140 °C with microwave for 10 min. The reaction was diluted with EtOAc and the organic layer was separated and concentrated. Purification by normal phase chromatography gave Intermediate 4a as tan oil (320 mg, 58.2%). LC-MS (ESI) m/z: 260.0[M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 9.99 (d, J=2.2 Hz, IH), 9.13 (s, IH), 8.94 (d, J=5.1 Hz, IH), 7.94 (dd, J=7.9, 1.5 Hz, IH), 7.84 (dd, J=10.3, 1.5 Hz, IH), 7.68 (t, J=7.6 Hz, IH), 7.59 (d, J=5.1 Hz, IH), 3.92 (s, 3H).
Intermediate -fluoro-4-(3-(l -hydroxy ethyl)pyridin-4-yl)benzoate
Figure imgf000103_0003
To a solution of 4a (320 mg, 1.234 mmol) in THF (10 mL) was added methyl magnesium bromide (0.970 mL, 1.358 mmol, 1.4 M in toluene/THF) dropwise over 30 min. The resulted mixture was stirred at rt for 20 min. The reaction was cooled to 0 °C and quenched with sat. NH4CI solution. The reaction mixture was extracted with EtOAc. The organic layer was concentrated and then purified by normal phase chromatography to give Intermediate 4b as oil (258 mg, 68.3%). LC-MS (ESI) m/z: 276.0[M+H]+; 'H NMR (400MHz, CDC13) δ 8.89 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.90 (dd, J=7.9, 1.3 Hz, 1H), 7.81 (dd, J=9.9, 1.3 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.08 (d, J=5.1 Hz, 1H), 4.81 (q, J=5.9 Hz, 1H), 3.95 (s, 3H), 1.39 (d, J=6.2 Hz, 3H).
Intermediate 4
Figure imgf000104_0001
To a solution of Intermediate 4b (258 mg, 0.937 mmol) in THF (5 mL) was added NaH (75.0 mg, 1.874 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for 1 h and then at rt for 2 h. Water was added carefully to quench the reaction. The pH was adjusted to ~8 with 4 N HC1. The solvent was removed. Purification by reverse phase chromatography provided Intermediate 4 as white solid (195 mg, 55.6%). LC-MS (ESI) m/z: 242.0 M+H]+; 'H NMR (400MHZ, CD3OD) δ 8.91 - 8.63 (m, 1H), 8.38 (d, J=6.2 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.81 (dd, J=8.3, 1.7 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 5.60 (q, J=6.5 Hz, 1H), 1.74 (d, J=6.6 Hz, 3H).
Intermediate 5: N-(3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-5H- -c]pyridine-8-carboxamide
Figure imgf000104_0002
To a suspension of Intermediate 1 (792 mg, 3.49 mmol) in DMF (12 mL) were added (3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanamine,HCl salt (940 mg, 3.49 mmol), DIEA (2.436 mL, 13.95 mmol) and HATU (1856 mg, 4.88 mmol) at rt. The reaction was stirred under argon at rt overnight. The reaction was diluted with EtOAc. The organic phase was washed with water and brine, dried over Na2S04 and concentrated. Purification by normal phase chromatography gave Intermediate 5 as white solid (910 mg, 41%). LC-MS (ESI) m/z: 443.2[M+H]+. Intermediate 6: 6-Methyl-6 -isochromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000105_0001
Intermediate 6a: Methyl 4-(3-fluoropyridin-4-yl)-3-(l -hydroxy ethyl)benzoate
Figure imgf000105_0002
To a solution of Intermediate 2a (368 mg, 1.420 mmol) in THF (14 mL) was added methyl magnesium bromide (1.014 mL, 1.420 mmol, 1.4 M in toluene/THF) dropwise over 40 min. The resulted reaction mixture was stirred at rt for 30 min. It was then cooled to 0 °C and quenched with sat. NH4C1 solution. The reaction mixture was extracted with EtOAc (3x). Organic phase was dried over Na2S04 and concentrated. Purification by normal phase chromatography gave Intermediate 6a as oil (280 mg, 72%). LC-MS (ESI) m/z 276.0[M+H]+; XH NMR (400MHz, CD3OD) δ 8.57 (d, J=l. l Hz, IH), 8.49 (d, J=4.8 Hz, IH), 8.40 (d, J=1.8 Hz, IH), 8.00 (dd, J=8.1, 1.8 Hz, IH), 7.42 (dd, J=6.2, 5.3 Hz, IH), 7.32 (d, J=8.1 Hz, IH), 4.72 (q, J=6.2 Hz, IH), 3.95 (s, 3H), 1.31 (d, J=6.4 Hz, 3H).
Intermediate 6:
Figure imgf000105_0003
To a solution of methyl 4-(3-fluoropyridin-4-yl)-3-(l -hydroxy ethyl)benzoate (280 mg, 1.017 mmol) in THF (5 mL) was added NaH (60%, 102 mg, 2.54 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for 20 min and then at rt overnight. Water was added carefully to quench the reaction and then 4 N HC1 was added to adjust the pH to ~8. The solvent was removed. Purification by reverse phase chromatography provided Intermediate 6 as white solid (195 mg, 51%). LC-MS (ESI) m/z: 242.0[M+H]+.
Intermediate 7: 6-Ethyl-6 -isochromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000106_0001
Intermediate 7 was prepared by following a similar procedure as described in Intermediate 6 by replacing methyl magnesium bromide with ethyl magnesium bromide in step 6a. LC-MS (ESI) m/z: 256.0[M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 8.45 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.07 - 7.98 (m, 2H), 7.91 (s, 1H), 5.47 (dd, J=8.6, 4.8 Hz, 1H), 1.91 - 1.61 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).
Intermediate 8: 6-Cyclopropy -6H-isochromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000106_0002
Intermediate 8 was prepared by following a similar procedure as described in Intermediate 6 by replacing methyl magnesium bromide with cyclopropyl magnesium bromide in step 6a. LC-MS (ESI) m/z: 268.0[M+H]+.
Intermediate 9: Methyl 5-(aminomethyl)-2-fluorobenzoate
Figure imgf000106_0003
Intermediate 9a: Methyl 5-(azidomethyl)-2-fluorobenzoate
Figure imgf000106_0004
To a solution of methyl 5-(bromomethyl)-2-fluorobenzoate (500 mg, 2.024 mmol) in DMF (4 mL) was added a 3 (395 mg, 6.07 mmol) at rt. The reaction was stirred under argon at 60 °C overnight. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. Purification by normal phase chromatography afforded Intermediate 9a as colorless oil (415 mg, 98%). LC-MS (ESI) m/z: 210.0[M+H]+; ¾ NMR (400MHz, CDC13) δ 7.91 (dd, J=6.8, 2.2 Hz, 1H), 7.49 (ddd, J=8.5, 4.5, 2.4 Hz, 1H), 7.17 (dd, J=10.3, 8.6 Hz, 1H), 4.38 (s, 2H), 3.95 (s, 3H). Intermediate 9:
Figure imgf000107_0001
To a solution of Intermediate 9a (415 mg, 1.984 mmol) in MeOH (10 mL) was added catalytic amount of 5% Pd/C. The reaction was stirred under a hydrogen balloon at rt for 5 h. The catalyst was filtered off and the solvent was removed to afford
Intermediate 9 as white solid (342 mg, 94%). LC-MS (ESI) m/z: 184.0[M+H]+.
Intermediate 10: 6-Allyl-6 -isochromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000107_0002
Intermediate 10 was prepared by following a similar procedure as described in Intermediate 6 by replacing methyl magnesium bromide with allyl magnesium bromide step 6a. LC-MS (ESI) m/z: 268.0[M+H]+.
Intermediate 1 1 : 1 -(6-Methoxypyridin-2-yl)ethanamine HC1 salt
Figure imgf000107_0003
Intermediate 1 1A: (R)-N-((6-Methoxypyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide
Figure imgf000108_0001
To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (1.0 g, 8.3 mmol) and CS2CO3 (4.0 g, 12 mmol) in DCM (15 mL), was added a solution of 6- methoxypicolinaldehyde in DCM (1.1 mL, 9.1 mmol, in 3 mL DCM) dropwise. The solution was then stirred at rt for 5 h. The solid was filtered off, and the solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 11A (1.9 g, 96%) as a clear colorless oil. LC-MS (ESI) m/z: 241.0 [M+H]+; XH NMR (400MHz, CDC13) δ 8.59 (s, 1H), 7.72 - 7.58 (m, 2H), 6.85 (dd, J= 7.9, 1.1 Hz, 1H), 3.99 (s, 3H), 1.29 (s, 9H).
Intermediate 1 IB: (R)-N-(l-(6-Methoxypyridin-2-yl)ethyl)-2-methylpropane-2- sulfinamide
Figure imgf000108_0002
To a solution of Intermediate 1 1A (0.65 g, 2.7 mmol) in THF (6 mL), was added methylmagnesium bromide (1.4 M in toluene/THF, 2.9 mL, 4.1 mmol) at 0 °C. The reaction was stirred under argon from 0 °C to rt for 2 h. It was cooled to 0 °C, and NH4CI solution was carefully added. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by normal phase chromatography to afford Intermediate 11B (0.58 g, 83%) as a mixture of two diastereomers as a clear colorless oil. LC-MS (ESI) m/z: 257.0 [M+H]+; XH NMR (400MHz, CDC13) δ 7.53 (dt, J= 8.3, 7.1 Hz, 2H), 6.86 (d, J= 7.3 Hz, 1H), 6.82 (d, J= 7.0 Hz, 1H), 6.62 (d, J= 8.1 Hz, 2H), 4.83 (br. d, J= 4.6 Hz, NH) 4.59 - 4.44 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 1.60 (d, J= 6.8 Hz, 3H), 1.50 (d, J= 6.6 Hz, 3H), 1.26 (s, 6H), 1.21 (s, 6H).
Intermediate 11 :
Figure imgf000109_0001
To a solution of Intermediate 1 IB (0.58, 2.3 mmol) in MeOH (5 mL), was added HC1 (4 M in dioxane, 2.8 ml, 1 1 mmol) at rt. The reaction was stirred under argon at rt for 2 h. The solvent was removed to give Intermediate 11 (0.52 g, 100%) as white solid. LC-MS (ESI) m/z: 153.0 [M+H]+.
Intermediate 12: 2-Ac ridine-8-carboxylic acid
Figure imgf000109_0002
Intermediate 12A: -Bromo-4-chloropyridin-2-amine
Figure imgf000109_0003
To a solution of 4-chloropyridin-2-amine (5.0 g, 39 mmol) in MeCN (200 mL) at 0 °C was added B¾ (2.2 mL, 43 mmol) in portions over a period of 30 min. The reaction was warmed to rt and stirred overnight. The solid was filtered, washed with hexane (3x), and dried to afford Intermediate 12A (9.1 g, 81%) as an off-white solid. LC-MS (ESI) m/z: 206.9/208.9 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 8.30 (s, 1H), 7.02 (s, 1H).
Intermediate 12B: -(5-Bromo-4-chloropyridin-2-yl)acetamide
Figure imgf000109_0004
To a solution of Intermediate 12A (5.0 g, 17 mmol) in pyridine (40 mL) at 0 °C, was added acetyl chloride (3.5 mL, 49 mmol) dropwise over 30 min. The reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was cooled to 0 °C, and it was added acetyl chloride (6.2 mL, 87 mmol) dropwise. The reaction mixture was allowed to warm to rt and stirred for 2 h. It was diluted with DCM, and the solid was filtered off. The filtrate was concentrated. The residue was dissolved in EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to afford Intermediate 12B (3.6 g, 82%) as an off-white solid. LC-MS (ESI) m/z: 248.9/250.9 [M+H]+; 'H NMR (400MHZ, CDC13) δ 8.45 (s, 1H), 8.40 - 8.28 (m, 2H), 2.23 (s, 3H).
Intermediate 12C: N-(4-Chloro-5-vinylpyridin-2-yl)acetamide
Figure imgf000110_0001
To a solution of Intermediate 12B (1.4 g, 5.4 mmol) in dioxane (12 mL) and water
(2.2 mL), were added 2,4,6-trivinyl-l,3,5,2,4,6-trioxatriborinane pyridine complex (0.79 g, 4.9 mmol) and K3PO4 (2.3 g, 1 1 mmol). The reaction mixture was bubbled with argon for 10 min. Then Pd(PPh3)4 (0.44 g, 0.38 mmol) was added, and the mixture was again bubbled with argon for 5 min. The reaction was heated at 150 °C in a microwave reactor for 5 min. It was filtered through CELITE® and was washed with EtOAc (50 ml). The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to afford Intermediate 12C (0.73 g, 69%) as a yellowish solid. LC-MS (ESI) m/z: 197.0 [M+H]+; 'H NMR (400MHZ, CDCI3) δ 8.40 (s, 1H), 8.29 (s, 1H), 7.95 (br. s., 1H), 6.94 (dd, J= 17.7, 1 1.6 Hz, 1H), 5.77 (dd, J= 17.6, 0.7 Hz, 1H), 5.42 (dd, J = 1 1.2, 0.9 Hz, 1H), 2.22 (s, 3H).
Intermediate 12D: N-(4-Chloro-5-formylpyridin-2-yl)acetamide
Figure imgf000110_0002
To a solution of Intermediate 12C (1.5 g, 7.8 mmol) and 2,6-lutidine (1.8 mL, 16 mmol) in dioxane (25 mL) and water (1.7 mL), was added sodium periodate (5.0 g, 23 mmol) at 0 °C, followed by the addition of osmium tetroxide (2.5% in /-butanol,2.4 mL, 0.21 mmol) over 10 min. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with EtOAc, washed with ¾0 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to afford Intermediate 12D (1.0 g, 66%) as a white solid. LC-MS (ESI) m/z: 199.0 [M+H]+; XH NMR (400MHz, CDC13) δ 10.38 (s, 1H), 8.76 (s, 1H), 8.39 (s, 1H), 8.19 (br. s., 1H), 2.27 (s, 3H).
Intermediate 12E: Methyl 4-(2-acetamido-5-formylpyridin-4-yl -3-fluorobenzoate
Figure imgf000111_0001
Intermediate 12D (0.92 g, 4.6 mmol), (2-fluoro-4-(methoxycarbonyl)phenyl) boronic acid (1.7 g, 8.3 mmol), K3PO4 (2.3 g, 1 1 mmol), dioxane (12 mL) and water (2 mL) were placed in a 20 mL microwave vial. The mixture was bubbled with argon for 10 min. Pd(PPh3)4 (0.32 g, 0.28 mmol) was added, and the mixture was again bubbled with argon for 7 min. The reaction was heated at 145 °C in a microwave reactor for 7 min. The reaction mixture was filtered through CELITE®, and was washed with EtOAc (55 ml). The solvent was removed under reduced pressure. The crude product was purified by normal phase chromatography to afford Intermediate 12E (1.4 g, 86%) as an off-white solid. LC-MS (ESI) m/z: 317.1 [M+H]+; 1H NMR (400MHz, CDC13) δ 9.87 (d, J = 2.9 Hz, 1H), 8.89 (s, 1H), 8.28 (s, 1H), 8.24 (br. s., 1H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.86 (dd, J = 10.0, 1.4 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 3.99 (s, 3H), 2.28 (s, 3H).
Intermediate 12F: Methyl 4-(2-acetamido-5-(hydroxymethyl)pyridin-4-yl)-3- fluorobenzoate
Figure imgf000111_0002
A suspension of Intermediate 12E (430 mg, 1.4 mmol) in ethanol (12 mL) was cooled to 0 °C. To the reaction was added sodium borohydride (51 mg, 1.4 mmol) portionwise. The reaction mixture was stirred for 20 min at 0 °C. Excess ethanol was removed under reduced pressure. Water was added to the mixture. The solid was filtered, washed with water, and dried to afford Intermediate 12F (380 mg, 87%) as a solid. LC- MS (ESI) m/z: 319.0 [M+H]+; XH NMR (400MHz, DMSO-d6) δ 10.64 (s, 1H), 8.46 (s, 1H), 7.99 (s, 1H), 7.90 (dd, J = 7.9, 1.3 Hz, 1H), 7.83 (dd, J = 10.3, 1.3 Hz, 1H), 7.58 (t, = 7.6 Hz, 1H), 5.16 (br. s., 1H), 4.32 (d, J = 3.1 Hz, 2H), 3.91 (s, 3H), 2.10 (s, 3H).
Figure imgf000112_0001
To a cooled a solution (-10 °C) of Intermediate 12F (370 mg, 1.2 mmol) in THF (10 mL) was added NaH (93 mg, 2.3 mmol) portionwise. The reaction was stirred at -10 °C for 50 min, then it was warmed to rt and stirred overnight. The reaction mixture was cooled to 0 °C, and EtOAc was added. The reaction was quenched with aq. NH4C1. The two layers were separated. The aqueous layer was concentrated. The crude product was purified by reverse phase chromatography to afford Intermediate 12 (15 mg, 4.5%) as an off-white solid. LC-MS (ESI) m/z: 285.0 [M+H]+. id
Figure imgf000112_0002
A suspension of Intermediate 12 (8.0 mg, 0.028 mmol) in concentrated HCI (160 μΐ, 2.0 mmol) in a sealed vial was heated at 100 °C for 70 min. The solvent was removed, and the residue was dried to afford Intermediate 13 (7.0 mg, 90%) as a yellow solid. LC- MS (ESI) m/z: 243.0 [M+H]+.
Intermediate 14: 2-Fluoro-6H-isochromeno[3,4-c]pyridine-8-carboxylic acid
- I l l -
Figure imgf000113_0001
Intermedia -bromo-3-(dibromomethyl)benzoate
Figure imgf000113_0002
To a solution of methyl 4-bromo-3-methylbenzoate (5.8 g, 25 mmol) in CC14 (70 mL), was added NBS (15 g, 84 mmol), followed by addition of benzoyl peroxide (0.61 g, 2.5 mmol). The mixture was heated at reflux for 8 h. The mixture was cooled to rt, and was allowed to stir overnight. The solvent was removed under reduced pressure.
Purification by normal phase chromatography afforded Intermediate 14A (9.7 g, 89%) as an off-white solid. LC-MS (ESI) m/z: 386.8/388.8 [M+H]+.; XH NMR (400MHz, CDC13) δ 8.68 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 3.97 (s, 3H).
Intermediate -bromo-3-formylbenzoate
Figure imgf000113_0003
Intermediate 14A (9.7 g, 23 mmol) was suspended in morpholine (22 ml, 170 mmol), and the mixture was stirred at rt for 2 days. The reaction mixture was diluted with EtOAc, and was stirred at rt for 30 min. The solid was removed by filtration and washed with EtOAc. The filtrate was transferred to a separatory funnel and was washed with 5% aq. citric acid (3x), water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase
chromatography to afford Intermediate 14B (5.6 g, 92%) as a white solid. LC-MS (ESI) m/z: 243.0/245.0 [M+H]+; 'H NMR (400MHZ, CDCI3) δ 10.39 (s, 1H), 8.54 (d, J Hz, 1H), 8.10 (dd, J = 8.4, 2.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H).
Intermediate 14C: (2-Formyl-4-(methoxycarbonyl)phenyl)boronic acid
Figure imgf000114_0001
A mixture of Intermediate 12B (2.3 g, 9.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (3.4 g, 13 mmol), PdCl2(dppf).CH2Cl2 adduct (0.69 g, 0.95 mmol) and potassium acetate (2.8 g, 28 mmol) in dioxane (30 mL) was heated in an oil- bath at 95 °C for 2 h. The reaction was diluted with EtOAc, filtered through CELITE®. The solution was concentrated, and the crude product was purified by normal phase chromatography to afford Intermediate 14C (3.0 g, 91%) as a brown oil. LC-MS (ESI) m/z: 191.0 [M+H-18]+; XH NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 8.43 (d, J = 1.3 Hz, 1H), 8.35 (br. s., 2H), 8.16 (dd, J = 7.6, 1.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 3.91 (s, 3H).
Intermediate 14D: Methyl 4-(2,5-difluoropyridin-4-yl)-3-formylbenzoate
Figure imgf000114_0002
To a microwave vial containing solution of 4-chloro-2,5-difluoropyridine (0.40 g, 2.7 mmol) in dioxane (7 mL), were added Intermediate 14C (1100 mg, 3.2 mmol), K3PO4 (1.30 g, 6.2 mmol), water (1.4 mL) and PdCl2(dppf)CH2Cl2 adduct (0.17 g, 0.21 mmol) at rt. The mixture was purged with nitrogen, and then was heated in a microwave reactor at 120 °C for 6 min. The reaction mixture was cooled to rt. The aqueous layer was removed with a pipette. The organic phase was concentrated and was purified by normal phase chromatography to afford Intermediate 14D (350 mg, 47%) as a tan solid. LC-MS (ESI) m/z: 278.0 [M+H]+. Intermediate 14E: Methyl 4-(2,5-difluoropyridin-4-yl)-3-(hydroxymethyl)benzoate
Figure imgf000115_0001
A suspension of Intermediate 14D (390 mg, 1.4 mmol) in ethanol (10 mL) was cooled to 0 °C. Then sodium borohydride (64 mg, 1.7 mmol) was added portionwise. The reaction mixture was stirred for 20 min at 0 °C. It was concentrated. The residue was dissolved in EtOAc (30 mL), and was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford Intermediate 14E (390 mg, 95%) as an oil. LC- MS (ESI) m/z: 280.0 [M+H]+;1H NMR (400MHz, CD30D) δ 8.31 (s, 1H), 8.20 (s, 1H), 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 4.6, 2.6 Hz, 1H), 4.53 (s, 2H), 3.96 (s, 3H).
Intermediate 1
Figure imgf000115_0002
To a solution of Intermediate 14E (390 mg, 1.4 mmol) in THF (7 mL) was added
NaH (180 mg, 4.6 mmol) at rt portionwise. The reaction mixture was stirred under argon at rt overnight. Water was added carefully to quench the reaction. Aqueous HC1 (4 N) was added to adjust the pH to ~8. The solvent was removed. The residue was dissolved in MeOH-DMSO, filtered and purified by reverse phase chromatography to afford
Intermediate 14 (50 mg, 6.0%) as an off-white solid. LC-MS (ESI) m/z: 246.0 [M+H]+.
Intermediate 15: 2-Acetamido-6H-isochromeno[3,4-c]pyridine-8-carboxylic acid Intermediate 15 A: 2-B
Figure imgf000116_0001
A solution of 2-bromo-5-fluoropyridine (2.0 g, 1 1 mmol) in THF (30 mL) was cooled to -78 °C. LDA (2 M in THF, 6.3 mL, 13 mmol) was added slowly, and the mixture was stirred for 20 min. To this mixture was added a solution of iodine (3.5 g, 14 mmol) in THF (7 mL), dropwise. The reaction mixture was warmed up and stirred at 0 °C for 30 min. It was quenched with 10% aq. a2S203 solution and was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford Intermediate 15A (2.5 g, 72%) as a brown solid. LC-MS (ESI) m/z: 301.8/303.8 [M+H]+; 'H NMR (400MHZ, CDC13) δ 8.14 (s, 1H), 7.92 (d, J = 4.4 Hz, 1H). Intermediate 15B: Methyl 4-(2-bromo-5-fluoropyridin-4-yl)-3-formylbenzoate
Figure imgf000116_0002
To a microwave vial containing a solution of Intermediate 15A (1.10 g, 3.3 mmol) in dioxane (10 mL), were added Intermediate 14C (0.90 g, 3.9 mmol), K3PO4 (1.60 g, 7.5 mmol), water (1.7 mL) and PdCi2(dppf) CH2CI2 adduct (0.21 g, 0.26 mmol). The mixture was purged with nitrogen, and then was heated with microwave at 120 °C for 5 min. The organic phase was separated and concentrated. Purification by normal phase
chromatography afforded Intermediate 15B (0.62 g, 56%) as an off-white solid. LC-MS (ESI) m/z: 337.9/339.9 [M+H]+; XH NMR (400MHz, CDC13) δ 10.00 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.43 - 8.28 (m, 2H), 7.54 - 7.41 (m, 2H), 4.02 (s, 3H). Intermediate 15C: Methyl 4-(2-bromo-5-fluoropyridin-4-yl)-3-(hydroxymethyl)benzoate
Figure imgf000117_0001
To a suspension of Intermediate 15B (610 mg, 1.8 mmol) in ethanol (10 mL) at 0 °C, was added Sodium borohydride (69 mg, 1.8 mmol), portionwise. The reaction mixture was stirred at 0 °C for 20 min, and then was concentrated. The residue was dissolved in EtOAc, washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford Intermediate 15C (610 mg, 67%) as a foam. LC-MS (ESI) m/z: 340.0/342.0 [M+H]+; 'H NMR (400MHZ, CDC13) δ 8.27 (s, 1H), 8.24 (s, 1H), 8.03 - 7.96 (m, 1H), 7.42 (d, J = 5.5 Hz, 1H), 8.25-7.20 (m, 1H), 4.54 (d, J = 4.2 Hz, 2H), 3.93 - 3.87 (s, 3H).
Intermedia -bromo-6H-isochromeno[3,4-c]pyridine-8-carboxylate
Figure imgf000117_0002
To a solution of Intermediate 15C (550 mg, 1.6 mmol) in THF (10 mL) at -10 °C, was added NaH (110 mg, 2.8 mmol), portionwise. The reaction mixture was stirred at -10 °C for 50 min. It was quenched with aq. NH4C1 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and purified by normal phase chromatography to afford Intermediate 15D (220 mg, 43%) as an off-white solid. LC-MS (ESI) m/z: 319.9/321.9 [M+H+MeOH]+; 'H NMR (400MHZ, CDCI3) δ 8.14 (s, 1H), 8.09 (dd, J = 8.1, 1.5 Hz, 1H), 7.88 (d, J = 0.7 Hz, 1H), 7.80 - 7.74 (m, 2H), 5.24 (s, 2H), 3.96 (s, 3H).
Intermediate 15E: Methyl 2-acetamido-6H-isochromeno[3,4-c]pyridine-8-carboxylate
Figure imgf000118_0001
Intermediate 15D (22 mg, 0.70 mmol), Xantphos (41 mg, 0.070 mmol), Pd(OAc)2 (7.9 mg, 0.035 mmol),Cs2C03 (680 mg, 2.1 mmol), 1,4-dioxane (4 mL), and acetamide (62 mg, 1.1 mmol) were placed in a sealed vial. The mixture was degassed by flushing with argon for 20 min. It was heated at 70 °C for 4.5 h. The mixture was cooled, and was water (8 mL) added. After stirring for 10 min, the resultant precipitate was filtered, washed with ether, and suction-dried to afford Intermediate 15E (210 mg, 90%) as a tan solid. LC-MS (ESI) m/z: 299.1 [M+H]+; XH NMR (400MHz, DMSO-d6) δ 10.47 (s, 1H), 8.51 (s, 1H), 8.1 1 (s, 1H), 8.08 - 8.02 (m, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 5.28 (s, 2H), 3.88 (s, 3H), 2.10 (s, 3H).
Interm -Acetamido-6H-isochromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000118_0002
To a suspension of Intermediate 15E (8.7 mg, 0.020 mmol) in EtOH (1 mL), was added NaOH (1 N, 0.16 mL, 0.16 mmol) at rt. The reaction was stirred under argon at rt for 90 min, then HCl (3.7 N, 0.039 mL, 0.14 mmol) was added to adjust the pH to ~8. It was diluted with MeOH. The solid was collected by filtration and dried to afford
Intermediate 15 (5.0 mg, 88%). LC-MS (ESI) m/z: 285.0 [M+H]+.
Figure imgf000118_0003
A suspension of Intermediate 15 (180 mg, 0.62 mmol) in concentrated HCl (23 μΐ, 28 mmol) in a sealed vial was heated 100 °C for 30 min. The reaction mixture was cooled to rt. It was diluted with water, and the solid was collected by filtration. The solid was washed with water and suction-dried to afford Intermediate 16 (130 mg, 77%) as a yellowish solid. LC-MS (ESI) m/z: 243.1 [M+H]+;1H NMR (400MHz, DMSO-d6) δ 8.12 - 8.07 (m, 1H), 8.03 - 7.95 (m, 2H), 7.89 (s, 1H), 7.48 (s, 1H), 5.28 (s, 2H).
Intermediate 17: 6,6-Dimethy -6H-isochromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000119_0001
Intermediate 17A: Methyl 5-chloro-2-(3-fluoropyridin-4-yl)benzoate
Figure imgf000119_0002
To a solution of methyl 2-bromo-5-chlorobenzoate (1.15g, 4.61 mmol) in dioxane
(2 mL), were added 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.234 g, 5.53 mmol), K3P04 (2.446 g, 11.52 mmol) and Pd(Ph3P)4 (0.266 g, 0.230 mmol) at rt. The reaction was stirred under argon at 80 °C for 2 h. The reaction was cooled to rt. The reaction mixture was diluted with EtOAc, washed with ¾0 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to afford Intermediate 17A as a clear colorless oil (0.50 g, 41%). LC-MS (ESI) m/z: 266.0 [M+H]+; XH NMR (400MHz, CDC13) δ 8.53 - 8.44 (m, 2H), 8.04 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.1, 2.2 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 6.3, 5.0 Hz, 1H), 3.74 (s, 3H).
Intermedi -(5-Chloro-2-(3-fluoropyridin-4-yl)phenyl)propan-2-ol
Figure imgf000119_0003
To a solution of Intermediate 17A (0.36 g, 1.4 mmol) in THF (10 mL), was added methylmagnesium bromide (3 M in ether, 1.0 mL, 3.0 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for 2 h. Aq. NH4C1 was added to quench the reaction. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to give Intermediate 17B as a white solid (259 mg, 72%). LC-MS (ESI) m/z: 266.0/268.0[M+H]+; XH NMR (400MHz, CDC13) δ 8.41 (s, 1H), 8.36 (d, J = 4.8 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.3, 2.1 Hz, 1H), 7.19 (dd, J = 6.2, 5.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 2.03 (s, 1H), 1.53 (s, 3H), 1.46 (s, 3H).
Intermediate 17 -Chloro-6,6-dimethyl-6H-isochromeno[3,4-c]pyridine
Figure imgf000120_0001
To a solution of Intermediate 17B (200 mg, 0.75 mmol) in THF (3 mL), was added NaH (90 mg, 2.3 mmol) at 0 °C. The reaction was stirred under argon from 0 °C to rt overnight. The reaction was quenched with NH4CI solution. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to give Intermediate 17C as a white solid (170 mg, 92%). LC-MS (ESI) m/z: 246.1 [M+H]+; ¾ NMR (400MHz, CDC13) δ 8.32 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.37 (dd, J = 8.4, 2.2 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 1.65 (s, 6H).
Intermed -Dimethyl-6H-isochromeno[3,4-c]pyridine-8-carbonitrile
Figure imgf000120_0002
To a solution of Intermediate 17C (170 mg, 0.69 mmol) in DMAc (8 mL), were added Pd(OAc)2 (7.8 mg, 0.035 mmol), XPhos (33 mg, 0.069 mmol), zinc powder (4.5 mg, 0.069 mmol), one drop of sulfuric acid and dicyanozinc (81 mg, 0.69 mmol) at rt. The reaction mixture was purged with argon before heated under argon at 120 °C for 5 h. The reaction was cooled to rt and then filtered. The crude product was purified by reverse phase chromatography to afford Intermediate 17D as a white solid (185 mg, 76%). LC- MS (ESI) m/z: 237.1 [M+H]+; XH NMR (400MHz, CDC13/CD30D mixture) δ 8.27 (s, IH), 8.23 (d, J = 5.5 Hz, IH), 7.85 (d, J = 8.1 Hz, IH), 7.69 (d, J = 5.3 Hz, IH), 7.66 (dd, J = 7.9, 1.5 Hz, IH), 7.54 (d, J = 1.5 Hz, IH), 1.63 (d, J = 3.5 Hz, 6H).
Intermediate
Figure imgf000121_0001
A solution of Intermediate 17D (100 mg, 0.42 mmol) in 50% H2SO4 solution was heated in a microwave reactor at 160 °C for 15 min. The reaction was diluted with water. The aqueous solution was purified by reverse phase chromatography to give Intermediate 17 as a white solid (92 mg, 85%). LC-MS (ESI) m/z: 256.1 [M+H]+; XH NMR (400MHz, DMSO-d6) δ 8.38 (s, IH), 8.34 (d, J = 5.3 Hz, IH), 8.15 (d, J = 7.9 Hz, IH), 8.05 - 7.98 (m, 2H), 7.95 (d, J = 1.3 Hz, IH), 1.67 (s, 6H). Example 1-1: (R)-N-(l-(3-Methoxyphenyl)ethyl)-5H-chromeno[3,4-c]pyridine-8- carboxamide
Figure imgf000121_0002
To a solution of Intermediate 1 (33 mg, 0.145 mmol) in DMF (1 mL) were added (R)-l-(3-methoxyphenyl)ethanamine (26.4 mg, 0.174 mmol), DIEA (0.178 mL, 1.017 mmol), and HATU (94 mg, 0.247 mmol) at RT. The reaction was stirred under argon at rt overnight. Purification by reverse phase chromatography afforded Example 1-1 as white solid (25.2 mg, 47%). LC-MS (ESI) m/z: 361.1[M+H]+; XH NMR (500MHz, DMSO-d6) δ 8.86 (d, J=8.0 Hz, IH), 8.61 (d, J=5.0 Hz, IH), 8.53 (s, IH), 8.07 (d, J=8.0 Hz, IH), 7.86 (d, J=4.7 Hz, IH), 7.63 (d, J=8.0 Hz, IH), 7.54 (s, IH), 7.24 (t, J=7.8 Hz, IH), 6.96 (br. s., 2H), 6.80 (d, J=8.3 Hz, IH), 5.27 (s, 2H), 5.13 (quin, J=6.9 Hz, IH), 3.74 (s, 3H), 1.47 (d, J=6.9 Hz, 3H). Analytical HPLC RT E: 1.62 min, F: 1.30 min. The compounds listed in Table I were prepared by following the similar procedureibed in Example 1-1 via reactions of Intermediate 1 with the appropriate amines.
Table I
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Example II- 1 : (S)-Methyl 2-(2-chlorophenyl)-2-(5H-chromeno[3,4-c]pyridine-8- carboxamido)acetate
Figure imgf000189_0001
To a suspension of Intermediate 1 (40 mg, 0.176 mmol) in DCM (2 mL) were added (S)-methyl 2-amino-2-(2-chlorophenyl)acetate, HCl salt (49.9 mg, 0.211 mmol), DIEA (0.154 mL, 0.880 mmol), and T3P (50% in EtOAc, 0.293 mL, 0.493 mmol) at rt. The reaction was stirred under argon at rt for 3 h. Purification by reverse phase chromatography afforded Example II-l (12 mg, 13%). LC-MS (ESI) m/z: 409.1 [M+H]+; XH NMR (400MHz, CD3OD) δ 8.78 (d, J=6.2 Hz, 1H), 8.74 (s, 1H), 8.38 (d, J=6.2 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.68 (dd, J=8.3, 1.7 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.40 - 7.36 (m, 2H), 6.18 (s, 1H), 5.41 (s, 2H), 3.80 (s, 3H); Analytical HPLC RT A: 5.34 min, B: 6.41 min.
Example II-2: (S)-2-(2-Chlorophenyl)-2-(5H-chromeno[3,4-c]pyridine-8- carboxamido)acetic acid
Figure imgf000189_0002
To a solution of Example II- 1 (130 mg, 0.249 mmol) in EtOH (5mL) was added NaOH (IN, 1.740 mL, 1.740 mmol) at rt. The reaction was stirred under argon at RT for 1.5 h. To the reaction mixture was added HCl (4 N, 0.373 mL, 1.492 mmol) dropwise to adjust pH to ~4. Purification by reverse phase chromatography afforded Example II-2 as
TFA salt (95 mg, 75% yield). LC-MS (ESI) m/z: 395.0 [M+H]+; XH NMR (400MHz, CD3OD) δ 8.84 - 8.67 (m, 2H), 8.39 (d, J=6.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.66 (dd, J=8.1, 1.8 Hz, 1H), 7.58 - 7.45 (m, 3H), 7.41 - 7.30 (m, 2H), 6.14 (s, 1H), 5.40 (s, 2H), 2.03 (s, 1H); Analytical HPLC RT A: 4.40 min, B: 4.99 min. Example II-3 : (S)-N-(l -(2-Chlorophenyl)-2-(methylamino)-2-oxoethyl)-5H- -c]pyridine-8-carboxamide
Figure imgf000190_0001
To a solution of Example II-2 (20 mg, 0.039 mmol) in DMF (1 mL) were added methanamine hydrochloride (31.8 mg, 0.472 mmol), DIEA (0.124 mL, 0.708 mmol), and HATU (26.9 mg, 0.071 mmol) at rt. The reaction was stirred under argon at rt overnight. Purification by reverse phase chromatography afforded Example II-3 (10.6 mg, 66%). LC-MS (ESI) m/z 408.1[M+H]+; XH NMR (500MHz, DMSO-d6) δ 9.10 (d, J=7.7 Hz, IH), 8.61 (d, J=5.2 Hz, IH), 8.53 (s, IH), 8.13 (d, J=4.7 Hz, IH), 8.06 (d, J=8.0 Hz, IH), 7.87 (d, J=5.2 Hz, IH), 7.66 (dd, J=8.1, 1.5 Hz, IH), 7.59 (d, J=1.4 Hz, IH), 7.47 (dt, J=6.0, 2.9 Hz, 2H), 7.38 - 7.30 (m, 2H), 5.92 (d, J=7.7 Hz, IH), 5.26 (s, 2H), 2.65 (d, J=4.7 Hz, 3H); Analytical HPLC RT E: 0.96 min, F: 1.32 min.
The compounds listed in Table II were prepared following the similar procedures described in Examples II- 1 to II-3.
Table II
Figure imgf000191_0001
Figure imgf000191_0002
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
xample III- 1 : Methyl 3-((5H-chromeno[3,4-c]pyridine-8-carboxamido)methyl)benzoate
Figure imgf000196_0001
Example III- 1 was prepared by following a similar procedure as described in Example 1-1 by replacing (R)-l-(3-methoxyphenyl)ethanamine with methyl 3- (aminomethyl)benzoate, HC1 salt. LC-MS (ESI) m/z: 375.1 [M+H]+; XH NMR (400MHz, CD3OD) δ 8.79 (d, J=6.2 Hz, 1H), 8.76 (s, 1H), 8.41 (d, J=6.2 Hz, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.07 - 8.02 (m, 1H), 7.94 (dt, J=7.8, 1.4 Hz, 1H), 7.71 (dd, J=8.3, 1.7 Hz, 1H), 7.63 (dd, J=7.7, 0.7 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.51 - 7.44 (m, 1H), 5.43 (s, 2H), 4.68 - 4.63 (m, 2H), 3.91 (s, 3H); Analytical HPLC RT A: 4.70 min, B: 5.10 min.
Example III-2: 3-((5H-Chromeno[3,4-c]pyridine-8-carboxamido)methyl)benzoic acid
Figure imgf000196_0002
To a suspension of Example III-l (40 mg, 0.107 mmol) (estimated weight) in EtOH (3 mL) was added NaOH (IN, 0.855 mL, 0.855 mmol) at rt. After stirred under argon for 2.5 h, the reaction was neutralized with 6N HC1 to pH ~8. Purification by reverse phase chromatography afforded Example III-2 as white solid (40 mg, 77%). LC- MS (ESI) m/z: 361.0[M+H]+; ¾ NMR (400MHz, CD3OD) δ 8.74 (d, J=6.2 Hz, 1H), 8.70 (s, 1H), 8.30 (d, J=5.9 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.98 - 7.89 (m, 1H), 7.69 (dd, J=8.3, 1.7 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.51 - 7.42 (m, 1H), 5.39 (s, 2H), 4.65 (d, J=4.4 Hz, 2H); Analytical HPLC RT A: 3.98 min, B: 4.14 min.
Example III-3 : N-(3-(Methylcarbamoyl)benzyl)-5H-chromeno[3,4-c]pyridine-8- carboxamide
Figure imgf000196_0003
To a solution of Example III-2 (12 mg, 0.025 mmol) in DMF (1 mL) were added methanamine hydrochloride (17.08 mg, 0.253 mmol), DIEA (0.053 mL, 0.304 mmol), and HATU (17.31 mg, 0.046 mmol) at rt. The reaction was stirred under argon at rt for 3 h. Purification by reverse phase chromatography afforded Example III-3 as white solid (6.7 mg, 70%). LC-MS (ESI) m/z: 374.0[M+H]+; ¾ NMR (500MHz, DMSO-d6) δ 9.20 (t, J=5.9 Hz, 1H), 8.71 - 8.39 (m, 3H), 8.09 (d, J=8.3 Hz, 1H), 7.88 (d, J=5.2 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.54 (d, J=l. l Hz, 1H), 7.49 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 5.27 (s, 2H), 4.52 (d, J=5.8 Hz, 2H), 2.77 (d, J=4.7 Hz, 3H); Analytical HPLC RT E: 0.93 min, F: 1.15 min.
The compounds listed in Table III were prepared by following the similar procedure as described in Examples III-l to III-3.
Table III
Figure imgf000198_0001
Figure imgf000198_0002
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Example IV- 1: Ethyl 2-(3-((5H-chromeno[3,4-c]pyridine-8- carboxamido)methyl)phenyl)thiazole-4-carboxylate
Figure imgf000206_0001
To a solution of Intermediate 5 (47 mg, 0.106 mmol) in dioxane (1.2 mL) and H2O (0.324 mL) were added ethyl 2-bromothiazole-4-carboxylate (25.09 mg, 0.106 mmol), K3PO4 (56.4 mg, 0.266 mmol) and XPhos-G2-PreCat (4.19 mg, 5.31 μιηοΐ). The reaction was heated with microwave at 140 °C for 15 min. The solvent was removed. Purification by reverse phase chromatography afforded Example IV- 1 as white solid (21 mg, 41%). LC-MS (ESI) m/z: 472.2[M+H]+; XH NMR (500MHz, DMSO-d6) δ 9.25 (br. s., IH), 8.67 - 8.46 (m, 3H), 8.13 - 7.80 (m, 4H), 7.71 - 7.43 (m, 5H), 5.27 (br. s., 2H), 4.57 (br. s., 2H), 4.33 (br. s., 2H), 1.31 (br. s., 3H); Analytical HPLC RT E: 1.28 min, F: 1.59 min. -2: 2-(3-((5H-Chromeno[3,4-c]pyridine-8-carboxamido)
Figure imgf000206_0002
Example IV-2 was prepared by following a similar procedure as described in Example III-2. LC-MS (ESI) m/z: 444.0[M+H]+; XH NMR (500MHz, DMSO-d6) δ 9.25 (t, J=6.1 Hz, IH), 8.63 (d, J=5.2 Hz, IH), 8.54 (s, IH), 8.49 (s, IH), 8.10 (d, J=8.3 Hz, IH), 7.97 (s, IH), 7.89 (d, J=5.2 Hz, IH), 7.86 (dt, J=6.7, 1.9 Hz, IH), 7.66 (dd, J=8.0, 1.7 Hz, IH), 7.55 (d, J=1.7 Hz, IH), 7.49-53 (m, 2H), 5.28 (s, 2H), 4.58 (d, J=6.1 Hz, 2H); Analytical HPLC RT E: 1.13 min, F: 1.07 min.
The compounds listed in Table IV were prepared by following the similar procedures as described in Examples IV- 1 and IV-2. Table IV
Figure imgf000207_0001
Figure imgf000207_0002
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Example V-l: Methyl 3-((5-methyl-5H-chromeno[3,4-c]pyridine-8- carboxamido)methyl)benzoate
Figure imgf000216_0001
Example V-l was prepared by following the similar procedure as described in Example I- 1 by replacing Intermediate 1 with Intermediate 4. LC-MS (ESI) m/z:
389.0[M+H]+; 'H NMR (400MHZ, CD3OD) δ 8.57 (d, J=5.3 Hz, IH), 8.46 (s, IH), 8.08 8.00 (m, 2H), 7.98 - 7.91 (m, IH), 7.85 (d, J=5.3 Hz, IH), 7.68 - 7.55 (m, 2H), 7.54 - 7.42 (m, 2H), 5.49 (q, J=6.6 Hz, IH), 4.64 (s, 2H), 3.91 (s, 3H), 1.65 (d, J=6.6 Hz, 3H); Analytical HPLC RT A: 4.94 min, B: 5.40 min.
Example V-2: 3-((5-Methyl-5H-chromeno[3,4-c]pyridine-8-carboxamido)
methyl)benzoic acid
Figure imgf000216_0002
Example V-2 was prepared by following the similar procedure as described in Example III-2 using Example V-l . LC-MS (ESI) m/z: 375.0[M+H]+; XH NMR (400MHz, CD3OD) δ 8.73 (d, J=5.9 Hz, IH), 8.68 (s, IH), 8.28 (d, J=6.2 Hz, IH), 8.16 (d, J=8.1 Hz, IH), 8.05 (s, IH), 7.95 (dd, J=7.7, 1.3 Hz, IH), 7.68 (dd, J=8.3, 1.7 Hz, IH), 7.62 (d, J=7.7 Hz, IH), 7.57 (d, J=1.8 Hz, IH), 7.51 - 7.43 (m, IH), 5.60 (q, J=6.6 Hz, IH), 4.70 - 4.63 (m, 2H), 1.73 (d, J=6.6 Hz, 3H); Analytical HPLC RT A: 4.10 min, B: 4.35 min.
Example V-3 : N-(3-(2-Hydroxy-2-methylpropylcarbamoyl)benzyl)-5-methyl-5H-
Figure imgf000216_0003
To a solution of V-2 (10 mg, 0.020 mmol) in DMF (1 mL) were added l-amino-2- methylpropan-2-ol (9.13 mg, 0.102 mmol), DIEA (0.036 mL, 0.205 mmol) and HATU (14.01 mg, 0.037 mmol) at rt. The reaction was stirred under argon at rt for 1.5 h.
Purification by reverse phase chromatography afforded Example V-3 as white solid (9.0 mg, 98%). LC-MS (ESI) m/z: 446.1 [M+H]+; XH NMR (500MHz, DMSO-d6) 5 9.18 (br. s., 1H), 8.61 (d, J=4.7 Hz, 1H), 8.54 (s, 1H), 8.21 (br. s., 1H), 8.09 (d, J=8.0 Hz, 1H), 7.88 (d, J=5.0 Hz, 1H), 7.83 (s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.50 - 7.45 (m, 1H), 7.45 - 7.38 (m, 1H), 5.52 (q, J=6.2 Hz, 1H), 4.62 - 4.47 (m, 3H), 3.25 (d, J=5.8 Hz, 2H), 1.58 (d, J=6.3 Hz, 3H), 1.10 (s, 6H); Analytical HPLC RT E: 0.99 min, F: 1.27 min.
The compounds listed in Table V were prepared by following the similar procedures as described in Examples V-l to V-3.
Table V
Figure imgf000218_0001
Figure imgf000218_0002
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Example VI- 1: (R)-N-(l-Phenylethyl)-6H-isochromeno[3,4-c]pyridine-8-carboxamide
Figure imgf000223_0001
To a solution of Intermediate 3 (15 mg, 0.066 mmol) in DMF (1 mL) were added (R)-l-phenylethanamine (8.0 mg, 0.066 mmol), DIEA (0.058 mL, 0.330 mmol) and HATU (30.1 mg, 0.079 mmol) at rt. The reaction was stirred under argon at rt for lhr. Purification by reverse phase chromatography afforded Example VI- 1 as white solid (9.4 mg 42%). LC-MS (ESI) m/z 331.15 [M+H]+; 'H NMR (500MHZ, DMSO-d6) δ 8.93 (d, J=8.0 Hz, IH), 8.33 (s, IH), 8.30 (d, J=5.0 Hz, IH), 8.06 (d, J=8.0 Hz, IH), 7.96 (dd, J=8.3, 1.7 Hz, IH), 7.92 (d, J=5.0 Hz, IH), 7.84 (s, IH), 7.40 (d, J=7.2 Hz, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.25 - 7.20 (m, IH), 5.31 (s, 2H), 5.18 (quin, J=7.3 Hz, IH), 1.49 (d, J=6.9 Hz, 3H). Analytical HPLC RT E: 1.17 min; F: 1.53 min.
Example VI-2: (S)-N-(2 -Amino- 1 -phenylethyl)-6H-isochromeno[3,4-c]pyridine-8- carboxamide
Figure imgf000223_0002
Example VI-2a: ( -2-((ter?-Butoxycarbonyl)amino)-2-phenylethyl methanesulfonate
BocHN
Figure imgf000223_0003
To a solution of (S)-tert-butyl (2-hydroxy-l-phenylethyl)carbamate (3.45 g, 14.54 mmol) in DCM (40 mL) were added TEA (3.04 mL, 21.81 mmol) and methanesulfonyl chloride (1.246 mL, 15.99 mmol) at -5 °C. The reaction was stirred under argon at -5 °C for 2 h. The reaction mixture was diluted with DCM, washed with 1M HC1, sat aHC03 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. After dried in vacuo, VI-2a was obtained as white solid (4.59g, 100%). LC-MS (ESI) m/z: 316.0 [M+H]+; 'H NMR (400MHZ, CDC13) δ 7.43 - 7.36 (m, 2H), 7.36 - 7.29 (m, 3H), 5.14 (br. s., 1H), 5.02 (br. s., 1H), 4.55 - 4.34 (m, 2H), 2.89 (s, 3H), 1.45 (s, 9H). Example -2b: (S)-tert-Butyl (2-azido-l-phenylethyl)carbamate
Figure imgf000224_0001
To a solution of VI-2a (4.59 g, 14.55 mmol) in DMF (20 mL) was added NaN3 (1.892 g, 29.1 mmol) at rt. The reaction was stirred under argon at 65 °C for 3 h. The reaction was cooled to rt and diluted with water. The white precipitate formed was collected by filtration and was further washed with water, then was dried in vacuo to afford VI-2b as white solid (3.01 g, 79%). LC-MS (ESI) m/z: 263.1 [M+H]+; 1H NMR (400MHz, CDCI3) δ 7.43 - 7.35 (m, 2H), 7.35 - 7.29 (m, 3H), 5.05 (br. s., 1H), 4.88 (br. s., 1H), 3.76 - 3.52 (m, 2H), 1.45 (s, 9H). Example VI-2c: (S)-2 henylethanamine, TFA salt
BocHN
Figure imgf000224_0002
To a solution of VI-2b (295 mg, 1.125 mmol) in DCM (3 mL) was added TFA (1 mL) at rt. The reaction was stirred under argon at rt for 2 h. The solvent was removed and the resulted residue was dried in vacuo to give VI2-C as white solid (311 mg, 100%). LC- MS (ESI) m/z: 163.1 [M+H]+.
Example VI-2d: (S)-N-(2-Azido-l-phenylethyl)-6H-isochromeno[3,4-c]pyridine-8-
Figure imgf000224_0003
To a solution of Intermediate 2 (30 mg, 0.132 mmol) in DMF (1 mL) were added VI-2c (36.5 mg, 0.132 mmol), DIEA (0.115 mL, 0.660 mmol) and HATU (60.2 mg, 0.158 mmol) at rt. The reaction was stirred under argon at rt for 1.5 h. The crude product was purified by reverse phase chromatography to give VI-2d as white solid (22mg, 34.3%). LC-MS (ESI) m/z: 372.1 [M+H]+; XH NMR (400MHz, CD3OD) δ 8.54 (s, 1H), 8.47 - 8.43 (m, 1H), 8.42 - 8.37 (m, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.02 (dd, J=8.1, 1.8 Hz, 1H), 7.83 (d, J=0.9 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.41 - 7.35 (m, 2H), 7.34 - 7.28 (m, 1H), 5.51 (s, 2H), 5.41 - 5.29 (m, 1H), 3.83 - 3.65 (m, 2H). Example VI-2:
Figure imgf000225_0001
To a solution of VI-2d (22 mg, 0.045 mmol) in MeOH (3 mL) was added catalytic amount of 5% Pd/C. The reaction was stirred under a hydrogen balloon at rt for 2 h. The catalyst was filtered and the solvent was removed from the filtrate to afford Example VI- 2 as white solid (13.3 mg, 82%). LC-MS (ESI) m/z: 346.1 [M+H]+; ¾ NMR (400MHz, CD3OD) δ 8.28 (s, 1H), 8.26 (d, J=5.1 Hz, 1H), 8.02 (s, 2H), 7.91 - 7.83 (m, 2H), 7.54 - 7.49 (m, 2H), 7.45 (t, J=7.5 Hz, 2H), 7.41 - 7.35 (m, 1H), 5.50 (dd, J=9.7, 4.6 Hz, 1H), 5.31 (s, 2H), 3.56 - 3.41 (m, 2H); Analytical HPLC RT A: 5.14 min, B: 5.67 min. Example VI-3: (±)-N-(l-(6-Methoxypyridin-2-yl)ethyl)-6H-isochromeno[3,4-c]pyridine- -carboxamide
Figure imgf000225_0002
Example VI-3 a: (R,E)-N-((6-Methoxypyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide
Figure imgf000226_0001
To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (l.Og, 8.25 mmol) and Cs2C03 (4.03 g, 12.38 mmol) in DCM (15 mL) was added a solution of 6- methoxypicolinaldehyde (1.092 mL, 9.08 mmol) in DCM (2 mL) dropwise. The solution was then stirred at rt for 5 h. The solid was filtered and solvent was removed. The crude product was purified by normal phase chromatography to provide VI-3a as clear colorless oil (1.91 g, 96%). LC-MS (ESI) m/z: 241.0 [M+H]+; 'H NMR (400MHZ, CDCI3) δ 8.59 (s, 1H), 7.72 - 7.58 (m, 2H), 6.85 (dd, J=7.9, 1.1 Hz, 1H), 3.99 (s, 3H), 1.29 (s, 9H). Example VI-3b: (R)-N-(l-(6-Methoxypyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
Figure imgf000226_0002
To a solution of VI-3a (650 mg, 2.70 mmol) in THF (6 mL) was added methylmagnesium bromide (1.4 M in toluene, 2.90 mL, 4.06 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for 2 h and then was warmed up to rt. After stirred for another 30 min, it was cooled to 0 °C and NH4C1 solution was carefully added. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography. Two close peaks of two diastereomers were collected and combined. After removal of solvent, VI-3b was obtained as clear colorless oil (578 mg, 83%). LC-MS (ESI) m/z: 257.0 [M+H]+; XH NMR (400MHz, CDC13) δ 7.53 (dt, J=8.3, 7.1 Hz, 2H), 6.86 (d, J=7.3 Hz, 1H), 6.82 (d, J=7.0 Hz, 1H), 6.62 (d, J=8.1 Hz, 2H), 4.83 (br. d, J=4.6 Hz, NH) 4.59 - 4.44 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 1.60 (d, J=6.8 Hz, 3H), 1.50 (d, J=6.6 Hz, 3H), 1.26 (s, 6H), 1.21 (s, 6H). Example VI- -(6-Methoxypyridin-2-yl)ethanamine, 2 HC1
Figure imgf000226_0003
To a solution of VI-3b (578 mg, 2.255 mmol) in MeOH (5 mL) was added HC1 (4 M in dioxane, 2.818 mL, 11.27 mmol) at RT. The reaction was stirred under argon at rt for 2 h. The solvent was removed to give VI-3c as white solid (520 mg, 100%). LC-MS (ESI) m/z: 153.0[M+H]+.
Example VI-3 :
Figure imgf000227_0001
Example VI-3 was prepared by following a similar procedure as described in VI- 1 by replacing (R)-l-phenylethanamine with VI-3c. LC-MS (ESI) m/z: 362.15[M+H]+; ¾ NMR (500MHz, DMSO-d6) δ 8.87 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.00 (dd, J=8.1, 1.8 Hz, 1H), 7.94 (d, J=5.2 Hz, 1H), 7.87 (d, J=l.l Hz, 1H), 7.66 (dd, J=8.1, 7.6 Hz, 1H), 6.98 (d, J=7.4 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.32 (s, 2H), 5.12 (quin, J=7.2 Hz, 1H), 3.87 (s, 3H), 1.52 (d, J=7.2 Hz, 3H); Analytical HPLC RT E: 1.12 min, F: 1.59 min.
Example VI-4: N-((3 S,4R)-4-Phenylpyrrolidin-3-yl)-6H-isochromeno[3,4-c]pyridine-8- carboxamide
Figure imgf000227_0002
Amide coupling was carried out by following a similar procedure as described in Example VI- 1 by replacing (R)-l-phenylethanamine with (3S,4R)-tert-butyl 3-amino-4- phenylpyrrolidine-l-carboxylate. Thus obtained intermediate was treated with TFA in DCM to provide Example VI-4 as white solid after reverse phase chromatography purification. LC-MS (ESI) m/z: 372.20 [M+H]+; 'H NMR (500MHZ, DMSO-d6) δ 8.80 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.3 1 (d, J=5.0 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.78 (s, 1H), 7.41 - 7.37 (m, 2H), 7.36 - 7.31 (m, 2H), 7.28 - 7.22 (m, 1H), 5.3 1 (s, 2H), 4.61 (quin, J=7.7 Hz, 1H), 3.61 - 3.56 (m, 1H), 3.47 (dd, J=17.6, 9.4 Hz, IH), 3.08 (t, J=10.3 Hz, IH), 2.98 (dd, J=l 1.1, 7.6 Hz, IH); Analytical HPLC RT E: 0.92 min, F: 1.20 min.
The compounds listed in Table VI were prepared by following the similar procedure as described in Example VI- 1.
Table VI
Figure imgf000229_0001
Figure imgf000229_0002
Figure imgf000230_0001
Figure imgf000231_0001
Example VII- 1 : Methyl 3-((6H-isochromeno[3,4-c]pyridine-8- carboxamido)methyl)benzoate
Figure imgf000232_0001
Example VII- 1 was prepared by following a similar procedure as described in VI- 1 by replacing (R)-l-phenylethanamine with methyl 3-(aminomethyl)benzoate, HCl salt. LC-MS (ESI) m/z: 375.20[M+H]+; 'H NMR (500MHZ, DMSO-d6) δ 9.25 (t, J=5.9 Hz, IH), 8.40 (s, IH), 8.35 (d, J=5.0 Hz, IH), 8.11 (d, J=8.3 Hz, IH), 8.01 (d, J=5.2 Hz, IH), 7.98 (dd, J=8.0, 1.7 Hz, IH), 7.94 (s, IH), 7.88 - 7.83 (m, 2H), 7.62 (d, J=7.7 Hz, IH), 7.53 - 7.47 (m, IH), 5.35 (s, 2H), 4.56 (d, J=6.1 Hz, 2H), 3.85 (s, 3H). Analytical HPLC RT E: 1.19 min, F: 1.49 min.
Example VII-2: 3-((6H-Isochromeno[3,4-c]pyridine-8-carboxamido)methyl)benzoic acid
Figure imgf000232_0002
To a solution of Example VII-1 (220 mg, 0.588 mmol) in THF (5 mL) and H20 (2 mL) was added LiOH (42.2 mg, 1.763 mmol) at rt. The reaction was stirred under argon at rt for 4 h. The solvent was removed. Reverse phase purification gave VII-2 as white solid (200 mg, 94%). LC-MS (ESI) m/z: 361.12 [M+H]+; XH NMR (500MHz, DMSO-d6) δ 9.22 (t, J=5.9 Hz, IH), 8.33 (s, IH), 8.30 (d, J=5.2 Hz, IH), 8.08 (d, J=8.3 Hz, IH), 8.00 - 7.94 (m, IH), 7.91 (d, J=3.9 Hz, 2H), 7.86 (s, IH), 7.82 (d, J=7.7 Hz, IH), 7.56 (d, J=7.7 Hz, IH), 7.48 - 7.41 (m, IH), 5.31 (s, 2H), 4.55 (d, J=5.8 Hz, 2H); Analytical HPLC RT E: 0.96 min, F: 0.96 min.
Example VII-3: N-(3-((2-Hydroxy-2-methylpropyl)carbamoyl)bi
-c]pyridine-8-carboxamide
Figure imgf000232_0003
To a solution of VII-2 (30 mg, 0.083 mmol) in DMF (1.5 mL) were added 1- amino-2-methylpropan-2-ol (14.84 mg, 0.166 mmol), DIEA (0.044 mL, 0.250 mmol) and HATU (38.0 mg, 0.100 mmol) at rt. The reaction was stirred under argon at rt for 2 h. The crude product was purified by reverse phase chromatography to afford VII-3 as white solid (20.6 mg, 45%). LC-MS (ESI) m/z: 432.2 [M+H]+; XH NMR (400MHz, DMSO-d6) δ 9.22 (t, J=5.9 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J=5.3 Hz, 1H), 8.20 (t, J=5.9 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 8.09 (d, J=5.3 Hz, 1H), 8.00 (dd, J=8.1, 1.8 Hz, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.46 - 7.40 (m, 1H), 5.37 (s, 2H), 4.55 (d, J=5.9 Hz, 2H), 3.25 (d, J=6.2 Hz, 2H), 1.10 (s, 6H); Analytical HPLC RT A: 3.56 min, B: 3.72 min.
Example VII-4: N-(3-(Ethylcarbamoyl)-4-fluorobenzyl)-6H-isochromeno[3,4-c]pyridine- -carboxamide
Figure imgf000233_0001
Example VII-4 was prepared by following a similar procedure as described in
VII- 1, VII-2 and VII-3 by replacing methyl 3-(aminomethyl)benzoate, HC1 salt with Intermediate 9 in Example VII- 1. LC-MS (ESI) m/z: 406.20 [M+H]+; ¾ NMR (500MHz, DMSO-d6) δ 9.19 (t, J=5.9 Hz, 1H), 8.33 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 8.27 (br. s., 1H), 8.07 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.91 (d, J=5.0 Hz, 1H), 7.84 (s, 1H), 7.57 (dd, J=6.9, 2.2 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.23 (dd, J=10.3, 8.7 Hz, 1H), 5.31 (s, 2H), 4.49 (d, J=6.1 Hz, 2H), 3.28 - 3.23 (m, 2H), 1.10 (t, J=7.2 Hz, 3H); Analytical HPLC RT E: 1.06 min, F: 1.33 min.
The compounds listed in Table VII were prepared by following the similar procedure as described in example Examples VII- 1 to VII-4. Table VII
Figure imgf000234_0001
Figure imgf000234_0002
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Example VIII- 1: Methyl 3-((6-ethyl-6H-isochromeno[3,4-c]pyridine-8- carboxamido)methyl)benzoate
Figure imgf000238_0001
Example VIII- 1 was prepared by following the similar procedure as described in Example III- 1 using Intermediate 7 to replace Intermediate 1. LC-MS (ESI) m/z:
40.3.1 [M+H]+; ¾ NMR (400MHz, CD3OD) δ 8.25 (s, 1H), 8.21 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 8.03 - 7.98 (m, 1H), 7.97 - 7.89 (m, 2H), 7.85 (d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.50 - 7.42 (m, 1H), 5.28 (dd, J=8.8, 4.6 Hz, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 1.97 - 1.74 (m, 2H), 1.06 (t, J=7.4 Hz, 3H); Analytical HPLC RT A: 5.38 min, B: 5.91min.
Example VIII-2: 3-((6-Ethyl-6H-isochromeno[3,4-c]pyridine-8- carboxamido)methyl)benzoic acid
Example VIII-2 was prepared by following the similar procedure as described in
Example III-2 using Example VIII- 1 to replace Example III- 1. LC-MS (ESI) m/z:
389.0[M+H]+; 'H NMR (400MHZ, CD3OD) δ 8.57 (s, 1H), 8.43 (s, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.97 - 7.90 (m, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.62 (dd, J=7.7, 0.4 Hz, 1H), 7.51 - 7.41 (m, 1H), 5.54 (dd, J=8.6, 4.6 Hz, 1H), 4.66 (s, 2H), 2.08 - 1.82 (m, 2H), 1.09 (t, J=7.3 Hz, 3H); Analytical HPLC RT A: 4.49 min, B: 4.86 min.
Example VIII-3 : 6-Ethyl-N-(3 -(2 -hydroxy -2-methylpropylcarbamoyl)benzyl)-6H-
Figure imgf000238_0003
Example VIII-3 was prepared by following the similar procedure as described in Example III-3 using Example VIII-2 to replace Example III-2 to couple with l-amino-2- methylpropan-2-ol. LC-MS (ESI) m/z: 460.1[M+H]+; ¾ NMR (500MHz, DMSO-d6) δ 9.21 (t, J=5.8 Hz, IH), 8.33 (s, IH), 8.28 (d, J=5.2 Hz, IH), 8.24 (t, J=5.9 Hz, IH), 8.09 (d, J=8.0 Hz, IH), 7.97 (d, J=8.3 Hz, IH), 7.92 (d, J=5.2 Hz, IH), 7.83 (s, 2H), 7.75 (d, J=7.7 Hz, IH), 7.52 - 7.46 (m, IH), 7.46 - 7.39 (m, IH), 5.35 (dd, J=8.7, 4.5 Hz, IH), 4.58 - 4.53 (m, 2H), 3.24 (d, J=6.1 Hz, 2H), 1.85 - 1.69 (m, 2H), 1.09 (s, 6H), 0.98 (t, J=7.3 Hz, 3H); Analytical HPLC RT E: 1.08 min, F: 1.42 min.
The compounds listed in Table VIII were prepared by following the similar procedure as described in Example VII-1-3, by using Intermediates 6, 7, 8, 9 and 10.
Table VIII
Figure imgf000240_0001
Figure imgf000240_0002
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Example IX- 1 : (R)-N-(l-Phenylethyl)-6H-isochromeno[4,3-d]pyrimidine-8-carboxamide
Figure imgf000260_0001
Example IX- 1 was prepared by following a similar procedure as described in 1-1 by replacing Intermediate 1 with Intermediate 3. LC-MS (ESI) m/z: 332.10 [M+H]+; XH NMR (500MHz, DMSO-d6) δ 8.99 (d, J=8.0 Hz, IH), 8.89 (s, IH), 8.55 (s, IH), 8.21 (d, J=8.0 Hz, IH), 8.00 (d, J=8.0 Hz, IH), 7.84 (s, IH), 7.43 - 7.38 (m, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.26 - 7.21 (m, IH), 5.46 (s, 2H), 5.18 (quin, J=7.2 Hz, IH), 1.49 (d, J=7.2 Hz, 3H); Analytical HPLC RT E: 1.53 min, F: 1.58 min.
Example IX-2: (S)-N-(2-Amino-l-phenylethyl)-6H-isochromeno[4,3-d]pyrimidine-8- carboxamide
Figure imgf000260_0002
Example IX-2 was prepared by following a similar procedure as described in Example VI-2 by replacing Intermediate 2 with Intermediate 3 in VI-2d. LC-MS (ESI) m/z: 347.1[M+H]+; ¾ NMR (400MHz, CD3OD) δ 8.85 (s, IH), 8.47 (s, IH), 8.35 (d,
J=8.1 Hz, IH), 8.03 (dd, J=8.0, 1.7 Hz, IH), 7.82 (s, IH), 7.53 - 7.43 (m, 4H), 7.42 - 7.38 (m, IH), 5.51 (dd, J=9.2, 5.7 Hz, IH), 5.45 (s, 2H), 3.51 - 3.45 (m, 2H); Analytical HPLC RT A: 7.06 min, F: 7.41 min.
The compounds listed in Table IX were prepared by following the similar procedures as described in Examples IX- 1 and IX-2. Table IX
Figure imgf000261_0001
Figure imgf000261_0002
Figure imgf000262_0001
Figure imgf000263_0001
Example X-l: (R)-N-(l-(4-Fluorophenyl)ethyl)-5-oxo-5H-chromeno[3,4-c]pyridine-8- carboxamide
Figure imgf000264_0001
Example X-l a: Methyl 4-chloronicotinate
Figure imgf000264_0002
To a suspension of the 4-chloronicotinic acid (1.12g, 7.11 mmol) in DCM (10 mL) at rt was added oxalyl chloride (2M in DCM, 8.89 mL, 17.77 mmol) followed by addition of DMF (0.250 mL) dropwise. After stirred for 45 min at rt, the reaction was cooled to 0 °C and quenched with methanol. The crude oil was triturated with EtOAc, and the solid was collected by filtration, which was further washed with hexane and dried to afford X-a as white solid (1.2 g, 98%). LC-MS (ESI) m/z: 171.9[M+H]+; XH NMR (400MHz, DMSO-d6) δ 8.97 (s, IH), 8.70 (d, J=5.5 Hz, IH), 7.72 (d, J=5.5 Hz, IH), 3.91 (s, 3H).
Example X- -Methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile
Figure imgf000264_0003
A mixture of 4-bromo-3-methoxybenzonitrile(lg, 4.72 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.796 g, 7.07 mmol), K3P04 (1.157 g, 11.79 mmol) and PdCl2(dppf) CH2C12 adduct (0.207 g, 0.283 mmol) in dioxane (12 mL) was degassed and then heated at 90 °C for 3 h. The reaction was cooled to rt and was filtered through a pad of CELITE®. The solvent was removed. Normal phase chromatography afforded X-lb as brown oil (1.7 g, 5.76 mmol, 100%). LC-MS (ESI) of the boronic acid m/z: 178.0 [M+H]+. Example X-lc: Methyl 4-(4-cyano-2-methoxyphenyl)nicotinate
Figure imgf000265_0001
To a solution of X-la (1.12g, 6.53 mmol) in dioxane (10 mL) and H2O (2.5 mL) were added X-lb (1.733 g, 7.83 mmol), K3PO4 (3.05 g, 14.36 mmol) and XPhos-G2- PreCat (0.206 g, 0.261 mmol) at rt. The reaction was heated with microwave at 140 °C for 10 min. The solvent was removed. Normal phase chromatography afforded X-lc as pale solid (0.84 g, 48.0%) LC-MS (ESI) m/z: 269.0[M+H]+; 'H NMR (400MHZ, CDCI3) δ 9.14 (s, 1H), 8.80 (d, J=5.1 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.35 - 7.30 (m, 1H), 7.22 (d, J=5.1 Hz, 1H), 7.16 (d, J=1.3 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H).
Example X-ld: 5- -5H-chromeno[3,4-c]pyridine-8-carbonitrile
Figure imgf000265_0002
To a solution of X-lc (123 mg, 0.458 mmol) in DCM (3 mL) at 0 °C was added BBr3 (IM in heptane, 2.751 mL, 2.75 mmol) dropwise. The solution was warmed to rt and stirred overnight. The solvent was removed. Purification by reverse phase chromatography afforded X-ld. LC-MS (ESI) m/z: 223.0[M+H]+.
Example X-le: 5-Oxo-5H-chromeno[3,4-c]pyridine-8-carboxylic acid
Figure imgf000265_0003
A suspension of X-ld (14 mg, 0.042 mmol) in HC1 (aq. 7N, 0.297 ml, 2.082 mmol) was heated at 100 °C in a sealed vial for 8 h. The solvent was removed to afford X-le as solid (10.4 mg, 90%). LC-MS (ESI) m/z: 242.0[M+H]+. xample X- 1 :
Figure imgf000266_0001
To a suspension of X-le (10 mg, 0.036 mmol) in DCM (1 mL) were added (R)-l- (4-fluorophenyl)ethanamine, HC1 salt (6.96 mg, 0.040 mmol), DIEA (0.044 mL, 0.252 mmol) and T3P (0.060 mL, 0.101 mmol) at rt. The reaction was stirred under argon at rt for 1.5 h and then sat over weekend. Purification by reverse phase chromatography afforded Example X-l as white solid (7.2 mg, 51%). LC-MS (ESI) m/z: 363.0[M+H]+; ¾ NMR (500MHz, DMSO-d6) δ 9.39 (s, 1H), 9.11 - 9.02 (m, 2H), 8.55 (d, J=8.0 Hz, 1H), 8.43 (d, J=5.0 Hz, 1H), 7.98 - 7.92 (m, 2H), 7.45 (t, J=6.3 Hz, 2H), 7.16 (t, J=8.3 Hz, 2H), 5.20 (t, J=7.0 Hz, 1H), 1.51 (d, J=6.9 Hz, 3H); Analytical HPLC RT E: 1.50 min, F: 1.59 min.
Example X-2: (R)-5-Oxo-N-(l-phenylethyl)-5H-chromeno[3,4-c]pyridine-8-carboxamide
Figure imgf000266_0002
Example X-2 was prepared by following the similar procedure as described in
Example X-l. LC-MS (ESI) m/z: 345.0[M+H]+; XH NMR (400MHz, CD3OD) δ 9.47 (s, 1H), 8.99 (d, J=5.5 Hz, 1H), 8.44 (d, J=8.1 Hz, 1H), 8.36 (d, J=5.5 Hz, 1H), 7.99 - 7.84 (m, 2H), 7.50 - 7.40 (m, 2H), 7.35 (t, J=7.7 Hz, 2H), 7.30 - 7.21 (m, 1H), 5.37 - 5.21 (m, 1H), 1.61 (d, J=7.0 Hz, 3H); Analytical HPLC RT A: 5.67 min, F: 5.48 min.
Example X-3: (R)-N-(l-(3-Methoxyphenyl)ethyl)-5-oxo-5,6- dihy drobenzo [c] [2 , 7] naphthyridine- 8 -carboxamide
Figure imgf000267_0001
xample X-3a: 4-(2-Amino-4-(methoxycarbonyl)phenyl)nicotinic acid
Figure imgf000267_0002
To a solution of 4-chloronicotinic acid (110 mg, 0.698 mmol) in dioxane (3 mL) were added (2-amino-4-(methoxycarbonyl)phenyl)boronic acid, HCl salt (194 mg, 0.838 mmol), K3PO4 (1.745 mL, 1.745 mmol) and Pd(Ph3P)4 (40.3 mg, 0.035 mmol) at rt. The reaction was heated with microwave at 150 °C for 15 min. The solvent was removed. Purified by reverse phase chromatography afforded X-3a as white solid (85 mg, 24%). LC-MS (ESI) m/z: 273.0[M+H]+.
Example -3b: Methyl 5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-8-carboxylate
Figure imgf000267_0003
To a solution of X-3a (20 mg, 0.040 mmol) in DMF (1.5 mL) were added DIEA (0.035 mL, 0.200 mmol) and HATU (15.20 mg, 0.040 mmol) at rt. The reaction was stirred under argon at RT for 1.5 h. The crude product was purified by reverse phase chromatography to afford X-3b as light yellow solid (9 mg, 61%). LC-MS (ESI) m/z: 255.0[M+H]+; 'H NMR (400MHZ, CD3OD) δ 9.59 (s, IH), 8.95 (d, J=5.9 Hz, IH), 8.58 (d, J=5.9 Hz, IH), 8.54 (d, J=8.6 Hz, IH), 8.06 (d, J=1.3 Hz, IH), 7.99 (dd, J=8.4, 1.5 Hz, IH), 3.99 (s, 3H).
Example X-3c: 5-0x0-5, 6-dihydrobenzo[c][2,7]naphthyridine-8-carboxylic acid
Figure imgf000268_0001
To a solution of X-3b (9 mg, 0.024 mmol) in THF (1.5 mL) and H20 (0.5 mL) was added LiOH (5.85 mg, 0.244 mmol) at rt. The reaction was stirred under argon for 2 h. the solvent was removed to afford X-3c as light yellow solid (5.87 mg, 100%). LC-MS (ESI) m/z: 241.1 [M+H]+.
Example X-3 :
Figure imgf000268_0002
To a solution of X-3c (6 mg, 0.025 mmol) in DMF (1 mL) were added (R)-l-(3- methoxyphenyl)ethanamine (18.88 mg, 0.125 mmol), DIEA (0.044 mL, 0.250 mmol) and
HATU (18.99 mg, 0.050 mmol). The reaction was stirred under argon at rt for 1 h.
Purification by reverse phase chromatography afforded X-3 as white solid (2.5 mg, 26%).
LC-MS (ESI) m/z 374.20 [M+H]+; 'H NMR (500MHZ, DMSO-d6) δ 12.04 (s, 1H), 9.03
(d, J=8.0 Hz, 1H), 8.57 (d, J=8.3 Hz, 1H), 8.54 (br. s., 1H), 7.83 (s, 1H), 7.80 (dd, J=8.5, 1.4 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.01 - 6.95 (m, 2H), 6.81 (dd, J=8.1, 1.8 Hz, 1H), 5.16
(quin, J=7.3 Hz, 1H), 3.75 (s, 3H), 1.48 (d, J=7.2 Hz, 3H); Analytical HPLC RT E: 1.12 min, F: 1.29 min.
Example X-4: (R)-6-(2-(Dimethylamino)ethyl)-N-(l-(3-methoxyphenyl)ethyl)-5-oxo-5,6- dihydrobenzo[c] [2,7]naphthyridine-8-carboxamide
Figure imgf000268_0003
Example X-4a: Methyl 6-(2-(dimethylamino)ethyl)-5-oxo-5,6-dihydrobenzo[c][2,7] naphthyridine-8-carboxylate
Figure imgf000269_0001
To a solution of Intermediate 4a (54 mg, 0.208 mmol) in DCE (1.5 mL) were added l, l-dimethylethane-l,2-diamine (0.046 mL, 0.417 mmol) and acetic acid (0.036 mL, 0.625 mmol). The reaction was stirred under argon at rt for 1 h. and followed by addition of sodium triacetoxyborohydride (93 mg, 0.417 mmol). After stirring at rt for 1.5 h, it was heated at 50 °C for 4 h, and then cooled to rt. To the reaction mixture was added potassium carbonate (17.27 mg, 0.125 mmol) and the mixture was stirred at rt for 1.5 h. LCMS showed the reaction was completed. The solvent was removed. The residue was dissolved in DMF/MeOH/water and purified by reverse phase chromatography to afford X-4a as TFA salt (42.8mg, 37.1%). LCMS (ESI) m/z: 326.1 [M+H]+.
Example X-4b: 6-(2-(Dimethylamino)ethyl)-5-oxo-5,6-dihydrobenzo[c] [2,7]naphthyridine- -carboxylic acid
Figure imgf000269_0002
(IN aq.) (0.527 mL, 0.527 mmol). The reaction was stirred under argon at rt for 2 h. To the reaction mixture was added HC1 ((3.7N) (0.214 mL, 0.790 mmol) to adjust the PH~8. Purification by reverse phase chromatography afforded X-4b as TFA salt (41 mg, 57.7% yield). LC-MS (ESI) m/z: 312.1 [M+H]+
Example X-4:
Figure imgf000270_0001
To a solution of X-4b (17 mg, 0.032 mmol) in DMF (1 mL) were added (R)-l-(3- methoxyphenyl)ethanamine hydrochloride (17.74 mg, 0.095 mmol), DIEA (0.055 mL, 0.315 mmol), and HATU (21.57 mg, 0.057 mmol) at rt. The reaction was stirred under argon at rt overnight. Purification by reverse phase chromatography afforded X-4 as TFA salt (3.0 mg, 4.22 μιηοΐ, 13.39% yield). LC-MS (ESI) m/z: 445.1 [M+H]+; 'H NMR (400MHz, DMSO-d6) δ 9.53 (s, 1H), 9.29 (br. s., 1H), 9.07 (d, J=7.9 Hz, 1H), 9.00 (d, J=5.7 Hz, 1H), 8.74 (d, J=8.6 Hz, 1H), 8.56 (d, J=5.7 Hz, 1H), 8.02 - 7.93 (m, 2H), 7.27 (t, J=8.1 Hz, 1H), 7.01 (d, J=4.2 Hz, 2H), 6.88 - 6.79 (m, 1H), 5.21 (t, J=7.3 Hz, 1H), 4.82 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 3.52 (d, J=5.3 Hz, 2H), 2.97 (d, J=4.2 Hz, 6H), 1.54 (d, J=7.0 Hz, 3H); Analytical HPLC RT A: 7.13 min, B: 7.88 min.
Example X-5: (R)-6-Ethyl-5-oxo-N-(l-phenylethyl)-5,6- dihydrobenzo[c][2,7]naphthyridine-8-carboxamide
Figure imgf000270_0002
Example X-5a: 4-(2-Fluoro-4-(methoxycarbonyl)phenyl)nicotinic acid
Figure imgf000270_0003
To a solution of 4-chloronicotinic acid (580 mg, 3.68 mmol) in dioxane (20 mL) and water (5 mL) were added (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (802 mg, 4.05 mmol), K3P04 (1954 mg, 9.20 mmol) and PdCl2(dppf) (135 mg, 0.184 mmol) at rt. The reaction was stirred under argon at 90 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with H20. Solvent was removed. Purification by reverse phase chromatography afforded X-5a as white solid (150 mg, 15%). LC-MS (ESI) m/z: 276.2 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 13.34 (br. s., 1H), 9.07 (d, J=0.7 Hz, 1H), 8.85 (d, J=5.1 Hz, 1H), 7.89 (dd, J=7.9, 1.5 Hz, 1H), 7.75 (dd, J=10.6, 1.5 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.49 (dd, J=5.1, 0.7 Hz, 1H), 3.90 (s, 3H).
Example X-5b: Methyl 4-(3-(ethylcarbamoyl)pyridin-4-yl)-3-fluorobenzoate
Figure imgf000271_0001
To a solution of X-5a (20 mg, 0.073 mmol) in DMF (1.5 mL) were added ethanamine, HCl (11.85 mg, 0.145 mmol), HATU (41.4 mg, 0.109 mmol) and DIEA (0.1 mL) at rt. The reaction was stirred under argon at rt for 1 hr. Purification by reverse phase chromatography afforded X-5b as white solid (29 mg, 96%). LC-MS (ESI) m/z:
303.1 [M+H]+; 'H NMR (400MHZ, CDC13) δ 9.06 (s, 1H), 8.83 (d, J=5.5 Hz, 1H), 7.98 (dd, J=7.9, 1.5 Hz, 1H), 7.86 (dd, J=10.5, 1.4 Hz, 1H), 7.78 (d, J=5.7 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 6.75 (br. s., 1H), 3.97 (s, 3H), 3.44 - 3.32 (m, 2H), 1.14 (t, J=7.3 Hz, 3H).
Example X-5c: Methyl 6-ethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-8- carboxylate
Figure imgf000271_0002
To a solution of X-5b (29 mg, 0.070 mmol) in THF (3 mL) was added NaH (13.93 mg, 0.348 mmol) at 0 °C. The reaction was stirred under argon at 0 °C for lhr. The reaction was quenched by adding citric acid solution. The reaction mixture was diluted with EtOAc, washed with ¾0 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated to give X-5c as white solid (17 mg, 86%). LC-MS (ESI) m/z: 283.1[M+H]+; 'H NMR (400MHZ, CDC13) δ 9.76 (s, 1H), 8.94 (d, J=5.5 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.15 (d, J=l. l Hz, 1H), 8.06 (d, J=5.5 Hz, 1H), 7.99 (dd, J=8.3, 1.4 Hz, 1H), 4.51 (q, J=7.3 Hz, 2H), 4.02 (s, 3H), 1.46 (t, J=7.2 Hz, 3H).
Example X-5d, Example X-5:
Figure imgf000272_0001
To a solution of X-5c (17 mg, 0.060 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (7.21 mg, 0.301 mmol) at rt. The reaction was stirred under argon for lhr. Solvent was removed to give white solid. To this solid were added (R)-l- phenylethanamine (21.68 mg, 0.179 mmol), DIEA (0.052 mL, 0.298 mmol) and HATU (34.0 mg, 0.089 mmol) at rt. The reaction was stirred under argon for 2 h. Purification by reverse phase chromatography afforded X-5 as white solid (17.4 mg, 78%). LC-MS (ESI) m/z: 372.20[M+H]+; ¾ NMR (500MHz, DMSO-d6) δ 9.52 (br. s., 1H), 9.15 (d, J=7.4 Hz, 1H), 8.97 (br. s., 1H), 8.70 (d, J=8.0 Hz, 1H), 8.52 (br. s., 1H), 8.04 (br. s., 1H), 7.95 (d, J=7.4 Hz, 1H), 7.45 (d, J=6.9 Hz, 2H), 7.37 (br. s., 2H), 7.30 - 7.24 (m, J=6.6 Hz, 1H), 5.32 - 5.21 (m, J=6.5, 6.5 Hz, 1H), 4.47 (d, J=5.8 Hz, 2H), 1.56 (d, J=6.1 Hz, 3H), 1.33 (br. s., 3H); Analytical HPLC RT E: 1.31 min, F: 1.50 min.
Compounds listed in Table XI were prepared by following procedures similar to those described for Example 1-1 and Example VIII-3 using the appropriate intermediates described or purchased from commercial sources. Other coupling reagents than the one described, such as HATU, T3P, BOP, PyBop, and EDC/HOBt, could be used. Table XI
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Example XI-37: Methyl N-(8-{[(lR)-l-phenylethyl]carbamoyl}-6H-isochromeno[3,4- -2-yl)carbamate
Figure imgf000293_0001
Example XI-28 (9.3 mg, 0.020 mmol) was suspended in 2 mL of (¾(¾ and was cooled in an ice bath. To this mixture was added methyl carbonochloridate (7.82 μΐ, 0.101 mmol) and DIEA (0.035 mL, 0.202 mmol). The mixture was stirred at 0 °C for 10 minutes. The solvent was removed. The residue was dissolved in DMF, filtered, and purified by reverse phase HPLC (2.1 mg, 25%). LC-MS (ESI) m/z:404.1 [M+H]+; XH NMR (500MHz, DMSO-d6) δ 9.51 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 8.96 (d, J = 5.2 Hz, 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.52 (d, J = 5.8 Hz, 1H), 7.95 - 7.81 (m, 2H), 7.45 (dd, J = 8.2, 5.8 Hz, 2H), 7.19 - 7.10 (m, 2H), 6.08 - 5.94 (m, 1H), 5.30 - 5.14 (m, 2H), 5.06 (d, J = 15.3 Hz, 3H), 1.52 (d, J = 7.0 Hz, 3H).
Example XI-38: Propan-2-yl N-(8-{[(lR)-l-phenylethyl]carbamoyl} -6H-
Figure imgf000293_0002
Example XI-38 was prepared according to the procedures described for Example XI-37. LC-MS (ESI) m/z: 432.2 [M+H]+; 'H NMR (500MHZ, DMSO-d6) δ 9.97 (s, 1H), 8.96 (d, J = 8.1 Hz, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 8.01 - 7.95 (m, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.45 - 7.39 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.27 - 7.17 (m, 1H), 5.19 (t, J = 7.2 Hz, 1H), 4.94 (dt, J = 12.3, 6.3 Hz, 1H), 2.90 (s, 1H), 2.74 (s, 1H), 1.50 (d, J = 6.7 Hz, 3H), 1.28 (d, J = 6.4 Hz, 6H)
Intermediate 18: Methyl 5-oxo-5,6-dihydrobenzo[c] [2,7]naphthyridine-8-carboxylate
Figure imgf000294_0001
Intermediate 18 -chloronicotinate
Figure imgf000294_0002
To a suspension of 4-chloronicotinic acid (1.1 g, 7.1 mmol) in DCM (10 mL), was added oxalyl chloride (2 M in DCM) (8.9 mL, 18 mmol) followed by addition of DMF (0.25 mL), dropwise. The reaction mixture was stirred at rt for 45 min, cooled to 0 °C, and was quenched with methanol. The solvent was removed. The residue was suspended in EtOAc. White precipitate was filtered, washed with hexane and EtOAc, and dried to afford Intermediate 18A (1.2 g, 98%) as off-white solid. LC-MS (ESI) m/z: 172.0
[M+H]+; XH NMR (400MHz, DMSO-d6) δ 8.97 (s, 1H), 8.70 (d, J = 5.5 Hz, 1H), 7.72 (d, J = 5.5 Hz, 1H), 3.91 (s, 3H).
Intermediate 18:
Figure imgf000294_0003
To a solution of Intermediate 18A (780 mg, 3.9 mmol) in DMF (10 mL), were added (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (750 mg, 3.9 mmol), sodium acetate (1300 mg, 16 mmol), and PdCl2(dppf)-CH2Cl2 adduct (250 mg, 0.31 mmol). The reaction was purged with nitrogen and then was heated in a microwave reactor at 150 °C for 10 min. The reaction mixture was cooled to rt and water (70 mL) was added. The solid formed was filtered, washed with water (3x), ether (5x), and was dried to afford Intermediate 18 (540 mg, 55%) as a tan solid. LC-MS (ESI) m/z: 255.1 [M+H]+; ¾ NMR (400MHz, DMSO-d6) δ 12.06 (br. s., 1H), 9.46 (s, 1H), 8.96 (d, J = 5.3 Hz, 1H), 8.59 (d, J = 8.1 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H).
Intermedi -Oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-8-carboxylic acid
Figure imgf000295_0001
To a suspension of Intermediate 18 (40 mg, 0.13 mmol) in EtOH (1.5 mL), was added NaOH (1 N, 0.38 mL, 0.38 mmol). The reaction mixture was stirred under argon at rt for 1.5 h. To the mixture was added HCl (3.7 N, 0.07 mL, 0.25 mmol) to adjust the pH to ~8. Purification by reverse phase chromatography afforded Intermediate 19 (30 mg, 67%) as a brown solid. LC-MS (ESI) m/z: 241.1 [M+H]+.
Intermediate 20: 6-(2-Methoxyethyl)-5-oxo-5,6-dihydrobenzo[c] [2,7]naphthyridine-8- carboxylic acid
Figure imgf000295_0002
Intermediate 20A: Methyl 6-(2-methoxyethyl)-5-oxo-5,6-dihydrobenzo[c][2,7] naphthyridine-8-carboxylate
Figure imgf000295_0003
To a solution of 18 (70 mg, 0.28 mmol) and l-bromo-2-methoxyethane (120 mg, 0.83 mmol) in THF (2.5 mL), were added potassium tert-butoxide (1 M, 0.29 mL, 0.29 mmol) and magnesium isopropyloxide (94 mg, 0.55 mmol). The reaction was stirred at rt in a sealed tube for 1 h, and then was heated at 70 °C for 6 h. The solvent was removed. The residue was purified by reverse phase chromatography to afford Intermediate 20A (35 mg, 30%) as a yellowish solid. LC-MS (ESI) m/z: 313.1 [M+H]+; 'H NMR (400MHZ, CD3OD) δ 9.61 (s, 1H), 8.94 (d, J = 5.9 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 1.1 Hz, 1H), 8.02 (dd, J = 8.4, 1.3 Hz, 1H), 4.69 (t, J = 5.6 Hz, 2H), 4.01 (s, 3H), 3.84 (t, J = 5.6 Hz, 2H), 3.37 (s, 3H).
Intermediate 20:
Figure imgf000296_0001
(IN, 0.49 mL, 0.49 mmol). The reaction mixture was stirred under argon at rt for 1.5 h. Aqueous HC1 (3.7 N) (0.09 mL, 0.33 mmol) was added to adjust the pH to ~8.
Purification by reverse chromatography afforded Intermediate 20 (31mg, 90%) as yellow solid. LC-MS (ESI) m/z: 299.1 [M+H]+. c acid
Figure imgf000296_0002
NaH (60% suspension, 320 mg, 7.9 mmol) was added to a solution of
Intermediate 18 (500 mg, 1.6 mmol) in DMF (10 mL) at 0 °C, portionwise. The reaction temperature was stirred at 0 °C for 10 min. Allyl bromide (1.4 mL, 16 mmol) was then added dropwise. The ice bath was removed, and the reaction mixture was allowed to warm to rt. The reaction mixture was stirred at rt for 1 h. It was cooled with an ice bath, diluted with EtOAc, and was slowly quenched with water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and concentrated. Purification by normal phase chromatography afforded Intermediate 21A (120 mg, 25%) as an orange solid. LC-MS (ESI) m/z: 295.1 [M+H]+;1H MR (400MHz, CDC13) δ 9.77 (s, 1H), 8.97 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 1.3 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.99 (dd, J = 8.3, 1.4 Hz, 1H), 6.03 (ddt, J = 17.2, 10.5, 5.1 Hz, 1H), 5.31 (dd, J = 10.5, 0.8 Hz, 1H), 5.23 (dd, J = 17.3, 0.8 Hz, 1H), 5.13 - 5.00 (m, 2H), 4.00 (s, 3H). Intermediate 2 -Allyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-8-carboxylic acid
Figure imgf000297_0001
To a suspension of Intermediate 21A (150 mg, 0.50 mmol) in EtOH (3 mL), was added NaOH (1 N, 1.0 mL, 1.0 mmol). The reaction was stirred under argon at rt for 1.5 h. Aqueous HC1 (3.7 N) (0.14 mL, 0.51 mmol) was added to adjust the pH to ~8.
Purification by reverse chromatography afforded Intermediate 21 (120 mg, 85%) as yellow solid. LC-MS (ESI) m/z: 281.0 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 9.52 (s, 1H), 8.98 (d, J = 5.5 Hz, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 6.14 - 5.97 (m, 1H), 5.20 (d, J = 10.6 Hz, 1H), 5.09 - 4.97 (m, 3H).
Example XII-1 : (R)-6-Allyl-N-(l-(4-fluorophenyl)ethyl)-5-oxo-5,6- dihydrobenzo[c][2,7]naphthyridine-8-carboxamide
Figure imgf000298_0001
To a solution of Intermediate 21 (110 mg, 0.39 mmol) in DMF (3 mL) were added (R)-l-(4-fluorophenyl)ethanamine (1 10 mg, 0.78 mmol), HATU (250 mg, 0.67 mmol), and DIEA (0.34 mL, 1.9 mmol). The reaction mixture was stirred under argon at rt for 2 h. The reaction was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, and purified by normal phase chromatography to afford Example XII-1 (210 mg, 91%) as a foam. LC-MS (ESI) m/z: 402.2 [M+H]+; XH NMR (500MHz, DMSO-d6) 5 9.51 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 8.96 (d, J = 5.2 Hz, 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.52 (d, J = 5.8 Hz, 1H), 7.95 - 7.81 (m, 2H), 7.45 (dd, J = 8.2, 5.8 Hz, 2H), 7.19 - 7.10 (m, 2H), 6.08 - 5.94 (m, 1H), 5.30 - 5.14 (m, 2H), 5.06 (d, J = 15.3 Hz, 3H), 1.52 (d, J = 7.0 Hz, 3H). Example XII-2: (R)-N-(l-(4-Fluorophenyl)ethyl)-5-oxo-6-(2-(pyrrolidin-l-yl)ethyl)-5,6- dihydrobenzo[c][2,7]naphthyridine-8-carboxamide
Figure imgf000298_0002
Intermediate XII-2A: (R)-N-(l-(4-Fluorophenyl)ethyl)-5-oxo-6-(2-oxoethyl)-5,6- dihydrobenzo[c] [2,7]naphthyridine-8-carboxamide
Figure imgf000299_0001
To a solution of Example XII- 1 (50 mg, 0.13 mmol) in dioxane (5 mL) and water (0.5 mL), were added sodium periodate (80 mg, 0.37 mmol) and osmium tetroxide (4% in water, 0.016 mL, 2.5 μιηοΐ). The reaction was stirred under argon at rt overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate and concentrated. Purification by normal phase chromatography afforded Intermediate XII-2A (23 mg, 46%) as film of solid. LC-MS (ESI) m/z: 404.1 [M+H]+.
Example XII-2:
Figure imgf000299_0002
To a suspension of Intermediate XII-2A (23 mg, 0.06 mmol) in DCE (3 mL), were added pyrrolidine (20 mg, 0.28 mmol) and AcOH (0.07 mL, 1.1 mmol). The reaction mixture was stirred at rt for 20 min, and then sodium triacetoxyborohydride (85 mg, 0.40 mmol) was added in portions. The reaction was stirred under argon at rt for 30 min. The solvent was removed. The residue was dissolved in MeOH, and was purified by reverse chromatography to afford Example XII-2 (5.1 mg, 19%) as a solid. LC-MS (ESI) m/z: 459.2 [M+H]+; XH NMR (500MHz, DMSO-d6) δ 9.50 (br. s., 1H), 9.13 (d, J = 7.3 Hz, 1H), 8.96 (d, J = 4.6 Hz, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.50 (d, J = 4.6 Hz, 1H), 7.96 - 7.90 (m,lH), 7.47 (br. s., 2H), 7.27 - 7.12 (m, 3H), 6.64 (br. s., 1H), 5.39 - 5.27 (m, 2H), 5.25 - 5.17 (m, 1H), 3.06 (m, 2H),.2.04 - 1.77 (m, 10H), 1.53 (d, J = 6.7 Hz, 3H).
Example XII-3 : (R)-N-(l -(4-Fluorophenyl)ethyl)-6-(2-hydroxyethyl)-5- dihydrobenzo[c][2,7]naphthyridine-8-carboxamide
Figure imgf000300_0001
To a solution of Intermediate XII-2A (10 mg, 0.03 mmol) in MeOH (2 mL), was added NaBH4 (9.4 mg, 0.25 mmol). The reaction mixture was stirred under argon at rt for 50 min. Purification by reverse phase chromatography afforded Example XII-3. LC-MS (ESI) m/z: 406.1 [M+H] ]+; 'H NMR (500MHZ, DMSO-d6) δ 9.45 (br. s., 1H), 9.13 (d, J = 7.6 Hz, 1H), 8.90 (br. s., 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.42 (d, J = 4.9 Hz, 1H), 8.10 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 6.6 Hz, 2H), 7.14 (t, J = 8.7 Hz, 2H), 5.19 (t, J = 7.0 Hz, 1H), 4.47 (br. s., 2H), 3.70 - 3.60 (m, 3H), 1.51 (d, J = 6.7 Hz, 3H).
Compounds listed in Table XII were prepared by following procedures similar to those described for Example XII- 1 using the appropriate intermediates described or purchased from commercial sources. Other coupling reagents, such as HATU, T3P, BOP, PyBop, and EDC/HOBt, could be instead of the one described.
Table XII
Figure imgf000301_0001
Figure imgf000302_0001
Example XIII- 1 : N-(3-Methoxybenzyl)-5-methyl-6-oxo-5,6- dihydrobenzo[c][l,7]naphthyridine-8-carboxamide
Figure imgf000303_0001
Example XIII- -Hydroxy-5-(methoxycarbonyl)benzoic acid
Figure imgf000303_0002
Pyridine (140 ml, 1700 mmol) was added to dimethyl 4-hydroxyisophthalate (10 g, 48mmol) and the mixture was refluxed for 17 h. The mixture was then concentrated in vacuo, and the residue was acidified with 1.5 N HC1/H20 (1 :1) (120 mL). The resulting precipitate was collected by filtration, washed with water (3 x 20 mL), and dried in vacuo to give a brown solid, which was azeotroped with toluene to give Example XIII- 1 A as brown solid (9.0 g. 92%). LC-MS (ESI) m/z: 194.9 [M-H]".
Exam - IB: 3-tert-Butyl 1 -methyl 4-hydroxyisophthalate
Figure imgf000303_0003
To a solution of Example XIII-1A (5.0 g, 26 mmol) in toluene (100 mL), was added 1 , 1 -di-tert-butoxyltrimethylamine (25 mL, 100 mmol). The reaction was refluxed for 1.5 h. The reaction was cooled to rt, diluted with toluene (30 mL), washed with 10% percent citric acid solution (2 x 50 mL) and dried over Na2S04. The solvent was evaporated under reduced pressure to give a yellow liquid, which was purified by normal phase chromatography to give Example XIII- IB as a white solid (3.2 g, 48%). LC-MS (ESI) m/z: 251.0 [M-H]".
Example XIII- 1C: 3-tert-Butyl 1 -methyl 4-(((trifluoromethyl)sulfonyl)oxy)isophthalate
Figure imgf000304_0001
To a solution of Example XIII-1B (3.2 g, 13mmol) and pyridine (5.2 mL, 64 mmol) in DCM (70 mL), was added Tf20 (4.3 mL, 25 mmol). The reaction mixture was stirred at rt for 2.5 h. The reaction was quenched with water (50 mL), extracted with DCM (3 x 50 mL). The combined DCM layers were washed with brine, dried over Na2S04, filtered and concentrated. The crude product was purified by normal phase chromatography to give Example XIII-IC as a colorless viscous liquid (3.5 g, 70%). LC- MS (ESI) m/z: 402.0 [M+H+NH2]+. Example XIII- ID: 3-tert-Butyl 1 -methyl 4-(3-fluoropyridin-4-yl)isophthalate
Figure imgf000304_0002
A solution of Example XIII-IC (3.5 g, 9.1 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (2.0 g, 9.1 mmol) and K2CO3 (3.8 g, 27 mmol) in dioxane (60 mL) and water (10 mL) was purged with nitrogen for 10 minutes, and then was added PdC dppf) (0.40 g, 0.55 mmol). The reaction was heated at 80 °C for 2 h and then it was cooled to rt. The reaction was diluted with ethyl acetate (50 mL), washed with brine solution (2 x 30 mL), dried over a2S04, filtered and concentrated. The crude product was purified by normal phase chromatography to give Example XIII- ID as a brown solid (2.7 g, 89%). LC-MS (ESI) m/z: 332.1 [M+H]+.
Example X - IE: 2-(3-Fluoropyridin-4-yl)-5-(methoxycarbonyl)benzoic acid
Figure imgf000304_0003
To the solution of Example XIII-1D (2.7 g, 8.2 mmol) in DCM (25 mL) was added TFA (6 mL, 78 mmol). The reaction was stirred at rt for 18 h. The solvent was removed to give brown solid. It was washed with petroleum ether (2 x 25 mL), diethyl ether (2 x 15 mL) and dried in vacuo to give Example XIII- IE as an off-white solid (2.2 g, 68%). LC-MS (ESI) m/z: 276.0 [M+H]+.
Exa - IF: Methyl 4-(3-fluoropyridin-4-yl)-3-(methylcarbamoyl)benzoate
Figure imgf000305_0001
To the solution of Example XIII-1E (800 mg, 2.9 mmol) and methylamine HC1 salt (290 mg, 4.4 mmol) in DMF (5 mL) at 0 °C, were added TEA (2.0 mL, 15 mmol) and HATU (1100 mg, 2.9 mmol). The reaction was warmed to rt and stirred overnight. The solvent was removed to give brown solid, which was partitioned between water (15 mL) and ethyl acetate (25 mL). The organic solution was extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate layers were washed with brine solution, dried over a2S04, filtered and concentrated. Purification by normal phase chromatography gave an off-white solid. The solid was dissolved in DCM (4 mL) and reprecipitated by adding petroleum ether, and filtered to give Example XIII- IF as white solid (400 mg, 46%). LC- MS (ESI) m/z: 289.1 [M+H]+.
Example XIII-1G: Methyl 5-methyl-6-oxo-5,6-dihydrobenzo[c][l,7]naphthyridine-8- carboxylate, and
Example XIII- 1H: 5-Methyl-6-oxo-5,6-dihydrobenzo[c][l,7]naphthyridine-8-carboxylic acid
Figure imgf000305_0002
To the suspension of methyl 4-(3-fluoropyridin-4-yl)-3-(methylcarbamoyl) benzoate (440 mg, 1.5 mmol) in DMF (10 mL), was added Cs2C03 (1200 mg, 3.8 mmol). The reaction was refluxed at 85 °C overnight. The solvent was removed to give a yellow residue, which was dissolved in ethyl acetate (40 mL) and water (15 mL). Two layers were separated. The aqueous layer was saturated with NaCl and extracted with ethyl acetate (4 x 20 mL). The combined ethyl acetate layers were washed with brine solution (1 x 5 mL), dried over a2S04, filtered and concentrated to give Example XIII- 1G as an off-white solid (100 mg, 24%). LC-MS (ESI) m/z: 269.0 [M+H]+. The aqueous layer was acidified to pH 5 and solid was precipitated, which was filtered and dried in vacuo to give Example XIII-1H as an off-white solid (240 mg, 58%). LC-MS (ESI) m/z: 253.0 [M+H]+.
Example XIII- 1 :
Figure imgf000306_0001
To the suspension of Example XIII-1H (120 mg, 0.47 mmol) and (3- methoxyphenyl)methanamine (65 mg, 0.47 mmol) in DMF (4 mL) were added TEA (0.33 mL, 2.4 mmol) and HATU (270 mg, 0.71 mmol). The reaction was stirred at rt for overnight. Reaction was diluted with water (40 mL), and precipitated solid was collected and further purified by normal phase chromatography to give Example XIII- 1 as a white solid (25 mg, 13%). LC-MS (ESI) m/z: 3 '4.2 [M+H]+. XH NMR (400 MHz, DMSO-d6) δ ppm 9.46 (t, J = 5.96 Hz, 1 H) 8.93 - 9.02 (m, 2 H) 8.77 (d, J = 8.47 Hz, 1 H) 8.55 - 8.60 (m, 1 H) 8.47 (d, J = 5.21 Hz, 1 H) 8.39 (dd, J = 8.44, 1.98 Hz, 1 H) 7.24 - 7.30 (m, 1 H) 6.92 - 6.97 (m, 2 H) 6.82 - 6.87 (m, 1 H) 4.52 (d, J = 5.90 Hz, 2 H) 3.83 (s, 3 H) 3.75 (s, 3 H); Analytical HPLC RT A: 6.34 min, B: 6.39 min.
Compounds listed in Table XIII were prepared by following a similar procedure to that described for Example XIII- 1.
Table XIII
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Intermediate 22: 9H-Pyrido[3,4-Z?]indole-7-carboxylic acid
Figure imgf000312_0001
Intermediate 2 -amino-4-(3-fluoropyridin-4-yl)benzoate
Figure imgf000312_0002
Methyl 3-amino-4-bromobenzoate (4 g, 17.39 mmol), (3-fluoropyridin-4- yl)boronic acid (5.5 g, 39.0 mmol), dioxane (10 mL), water (2 mL) and potassium carbonate (8.41 g, 60.9 mmol) were taken in a dried two neck RB (25mL) and purged with nitrogen for 10 minutes. To this mixture was added PdCi2(dppf) (1.27 g, 1.74 mmol) at 50 °C. The mixture was flushed with nitrogen and heated at 80 °C for 8 h. The reaction mixture was cooled to room temperature, then was diluted with the DCM. The organic phase was washed with the water, dried over sodium sulfate. The crude compound was purified by silica gel chromatography (gradient elution, 30-65% ethyl acetate in petroleum ether) to afford 2.9 g (68%) of the title compound. LC-MS (ESI) m/z: 241.0 [M+H]+; XH NMR (400 MHz, chloroform-d) δ ppm 8.60 (d, J = 1.57 Hz, 1 H) 8.52 (dd, J = 4.86, 1.10 Hz, 1H) 7.48 - 7.52 (m, 2 H) 7.35 - 7.39 (m, 1H) 7.19 (d, J = 7.78 Hz, 1H) 3.93 (s, 3 H) 3.79 - 3.84 (m, 2 H).
Intermedia
Figure imgf000312_0003
To pyridine hydrochloride (1.5 g, 12.98 mmol) at 150 °C, was added Intermediate 22A (lg, 4.06 mmol) under nitrogen atmosphere. The mixture was heated to 170 °C for 2 h, then was allowed to cool to rt. The reaction mixture was quenched with aq. NaOH and stirred for 3 h. the reaction mixture was neutralized with acetic acid and concentrated under reduced pressure. The crude mass was treated with water and the solid was collected by filtration and dried to afford Intermediate 22 (450 mg, 52%). The material was used without further purification. LC-MS (ESI) m/z: 241.0 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 11.79 (bs, 1 H) 8.97 (s, 1 H) 8.37 (d, J = 5.27 Hz, 1 H) 8.11 - 8.29 (m, 3 H) 7.83 (d, J = 8.28 Hz, 1 H).
Intermediate 23: Ben oxylic acid, HC1 salt
Figure imgf000313_0001
Interme -(3-fluoropyridin-4-yl)-3-hydroxybenzoate
Figure imgf000313_0002
To a solution of methyl 4-bromo-3-hydroxybenzoate (1.0 g, 4.3 mmol) in dioxane (20 mL) and water (2 mL), was added K2CO3 (1.80 g, 13.0 mmol) and 3-fluoro-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.16 g, 5.19 mmol). The reaction mixture was degassed by bubbling with 2 for 5 mins. PdC dppf) (0.317 g, 0.433 mmol) was added to the reaction, which was degassed again. The mixture was then heated to 90 °C for 6 h. The reaction mixture was diluted with water (30 mL) and was extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with water and brine, dried over Na2S04 and concentrated to give crude product which was purified by flash chromatography (gradient elution, 0-60% EtO Ac/Hex) to afford Intermediate 23 A (0.65 g, 61% yield) as an off-white solid. LC-MS (ESI) m/z: 248.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6) δ ppm 10.36 (s, 1 H), 8.64 (d, J = 1.88 Hz, 1 H), 8.50 (dd, J = 4.86, 1.10 Hz, 1 H), 7.60 (d, J = 1.51 Hz, 1 H), 7.49 - 7.54 (m, 2 H), 7.42 (d, J = 7.97 Hz, 1 H), 3.88 (s, 3 H); 19F NMR: (400 MHz, DMSO-d6) : -128.57.
Intermediate 23B: Methyl benzofuro[2,3-c]pyridine-7-carboxylate
Figure imgf000314_0001
To a solution of Intermediate 23 A (0.450 g, 1.820 mmol) in DMF (5 mL), was added K2C03 (0.755 g, 5.46 mmol). The mixture was stirred at 100 °C for 2 hr. The DMF was evaporated and the mixture was diluted with water (50 mL). The obtained solid was filtered and washed with 50 ml of water and diethyl ether (10 ml) to afford Intermediate 23B (210 mg, 51%) as an off-white solid. LC-MS (ESI) m/z: 228.1 [M+H]+; ¾ NMR (400 MHz, DMSO-d6) δ ppm 9.19 (s, 1 H), 8.67 (d, J = 5.08 Hz, 1 H), 8.44 (d, J = 8.09 Hz, 1 H), 8.34 (s, 1 H), 8.30 (d, J = 5.02 Hz, 1 H), 8.10 (dd, J = 8.16, 1.25 Hz, 1 H), 3.94 (s, 3 H).
Intermediate 23 :
Figure imgf000314_0002
To a solution of Intermediate 23B (0.090 g, 0.40 mmol) in MeOH (3 mL) and water (1 mL), was added sodium hydroxide (0.024 g, 0.59 mmol). The reaction mixture was stirred at rt for 1 hr, then the solvent was evaporated. The crude mass was washed with diethyl ether (10 mL), and then the residue was treated with 4M HCI in dioxane for 30 min. The solvent was evaporated to give Intermediate 23 (0.10 g, 100%) as a white solid. LC-MS (ESI) m/z: 214.0 [M+H]+.
Intermediate 24: 9-Methyl-9H-pyrido[3,4-b]indole-7-carboxylic acid
Figure imgf000314_0003
Intermediate 24A: Methyl 4-bromo-3-(methylamino)benzoate
Figure imgf000315_0001
To a solution of methyl 3-amino-4-bromobenzoate (1.5 g, 6.52 mmol) in THF (30 mL) at 0 °C, was added NaH (0.203 g, 8.48 mmol). The mixture was stirred for 10 min, then iodomethane (1.11 g, 7.82 mmol) was added. The reaction mixture was stirred for 5 hr, then was quenched with addition of sat. ammonium chloride solution. The mixture was extracted with DCM. The organic phase was dried over a2S04 and concentrated. The crude compound was purified by flash chromatography (5 to 80% gradient of ethyl acetate in pet. ether) to afford 0.75 g (47%) of Intermediate 24A. LC-MS (ESI) m/z: 244.0 [M+H]+; ¾ NMR (400 MHz, chloroform-d) δ ppm 7.48 (d, J = 8.16 Hz, 1 H) 7.26 - 7.27 (m, 1 H) 7.24 (d, J = 2.01 Hz, 1 H) 7.22 (d, J = 2.01 Hz, 1 H) 3.90 (s, 3 H) 2.95 (d, J = 5.21 Hz, 3 H).
Intermediate 2 -(3-fluoropyridin-4-yl)-3-(methylamino)benzoate
Figure imgf000315_0002
To a degassed solution of Intermediate 24A (700 mg, 2.87 mmol) in dioxane (20 mL) and water (3 mL), were added 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (1.02 g, 4.59 mmol), potassium carbonate (1.39 g, 10.0 mmol) and
PdC dppf) (210 mg, 0.287 mmol) at rt. The reaction was stirred under argon at 90 °C for 6 h. The reaction mixture was cooled to rt, then was diluted with the DCM. The organic phase was washed with the water, dried over sodium sulfate and concentrated. The crude compound was purified by silica gel chromatography (30-60% ethyl acetate gradient in pet. ether) to afford Intermediate 24B (400 mg, 51%). LC-MS (ESI) m/z: 246.0 [M+H]+; XH NMR (400 MHz, chloroform-d) δ ppm 8.59 (d, J = 1.51 Hz, 2 H) 8.50 (dd, J = 4.83, 1.00 Hz, 2 H) 7.46 (dd, J = 7.81, 1.60 Hz, 2 H) 7.39 (d, J = 1.51 Hz, 2 H) 7.33 (s, 1 H) 7.14 (d, J = 7.78 Hz, 1 H) 3.94 (s, 3 H) 3.66 - 3.73 (m, 1 H) 2.89 (d, J = 5.15 Hz, 3H).
Intermediate 24:
Figure imgf000316_0001
To pyridine hydrochloride (250 mg, 2.16 mmol) at 150 °C, was add added Intermediate 24B (250 mg, 0.961 mmol). The mixture was heated at 175 °C for 2 h, then was cooled to rt. To the crude reaction mixture, was added 50% NaOH solution and the mixture was stirred for 2h. The reaction mixture was concentrated, then was neutralized with the addition of acetic acid. The mixture was concentrated in vacuo, then was treated with water and the solid was collected by filtration and dried to afford Intermediate 24 (90 mg, 41%). LC-MS (ESI) m/z: 227.0 [M+H]+; ¾ NMR (400 MHz, DMSO-d6) δ ppm 9.13 (s, 1 H) 8.44 (d, J = 5.27 Hz, 1 H) 8.38 (d, J = 8.09 Hz, 1 H) 8.28 (s, 1 H) 8.21 (dd, J = 5.21, 1.00 Hz, 1 H) 7.88 (dd, J = 8.16, 1.32 Hz, 1 H) 4.05 (s, 3 H).
Intermediate 25: Methyl 9H-pyrido[3,4-b]in
Figure imgf000316_0002
To a suspension of Intermediate 22 (3.1 g, 10.81 mmol) in methanol (75 mL), was added sulfuric acid (4.0 ml, 75 mmol). The mixture was heated at 68 °C for 3 h, then was concentrated. The crude material was basified with 10% aHC03 solution and extracted with EtOAc (3x). The combined organic fraction was again washed with 10% aHC03, followed by brine solution. The organic layer was dried with a2S04, filtered and concentrated to afford Intermediate 25 (0.721 g, 3.19 mmol, 29.5% yield) as a pale yellow solid. LC-MS (ESI) m/z: 227.0 [M+H]+; XH NMR (300MHz, DMSO-d6) δ 1 1.89 (s, 1H), 9.01 (s, 1H), 8.48 - 8.31 (m, 2H), 8.25 - 8.13 (m, 2H), 7.84 (dd, J = 8.3, 1.5 Hz, 1H), 3.92 (s, 3H).
Intermediate 26: 9-(2-Amino-2-oxoethyl)-9H-pyrido[3,4-b]indole-7-carboxylic acid compound with 9-(carboxymethyl)-9H-pyrido[3,4-b]indole-7-carboxylic acid (1 : 1)
Figure imgf000317_0001
Intermedia -(cyanomethyl)-9H-pyrido[3,4-b]indole-7-carboxylate
Figure imgf000317_0002
To the solution of Intermediate 25 (0.225 g, 0.995 mmol) in DMF (6 mL) at 0 °C, sodium hydride (0.119 g, 2.98 mmol) was added. The mixture was stirred at rt for 15 min. 2-Bromoacetonitrile (0.139 mL, 1.989 mmol) was added to the reaction mixture and stirred at rt for 2 h. Water was added to the reaction mixture, which was then extracted with EtOAc (2 x 60 mL). The combined organic layers were dried with Na2S04, filtered and concentrated. The crude product was purified by flash chromatography (0-4% gradient MeOH/CHCl3) to afford Intermediate 26A (0.29 g) as a dark yellow solid. LC- MS (ESI) m/z: 266.0 [M+H]+; 1H NMR (300MHz, DMSO-d6) δ 9.27 (s, 1 H), 8.59 - 8.43 (m, 3 H), 8.34 - 8.25 (m, 1 H), 7.98 - 7.92 (m, 1 H), 6.04 - 6.00 (m, 2 H), 3.96 (s, 3 H). Intermediate 26:
Figure imgf000317_0003
To the solution of Intermediate 26A (0.35 g, 1.32 mmol) in a mixture of MeOH (4 mL), water (4 mL) and THF (2 mL), lithium hydroxide hydrate (0.166 g, 3.96 mmol) was added and stirred at RT for 1.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was acidified by slow addition of 1.5 N HC1 at 0 °C. The resultant precipitate was collected by filtration and the residue was washed with ether to afford the mixture of products Intermediate 26 (0.102 g) as a yellow solid. MS (ESI) m/z: 270.1 and 271.0 [M+H]+. Intermed clopropylmethyl)-9H-py -b]indole-7-carboxylate
Figure imgf000318_0001
To a solution of Intermediate 25 (0.050 g, 0.22 mmol) in DMF (2 mL), were added K2C03 (0.061 g, 0.44 mmol) and (bromomethyl)cyclopropane (0.060 g, 0.442 mmol). The mixture was heated at 80 °C for 3 h. Water was added to the reaction mixture, which was extracted with EtOAc (2x). The combined organic layer was dried with a2S04, filtered and concentrated. The crude product was purified by flash chromatography (0-4% MeOH gradient in CHCI3) to afford 9-(cyclopropylmethyl)-9H- pyrido[3,4-b]indole-7-carboxylic acid. LC-MS (ESI) m/z: 281.1 [M+H]+. The material was dissolved in THF (4 mL) and water (2 mL), then lithium hydroxide hydrate (0.040 g, 0.95 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure to dryness. Then the crude was washed with ether for several times to get Intermediate 27 (0.085) as a yellow solid. MS (ESI) m/z: 267 [M+H]+.
Intermediate 28: 9-Eth -9H-pyrido[3,4-b]indole-7-carboxylic acid
Figure imgf000318_0002
Intermediate 2 3-(ethylamino)-4-(3-fluoropyridin-4- l)benzoate
Figure imgf000318_0003
To a solution of Intermediate 22A (800 mg, 3.25 mmol) in DMF (5 mL), was added potassium carbonate (674 mg, 4.87 mmol). The mixture was stirred at 50 °C for 10 min, then was cooled to RT. To this mixture, diethyl sulfate (751 mg, 4.87 mmol) was added, then the mixture was heated for 5 h at 120 °C. The reaction mixture was cooled to room temperature, diluted with the DCM, washed with water, dried over sodium sulfate and concentrated. The crude compound was purified by silica gel chromatography (30- 80% gradient of ethyl acetate in pet. ether) to afford Intermediate 28A (300 mg, 34%). MS (ESI) m/z: 241.1 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J = 1.63 Hz, 1 H) 8.50 (dd, J = 4.86, 1.04 Hz, 1 H) 7.45 (dd, J = 6.37, 4.86 Hz, 1 H) 7.22 - 7.27 (m, 2 H) 7.15 (d, J = 7.72 Hz, 1 H) 5.13 (t, J = 5.6 Hz, 1 H) 3.86 (s, 3 H) 3.13 (dd, J = 6.93, 5.80 Hz, 2 H) 1.10 (t, J = 7.09 Hz, 3 H).
Intermediat
Figure imgf000319_0001
To melted pyridine hydrochloride (379 mg, 3.28 mmol) at 150 °C, was added
Intermediate 28A (300 mg, 1.09 mmol). The mixture was heated at 175 °C for 2 h. To the crude reaction mixture was added 50% NaOH solution to reach pH 11. The reaction mixture was stirred for 3 h, then was concentrated. The reaction mixture was neutralized with acetic acid. Excess acetic acid was evaporated and the mixture was treated with water and the solid was collected to afford Intermediate 28 (250 mg, 95%). LC-MS (ESI) m/z: 241.1 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 9.14 (s, 1 H) 8.43 (d, J = 5.27 Hz, 1 H) 8.36 (d, J = 8.16 Hz, 1 H) 8.27 (s, 1 H) 8.21 (dd, J = 5.21, 0.88 Hz, 1 H) 7.87 (dd, J = 8.19, 1.22 Hz, 1 H) 4.63 (q, J = 7.13 Hz, 2 H) 1.38 (t, J = 7.12 Hz, 3 H).
Intermediate 29: 4-Fluoro-9H-pyrido[3,4-b]indole-7-carboxylic acid
Figure imgf000319_0002
Intermediate 29A: Methyl 4-(3-fluoropyridin-4-yl)-3-nitrobenzoate
Figure imgf000320_0001
A solution of methyl 4-bromo-3-nitrobenzoate (0.8 g, 3.1 mmol) and K2CO3 (1.276 g, 9.23 mmol) in dioxane (10 mL) and water (2 mL) was bubbled with nitrogen for 10 min. To this solution was added 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (0.686 g, 3.08 mmol) and PdCl2(dppf) (0.135 g, 0.185 mmol). The mixture was heated at 80 °C overnight. The mixture was diluted with ethyl acetate (30 mL), washed with brine (2x), dried over a2S04, filtered and concentrated. The crude product was purified by flash chromatography (gradient elution; 0-100% EtO Ac/Hex) to afford Intermediate 29A (0.58 g, 68% yield). LC-MS (ESI) m/z: 277.0 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 8.71 (s, 1 H) 8.60 - 8.64 (m, 2 H) 8.41 (d, J = 7.97 Hz, 1 H) 7.85 (d, J = 7.91 Hz, 1 H) 7.67 (t, J = 5.65 Hz, 1 H) 3.96 (s, 3 H). Intermediate -fluoro-9H-pyrido[3,4-b]indole-7-carboxylate
Figure imgf000320_0002
To a solution of Intermediate 29A (580 mg, 2.1 mmol) in 1,2-dichlorobenzene (6 mL) was added triphenylphosphine (1.38 g, 5.25 mmol). The mixture was heated at 170 °C for 4 h. To the cooled reaction mixture was added pet. ether (50 mL). The precipitate was filtered and washed with pet. ether (2x). The crude product was purified by flash chromatography (0-100% EtOAc/Hex). The solid was further purified by suspension in DCM (5 mL) and pet. ether (30 mL). The precipitate was collected by filtration to afford Intermediate 29B as a light brown solid (105 mg, 19%). LC-MS (ESI) m/z: 245.0
[M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 12.26 (s, 1 H) 8.91 (d, J = 2.64 Hz, 1 H) 8.37 (d, J = 1.19 Hz, 1 H) 8.26 - 8.30 (m, 2 H) 7.90 - 7.94 (m, 1 H) 3.94 (s, 3 H).
Intermediate 29:
Figure imgf000321_0001
To a suspension of Intermediate 29B (105 mg, 0.430 mmol) in THF (3 mL) and water (1 mL), was added LiOH (25.7 mg, 1.08 mmol). The resultant clear yellow solution was stirred overnight. The reaction mixture was concentrated, then the residue was dissolved in THF (1.5 mL) and water (0.5 mL). To this mixture was added LiOH (25.7 mg, 1.075 mmol). The mixture was stirred overnight, then was concentrated. The residue was dissolved in water, then was acidified to pH 3 with 1.5 N HCl. The precipitated solid was collected by filtration, washed with water and hexane, and dried in vacuo to afford Intermediate 29 as a brown solid (75 mg). LC-MS (ESI) m/z: 231.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (s, 1 H) 8.89 (d, J = 2.64 Hz, l H) 8.37 (d, J = 1.44 Hz, 1 H) 8.24 - 8.27 (m, 2 H) 7.89 - 7.92 (m, 1 H).
Intermediate 30: l-Fluoro-9H-pyrido[3,4-b]indole-7-carboxylic
Figure imgf000321_0002
Intermediate 30A: Methyl 4-(2-fluoropyridin-4-yl)-3-nitrobenzoate
Figure imgf000321_0003
A solution of methyl 4-bromo-3-nitrobenzoate (1.0 g, 3.85 mmol), 2-fluoro-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.858 g, 3.85 mmol) and K2CO3 (1.59 g, 11.5 mmol) in dioxane (20 mL) and water (4 mL) was bubbled with nitrogen for 10 minutes. To this mixture were added 2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (0.858 g, 3.85 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.188 g, 0.231 mmol). The mixture was heated at 80 °C for 4 h, then was diluted with EtOAc. The organic phase was washed with brine (2x), dried with Na2S04, filtered and concentrated. The crude product was purified by flash chromatography (0-100% gradient of EtOAc/Hex.) to afford Intermediate 30A as a yellow solid (0.8 g, 73%). LC-MS (ESI) m/z: 277.0 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 8.60 (d, J = 1.63 Hz, 1 H) 8.34 - 8.38 (m, 2 H) 7.80 (d, J = 7.97 Hz, 1 H) 7.38 - 7.46 (m, 2 H) 3.96 (s, 3 H). Intermediate 30B: Methyl l-fluoro-9H-pyrido[3,4-b]indole-7-carboxylate
Intermediate 30C: Methyl 3-fluoro-9H-pyrido[3,4-b]indole-7-carboxylate
Figure imgf000322_0001
To a solution of Intermediate 30A (800 mg, 2.90 mmol) in 1,2-dichlorobenzene (8 mL), was added triphenylphosphine (1.9 g, 7.24 mmol). The mixture was heated at 170 °C overnight, then was concentrated. The crude product was purified by flash
chromatography (0-100% EtOAc/Hex.) to afford Intermediate 30B (240 mg) as a yellow solid and Intermediate 30C, which was repurified by flash chromatography (0-100% EtOAc/Hex.) to afford 55 mg.
Intermediate 30B: LC-MS (ESI) m/z: 245.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (s, 1 H) 8.41 (d, J = 8.34 Hz, 1 H) 8.23 (dd, J = 1.44, 0.69 Hz, 1 H) 8.18 (dd, J = 5.36, 3.17 Hz, 1 H) 7.96 (dd, J = 5.36, 1.85 Hz, 1 H) 7.89 (dd, J = 8.31, 1.47 Hz, 1 H) 3.94 (s, 3 H).
Intermediate 30C: LC-MS (ESI) m/z: 245.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 ppm 11.88 (s, 1 H) 8.60 (dd, J = 1.51, 0.94 Hz, 1 H) 8.40 (d, J = 8.28 Hz, 1 H) 8.21 (dd, J = 1.38, 0.69 Hz, 1 H) 7.99 (d, J = 2.20 Hz, 1 H) 7.83 (dd, J = 8.28, 1.51 Hz, 1 H) 3.92 - 3.95 (m, 3 H).
Figure imgf000322_0002
To a suspension of Intermediate 30B (230 mg, 0.942 mmol) in THF (2 mL) and water (0.5 mL), was added LiOH (67.7 mg, 2.83 mmol). The yellow solution was allowed to stir at rt overnight. The reaction mixture was concentrated to gave yellow residue, which was dissolved in water (8 mL) and acidified with 1.5 N HC1 to pH 3. The precipitated solid was filtered and washed with water, hexane, and dried to afford Intermediate 30 (190 mg, 64%) as a brown solid. LC-MS (ESI) m/z: 231.0 [M+H]+; XH NMR (300 MHz, DMSO-d6) 5 ppm 13.11 (s, 1 H) 12.39 (s, 1 H) 8.38 (d, J = 8.17 Hz, 1 H) 8.14 - 8.22 (m, 2 H) 7.94 (d, J = 5.15 Hz, 1 H) 7.87 (d, J = 8.26 Hz, 1 H).
Intermediate 31: 3-Fluoro-9H-pyrido[3,4-b]indole-7-carboxylic acid
Figure imgf000323_0001
To a suspension of Intermediate 30C (55 mg, 0.23 mmol) in THF (2 mL) and water (0.5 mL), was added LiOH (16.2 mg, 0.676 mmol). The resultant yellow solution was allowed to stir at rt overnight. The reaction mixture was concentrated to gave yellow residue, which was dissolved in water (8 mL) and acidified with 1.5 N HC1 to pH 3. The precipitated solid was filtered and washed with water and hexane, and dried to afford Intermediate 31(42 mg, 57%) as a brown solid. LC-MS (ESI) m/z: 231.0 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 11.86 (s, 1 H) 8.58 (s, 1 H) 8.37 (d, J = 8.28 Hz, 1 H) 8.19 (d, J = 0.63 Hz, 1 H) 7.97 (d, J = 2.13 Hz, 1 H) 7.82 (dd, J = 8.28, 1.38 Hz, 1 H).
Intermediate 32: 9-(2,2,2-Trifluoroethyl)-9H-pyrido[3,4-b]indole-7-carboxylic acid
Figure imgf000323_0002
Intermediat -(2,2,2-trifluoroethyl)-9H-pyrido[3,4-b]indole-7-carboxylate
Figure imgf000323_0003
To a suspension of Intermediate 22 (0.20 g, 0.88 mmol) in DMF (5 mL), was added K2C03 (0.611 g, 4.42 mmol), followed by the addition of l,l,l-trifluoro-2- iodoethane (0.436 mL, 4.42 mmol). The mixture was heated at 100 °C overnight. Water was added to the reaction mixture, which was then extracted with EtOAc (2x). The combined organic phase was dried with a2S04, filtered and concentrated. The crude product was purified by flash chromatography (0-4% ΜεΟΗ/ΟΗ(¾) to afford
Intermediate 32A (0.14 g, 22% yield) as yellow semi-solid. LC-MS (ESI) m/z: 309.0 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 9.25 (s, 1H), 8.56 - 8.41 (m, 3H), 8.30 - 8.24 (m, 1H), 7.99 - 7.93 (m, 1H), 5.72 (q, J = 9.4 Hz, 2H), 3.95 (s, 3H).
Figure imgf000324_0001
To a solution of Intermediate 32A (0.14 g, 0.45 mmol) in THF (2 mL) and water (2 mL), was added lithium hydroxide hydrate (0.076 g, 1.817 mmol). The mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure to dryness. Then the crude product was washed with ether several times to afford
Intermediate 32 (0.161 g, 82% yield) as a yellow solid. MS (ES): m/z = 295.0 [M+H]+.
Intermediate 33: Sodium 4-methyl-9H-pyrido[3,4-b]indole-7-carboxylate
Figure imgf000324_0002
Intermediate 33A: Methyl 4-(3-methylpyridin-4-yl)-3-nitrobenzoate
Figure imgf000324_0003
A solution of (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (0.445 g, 1.98 mmol), 4-bromo-3-methylpyridine, hydrobromide (0.50 g, 1.98 mmol) and K2CO3 (0.820 g, 5.93 mmol) in dioxane (20 mL) and water (4 mL) was bubbled nitrogen for 10 minutes. To this mixture was added PdCi2(dppf)-CH2Ci2 adduct (0.097 g, 0.12 mmol). The mixture was heated at 80 °C overnight. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with brine solution (2x), dried over Na2S04, filtered and concentrated. The crude product was purified by flash chromatography (gradient elution; 0-100% EtOAc/Hex.) to afford Intermediate 33A as a yellow solid (0.100 g, 18%). MS (ES): m/z = 273.8 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 8.61 - 8.64 (m, 1 H) 8.57 (s, 1 H) 8.48 (d, J = 4.96 Hz, 1 H) 8.35 (dd, J = 7.97, 1.69 Hz, 1 H) 7.66 (d, J = 7.97 Hz, 1 H) 7.23 (d, J = 4.96 Hz, 1 H) 3.96 (s, 3 H) 2.05 (s, 3 H).
Intermediate -methyl-9H-pyrido[3,4-b]indole-7-carboxylate
Figure imgf000325_0001
To a solution of Intermediate 33A (100 mg, 0.367 mmol) in 1,2-dichlorobenzene (3 mL), was added triphenylphosphine (241 mg, 0.918 mmol). The mixture was heated at 170 °C for 5 h. The reaction mixture was cooled to rt, then was diluted with pet. ether. The precipitate was collected by filtration. The solid was purified twice by flash chromatography (gradient elution; 0-100% EtO Ac/Hex) to afford Intermediate 33B (100 mg, 29%) as a yellow solid. MS (ES): m/z = 241.5 [M+H]+. Intermediate 33:
Figure imgf000325_0002
To a solution of Intermediate 33B (100 mg, 0.416 mmol) in MeOH (2 mL) and water (0.67 mL), was added NaOH (0.050 g, 1.25 mmol). The mixture was stirred at rt overnight. The solvent was evaporated, then the mixture was coevaporated with toluene to afford a 100 mg of a yellow solid that was used as without further purification. MS (ES): m/z = 227.5 [M+H]+; XH NMR (300MHz, DMSO-d6) δ 13.20 (br. s., 1H), 9.26 (s, 1H), 8.52 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.41 (d, J = 0.8 Hz, 1H), 7.98 (dd, J = 8.3, 1.5 Hz, 1H), 2.99 (s, 3H). Intermediate 34: l-(Difluoromethyl)benzofuro[2,3-c]pyridine-7-carboxylic acid
Figure imgf000325_0003
Intermediate 34A: methyl l-(difluoromethyl)benzofuro[2,3-c]pyridine-7-carboxylate
Figure imgf000326_0001
To s suspension of methyl benzofuro[2,3-c]pyridine-7-carboxylate (90 mg, 0.40 mmol) and zinc difluoromethanesulfinate (389 mg, 1.19 mmol) in DCM (5 mL) and water (2 mL) at 0 °C, was added tert-butyl hydroperoxide(0.192 mL, 1.98 mmol). The reaction mixture was stirred at rt overnight, then was diluted with DCM. The phases were separated, then the aqueous phase was extracted with DCM. The combined DCM phase was washed with brine, dried over Na2S04, filtered and concentrated. The crude product was purified by flash chromatography (gradient elution; 0-80% EtOAc/Hex.) to afford Intermediate 34A (70 mg, 44%) as an off-white solid. MS (ES): m/z = 278.4 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d, J = 5.02 Hz, 1 H) 8.49 - 8.55 (m, 2 H) 8.40 (dd, J = 1.29, 0.60 Hz, 1 H) 8.15 (dd, J = 8.16, 1.38 Hz, 1 H) 7.23 - 7.53 (t, J = 56, 1 H) 3.95 (s, 3 H).
Intermediate 34:
Figure imgf000326_0002
To s solution of Intermediate 34A (70 mg, 0.25 mmol) in methanol (3 mL) and water (1 mL), was added NaOH (30.3 mg, 0.758 mmol). The mixture was stirred at rt for 4 h. The solvent was evaporated, then the residue was dissolved water (15 mL) and washed with ethyl acetate (x2). The aqueous was acidified with 1.5 N HC1 to pH 2 then was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated to afford Intermediate 34 (50 mg, 59% yield) as a yellow solid. MS (ES): m/z = 278.4 [M+H]+; ¾ NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d, J = 5.02 Hz, 1 H) 8.52 (d, J = 5.08 Hz, 1 H) 8.48 (dd, J = 8.13, 0.53 Hz, 1 H) 8.36 (d, J = 0.69 Hz, 1 H) 8.13 (dd, J = 8.09, 1.32 Hz, 1 H) 7.25 - 7.53 (t, J = 56.8 Hz, 1 H).
Intermediate 35: Lithium 4-fluorobenzofuro[2,3-c]pyridine-7-carboxylate
Figure imgf000327_0001
Intermediate 35A: Methyl 3-acetoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoate
Figure imgf000327_0002
To a solution of methyl 3-acetoxy-4-bromobenzoate (540 mg, 1.98 mmol) in dioxane (20 mL), was added potassium acetate (485 mg, 4.94 mmol). The mixture was bubbled with nitrogen for 10 minutes, then bis(pinacolato)diboron (753 mg, 2.97 mmol) and PdCl2(dppf) (87 mg, 0.12 mmol) were added. The mixture was bubbled with nitrogen for 5 minutes, then was heated at 100 °C overnight. The reaction mixture was cooled to rt, filtered through a CELITE® bed, rinsing with ethyl acetate. The filtrate was concentrated. The residue was purified by flash chromatography (gradient elution; 0-100%
EtO Ac/Hex.) to afford Intermediate 35A (450 mg, 71% yield) as a yellow gummy solid. MS (ES): m/z = 239 [M+H]+.
Intermediate 35B: Methyl 4-(3,5-difluoropyridin-4-yl)-3-hydroxybenzoate
Figure imgf000327_0003
A solution of Intermediate 35A (248 mg, 0.773 mmol), 4-bromo-3,5- difluoropyridine (100 mg, 0.516 mmol) and K2CO3 (214 mg, 1.55 mmol) in dioxane (10 mL) and water (2 mL) was bubbled with nitrogen for 10 minutes then, PdC dppf)-
CH2CI2 Adduct (25.3 mg, 0.031 mmol) were added. The mixture was heated at 80 °C for 4 h. The mixture was diluted with ethyl acetate (30 mL), washed with brine (2x), dried over Na2S04, filtered and concentrated. The residue was purified by flash
chromatography (gradient elution; 0-100% EtOAc/Hex.) to afford Intermediate 35B (37 mg, 0.092 mmol, 17.93% yield) as a yellow solid. MS (ES): m/z = 266.0 [M+H]+; XH NMR (400MHz, DMSO-d6) δ 10.49 (s, 1H), 8.62 (s, 2H), 7.60 (d, J = 1.5 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.48 - 7.40 (m, 1H), 3.87 (s, 3H).
Intermediate 35:
Figure imgf000328_0001
To the solution of Intermediate 35B (37 mg, 0.14 mmol) in DMF (1 mL), was added potassium carbonate (57.8 mg, 0.419 mmol). The mixture was heated at 120 °C for 4 h. The reaction mixture was cooled to rt and the solvent was evaporated to give an off- white solid. The solid was dissolved in THF (2.5 mL) and water (1 mL), then was treated with LiOH (9.77 mg, 0.408 mmol). The mixture was stirred at rt for 3 h. The mixture was concentrated, then was coevaporated with toluene (2x) to afford Intermediate 35 (45 mg) as an off-white solid, which was used as is without further purification. MS (ESI): m/z = 232.0 [M+H]+; ¾ NMR (400 MHz, DMSO-d6) δ ppm 8.98 - 9.00 (m, 1 H) 8.59 (m, 1 H) 8.15 (s, 1 H) 8.03 - 8.07 (m, 1 H) 7.98 - 8.02 (m, 1 H).
Compounds listed in Table XIV were prepared by following similar procedures to those described for Example 1-1 using the appropriate intermediates described or purchased from commercial sources. Coupling reagents, such as HATU, T3P, BOP, PyBop, and EDC/HOBt, could be used instead of the one described.
Table XIV
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Compounds listed in Table XV were prepared by following similar procedures to those described for Example I-l using the appropriate intermediates described or purchased from commercial sources. Coupling reagents, such as HATU, T3P, BOP, PyBop, and EDC/HOBt, could be used instead of the one described.
Table XV
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Example XVI- 1 : (R)-9-(Cyanomethyl)-N-(l-phenylethyl)-9H-pyrido[3,4-b]indole-7- carboxamide
Figure imgf000357_0001
Example XVI- 1 A: (R)-N-(l-Phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide
Figure imgf000357_0002
To a solution of Intermediate 22 (0.100 g, 0.471 mmol) in DMF (2 mL), HATU (0.358 g, 0.942 mmol) was added. The mixture was stirred for 20 min, then (R)-l- phenylethanamine (0.120 mL, 0.942 mmol) was added to the reaction mixture, followed by the addition of DIEA (0.247 mL, 1.41 mmol). The mixture was stirred at rt overnight. Water was added, then the reaction mixture was extracted with EtOAc (2x). The combined organic phase was dried with Na2S04, filtered and concentrated. The product was purified by flash chromatography (gradient, 0-5% ΜεΟΗ/ΟΗ(¾) to afford Example XVI-1A (139 mg) as a yellow semi-solid. LC-MS (ESI) m/z: 316.1 [M+H]+. - 1 :
Figure imgf000357_0003
To s solution of Example XVI- 1 A (0.139 g, 0.295 mmol) in DMF (2 mL) at 0 °C, sodium hydride (0.014 g, 0.35 mmol) was added. The mixture was stirred at RT for 15 min, then 2-bromoacetonitrile (0.031 mL, 0.44 mmol) was added. The mixture was stirred at rt for 1 h. Water was added, then the mixture was extracted with EtOAc (2x). The combined organic phase was dried over Na2S04, filtered and concentrated. The crude product was purified by preparative HPLC (Acetonitrile/water/NH4OAc) to afford Example XVI- 1 (2 mg, 2% yield). MS (ESI) m/z: 355 [M+H]+; XH NMR (400MHz, DMSO-d6) δ = 9.24 (s, 1 H), 8.97 (d, J = 8.0 Hz, 1 H), 8.54 (d, J = 5.0 Hz, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.38 (s, 1 H), 8.27 (dd, J = 1.0, 5.0 Hz, 1 H), 7.93 (dd, J = 1.5, 8.0 Hz, 1 H), 7.49 - 7.44 (m, 2 H), 7.39 - 7.33 (m, 2 H), 7.28 - 7.22 (m, 1 H), 5.95 (s, 2 H), 5.28 (quin, J = 7.2 Hz, 1 H), 1.56 (d, J = 7.0 Hz, 3 H).
Example XVI-2: N-(2-Chlorobenzyl)-l-methyl-9H-pyrido[3,4-b]indole-7-carboxamide
Figure imgf000358_0001
Example XVI-2A: Methyl 4-(2-methylpyridin-4-yl)-3-nitrobenzoate
Figure imgf000358_0002
A solution of 4-bromo-2-methylpyridine (1.0 g, 5.81 mmol) and K2CO3 (2.41 g, 17.4 mmol) in dioxane (20 mL) and water (4 mL) was bubbled with nitrogen for 10 minutes. To this mixture were added (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (1.308 g, 5.81 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.285 g, 0.349 mmol). The mixture was heated at 80 °C overnight. The reaction mixture was cooled to rt and diluted with EtO Ac. The mixture was washed with brine solution (2x), dried with Na2S04, filtered and concentrated. The crude product was purified by flash chromatography (gradient elution; 0-100% EtO Ac/Hex.) to afford Example XVI-2A (520 mg, 30% yield) as a yellow solid. LC-MS (ESI) m/z: 273.5 [M+H]+; ¾ NMR (400 MHz, DMSO-d6) δ ppm 8.51 - 8.56 (m, 2 H) 8.32 (dd, J = 8.00, 1.73 Hz, 1 H) 7.75 (d, J = 8.03 Hz, 1 H) 7.31 - 7.34 (m, 1 H) 7.22 (ddd, J = 5.11, 1.73, 0.56 Hz, 1 H) 3.95 (s, 3 H) 2.53 (s, 3 H).
Example XVI-2B: Methyl l-methyl-9H-pyrido[3,4-b]indole-7-carboxylate and methyl 3- methyl-9H-pyrido[3,4-b]indole-7-carboxylate (~1 : 1 mixture)
Figure imgf000359_0001
Mixture of two regioisomers
To a solution of Example XVI-2A (800 mg, 2.94 mmol) in 1,2-dichlorobenzene (8 mL), was added triphenylphosphine (1.93 g, 7.35 mmol). The mixture was heated at 170 °C for 5 h, then was cooled to rt. Pet. ether was added and the resultant precipitate was collected by filtration. The solid was purified by flash chromatography (gradient elution; 0-100% EtO Ac/Hex.) to afford Example XVI-2B (690 mg) as a mixture of isomers. The mixture was contaminated with triphenylphosphine oxide and was taken onto the following step without further purification. LC-MS (ESI) m/z: 241.5 [M+H]+.
Example XVI-2C: 3-Methyl-9H-pyrido[3,4-b]indole-7-carboxylic acid and l-methyl-9H- pyrido[3,4-b]indole-7-carboxylic acid (~1 : 1 mixture)
Figure imgf000359_0002
To a solution of Example XVI-2B (0.69 g, 2.87 mmol) in MeOH (6 mL) and water (2 mL), was added NaOH (0.345 g, 8.62 mmol). The mixture was stirred at rt overnight, then was concentrated. The mixture was taken up in water (10 mL) and the solid was removed by filtration. The filtrate was washed with ethyl acetate. The aqueous phase was acidified to pH 4 with 1.5N HC1 and the resultant precipitated solid was collected by filtration. The solid was washed with water and pet. ether to gave Example XVI-2C (260 mg) as a yellow solid. LC-MS (ESI) m/z: 227.5 [M+H]+.
Example XVI-2:
Figure imgf000359_0003
Mixture of two regioisomers
To a solution of Example XVI-2C (60 mg, 0.27 mmol) in DMF (2 mL), was added (2-chlorophenyl)methanamine (75 mg, 0.53 mmol), TEA (0.185 mL, 1.33 mmol) and HATU (1 11 mg, 0.292 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with ice cold water (15 mL) and stirred for 15 minutes. The precipitate was collected by filtration, washed with water and pet. ether and dried. The material was purified by Supercritical Fluid Chromatography (SFC) to afford Example XVI-2. LC-MS (ESI) m/z: 350.2 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 11.79 (br. s., 1 H) 9.21 (t, J = 5.77 Hz, 1 H) 8.28 - 8.33 (m, 1 H) 8.25 (d, J = 5.33 Hz, 1 H) 8.14 (d, J = 0.75 Hz, 1 H) 7.99 (dd, J = 5.33, 0.44 Hz, 1 H) 7.80 (dd, J = 8.28, 1.51 Hz, 1 H) 7.46 - 7.51 (m, 1 H) 7.39 - 7.44 (m, 1 H) 7.28 - 7.38 (m, 2 H) 4.61 (d, J = 5.77 Hz, 2 H) 2.79 (s, 3 H). Example XVI-3: (R)-N-(l-(3-Methoxyphenyl)ethyl)-l-methyl-9H-pyrido[3,4-b]indole-7- carboxamide, and
Example XVI-4: (R)-N-(l-(3-Methoxyphenyl)ethyl)-3-methyl-9H-pyrido[3,4-b]indole-7- carboxamide
Figure imgf000360_0001
To a solution of Example XVI-2C (60 mg, 0.265 mmol) in DMF (2 mL), were added (R)-l-(3-methoxyphenyl)ethanamine (80 mg, 0.530 mmol), TEA (0.185 mL, 1.33 mmol) and HATU (111 mg, 0.292 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with ice cold water (15 mL) and stirred for 15 minutes. The precipitate was collected by filtration, washed with water and pet. ether and dried. The material was purified by Supercritical Fluid Chromatography (Co-Solvent 0.3% DEA in methanol) to afford Example XVI-3 and Example XVI-4.
Example XVI-3: 40 mg. LC-MS (ESI) m/z: 360.2 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 11.76 (s, 1 H) 8.94 (d, J = 8.22 Hz, 1 H) 8.22 - 8.31 (m, 2 H) 8.08 (d, J = 0.69 Hz, 1 H) 7.98 (d, J = 5.33 Hz, 1 H) 7.77 (dd, J = 8.28, 1.44 Hz, 1 H) 7.23 - 7.29 (m, 1 H) 6.98 - 7.04 (m, 2 H) 6.78 - 6.84 (m, 1 H) 5.20 (quin, J = 7.29 Hz, 1 H) 3.76 (s, 3 H) 2.78 (s, 3 H) 1.51 (d, J = 7.09 Hz, 3 H).
Example XVI-4: 12 mg. LC-MS (ESI) m/z: 360.2 [M+H]+; XH NMR (400 MHz, DMSO-d6) 5 ppm 11.61 (s, 1 H) 8.92 (d, J = 8.16 Hz, 1 H) 8.82 (d, J = 1.07 Hz, 1 H) 8.26 (d, J = 8.22 Hz, 1 H) 8.06 (d, J = 0.75 Hz, 1 H) 7.99 (s, 1 H) 7.73 (dd, J = 8.25, 1.47 Hz, 1 H) 7.22 - 7.29 (m, 1 H) 6.98 - 7.03 (m, 2 H) 6.81 (ddd, J = 8.20, 2.46, 1.00 Hz, 1 H) 5.15 - 5.24 (quin, J = 7.29 Hz, 1 H) 3.75 (s, 3 H) 2.62 (s, 3 H) 1.51 (d, J = 7.03 Hz, 3 H). -5: N-(2-Fluoro-5-methoxybenzyl)-l-methyl-9H-pyrido[3,4-b]indole-7-
Figure imgf000361_0001
To a solution of Example XVI-2C (60 mg, 0.265 mmol) in DMF (2 mL), were added (2-fluoro-5-methoxyphenyl)methanamine (82 mg, 0.53 mmol), TEA (0.185 mL, 1.33 mmol) and HATU (111 mg, 0.292 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with ice cold water (15 mL) and stirred for 15 minutes. The precipitate was collected by filtration, washed with water and pet. ether, and dried. The material was purified by Supercritical Fluid Chromatography (Co-Solvent 0.3% DEA in methanol) to afford 37 mg (38%) of Example XVI-5. LC-MS (ESI) m/z: 364.2 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 11.78 (s, 1 H) 9.16 (t, J = 5.84 Hz, 1 H) 8.29 (dd, J = 8.25, 0.47 Hz, 1 H) 8.24 (d, J = 5.33 Hz, 1 H) 8.11 (d, J = 0.82 Hz, 1 H) 7.99 (d, J = 5.33 Hz, 1 H) 7.77 (dd, J = 8.28, 1.51 Hz, 1 H) 7.14 (t, J = 9.32 Hz, 1 H) 6.95 (dd, J = 6.12, 3.17 Hz, 1 H) 6.86 (dt, J = 8.82, 3.66 Hz, 1 H) 4.54 (d, J = 5.77 Hz, 2 H) 3.71 (s, 3 H) 2.79 (s, 3 H). Example XVI-6: N-(3-Methoxybenzyl)-l-methyl-9H-pyrido[3,4-b]indole-7-carboxamide
Figure imgf000361_0002
To a solution of Example XVI-2C (60 mg, 0.265 mmol) in DMF (2 mL), were added (3-methoxyphenyl)methanamine (72.8 mg, 0.530 mmol), TEA (0.185 mL, 1.33 mmol) and HATU (111 mg, 0.292 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with ice cold water (15 mL) and stirred for 15 minutes. The precipitate was collected by filtration, washed with water and pet. ether, and dried. The material was purified by Supercritical Fluid Chromatography (Co-Solvent 0.3% DEA in methanol) to afford 34 mg (37%) of Example XVI-6. LC-MS (ESI) m/z: 346.2 [M+H] ; XH NMR (400 MHz, DMSO-d6) δ ppm 11.76 (s, 1 H) 9.18 (t, J = 5.99 Hz, 1 H) 8.29 (dd, J = 8.25, 0.53 Hz, 1 H) 8.24 (d, J = 5.33 Hz, 1 H) 8.12 (d, J = 0.75 Hz, 1 H) 7.98 (dd, J = 5.33, 0.50 Hz, 1 H) 7.77 (dd, J = 8.28, 1.51 Hz, 1 H) 7.24 - 7.30 (m, 1 H) 6.92 - 6.97 (m, 2 H) 6.80 - 6.86 (m, 1 H) 4.52 (d, J = 5.96 Hz, 2 H) 3.75 (s, 3 H) 2.79 (s, 3 H).

Claims

WHAT IS CLAIMED IS:
1. A compound according to formula (I):
Figure imgf000363_0001
(I)
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
Ai and A2 are CRi;
A3 is independently selected from and CRi;
B is independently selected from -0-, -CR3R4O-, -OCR3R4-, -NRa-, -C(0)0-, -OC(O)-, -C(0)NRa-, -NRaC(O)-, and -S-;
L is independently selected from - -(CR6R7)sO(CR6R7)q-, and
Figure imgf000363_0002
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -(CH2)rS(0)pRc,
-(CH2)rC(=0)Rb, -(CH2)rNRaRa, -(CH2)rC(=0)NRaRa, -(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rCN, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb, -(CH2)rS(0)pNRaRa,
-(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc, (CH2)r-C3-6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H, F, OH, CN, NRaRa, C1-4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3 Re, -(CH2)rORb, (CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)NRaRa, -(CH2)rC(=0)(CH2)rNRaRa, (CH2)rCN, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa,
-(CH2)rC(=0)ORb, -(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa,
-(CH2)rNRaS(0)pRc, (CH2)r-C3-6 carbocyclyl substituted with 0-3 Re, and
-(CH2)r-heterocyclyl substituted with 0-3 Re; R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000364_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from C3-10 carbocyclyl and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br,
Figure imgf000364_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro, -(CHRd)rS(<¾Re, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl, -(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2_6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re,
C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000365_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
s, at each occurrence, is independently selected from 1, and 2; provided when s and q are in the same term, s + q < 3.
2. The compound of claim 1, having Formula (II):
Figure imgf000365_0002
(II)
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein B is independently selected from -O- and -NRa-;
L is -(CR6R7)q;
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R5 is independently selected from H and C1-4 alkyl;
Re and R7 are independently selected from H,
Figure imgf000366_0001
substituted with 0-4 Re, and
-(CH2)rC(=0)ORb;
Rs is selected from phenyl, C3-6 cycloalkyl and heterocyclyl, each substituted with 0-5 R9; R9 is independently selected from F, CI, Ci-4alkyl substituted with 0-5 Re,
Figure imgf000366_0002
alkyl, -ORb, and -CN;
Ra, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H and C e alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), F, CI, Br, CN, N02, -(CH2)rOCi_5 alkyl, and -(CH2)rOH; p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
3. The compound of claim 1, having Formula (III):
Figure imgf000366_0003
(III)
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein L is independently selected from -(CR6 7)q-, -(CR6R7)SNR5-, -(CR6R?)sO-, and
-(CR^ O)-;
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NRaC(=0)Rb, and -NRaC(=0)ORb;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with
0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H, F, OH, CN, and C1-4 alkyl substituted with
0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3
Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000367_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3-6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br,
Figure imgf000367_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Re, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHR<i)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb, -(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRa)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from Ci-6 alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1 and 2. compound of claim 3, having Formula (IV)
Figure imgf000369_0001
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NRaC(=0)Rb, and -NRaC(=0)ORb;
R2 is independently selected from H, F, CI, Br, CN, and NRaRa;
R3 is independently selected from H and C1-4 alkyl substituted with 0-3 Re, C1-4 alkenyl substituted with 0-3 Re, and C1-4 alkynyl substituted with 0-3 Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, Re and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; Rg is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(0)pNRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent Rg groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
R<i, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-5alkyl, and C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
5. The compound of claim 4 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
Ri and R2 are H;
R3 is independently selected from H and Me;
R5 is H;
Re and R7 are independently selected from H,
Figure imgf000371_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb,
-(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br,
Figure imgf000371_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
Figure imgf000371_0003
-(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHR<i)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re; alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with
0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Ra, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOCi-5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000372_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4. 6. The compound of claim 5 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
¾ and R7 are independently selected from H and Ci_4alkyl substituted with 0-4 Re; Rg is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, =0, nitro, -(CHRd)rS(0)pRc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa,
-(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb,
-(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb, -(CHRd)rC(=0)NRaRa,
-(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl, -(CHRd)r-aryl, and
-(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent Rg groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
R<i, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-5alkyl, and C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
7. The compound of claim 1, having Formula (V)
Figure imgf000374_0001
(V)
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
L is independently selected from -(CR6R7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
Figure imgf000374_0002
Ri is independently selected from H, F, CI, Br, CN, RaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NRaC(=0)Rb, and
-NRaC(=0)ORb;
R2 is independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H, F, CI, Br, OH, CN, C1-4 alkyl substituted with 0-3 Re, and C3-6 carbocyclyl substituted with 0-3 Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
¾ and R7 are independently selected from H,
Figure imgf000374_0003
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa, -(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9;
R9 is independently selected from F, CI, Br,
Figure imgf000375_0001
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2_6alkenyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000376_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1 and 2.
8. The compound of claim 7, having Formula (Via):
Figure imgf000376_0002
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
Ri is independently selected from H, F, CI, Br, CN, NRaRa, -OCi_4 alkyl substituted with
0-3 Re, Ci-4 alkyl substituted with 0-3 Re, -(CH2)rORb, -NHC(=0)Rb, and -NHC(=0)ORb;
R2 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 Re; R3 and R4 are independently selected from H, C1-4 alkyl substituted with 0-3 Re, and C3-6 cycloalkyl substituted with 0-3 Re;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
¾ and R7 are independently selected from H, Ci-4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(0)pRc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHR<i)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd), OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2_6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C e 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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from C e alkyl substituted with 0-5 Re,
C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Ra, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from C e alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl, -(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf,
Figure imgf000378_0001
-C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from 1 and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
9. The compound of claim 1, having Formula (VII):
Figure imgf000378_0002
(VII)
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein L is independently selected from -(CR6 7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
-(CR6R7)SC(0)-;
Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl
substituted with 0-3 Re, C1-4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R5 is independently selected from H and C1-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
R6 and R7 are independently selected from H,
Figure imgf000379_0001
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRc, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRc,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3-6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9; R9 is independently selected from F, CI, Br,
Figure imgf000379_0002
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa,
-(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from N, O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re; Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rd, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl,
-(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1, and 2.
10. The compound of claim 1, having Formula (VIII):
Figure imgf000381_0001
(VIII)
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
L is independently selected from -(CR6 7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
Figure imgf000381_0002
Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OC1-4 alkyl
substituted with 0-3 Re, C1-4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R5 is independently selected from H and Ci-4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN, -NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb,
-S(0)pNRaRa, -NRaS(0)pNRaRa, and -NRaS(0)pRc, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Re and R7 are independently selected from H,
Figure imgf000381_0003
substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb,
-(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb,
-(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 R9; R9 is independently selected from F, CI, Br,
Figure imgf000381_0004
substituted with 0-5 Re, C2_4alkenyl substituted with 0-5 Re, C2_4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Re, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2_6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
Rj, at each occurrence, is independently selected from H and Ci-4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2_6 alkenyl, C2_6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOd_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl;
Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3; r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1, and 2.
Figure imgf000383_0001
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
L is independently selected from -(CR6 7)q, -(CR6R7)SNR5-, -(CR6R?)sO-, and
-(CR^ O)-;
Ri and R2 are independently selected from H, F, CI, Br, CN, NRaRa, -OCi_4 alkyl
substituted with 0-3 Re, Ci-4 alkyl substituted with 0-3 Re, and -(CH2)rORb;
R3 and R4 are independently selected from H and Ci_4 alkyl substituted with 0-3 Re, Ci-4 alkenyl substituted with 0-3 Re, and Ci_4 alkynyl substituted with 0-3 Re; R5 is independently selected from H and Ci_4 alkyl optionally substituted with F, CI, Br, CN, -ORb, -S(0)pRc, -C(=0)Rb, -NRaRa, -C(=0)NRaRa, -C(=0)(CH2)rNRaRa, CN,
-NRaC(=0)Rb, -NRaC(=0)ORb, -OC(=0)NRaRa, -NRaC(=0)NRaRa, -C(=0)ORb, -S(0)pNRaRa, -NRaS(0)pNRaRa, -NRaS(0)pRe, -(CH2)r-C3-io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
¾ and R7 are independently selected from H, Ci_4alkyl substituted with 0-4 Re,
-(CH2)rORb, -(CH2)rS(0)pRe, -(CH2)rC(=0)Rb, -(CH2)rNRaRa,
-(CH2)rC(=0)(CH2)rNRaRa, -(CH2)rNRaC(=0)Rb, -(CH2)rNRaC(=0)ORb, -(CH2)rOC(=0)NRaRa, -(CH2)rNRaC(=0)NRaRa, -(CH2)rC(=0)ORb, -(CH2)rS(0)pNRaRa, -(CH2)rNRaS(0)pNRaRa, -(CH2)rNRaS(0)pRe,
(CH2)r-C3_6 carbocyclyl substituted with 0-3 Re, and -(CH2)r-heterocyclyl substituted with 0-3 Re;
alternatively, R6 and R7 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re; alternatively, when q is 2 or 3, two adjacent R6 groups form a cycloalkyl or heterocyclyl, each substituted with 0-5 Re;
Rs is selected from aryl, C3_6cycloalkyl, and heterocyclyl, each substituted with 0-5 Rg;
Rg is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
-(CHRd)rS(<¾Rc, -(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(<¾Rc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, -(CHRd)r OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
alternatively, two adjacent R9 groups are combined to form a carbocyclic or heterocyclic ring comprising carbon atoms and 1-3 hetero atoms selected from , O, and S(0)p, wherein the carbocyclic and heterocyclic rings are substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci_6 alkyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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-io carbocyclyl substituted with 0-5 Re, and -(CEtyheterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci_6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
R<i, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-5alkyl, and C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1, and 2;
q, at each occurrence, is independently selected from zero, 1, 2, and 3;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
s, at each occurrence, is independently selected from 1, and 2.
12. The compound of claim 11 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
L is -(CR6R7)q;
Ri and R2 are H;
R3 and R4 are independently selected from H and Ci-4alkyl substituted with 0-3 Re R5 is H;
R6 and R7 are independently selected from H and Ci-4alkyl;
Rs is selected from aryl and heterocyclyl, each substituted with 0-5 R9; and
R9 is independently selected from F, CI, Br, Ci-4alkyl, OH, OC1-4 alkyl,
-C(=0)OCi_4 alkyl, -C(=0)NH2, -C(=0)NHCi_4 alkyl, -C(=0)NHC3-6 cycloalkyl,
C3_6cycloalkyl, heterocyclyl, aryl, and heteroaryl.
13. The compound of claim 1, having Formula (X):
Figure imgf000385_0001
(X)
or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein
L is -(CR6R7)q;
Ri and R2 are independently selected from H, F, CI, Br, CN, RaRa, -OC1-4 alkyl
substituted with 0-3 Re, Ci_4 alkyl substituted with 0-3 Re, and -(CH2)rORb R5 is independently selected from H and C1-4 alkyl;
¾ and R7 are independently selected from H and Ci-4alkyl substituted with 0-4 Re; Rs is aryl substituted with 0-5 R9;
R9 is independently selected from F, CI, Br, Ci-4alkyl substituted with 0-5 Re, C2-4alkenyl substituted with 0-5 Re, C2-4alkynyl substituted with 0-5 Re, =0, nitro,
Figure imgf000386_0001
-(CHRd)rS(<¾NRaRa, -(CHRd)rNRaS(0)pRc, -(CHRd)rORb, -(CHRd)rCN, -(CHRd)rNRaRa, -(CHRd)rNRaC(=0)Rb, -(CHRd)rNRaC(=0)NRaRa, -(CHRd)rC(=0)ORb, -(CHRd)rC(=0)Rb, - CHR^ OC(=0)Rb,
-(CHRd)rC(=0)NRaRa, -(CHRd)r-cycloalkyl, -(CHRd)r-heterocyclyl,
-(CHRd)r-aryl, and -(CHRd)r-heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 Re;
Ra, at each occurrence, is independently selected from H, Ci-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, -(CH2)r-C3_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
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_io carbocyclyl substituted with 0-5 Re, and -(CH2)r-heterocyclyl substituted with 0-5 Re;
Rc, at each occurrence, is independently selected from Ci-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re,
C3-6 carbocyclyl, and heterocyclyl;
R<i, at each occurrence, is independently selected from H and Ci_4alkyl substituted with
Re, at each occurrence, is independently selected from Ci_6 alkyl (optionally substituted with F, CI, Br, and OH), C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3_io carbocyclyl, -(CH2)r-heterocyclyl, F, CI, Br, CN, N02, =0, C02H, C02Ci_6 alkyl,
-(CH2)rOC!_5 alkyl, -(CH2)rOH, -(CH2)rNRfRf, -(CH2)rNRfRfC(=0)C1_4alkyl, -C(=0)NRfRf, -C(=0)Rf, S(0)pNRfRf, -NRfRfS(0)pCi_4alkyl, and S(0)pCi_4alkyl; Rf, at each occurrence, is independently selected from H, F, CI, Br, Ci-salkyl, and
C3-6 cycloalkyl; or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring;
p, at each occurrence, is independently selected from zero, 1 , and 2;
q, at each occurrence, is independently selected from zero, 1 , 2, and 3; and
r, at each occurrence, is independently selected from zero, 1 , 2, 3, and 4.
14. A pharmaceutical composition comprising one or more compounds according to any of claims 1 -13 and a pharmaceutically acceptable carrier or diluent.
15. A compound according to any one of claims 1- 13 for use in therapy.
16. Use of a compound according to any one of claims 1- 13 for prophylaxis and/or treatment of diseases associated with the enzyme ROCK2.
17. Use of a compound according to claim 16 for prophylaxis and/or treatment of cancers, inflammation, infectious diseases, HIV, erectile dysfunction, cardiovascular diseases and disorders, hypertension, angina pectoris, cerebral ischaemia, cerebral vasospasm, myocardial ischemia, coronary vasospasm, heart failure, myocardial hypertrophy, atherosclerosis, restenosis, spinal cord injuries, neuronal degeneration, thrombotic disorders, asthma, glaucoma, and osteoporosis.
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US9914740B2 (en) 2018-03-13
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CN105492444A (en) 2016-04-13
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JP6434968B2 (en) 2018-12-05
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